U.S. patent application number 14/945616 was filed with the patent office on 2016-03-10 for halogenated aliphatic carboxylic acids, oligomers and/or polymers thereof and their use in devitalizing external and internal neoplasms.
This patent application is currently assigned to Cimas Limited. The applicant listed for this patent is Cimas Limited. Invention is credited to Gymsher MARDI, Laura MARDI, Rosa MARDI, Shalva MARDI, Shimon SLAVIN.
Application Number | 20160067198 14/945616 |
Document ID | / |
Family ID | 42578223 |
Filed Date | 2016-03-10 |
United States Patent
Application |
20160067198 |
Kind Code |
A1 |
MARDI; Shalva ; et
al. |
March 10, 2016 |
HALOGENATED ALIPHATIC CARBOXYLIC ACIDS, OLIGOMERS AND/OR POLYMERS
THEREOF AND THEIR USE IN DEVITALIZING EXTERNAL AND INTERNAL
NEOPLASMS
Abstract
Halogenated aliphatic carboxylic acids, salts and/or oligomers
or polymers thereof, which exhibit a devitalizing effect of
neoplastic tissues, are disclosed. Methods and uses that utilize
these compounds for the treatment of medical conditions associated
with a neoplastic tissue are also disclosed. Further disclosed are
methods and uses that utilize these compounds for reducing or
abolishing blood and lymph as well local dissemination of malignant
neoplastic cells during a surgical removal thereof, thereby
preventing recurrences and distance metastases, and/or inducing
immune response to potentially malignant, pre-malignant and/or
malignant cells. Further disclosed are novel oligomeric forms of
halogenated aliphatic carboxylic acids, pharmaceutical compositions
containing same and uses thereof.
Inventors: |
MARDI; Shalva; (Binningen -
BL, CH) ; MARDI; Rosa; (Binningen - BL, CH) ;
MARDI; Gymsher; (Binningen - BL, CH) ; MARDI;
Laura; (Binningen - BL, CH) ; SLAVIN; Shimon;
(Tel-Aviv, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cimas Limited |
Nicosia |
|
CY |
|
|
Assignee: |
Cimas Limited
Nicosia
CY
|
Family ID: |
42578223 |
Appl. No.: |
14/945616 |
Filed: |
November 19, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12796804 |
Jun 9, 2010 |
|
|
|
14945616 |
|
|
|
|
61185226 |
Jun 9, 2009 |
|
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Current U.S.
Class: |
514/557 |
Current CPC
Class: |
C07C 69/708 20130101;
C07C 69/63 20130101; A61K 31/19 20130101; A61P 35/04 20180101; A61P
35/00 20180101; A61P 37/02 20180101; A61K 31/22 20130101; A61K
31/194 20130101; C07C 59/315 20130101 |
International
Class: |
A61K 31/19 20060101
A61K031/19 |
Claims
1. A method of treating a medical condition associated with
neoplastic tissue in a subject in need thereof, the method
comprising administering to the subject a devitalizing effective
amount of a compound which is 2,2-dichloropropanoic acid or a
pharmaceutical acceptable salt thereof, by locally administering
the compound onto and/or into said neoplastic tissue, wherein said
salt does not comprise selenium.
2. The method of claim 1, wherein said compound forms a part of a
pharmaceutical composition which further comprises a
pharmaceutically acceptable carrier.
3. The method of claim 2, wherein a concentration of said compound
in said composition ranges from 70 weight percents to 90 weight
percents of the total weight of said composition.
4. The method of claim 2, wherein a devitalizing effective amount
of said compound ranges from 0.001 ml to 5 ml of said composition
per a neoplastic tissue diameter of 1 cm.
5. The method of claim 1, further comprising surgically removing at
least a portion of said neoplastic tissue.
6. The method of claim 1, wherein said disorder is associated with
malignant neoplastic tissue, the method being for reducing or
abolishing dissemination of malignant cells into blood or lymph
vessels.
7. The method of claim 1, wherein said neoplastic tissue is
selected from the group consisting of a skin or mucosal tissue and
an internal tissue.
8. The method of claim 1, wherein said neoplastic tissue is a solid
malignant tumor.
9. A method of reducing or abolishing dissemination of malignant
cells into a blood and/or lymph vessel of a subject having a
medical condition associated with malignant neoplastic tissue and
subjected to a surgical procedure for removing at least a portion
of said malignant neoplastic tissue, the method comprising
administering to the subject, prior to, concomitant with or
subsequent to the surgical procedure, a devitalizing effective
amount of a compound which is 2,2-dichloropropanoic acid or a
pharmaceutical acceptable salt thereof, by locally administering
the compound onto and/or into said neoplastic tissue, wherein said
salt does not comprise selenium.
10. The method of claim 9, wherein a devitalizing effective amount
of said compound ranges from 0.001 ml to 5 ml of said composition
per a neoplastic tissue diameter of 1 cm.
11. The method of claim 9, wherein said neoplastic tissue is skin
or mucosal tissue.
12. The method of claim 11, wherein said medical condition is a
metastasizing malignant skin or mucosal tumor.
13. The method of claim 11, wherein said medical condition is a
malignant solid tumor.
14. The method of claim 11 wherein said administering is effected
topically.
15. The method of claim 9, wherein said neoplastic tissue is an
internal tissue.
16. The method of claim 15, wherein said administering is effected
intracorporeally.
17. The method of claim 15, wherein said administering is performed
during a surgical procedure.
18. A method of treating a medical condition associated with
neoplastic tissue in a subject in need thereof, the method
comprising administering to the subject a devitalizing effective
amount of a compound which is 2,2-dichloropropanoic acid or a
pharmaceutical acceptable salt or complex thereof, said
administering being performed by locally administering the compound
onto and/or into said neoplastic tissue during a surgical procedure
for removing at least a portion of said neoplastic tissue.
19. The method of claim 18, wherein said compound forms a part of a
pharmaceutical composition which further comprises a
pharmaceutically acceptable carrier.
20. The method of claim 19, wherein a concentration of said
compound in said composition ranges from 70 weight percents to 90
weight percents of the total weight of said composition.
21. The method of claim 19, wherein a devitalizing effective amount
of said compound ranges from 0.001 ml to 5 ml of said composition
per a neoplastic tissue diameter of 1 cm.
22. The method of claim 18, wherein said disorder is associated
with malignant neoplastic tissue, the method being for reducing or
abolishing dissemination of malignant cells into blood or lymph
vessels.
23. The method of claim 18, wherein said neoplastic tissue is
selected from the group consisting of a skin or mucosal tissue and
an internal tissue.
24. The method of claim 18, wherein said neoplastic tissue is a
solid malignant tumor.
25. A method of reducing or abolishing dissemination of malignant
cells into a blood and/or lymph vessel of a subject having a
medical condition associated with malignant neoplastic tissue and
subjected to a surgical procedure for removing at least a portion
of said malignant neoplastic tissue, the method comprising
administering to the subject, prior to, concomitant with or
subsequent to the surgical procedure, a devitalizing effective
amount of a compound which is 2,2-dichloropropanoic acid or a
pharmaceutical acceptable salt thereof, wherein said administering
is performed by locally administering the compound onto and/or into
said neoplastic tissue during the surgical procedure.
26. The method of claim 25, wherein a devitalizing effective amount
of said compound ranges from 0.001 ml to 5 ml of said composition
per a neoplastic tissue diameter of 1 cm.
27. The method of claim 25, wherein said neoplastic tissue is skin
or mucosal tissue.
28. The method of claim 27, wherein said medical condition is a
metastasizing malignant skin or mucosal tumor.
29. The method of claim 27, wherein said medical condition is a
malignant solid tumor.
30. The method of claim 27 wherein said administering is effected
topically.
31. The method of claim 25, wherein said neoplastic tissue is an
internal tissue.
32. The method of claim 31, wherein said administering is effected
intracorporeally.
Description
RELATED APPLICATIONS
[0001] This application is a division of U.S. patent application
Ser. No. 12/796,804 filed on Jun. 9, 2010, which claims the benefit
of priority under 35 USC 119(e) of U.S. Provisional Patent
Application No. 61/185,226 filed Jun. 9, 2009. The contents of the
above applications are all incorporated by reference as if fully
set forth herein in their entirety.
FIELD AND BACKGROUND OF THE INVENTION
[0002] The present invention, in some embodiments thereof, relates
to compounds, compositions and methods for treating disorders
associated with pathological hyperplasia, metaplasia, dysplasia and
neoplasia (oncoplasia) tissues, such as, for example, skin and
visible mucosal tumors and lesions and internal neoplasms.
[0003] Neoplasia is a general term used to describe abnormal
proliferation of cells (such as malignant neoplasia). This abnormal
proliferation may be a result of many disorders (such as a viral
infection or cancerogenesis) and usually causes a lump or tumor.
Neoplastic tissue may be characterized as being viral, benign,
pre-malignant or malignant.
[0004] Cell proliferation is regulated by a balance between
growth-promoting proto-oncogenes and growth-constraining
tumor-suppressor genes. Oncogenesis can be caused by genetic
alterations to the genome that result in the mutation of those
cellular elements that govern the interpretation of cellular
signals, such as potentiation of proto-oncogene activity or
inactivation of tumor suppression. It is believed that the
interpretation of these signals ultimately influences the growth
and differentiation of a cell, and that misinterpretation of these
signals can result in neoplastic growth (neoplasia).
[0005] Current methods of treating neoplasia include surgery, laser
surgery, photodynamic therapy, cryotherapy, chemotherapy and
radiation. Chemotherapy involves administration of compounds having
antitumor activity, such as alkylating agents, antimetabolites and
antitumor antibiotics. The efficacy of chemotherapy is often
limited by severe side effects, including nausea and vomiting, bone
marrow depression, renal damage and central nervous system
depression.
[0006] Radiation therapy (radiotherapy) relies on the greater
ability of normal cells, in contrast to neoplastic cells, to repair
themselves after treatment with radiation. Radiotherapy, however,
is limited by possible sensitivity of the tissue surrounding the
tumor and further by development of resistance thereto.
[0007] Surgery involves the bulk removal of diseased (e.g.,
neoplastic) tissue. When tumor growth is recognized, excision of
the tumor mass by surgery is regarded as the therapy of choice.
However, during the surgical manipulation, dissemination of
malignant tumor cells into the blood and lymph vessels may occur,
resulting in metastasis to other body locations and postoperative
recurrence resulting in a poor prognosis.
[0008] The skin is the largest organ of the body, covering the
entire exterior of the body, and includes the epidermis, dermis and
subcutaneous layers. Numerous disorders of the skin are known,
ranging from those which merely cause discomfort or psychological
stress, such as rashes, through benign or cancerous skin lesions,
to life-threatening conditions such as skin cancer.
[0009] With the increase in the worlds ageing population there is a
concomitant increase in occurrence of skin disorders that are
characterized by skin neoplasia, such as skin lesions and skin
cancer, which are often caused by extensive exposure of the skin to
ultraviolet beta rays and chemicals in various cosmetic and skin
care products. There are several types of skin cancers, the most
common being basal cell carcinoma and squamous cell carcinoma,
which are both non-melanoma skin cancers.
[0010] Basel cell carcinoma develops from abnormal growth of the
cells in the lowest layer of the epidermis. Squamous cell cancer
involves changes in the squamous cells, found in the middle layer
of the epidermis. Malignant melanoma, which occurs in the
melanocytes, is less common than squamous or basal cell carcinoma
but is much more dangerous. Melanoma is the leading cause of death
from skin malignant disease.
[0011] Actinic keratosis is a skin condition that sometimes
develops into squamous cell carcinoma. Actinic keratosis (also
known as a solar keratosis) is a precancerous skin growth usually
caused by sun exposure. The most common sites for these lesions are
the face, ears, scalp, neck, forearms and hands. Actinic cheilitis
is a form of labial mucosa actinic keratosis which occurs on the
lips and causes them to become dry, cracked, scaly and pale or
white.
[0012] Leukoplakia, representing another precursor condition, is
manifested by white patches on the tongue or inside the mouth,
which have the potential to develop into squamous cell
carcinoma.
[0013] Benign (non-cancerous) skin tumors may be present at birth,
be genetic or develop later. Some benign skin tumors are known to
be caused by viruses (for example, warts), systemic disease (for
example, xanthelasmas or xanthomas caused by excess cholesterol and
fats in the blood), and environmental factors (for example, moles
(nevi) and epidermal cysts stimulated by sunlight). Other examples
of benign skin tumors are dermatofibromas; angiomas (such as
hemangiomas, port-wine stains, lymphangiomas, and pyogenic
granulomas); seborrheic keratoses; and acrochordons, or skin
tags.
[0014] Keratoacanthomas are rapidly growing lesions that occur
primarily on sun-exposed skin in older persons. Keratoacanthomas
are usually solitary, but multiple lesions may be present. Possible
causative agents include ultraviolet light, human papilloma virus,
and prolonged contact with coal tar derivatives.
[0015] The standard therapy used in benign, pre-malignant and
malignant skin tumors is determined by many factors, including the
exact hislologic subtype, the tumor size, the growth
characteristics and the anatomic location. Treatment is also
determined by the previous treatment received, current medical
problems and patient's expectations.
[0016] Treatment options may be categorized as surgical and
non-surgical. Surgical treatments include laser or
electrodessication and curettage, simple or wide local excision of
the lesion or Mohs micrographic surgery. Non-surgical treatments
include radiation therapy, photodynamic therapy, cryotherapy and
topical drug therapy.
[0017] A surgical treatment of benign, pre-malignant and malignant
skin tumors might not be applicable in all patients. The
aggressiveness nature of the surgical techniques (as compared to
non-surgical procedures) may lead, in some cases, to severe
disfigurement due to bony involvement, loss of vision (in cases of
tumors located near the eyes) and even death.
[0018] Surgical treatment is particularly problematic in treating
skin tumors located near the eyes or in the nose region as well as
in treating patients suffering from multiple tumors and
reoccurrences.
[0019] Furthermore, surgical treatment is associated with
complications such as bleaching, infections, ulcerations, pain,
allergical and exematic reactions, healing problems as well as
hypertrophic, kelloidal and painful scars. Such complications often
require the administration of additional drugs such as steroids
(either topically or systemically), antibiotics, antiseptics,
anticoagulants and different kinds of tissue-stimulated creams or
drugs, as well as occlusive hydrophilic dressings and laminates
(silicon/nylon mesh, collagen, fibrin, etc.).
[0020] One of the main concerns when using a surgical procedure for
treating skin and mucosal related cancer is the intraoperative
dissemination of cancer cells and the subsequent penetration of the
cells into blood or lymph vessels. Shedding of cancer cells into
the blood and lymph circulation of a patient during surgery is one
of the factors of development of postoperative tumor recurrences
and distance metastasis associated with a very poor prognosis.
[0021] An alternative to surgical treatment is radiation therapy
which works by damaging the DNA of cells. Because this therapy is
expensive and requires frequent visits over several weeks, it is
often not an option for elderly patients with a limited support
system. Long term cosmetic results may be poor and the
complications of tissue necrosis, chondritis and osteoradionecrosis
may occur. Another drawback is the risk of a radiation-induced
malignant growth that may occur later, thus radiation is generally
not recommended as the primary treatment in patients younger than
50 years of age.
[0022] Photodynamic therapy involves the topical administration of
photoreactive chemicals and irradiation with light strong enough to
activate the chemicals, causing them to emit free radicals and
destroy pathologic cells. This therapy is currently limited by its
high cost and by persistent skin photosensitivity that lasts
weeks.
[0023] Cryotherapy is the application of extreme cold to destroy
abnormal or diseased tissue. Warts, moles, skin tags, solar
keratoses and small skin cancers are candidates for cryosurgical
treatment. Disadvantages are the lack of margin control, tissue
necrosis, over or under treatment of the tumor, and long recovery
time.
[0024] Topical drug therapy is limited by superficial basaliomas
and actinic keratosis only, to lesions confined to the epidermis. A
5% of 5-fluorouracil (5-FU) cream (Efudex.RTM., Valeant
Pharmaceuticals) used in conjugation with topical retinoids may
deepen the therapeutic effect and minimize the risk of the disease
persisting at the adnexal level but, the treatment is associated
with many side effects.
[0025] A 5% preparation of Imiquimod cream (Aldara.TM., 3M
Pharmaceuticals), an antiviral agent and as an interferon inducer,
applied for 6 weeks has also been shown to eradicate superficial
basal cell carcinoma in more than 80% of the cases but the use of
imiquimod may be limited by its cost, drug contraindications and
side effect. An injection of 5-FU Adrucil.RTM., Teva Parenteral
Medicines, Inc. or methotrexate (Rheumatrex.RTM., DAVA
Pharmaceuticals) is primarily limited to lesions whose clinical
characteristics and histology are consistent with keratoacanthoma.
Intralesional administration of interferon (Roferon-A.RTM., Roche
Pharmaceuticals) has been effective for treating basal cell
carcinoma but this regimen requires multiple injections for several
weeks, is expensive and is associated with flu-like symptoms.
[0026] Solcoderm.RTM. (Invented by S. Mardi) is an aqueous solution
containing organic and inorganic acids in the presence of copper
ions. The solution destroys a lesion by tissue mummification. It
has been used for the treatment of a variety of benign skin
lesions, including solar keratosis, verrucae, condyloma acuminata,
hemangiomas and papillomas. The use of Solcoderm in benign skin
lesions gives usually good cosmetic results. Solcoderm has also
been used in the treatment of malignant lesions including basal and
squamous cell carcinoma.
[0027] Topical drug treatments of benign, pre-malignant and
malignant skin tumors have been also disclosed, for example, in
U.S. patent application Ser. Nos. 11/275,258, 11/924,354,
11/506,469, 10/530,723, 10/310,824 and 10/071,124.
[0028] Mardi et al. describe a selenium compound of halogenated and
polymerized carboxylic acid complex hydrate for treatment of
benign, viral, premalignant and malignant non metastizing pigmented
and non-pigmented skin and visible membranous mucosal lesions or
tumors [2001; International journal of Immunorehabilitation
3:23-31].
[0029] 2,2-Dichloropropanoic acid
(CH.sub.3--CCl.sub.2--C(.dbd.O)OH; DPA; Dalaphon; CAS No. 75-99-0)
is a chemical widely used as a water disinfectant and is also used
as an organochloride herbicide as well as a plant growth regulator
used to control specific annual and perennial grasses. The major
food crop use of DPA is on sugarcane and sugar beets. It is also
used on various fruits, potatoes, carrots, asparagus, alfalfa, and
flax, as well as in forestry, home gardening, and in or near water
to control reed and sedge growth.
[0030] The following art describes some of the currently known
activities and uses of DPA as a herbicide and water disinfectant:
Appl Environ Microbiol. 2003; 69(8):4375-82; Environ Microbiol.
2003; 5(1):48-54; Chem Res Toxicol. 1998 11(11):1332-8; Bull
Environ Contam Toxicol. 1990; 45(3):343-9; Radiat Res. 1973;
54(3):388-97; J Agric Food Chem. 1971; 19(1):189-91; Can J
Microbiol. 1964; 10:843-52; Appl Microbiol. 1962; 10:206-10; Plant
Physiol. 1961; 36(5):698-709; Plant Physiol. 1961; 36(5):688-97;
Can J Microbiol. 1959; 5(3):255-60; and Science. 1954;
120(3113):346-347.
[0031] DPA is commercially available as its sodium salt or mixed
sodium and magnesium salts. In its pure acid form, DPA is a
colorless liquid with an acrid odor. As sodium-magnesium salts, it
is a white to off-white powder.
[0032] DPA has a molecular weight of 142.97 grams/mol; a boiling
point of 185-190.degree. C.; a melting point of 20.degree. C.; a
relative density of 1.40 (water=1), a solubility in water of 90
g/100 ml at 25.degree. C. and octanol/water partition coefficient
of 0.76.
[0033] The half-life of DPA in human blood is 1.5-3 days. DPA and
all of its known breakdown products dissolve easily in water. They
are readily washed from cells and tissues. Because DPA is insoluble
in organic solvents and lipids, it does not build up in animal
tissues. A non-metabolized form of DPA was excreted in the urine of
animals fed the herbicide. Less than 1% of the ingested dose
appeared as residues in the milk of dairy cows that were fed DPA.
The safety profile of DPA is very good with no observed
teratogenic, mitogenic or any other significant systemic adverse
effects reported.
[0034] Epple and Kirschnick, Leibigs Annalen, 1997, issue 1, pages
81-85, teach oligomerization and polymerization in sodium salts of
chlorocarboxylic acids such as sodium 2-chloropropionate, sodium
3-chloropropionate and sodium 2-chlorobutyrate.
SUMMARY OF THE INVENTION
[0035] The present inventors have surprisingly uncovered that
halogenated aliphatic acids, such as dichloropropionic acid (DPA),
including salts, complexes and oligomers thereof, are
therapeutically potent agents in the treatment of medical
conditions associated with neoplastic tissues such as skin and
mucosal lesions and tumors. Such halogenated aliphatic acids can
further be used intracorporeally, for the treatment of internal
neoplasms such as solid malignant tumors.
[0036] The present inventors have further uncovered that an
oligomer of DPA, a tetramer in particular, is highly efficient in
devitalization of all types of neoplastic cells, including
malignant cells, a feature that allows performing, subsequent to,
prior to or concomitant with the DPA treatment, a surgical
procedure to remove the neoplastic tissue, while reducing and even
abolishing dissemination of the malignant cells into blood and
lymph vessels and thus avoiding distant metastases which may be
fatal.
[0037] The present inventors have further uncovered that DPA,
including salts and oligomers thereof, is capable of inducing
systemic immunity and hence can be efficiently utilized in, for
example, reducing or preventing appearance or re-appearance of
malignant cells, in cases where these are likely to occur.
[0038] The present inventors have further designed and successfully
prepared and practiced novel oligomers and polymers of DPA,
including dimers, tetramers and longer oligomers.
[0039] According to an aspect of embodiments of the invention there
is provided a method of treating a medical condition associated
with neoplastic tissue in a subject in need thereof, the method
comprising administering to the subject a devitalizing effective
amount of a compound having the general Formula I:
##STR00001##
a pharmaceutical acceptable salt or complex thereof, or an oligomer
thereof; wherein:
[0040] Y is O or S;
[0041] Z is hydroxy or thiol;
[0042] A is a branched or non-branched, substituted on
non-substituted, saturated or unsaturated aliphatic hydrocarbon
chain having 1-20 carbon atoms in its backbone chain;
[0043] X is a halogen substituent of the aliphatic hydrocarbon
chain; and
[0044] n is an integer from 1 to 10, representing the number of
halogen substituents.
[0045] According to some embodiments of the invention, the method
further comprises surgically removing at least a portion of the
neoplastic tissue.
[0046] According to an aspect of embodiments of the invention there
is provided a use of a compound as described herein in the
manufacture of a medicament for treating a medical condition
associated with neoplastic tissue.
[0047] According to an aspect of embodiments of the invention there
is provided a compound as described herein, for use in the
treatment of a medical condition associated with neoplastic
tissue.
[0048] According to some embodiments of the invention Y is O.
[0049] According to some embodiments of the invention Z is
hydroxy.
[0050] According to some embodiments of the invention n is an
integer from 1 to 4.
[0051] According to some embodiments of the invention, A is
selected from the group consisting of methyl, ethyl, propyl, butyl,
pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,
tridecyl, tetradecyl, pentadecyl, heptadecyl, octadecyl and
nonadecyl.
[0052] According to some embodiments of the invention, A is
selected from the group consisting of methyl, ethyl and propyl.
[0053] According to some embodiments of the invention, the compound
is selected from the group consisting of ethanoic acid, propanoic
acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid,
octanoic acid, nonanoic acid, decanoic acid undecanoic acid,
dodecanoic acid tridecanoic acid, tetradecanoic acid, pentadecanoic
acid, hexadecanoic acid heptadecanoic acid and octadecanoic acid,
each being independently substituted by at least one halogen
atom.
[0054] According to some embodiments of the invention, the compound
is selected from the group consisting of ethanoic acid, propanoic
acid and butanoic acid, each being independently substituted by at
least one halogen atom.
[0055] According to some embodiments of the invention, the compound
comprises two halogen substituents.
[0056] According to some embodiments of the invention, each of the
halogen atoms is independently selected from the group consisting
of chloro and fluoro.
[0057] According to some embodiments of the invention, each of the
halogen atoms is chloro.
[0058] According to some embodiments of the invention, X is a
substituent of a carbon atom positioned from 0 to 2 carbon atoms
away from the C(.dbd.Y)Z moiety in the hydrocarbon chain.
[0059] According to some embodiments of the invention, X is a
substituent of a carbon atom adjacent to the C(.dbd.Y)Z moiety in
the hydrocarbon chain.
[0060] According to some embodiments of the invention, A is
ethyl.
[0061] According to some embodiments of the invention, X is chloro
and n is 2.
[0062] According to some embodiments of the invention, the compound
is 2,2-dichloropropanoic acid.
[0063] According to some embodiments of the invention, the compound
is in a form of an oligomer thereof.
[0064] According to some embodiments of the invention, the oligomer
is selected from the group consisting of a trimer, a tetramer, a
pentamer, a hexamer, a heptamer, an octamer, a nonamer and a
decamer.
[0065] According to some embodiments of the invention, the oligomer
is selected such that its size selectively fits an intercellular
space in the neoplastic tissue and does not fit a normal tissue in
close proximity to the neoplastic tissue.
[0066] According to some embodiments of the invention, the oligomer
is a tetramer.
[0067] According to some embodiments of the invention, the oligomer
is selected from the group consisting of:
##STR00002##
[0068] According to some embodiments of the invention, the compound
is in a form of a pharmaceutically acceptable salt or a complex of
the salt.
[0069] According to some embodiments of the invention, the
pharmaceutically acceptable salt or complex thereof is selected
from the group consisting of a selenium salt, a magnesium salt, a
potassium salt, a calcium salt, a zinc salt, a copper salt and an
iron salt.
[0070] According to some embodiments of the invention, the compound
forms a part of a pharmaceutical composition which further
comprises a pharmaceutically acceptable carrier.
[0071] According to some embodiments of the invention, a
concentration of the compound in the composition ranges from 20
weight percents to 100 weight percents of the total weight of the
composition. According to some embodiments of the invention, a
concentration of the compound in the composition ranges from 70
weight percents to 90 weight percents of the total weight of the
composition.
[0072] According to some embodiments of the invention, a
devitalizing effective amount of the compound ranges from 0.001 ml
to 5 ml of the composition per a neoplastic tissue diameter of 1
cm.
[0073] According to some embodiments of the invention the
neoplastic tissue is selected from the group consisting of viral,
benign, premalignant and malignant tissue.
[0074] According to some embodiments of the invention the method
further comprises surgically removing at least a portion of the
neoplastic tissue.
[0075] According to some embodiments of the invention, the method
is further comprising, subsequent to administering the compound,
histologically evaluating the neoplastic tissue.
[0076] According to some embodiments of the invention, the
medicament is for use in combination with surgically removing at
least a portion of the neoplastic tissue.
[0077] According to some embodiments of the invention, the
medicament is administered prior to, concomitant with, or
subsequent to surgically removing the neoplastic tissue.
[0078] According to some embodiments of the invention, the
medicament is such that subsequent to administering the compound,
histologically evaluating the neoplastic tissue can be
performed.
[0079] According to some embodiments of the invention, the compound
is being for use in combination with surgically removing at least a
portion of the neoplastic tissue.
[0080] According to some embodiments of the invention the compound
is being administered prior to, concomitant with, or subsequent to
surgically removing the neoplastic tissue.
[0081] According to some embodiments of the invention, the compound
is being such that subsequent to administering the compound,
histologically evaluating the neoplastic tissue can be
performed.
[0082] According to some embodiments of the invention, the medical
condition is associated with malignant neoplastic tissue, the
method being for reducing or abolishing dissemination of malignant
cells into blood or lymph vessels.
[0083] According to some embodiments of the invention, the medical
condition is associated with malignant neoplastic tissue, and the
medicament is being for reducing or abolishing dissemination of
malignant cells into blood or lymph vessels.
[0084] According to some embodiments of the invention, the medical
condition is associated with malignant neoplastic tissue, and the
compound is being for reducing or abolishing dissemination of
malignant cells into blood or lymph vessels
[0085] According to some embodiments of the invention, the
dissemination of the malignant cells is associated with a surgical
procedure.
[0086] According to some embodiments of the invention, the
neoplastic tissue is a skin or mucosal tissue.
[0087] According to some embodiments of the invention, the medical
condition is selected from the group consisting of Seborrheic
keratosis, Epidermal Nevus, Linear epidermal nevus (unius
lateralis), Nevus sebaceus of Jadassohn, Intradermal Nevus, Nevus
pilosus, Skin tags and acrochordons, Epidermal inclusion cysts,
Sebaceous hyperplasia, Multiple syringomas, Clear cell acanthoma,
Compound nevus, Halo Nevi, Spindle cell (Spitz) nevus (epitheloid),
Giant Hairy Nevus, Blue Nevus, Nevus of Ota, Dermatofibroma,
Angiofibroma, Multiple cherry hemangioma, Pyogenic granuloma,
Angiokeratoma, Lymphangioma, Junctional Nevus, Nevus Araneus
(Spider telangiectasia), Reclingausen disease, Neurofibromatisis,
Steroide form Hyperkeratosis and Papillomatosis, Nevus vasculosus,
Nevus depigmentasus, Nevus flammeus (Port-wine stain), Xanthelasma,
Verruca vulgaris, Verruca plana, Condiloma acuminatum, Molluscum
contagiosum, Actinic keratosis, Cutaneus horn, Bowens disease,
Lentigo simplex and senilis, Lentigo maligna, Keratoacanthoma,
Trychoepitheliomas, Multiple displastic Nevi, Arsenal keratosis,
Juvinel pseudomelanoma, Superficial basal cell carcinoma, Basal
cell carcinoma, Nodular basal cell carcinoma, Basal cell pigmented
nevus syndrome-Basaliomas, Squamous cell carcinoma,
Merkel-trabecular cell carcinoma, Nevus sebaceus of Jadassohn with
basal cell carcinoma, Superficial spreading melanoma in situ and
stage 1a, Nodullar malignant melanoma in situ and stage 1a, Kaposis
hemorrhagic sarcoma (Early macular lesion, non-AIDS related), oral
visible lesions, Lentigo malignant melanoma, Papillomas,
Fibroepitheliomas, Hemangiomas and Hyperplastic or Hypertrophic
Lesions, Neurofibromatosis-1 (Recklinghausen disease),
Neurofibromatosis-2, Erosionen (ectopie), Polipus,
Posthysterectomie, granuloma, Endocervicitis, cervical viral warts
such as molluscus contagious and condiloma acuminate; nabothian
cysts; Epistaxis (contact bleeding from erosion of cervix).
[0088] According to some embodiments of the invention the medical
condition is characterized by multiple skin and/or mucosal
lesions.
[0089] According to some embodiments of the invention the medical
condition is peripheral Neurofibromatosis (Recklinghausen
disease).
[0090] According to some embodiments of the invention the medical
condition is caused by irradiation (e.g., sun irradiation and/or
photoirradiation).
[0091] According to some embodiments of the invention the
administering is effected topically.
[0092] According to some embodiments of the invention the
medicament is formulated for topical administration.
[0093] According to some embodiments of the invention the
neoplastic tissue is an internal tissue.
[0094] According to some embodiments of the invention the medical
condition is selected from the group consisting of acoustic
neuroma, adenocarcinoma, angiosarcoma, astrocytoma, bile duct
carcinoma, bladder carcinoma, thyroid cancer, tracheal cancer, bone
originated tumor such as bone sarcoma, brain tumor such as glioma
and neuroblastoma; breast cancer, cervical cancer, chondrosarcoma,
chordoma, choriocarcinoma, colon carcinoma, craniopharyngioma,
cystadenocarcinoma, embryonal carcinoma, endotheliosarcoma,
ependymoma, epithelial carcinoma, esophageal carcinoma, Ewing's
tumor, fibrosarcoma, hemangioblastoma, hepatic carcinoma,
leiomyosarcoma, liposarcoma, lung carcinoma such as bronchogenic
carcinoma, small cell lung carcinoma; lymphangioendotheliosarcoma,
lymphangiosarcoma, medullary carcinoma, medulloblastoma,
mesothelioma, myxosarcoma, pancreatic cancer, oligodendroglioma,
osteogenic sarcoma, ovarian cancer, pancreatic carcinoma, papillary
carcinoma, papillary adenocarcinoma, pinealoma, prostate cancer,
rectal cancer, kidney cancer such as renal cell carcinoma and
Wilms' tumor; retinoblastoma, rhabdomyosarcoma, sebaceous gland
carcinoma, seminoma, stomach carcinoma, synovioma, sweat gland
carcinoma, testicular tumor, uterus carcinoma, and metastatic
disease of the respective primary cancer.
[0095] According to some embodiments of the invention the
administering of the compound is effected by contacting the
neoplastic tissue with the compound.
[0096] According to some embodiments of the invention the
administering is effected incorporeally.
[0097] According to some embodiments of the invention the
administering is effected locally, stereotactically or
intravascularly.
[0098] According to some embodiments of the invention the
medicament is formulated for intracorporeal administration.
[0099] According to some embodiments of the invention the
administration is effected locally, stereotactically or
intravascularly.
[0100] According to an aspect of embodiments of the invention there
is provided a method of reducing or abolishing dissemination of
malignant cells into a blood and/or lymph vessel of a subject
having a medical condition associated with malignant neoplastic
tissue and subjected to a surgical procedure for removing at least
a portion of the malignant neoplastic tissue, the method comprising
administering to the subject, prior to or concomitant with the
surgical procedure, a devitalizing effective amount of a compound
as described herein.
[0101] According to an aspect of embodiments of the invention there
is provided a use of a compound as described herein in the
manufacture of a medicament for reducing or abolishing
dissemination of malignant cells into a blood and/or lymph vessel
of a subject having a medical condition associated with malignant
neoplastic tissue and subjected to a surgical procedure for
removing at least a portion of the malignant neoplastic tissue.
[0102] According to an aspect of embodiments of the invention there
is provided a compound as described herein, identified for reducing
or abolishing dissemination of malignant cells into a blood and/or
lymph vessel of a subject having a medical condition associated
with malignant neoplastic tissue and subjected to a surgical
procedure for removing at least a portion of the malignant
neoplastic tissue.
[0103] According to some embodiments of the invention a
devitalizing effective amount of the compound ranges from 0.001 ml
to 5 ml of the composition per an neoplastic tissue diameter of 1
cm.
[0104] According to some embodiments of the invention the
neoplastic tissue is skin or mucosal tissue.
[0105] According to some embodiments of the invention the medical
condition is a metastasizing malignant skin or mucosal tumor.
[0106] According to some embodiments of the invention the medical
condition is selected from the group consisting of Superficial
basal cell carcinoma, Basal cell carcinoma, Nodular basal cell
carcinoma, Basal cell pigmented nevus syndrome-Basaliomas, Squamous
cell carcinoma, Merkel-trabecular cell carcinoma, Nevus sebaceus of
Jadassohn with basal cell carcinoma, Superficial spreading melanoma
in situ and stage 1a, Nodullar malignant melanoma in situ and stage
1a, Kaposis hemorrhagic sarcoma (Early macular lesion, non-AIDS
related) and Lentigo malignant melanoma.
[0107] According to some embodiments of the invention the medical
condition is characterized by multiple skin and/or mucosal
lesions.
[0108] According to some embodiments of the invention the medical
condition is caused by irradiation (e.g., sun irradiation and/or
photoirradiation).
[0109] According to some embodiments of the invention the
administering is effected topically.
[0110] According to some embodiments of the invention the
medicament is formulated for topical administration.
[0111] According to some embodiments of the invention the
neoplastic tissue is an internal tissue.
[0112] According to some embodiments of the invention the
administering of the compound is effected by contacting the
neoplastic tissue with the compound.
[0113] According to some embodiments of the invention the
administering is effected intracorporeally.
[0114] According to some embodiments of the invention the
administering is effected locally, stereotactically and/or
intravascularly.
[0115] According to some embodiments of the invention the
administering is performed during a surgical procedure.
[0116] According to some embodiments of the invention the
medicament is formulated for intracorporeal administration.
[0117] According to some embodiments of the invention the medical
condition is selected from the group consisting of acoustic
neuroma, adenocarcinoma, angiosarcoma, astrocytoma, bile duct
carcinoma, bladder carcinoma, thyroid cancer, tracheal cancer, bone
originated tumor such as bone sarcoma, brain tumor such as glioma
and neuroblastoma; breast cancer, cervical cancer, chondrosarcoma,
chordoma, choriocarcinoma, colon carcinoma, craniopharyngioma,
cystadenocarcinoma, embryonal carcinoma, endotheliosarcoma,
ependymoma, epithelial carcinoma, esophageal carcinoma, Ewing's
tumor, fibrosarcoma, hemangioblastoma, hepatic carcinoma,
leiomyosarcoma, liposarcoma, lung carcinoma such as bronchogenic
carcinoma, small cell lung carcinoma; lymphangioendotheliosarcoma,
lymphangiosarcoma, medullary carcinoma, medulloblastoma,
mesothelioma, myxosarcoma, pancreatic cancer, oligodendroglioma,
osteogenic sarcoma, ovarian cancer, pancreatic carcinoma, papillary
carcinoma, papillary adenocarcinoma, pinealoma, prostate cancer,
rectal cancer, kidney cancer such as renal cell carcinoma and
Wilms' tumor; retinoblastoma, rhabdomyosarcoma, sebaceous gland
carcinoma, seminoma, stomach carcinoma, synovioma, sweat gland
carcinoma, testicular tumor, uterus carcinoma, or metastatic
disease of the respective primary cancer.
[0118] According to an aspect of embodiments of the invention there
is provided a method of inducing a systemic immune response to
pre-malignant, and/or potentially malignant cells, the method
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound as described
herein.
[0119] According to an aspect of embodiments of the invention there
is provided a use of a compound as described herein in the
manufacture of a medicament for inducing a systemic immune response
to pre-malignant, and/or potentially malignant cells.
[0120] According to an aspect of embodiments of the invention there
is provided a compound as described herein for reducing or
abolishing dissemination of malignant cells into a blood and/or
lymph vessel of a subject having a medical condition associated
with malignant neoplastic tissue and subjected to a surgical
procedure for removing at least a portion of the malignant
neoplastic tissue.
[0121] According to an aspect of embodiments of the invention there
is provided a method of inducing a systemic immune response to
malignant cells, the method comprising administering to a subject
in need thereof a therapeutically effective amount of a compound as
described herein.
[0122] According to an aspect of embodiments of the invention there
is provided a use of a compound as described herein in the
manufacture of a medicament for inducing a systemic immune response
to malignant cells According to an aspect of embodiments of the
invention there is provided a compound as described herein for
inducing a systemic immune response to malignant cells
[0123] According to some embodiments of the invention, the
administering is effected topically.
[0124] According to some embodiments of the invention, the
administering is effected intracorporeally.
[0125] According to some embodiments of the invention, the
medicament is formulated for topical administration.
[0126] According to some embodiments of the invention, the
medicament is formulated for intracorporeal administration.
[0127] According to some embodiments of the invention, the systemic
immune response is an innate immune response or an acquired immune
response.
[0128] According to some embodiments of the invention, the method
is further comprising administering to the subject at least one
immunostimulating agent.
[0129] According to some embodiments of the invention, the
medicament further comprises at least one immunostimulating
agent.
[0130] According to some embodiments of the invention, the compound
is for use in combination with at least one immunostimulating
agent.
[0131] According to some embodiments of the invention, the
immunostimulating agent is Granulocyte-macrophage
colony-stimulating factor.
[0132] According to an aspect of embodiments of the invention there
is provided a use of a compound as described herein in the
manufacture of a medicament.
[0133] According to an aspect of embodiments of the invention there
is provided a pharmaceutical composition comprising, as an active
ingredient, the compound as described herein, and a
pharmaceutically acceptable carrier.
[0134] According to some embodiments of the invention, the
composition is being packaged in a packaging material and
identified in print, in or on the packaging material, for use in
the treatment of a medical condition associated with a neoplastic
tissue.
[0135] According to some embodiments of the invention, the
composition is being packaged in a packaging material and
identified in print, in or on the packaging material, for use in
reducing or preventing dissemination of malignant cells into a
blood and/or lymph vessel of a subject having a medical condition
associated with malignant neoplastic tissue and subjected to a
surgical procedure for removing at least a portion of the malignant
neoplastic tissue
[0136] According to an aspect of embodiments of the invention there
is provided an oligomer of a compound having a general Formula I,
as described herein.
[0137] According to some embodiments of the invention, the oligomer
is being selected from the group consisting of a trimer, a
tetramer, a pentamer, a hexamer, a heptamer, an octamer, a nonamer
and a decamer.
[0138] According to some embodiments of the invention, the oligomer
is being a tetramer.
[0139] According to some embodiments of the invention, the oligomer
is selected from the group consisting of:
##STR00003##
[0140] According to an aspect of embodiments of the invention there
is provided a pharmaceutical composition comprising, as an active
ingredient, the oligomer as described herein and a pharmaceutically
acceptable carrier.
[0141] According to some embodiments of the invention, the
composition further comprises at least one selenium-containing
compound.
[0142] According to some embodiments of the invention, the
selenium-containing compound is selected from the group consisting
of a selenium salt, a selenium oxide, a selenium halide, a selenium
acid or a combination thereof.
[0143] According to an aspect of embodiments of the invention there
is provided a process of preparing the oligomer as described
herein, the process comprising heating a compound as described
herein, in a monomer form thereof, in the presence of an aqueous
solution, at a temperature ranging between 150.degree. C. and
250.degree. C., thereby obtaining the oligomer.
[0144] According to some embodiments of the invention, an amount of
the aqueous solution ranges from 0 to 50 weight percents.
[0145] According to some embodiments of the invention, the heating
is at a temperature of 190.degree. C.
[0146] According to some embodiments of the invention, the heating
is for a time period that ranges from 0 to 12 hours.
[0147] According to some embodiments of the invention, the heating
is for a time period of at least two hours.
[0148] According to some embodiments of the invention, the heating
is for a time period of at least four hours.
[0149] According to some embodiments of the invention, the heating
is for a time period of at least six hours.
[0150] According to some embodiments of the invention, the process
further comprises admixing with the oligomer an additional
agent.
[0151] Unless otherwise defined, all technical and/or scientific
terms used herein have the same meaning as commonly understood by
one of ordinary skill in the art to which the invention pertains.
Although methods and materials similar or equivalent to those
described herein can be used in the practice or testing of
embodiments of the invention, exemplary methods and/or materials
are described below. In case of conflict, the patent specification,
including definitions, will control. In addition, the materials,
methods, and examples are illustrative only and are not intended to
be necessarily limiting.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0152] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawings will be provided by the Office upon
request and payment of the necessary fee.
[0153] The invention is herein described, by way of example only,
with reference to the accompanying drawings. With specific
reference now to the drawings in detail, it is stressed that the
particulars shown are by way of example and for purposes of
illustrative discussion of the preferred embodiments of the present
invention only, and are presented in the cause of providing what is
believed to be the most useful and readily understood description
of the principles and conceptual aspects of the invention. In this
regard, no attempt is made to show structural details of the
invention in more detail than is necessary for a fundamental
understanding of the invention, the description taken with the
drawings making apparent to those skilled in the art how the
several forms of the invention may be embodied in practice.
[0154] In the drawings:
[0155] FIGS. 1A-1D present photographs showing data obtained during
treating of meningioma with a DPA oligomer according to exemplary
embodiments of the invention.
[0156] FIG. 1A present images obtained by CTA 3D-MPR, showing the
presence of a base skull meningioma.
[0157] FIG. 1B is an image of the tumor a day after its removal by
LT Pterional craniotomy, and 1 minute after injecting to the tumor
a solution containing 0.3% by weight a DPA oligomer according to
exemplary embodiments of the invention.
[0158] FIG. 1C is an image of the tumor 3 minutes after injecting
thereto a solution containing a DPA oligomer.
[0159] FIG. 1D presents the devitalization process that occurred in
the excised meningioma following treatment with a solution
containing a DPA oligomer according to exemplary embodiments of the
invention.
DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION
[0160] The present invention, in some embodiments thereof, relates
to compounds, compositions, uses thereof and methods utilizing same
for treating disorders associated with neoplastic tissues, such as,
for example, skin and mucosal tumors and lesions, as well as
internal tumors.
[0161] Before explaining at least one embodiment of the invention
in detail, it is to be understood that the invention is not
necessarily limited in its application to the details set forth in
the following description or exemplified by the Examples. The
invention is capable of other embodiments or of being practiced or
carried out in various ways.
[0162] Neoplasia is defined as the abnormal proliferation of cells,
and mostly results in a lump or a tumor. Disorders associated with
neoplastic tissue include, for example, viral infections and
cancer. Current methods of treating neoplasia include surgery,
chemotherapy and radiation. None of these methods are optimal and
each suffer from drawbacks such as life threatening adverse effects
and complications, pain, high cost as well as, in the case of
chemotherapy and radiation, development of resistance to
therapy.
[0163] One of the main concerns when using a surgical procedure for
treating cancer such as skin and mucosal related cancer is the
intraoperative dissemination of malignant cells into blood or lymph
vessels. Shedding of malignant cells into the circulation of a
patient during surgery is one of the mechanisms of postoperative
tumor metastasis and is associated with a very poor prognosis.
[0164] The present inventors have surprisingly uncovered that
halogenated aliphatic acids, such as dichloropropionic acid (DPA),
including salts, oligomers and complexes thereof, are
therapeutically potent agents in the treatment of medical
conditions associated with neoplastic tissue such as skin and
mucosal lesions and tumors.
[0165] 2,2-Dichloropropanoic acid
(CH.sub.3--CCl.sub.2--C(.dbd.O)OH; DPA; Dalaphon; CAS No. 75-99-0)
is a chemical widely used as a water disinfectant and is also used
as an organochloride herbicide and as a plant growth regulator used
to control specific annual and perennial grasses. DPA is
commercially available as its sodium salt or mixed sodium and
magnesium salts.
[0166] The half-life of DPA in human blood is 1.5-3 days. DPA and
all of its known breakdown products dissolve easily in water. They
are readily washed from cells and tissues. Because DPA is insoluble
in organic solvents and lipids, it does not build up in animal
tissues. The safety profile of DPA is very good, with no observed
teratogenic, mitogenic or any other significant systemic adverse
effects reported.
[0167] The use of DPA in the treatment of medical disorders has
never been reported hitherto.
[0168] As detailed in the Examples section that follows, the
present inventors have now surprisingly uncovered that the
halogenated aliphatic acid DPA and oligomers thereof are
therapeutically potent agents for treating neoplasia conditions of
the skin and mucosal tissue. Specifically, in clinical studies
which included 6938 patients suffering from various skin
pathologies, topical administration of DPA and DPA oligomers onto
benign, viral, pre-malignant, non-metastizing malignant and mucosal
neoplasms, resulted in effective treatment of these neoplasms with
very good clinical results observed in 82.1% of the neoplasms and a
satisfactory level of clinical results observed in 99.1% of the
neoplasms (see, Table 10). The level of neoplasm recurrence
following DPA and DPA oligomer treatment during the 2-8 year
follow-up period was only 2.3%, 6.1%, 3.5%, 2.8% and 1.2% for
benign, viral, pre-malignant, non-metastizing malignant and mucosal
tumors, respectively (see, Table 11). Furthermore, no occurrences
of regional and distant metastases of the skin tumors as well as
lethality cases were observed. The results further show that the
high efficacy of DPA and DPA oligomer treatment was observed in all
treated skin tumor or lesion and was not dependent on the type of
tumor/lesion, age, skin color or gender of the patient. With regard
to the safety of DPA, no systemic toxicity was detected in any of
the treated patients and only a short term local allergic reaction,
pain and itching were observed in 5.8% of the patients during the
treatment period, with a possible development of visible skin hypo-
or hyperpigmentation, as well as scar and kelloid formation.
[0169] Additional studies have also shown a similar therapeutic
pattern (see, Example 2 in the Examples section that follows). Upon
treatment with DPA or DPA oligomer, and a 2-year follow-up period,
less then 2% neoplasm recurrence was observed for benign and
pre-malignant neoplasms, and no neoplasm recurrence was observed
for malignant neoplasms.
[0170] In vivo animal studies have shown that treatment with DPA or
a DPA oligomer do not adversely affect the immunological response
of the treated animals (see, Example 3).
[0171] Additional in vivo studies have shown that treatment of mice
having breast cancer with DPA oligomer during a surgical removal of
the tumor resulted in reduced metastases and enhanced survivability
of the treated animals as compared to untreated control (see,
Example 5).
[0172] Studies conducted on meningioma have shown that treating a
surgically removed tumor with a DPA oligomer resulted in
devitalization of the tumor (see, Example 6, and FIGS. 1A-D).
[0173] Thus, it has been observed that the practiced halogenated
aliphatic acid, DPA and oligomeric forms thereof, are practically
non-toxic, exhibit a strongly localized action, are not absorbed
into the organism and have no systemic, teratogenic, embryotoxic or
carcinogenic properties. These compounds exhibit neither
significant side effects nor contraindication for use.
[0174] These results further demonstrate the beneficial and high
therapeutic efficacy of halogenated aliphatic carboxylic acids such
as DPA, and of oligomers thereof, in the treatment of medical
conditions associated with neoplastic tissue, including, for
example, viral, benign, premalignant and malignant tumors.
[0175] Thus, in accordance with an aspect of some embodiments the
present invention, there is provided a method of treating a medical
condition associated with neoplastic tissue in a subject in need
thereof. The method, according to these embodiments, is effected by
administering to the subject a devitalizing effective amount of a
compound, as described herein.
[0176] The phrase "neoplastic tissue", as used herein, describes a
tissue, as defined herein, that is formed by uncontrolled,
progressive proliferation of cells, and which is no longer under
normal bodily control and serving no physiological function. The
growth of a neoplastic tissue typically exceeds, and is
uncoordinated with, that of the normal tissues around it and
usually causes a lump or tumor. The phrase "neoplastic tissue" is
also referred to herein and in the art as "tumor" and encompasses
benign, viral, pro-malignant and malignant tumors.
[0177] The term "tissue" describes an ensemble of cells, not
necessarily identical, but from the same origin, that together
carry out a specific function.
[0178] Tissue cells proliferate up to normal limits with various
physiological signal molecules such as apoptotic factors and growth
factors regulating their proliferation (for example toxins,
hormones, growth factors, nitric oxide, or cytokines). In the case
of neoplastic tissue, the growth of a clone of cells is less
controlled than, and is uncoordinated with, that of the normal
tissues surrounding it.
[0179] The term "devitalizing" describes the ability of a substance
to incapacitate a cell such that it is no longer functional (or
vital), while not necessarily affecting its structure and content
(as opposed to apoptosis, lysis, etc.). A "devitalized" cell is
unable to function in the same manner it did before devitalization
and hence, for example, can no longer grow or divide. For example,
a metastatic cancer cell could be devitalized not only by killing
the cell via lysis, necrosis, or programmed cell death (apoptosis),
but could be made to be no longer able to divide. In another
example, devitalizing a cell can be affected via dehydration or
freezing.
[0180] The term "a devitalizing effective amount" describes an
amount of a compound as described herein effective to devitalize a
neoplastic tissue to an extent which significantly reduces the size
and/or growth of, or completely abolishes, the neoplastic tissue of
the subject being treated.
[0181] Accordingly, in the case of a medical condition associated
with the neoplastic tissue, the term "a devitalizing effective
amount" describes an amount of a compound as described herein
effective to devitalize a neoplastic tissue to an extent which
prevents, alleviates or ameliorates symptoms of the medical
condition and/or prolongs the survival of the subject being treated
Determination of a devitalizing effective amount is well within the
capability of those skilled in the art, especially in light of the
detailed disclosure provided herein.
[0182] The term "subject" (alternatively referred to herein as
"patient"), as used herein, refers to an animal, preferably a
mammal, most preferably a human, who has been the object of
treatment, observation or experiment.
[0183] Accordingly, in accordance with another aspect of some
embodiments of the present invention there is provided a use of a
compound as described herein in the manufacture of a medicament for
treating a medical condition associated with neoplastic tissue.
[0184] The compounds, according to embodiments of the present
invention, can be collectively represented by the general formula I
as follows:
##STR00004##
a pharmaceutical acceptable salt or complex thereof or an oligomer
form thereof; wherein:
[0185] Y is O or S;
[0186] Z is hydroxy or thiol;
[0187] A is a branched or non-branched, substituted on
non-substituted, saturated or unsaturated aliphatic hydrocarbon
chain having 1-20 carbon atoms in its backbone chain;
[0188] X is a halogen substituent of said aliphatic hydrocarbon
chain; and
[0189] n is an integer from 1 to 10, representing the number of
halogen substituents.
[0190] In some embodiments Y is O, such that the compounds
described herein are halogenated aliphatic carboxylic acids
[0191] In some embodiments Z is hydroxy.
[0192] In other embodiments, the compounds described herein are
halogenated aliphatic thiocarboxylic acids, such that Y is S and/or
Z is thiol.
[0193] In some embodiments, n is an integer from 1 to 4.
[0194] Compounds in which n is 1 are referred to as
monohalogenated; compounds in which n is 2 are referred to as
dihalogenated and compounds on which n is greater than 2 are
referred to as polyhalogenated.
[0195] The term "hydroxy" describes an --OH group.
[0196] The term "thiol" describes an --SH group.
[0197] The phrase "aliphatic hydrocarbon chain" describes an
organic moiety composed mainly of carbon and hydrogen atoms, in
which the carbon atoms are linked to one another and forming an
aliphatic (non-cyclic) backbone chain. The aliphatic hydrocarbon
chain can be saturated or unsaturated, linear or branched, and can
be interrupted by one or more heteroatoms such as oxygen, sulfur
and/or nitrogen (e.g., --NH--).
[0198] In some embodiments, the term "aliphatic hydrocarbon chain"
encompasses any one or a combination of alkyl, alkenyl, and
alkynyl.
[0199] The term "alkyl" describes a saturated aliphatic hydrocarbon
including straight chain and branched chain groups. Preferably, the
alkyl group has 1 to 30 carbon atoms. Whenever a numerical range;
e.g., "1-30", is stated herein, it means that the group, in this
case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3
carbon atoms, etc., up to and including 30 carbon atoms. In some
embodiments the alkyl group has 1-20 carbon atoms. In some
embodiments, the alkyl group has 1-10 carbon atoms. In some
embodiments, the alkyl group has 1-4 carbon atoms. Exemplary alkyl
groups include, but are not limited to methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,
dodecyl, tridecyl, tetradecyl, pentadecyl, heptadecyl, octadecyl
and nonadecyl.
[0200] The term "alkenyl" describes an alkyl group, as defined
herein, which consists of at least two carbon atoms and at least
one carbon-carbon double bond.
[0201] The term "alkynyl" describes an alkyl group, as defined
herein, which consists of at least two carbon atoms and at least
one carbon-carbon triple bond.
[0202] The aliphatic hydrocarbon chain may be unsubstituted or
substituted by one or more substituents other then hydrogen or the
halogen represented by X in the general formula hereinabove. When
substituted, the substituent group can be, for example, alkyl,
cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy,
aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, carbonyl,
thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro,
sulfonamido, trihalomethanesulfonamido, silyl, guanyl, guanidino,
ureido, amino or NRaRb, as defined herein, wherein Ra and Rb are
each independently hydrogen, alkyl, cycloalkyl, aryl, carbonyl,
sulfonyl, trihalomethysulfonyl and, when combined, a five- or
six-member heteroalicyclic ring.
[0203] The term "cycloalkyl" describes an all-carbon monocyclic or
fused ring (i.e., rings which share an adjacent pair of carbon
atoms) group wherein one of more of the rings does not have a
completely conjugated pi-electron system. Examples, without
limitation, of cycloalkyl groups are cyclopropane, cyclobutane,
cyclopentane, cyclopentene, cyclohexane, cyclohexadiene,
cycloheptane, cycloheptatriene, and adamantane. A cycloalkyl group
may be substituted or unsubstituted. When substituted, the
substituent group can be, for example, alkyl, aryl, heteroaryl,
heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy,
thioaryloxy, cyano, halo, carbonyl, thiocarbonyl, C-carboxy,
O-carboxy, O-carbamyl, N-carbamyl, C-amido, N-amido, nitro, amino
and NRaRb as defined hereinabove.
[0204] The term "aryl" describes an all-carbon monocyclic or
fused-ring polycyclic (i.e., rings which share adjacent pairs of
carbon atoms) groups having a completely conjugated pi-electron
system. Examples, without limitation, of aryl groups are phenyl,
naphthalenyl and anthracenyl. The aryl group may be substituted or
unsubstituted. When substituted, the substituent group can be, for
example, halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy,
thiohydroxy, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,
sulfinyl, sulfonyl, amino and NRaRb as defined hereinabove.
[0205] The term "heteroaryl" describes a monocyclic or fused ring
(i.e., rings which share an adjacent pair of atoms) group having in
the ring(s) one or more atoms, such as, for example, nitrogen,
oxygen and sulfur and, in addition, having a completely conjugated
pi-electron system. Examples, without limitation, of heteroaryl
groups include pyrrole, furane, thiophene, imidazole, oxazole,
thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline
and purine. The heteroaryl group may be substituted or
unsubstituted. When substituted, the substituent group can be, for
example, alkyl, cycloalkyl, halo, trihalomethyl, hydroxy, alkoxy,
aryloxy, thiohydroxy, thiocarbonyl, sulfonamido, C-carboxy,
O-carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amino or NRaRb as
defined above.
[0206] The term "heteroalicyclic" describes a monocyclic or fused
ring group having in the ring(s) one or more atoms such as
nitrogen, oxygen and sulfur. The rings may also have one or more
double bonds. However, the rings do not have a completely
conjugated pi-electron system. The heteroalicyclic may be
substituted or unsubstituted. When substituted, the substituted
group can be, for example, alkyl, cycloalkyl, aryl, heteroaryl,
halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy,
thioalkoxy, thioaryloxy, cyano, nitro, carbonyl, thiocarbonyl,
C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, sulfinyl, sulfonyl, C-amido, N-amido, amino and
NRaRb as defined above.
[0207] The term "alkoxy" describes both an --O-alkyl and an
--O-cycloalkyl group, as defined herein.
[0208] The term "aryloxy" describes both an --O-aryl and an
--O-heteroaryl group, as defined herein.
[0209] The term "thioalkoxy" describes both an --S-alkyl group, and
an --S-cycloalkyl group, as defined herein.
[0210] The term "thioaryloxy" refers to both an --S-aryl and an
--S-heteroaryl group, as defined herein
[0211] The term "cyano" describes a --C.ident.N group.
[0212] The term "carbonyl" describes a --C(.dbd.O)--R' group, where
R' is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through
a ring carbon) or heteroalicyclic (bonded through a ring carbon) as
defined herein.
[0213] The term "thiocarbonyl" describes a --C(.dbd.S)--R' group,
where R' is as defined herein.
[0214] The term "O-carbamyl" describes an --OC(.dbd.O)--NR'R''
group, where R' is as defined herein and R'' is hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) or
heteroalicyclic (bonded through a ring carbon) as defined
herein.
[0215] The term "N-carbamyl" describes an R'OC(.dbd.O)--NR''--
group, where R' and R'' are as defined herein.
[0216] The term "O-thiocarbamyl" describes an --OC(.dbd.S)--NR'R''
group, where R' and R'' are as defined herein.
[0217] The term "N-thiocarbamyl" describes an R''OC(.dbd.S)NR'--
group, where R' and R'' are as defined herein.
[0218] The term "C-amido" describes a --C(.dbd.O)--NR'R'' group,
where R' and R'' are as defined herein.
[0219] The term "N-amido" describes an R'C(.dbd.O)--NR'' group,
where R' and R'' are as defined herein.
[0220] The term "C-carboxy" describes a --C(.dbd.O)--O--R' groups,
where R' is as defined herein.
[0221] The term "O-carboxy" describes an R'C(.dbd.O)--O-- group,
where R' is as defined herein.
[0222] The term "nitro" group describes an --NO.sub.2 group.
[0223] The term "sulfonamide", encompasses both an "S-sulfonamido"
and "N-sulfonamido" wherein an "S-sulfonamido" group describes a
--S(.dbd.O).sub.2--NR'R'' group, with R' is as defined herein and
R'' is as defined for R'. An "N-sulfonamido" group describes an
R'S(.dbd.O).sub.2--NR'' group, where R' and R'' are as defined
herein.
[0224] The term "trihalomethanesulfonamido" group refers to an
T.sub.3CS(.dbd.O).sub.2NR'-- group, wherein T is a halo group as
defined herein and R' is as defined herein.
[0225] The term "guanidino" group describes an
--R'NC(.dbd.N)--NR''R''' group, where R', R'' and R' is hydrogen,
alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon)
or heteroalicyclic (bonded through a ring carbon) as defined
herein.
[0226] The term "guanyl" group describes an R'R''NC(.dbd.N)--
group, where R' and R'' are as defined herein.
[0227] The term "silyl" describes a --SiR'R''R'', where R', R'' and
R' are as defined herein.
[0228] The term "ureido" group describes an
--NR'C(.dbd.O)--NR''R''' group, where R', R'' and R''' are as
defined herein.
[0229] The term "amino" group describes an --NH.sub.2 group.
[0230] The term "sulfonyl" group describes an --S(.dbd.O).sub.2--R'
group, where R' is as defined herein.
[0231] The term "halogen" or "halo" describes fluoro, chloro, bromo
or iodo atom.
[0232] In some embodiments, A is methyl, ethyl, propyl, butyl,
pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,
tridecyl, tetradecyl, pentadecyl, heptadecyl, octadecyl or
nonadecyl. In some embodiments, A is methyl, ethyl or propyl. In
some embodiments, A is ethyl.
[0233] In some embodiments, the compound is ethanoic acid (acetic
acid), propanoic acid, butanoic acid, pentanoic acid, hexanoic
acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid
undecanoic acid, dodecanoic acid tridecanoic acid, tetradecanoic
acid, pentadecanoic acid, hexadecanoic acid heptadecanoic acid or
octadecanoic acid, each being independently substituted by at least
one halogen atom.
[0234] In some embodiments, the compound is ethanoic acid,
propanoic acid and butanoic acid, each being independently
substituted by at least one halogen atom.
[0235] In some embodiments, the compound having general formula I
comprises two or more halogen substituents (such that n is greater
than 1). The halogen substituents can be the same or different. In
cases where the hydrocarbon chain comprises more than one carbon
atom, the halogen substituents can be on the same carbon atom in
the hydrocarbon chain, or on different carbon atoms in the
hydrocarbon chain.
[0236] In some embodiments, each of the halogen atoms is
independently chloro or fluoro.
[0237] In some embodiments, the compound comprises two halogen
substituents.
[0238] Without being bound by any particular theory, it is
speculated that the high devitalizing activity of the halogenated
aliphatic acids described herein is due to the positioning of the
halogen atoms in close proximity to the carboxylic (or
thiocarboxylic) moiety, which enhances the acidity of the compound
due to the electron withdrawing effect of the halogen
substituent.
[0239] Accordingly, in some embodiments, X in the general formula
described herein is a halogen substituent or substituents of a
carbon atom positioned from 0 to 2 carbon atoms away from the
C(.dbd.Y)Z moiety in the hydrocarbon chain.
[0240] In some embodiments, X is a substituent of a carbon atom
adjacent to the C(.dbd.Y)Z moiety in the hydrocarbon chain. The
phrase "adjacent to the C(.dbd.Y)Z moiety", as used herein, is to
indicate that the X substituent is located 0 carbons away from the
C(.dbd.Y)Z moiety, namely, at position a to the carboxylic (or
thiocarboxylic) moiety.
[0241] A carbon atom positioned 1 carbon away from the carboxylic
(or thiocarboxylic moiety) is located at position 13 to the
carboxylic (or thiocarboxylic) moiety.
[0242] In some embodiments, A in the general formula I is ethyl,
such that the compound is a halogenated propionic acid (also
referred to herein as halogenated propanoic acid).
[0243] In some embodiments, X is chloro and n is 2, such that the
compound is dihalogenated, namely, dichlorinated.
[0244] In some embodiments, the compound is 2,2-dichloropropanoic
acid (DPA).
[0245] Additional exemplary compounds include, but are not limited
to, 2-chloropropanoic acid, 3-chloropropanoic acid,
2,3-dichloropropanoic acid, 3,3-dichloropropanoic acid,
2-chlorobutanoic acid, 2,2-dichlorobutanoic acid, 3-chlorobutanoic
acid, 2,3-dichlorobutanoic acid, 3,3-dichlorobutanoic acid,
2,2,-dichloropentanoic acid, 2-chloropentanoic acid,
3-chloropentanoic acid, 2,3-dichloropentanoic acid,
3,3-dichloropentanoic acid, 2-chlorohexanoic acid,
2,2-dichlorohexanoic acid, 3-chlorohexanoic acid,
2,3-dichlorohexanoic acid, 3,3-dichlorohexanoic acid,
2-fluoropropanoic acid, 3-fluoropropanoic acid,
2,3-difluoropropanoic acid, 3,3-difluoropropanoic acid,
2-fluorobutanoic acid, 2,2-difluorobutanoic acid, 3-fluorobutanoic
acid, 2,3-difluorobutanoic acid, 3,3-difluorobutanoic acid,
2,2,-difluoropentanoic acid, 2-fluoropentanoic acid,
3-fluoropentanoic acid, 2,3-difluoropentanoic acid,
3,3-difluoropentanoic acid, 2-fluorohexanoic acid,
2,2-difluorohexanoic acid, 3-fluorohexanoic acid,
2,3-difluorohexanoic acid, 3,3-difluorohexanoic acid,
2,2-fluorochloropropanoic acid, 2,3-fluorochloropropanoic acid,
3,3-fluorchloropropanoic acid, 2,2-fluorochlorobutanoic acid,
2,3-fluorochlorobutanoic acid, 3,3-fluorochlorobutanoic acid,
2,2-fluorochloropentanoic acid, 2,3-fluorochloropentanoic acid,
3,3-fluorochloropentanoic acid, 2,2-fluorochlorohexanoic acid,
2,3-fluorochlorohexanoic acid, 3,3-fluorochlorohexanoic acid,
2,2,3-trichloropropanoic acid, 2,3,3-trichloropropanoic acid,
3,3,3-trichloropropanoic acid, 2,2,3-trifluropropanoic acid,
2,3,3-trifluropropanoic acid, 3,3,3-trifluoropropanoic acid,
2-chloro-2,3-difluloropropanoic acid,
2-chloro-3,3-difluoropropanoic acid, 2,2-dichloro-3-fluoropropanoic
acid, 2,2-difluoro-3-chloropropanoic acid, 2,2,3-trichlorobutanoic
acid, 2,3,3-trichlorobutanoic acid, 3,3,3-trichlorobutanoic acid,
2,2,3-triflurobutanoic acid, 2,3,3-triflurobutanoic acid,
3,3,3-trifluorobutanoic acid, 2-chloro-2,3-diflulorobutanoic acid,
2-chloro-3,3-difluorobutanoic acid, 2,2-dichloro-3-fluorobutanoic
acid, 2,2-difluoro-3-chlorobutanoic acid, 2,2,3-trichloropentanoic
acid, 2,3,3-trichloropentanoic acid, 3,3,3-trichloropentanoic acid,
2,2,3-trifluropentanoic acid, 2,3,3-trifluropentanoic acid,
3,3,3-trifluoropentanoic acid, 2-chloro-2,3-difluloropentanoic
acid, 2-chloro-3,3-difluoropentanoic acid,
2,2-dichloro-3-fluoropentanoic acid, 2,2-difluoro-3-chloropentanoic
acid, 2,2,3-trichlorohexanoic acid, 2,3,3-trichlorohexanoic acid,
3,3,3-trichlorohexanoic acid, 2,2,3-triflurohexanoic acid,
2,3,3-triflurohexanoic acid, 3,3,3-trifluorohexanoic acid,
2-chloro-2,3-diflulorohexanoic acid, 2-chloro-3,3-difluorohexanoic
acid, 2,2-dichloro-3-fluorohexanoic acid,
2,2-difluoro-3-chlorohexanoic acid, and any additional structural
analogs thereof.
[0246] The present embodiments further encompass any
pharmaceutically acceptable salt, complexes, prodrugs, solvates,
hydrates and, if present, purified enantiomers of each of the
compounds described herein.
[0247] The phrase "pharmaceutically acceptable salt" refers to a
charged species of the parent compound and its counter ion. A
"pharmaceutically acceptable salt" is typically used to modify the
solubility characteristics of the parent compound and/or to reduce
any significant irritation to an organism by the parent compound,
while not abrogating the biological activity and properties of the
administered compound. In the context of the present embodiments, a
pharmaceutically acceptable salt can be, for example, an ionized
form of the carboxylic or thiocarboxylic moiety, as a carboxylate
or thiocarboxylate anion, and a cation.
[0248] In some cases, a pharmaceutically acceptable complex of the
compound is formed when the parent compound interacts with another
species via coordinative interactions (as opposed to the
electrostatic interactions involved in salts). Such complexes can
be formed, for example, between the carboxylic (or thiocarboxylic)
moiety and a species that can coordinatively bind to this moiety.
Exemplary complexes can be formed with species such as, but not
limited to metallic selenium, zinc, copper, iron, and the like,
including salts and oxides thereof. Exemplary complexes are formed
with selenium, selenium oxide or selenium salt.
[0249] In some embodiments, the pharmaceutically acceptable salt is
selected from the group consisting of a sodium salt, a magnesium
salt, a potassium salt, and a calcium salt.
[0250] As discussed in detail hereinbelow, in some embodiments,
pharmaceutically acceptable salts and complexes of the compounds
described herein are used for improving the performance of the
compounds described herein.
[0251] As used herein, the term "prodrug" refers to an agent, which
is converted into the active compound (the active parent drug) in
vivo. Prodrugs are typically useful for facilitating the
administration of the parent drug. They may, for instance, be
bioavailable by oral administration whereas the parent drug is not.
The prodrug may also have improved solubility as compared with the
parent drug in pharmaceutical compositions. Prodrugs are also often
used to achieve a sustained release of the active compound in
vivo.
[0252] The term "solvate" refers to a complex of variable
stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, and so on),
which is formed by a solute (the compound described herein) and a
solvent, whereby the solvent does not interfere with the biological
activity of the solute. Suitable solvents include, for example,
ethanol, acetic acid and the like.
[0253] The term "hydrate" refers to a solvate, as defined
hereinabove, where the solvent is water.
[0254] In some embodiments, the compound is in a form of an
oligomer thereof, as defined hereinunder.
[0255] Oligomeric forms of such compounds in general and of DPA in
particular have not been described hitherto and hence, according to
another aspect of some embodiments of the present invention there
is provided an oligomer of a compound having a general Formula I,
as described herein. The present embodiments further encompass any
pharmaceutically acceptable salts and complexes, prodrugs,
solvates, hydrates and, if present, purified stereomers of each of
the oligomers described herein.
[0256] The term "oligomer", as used herein, describes a compound
that comprises two or more repeating units condensed one with
another. An "oligomer", as described herein, is therefore produced
by the condensation of two or more monomeric units composing the
same. Accordingly, an oligomeric form of a compound as described
herein describes a plurality of repeating units of the monomeric
form of the compound as described herein. The term "oligomer" is
meant to encompass, without limitation, oligomers incorporating up
to, e.g., 50 monomeric units, including, but not limited to,
oligomers composed of 2 monomeric units (i.e. dimmer), 3 monomeric
units (i.e. trimmer), 4 monomeric units (i.e. tetramer), 5
monomeric units (i.e. pentamer), 6 monomeric units (i.e. hexamer),
7 monomeric units (i.e. heptamer), 8 monomeric units (i.e.
octamer), 9 monomeric units (i.e. nanomer), 10 monomeric units
(i.e. decamer), 11 monomeric units, 12 monomeric units, 13
monomeric units, 14 monomeric units, 15 monomeric units, 16
monomeric units, 17 monomeric units, 18 monomeric units, 19
monomeric units, 20 monomeric units, 21 monomeric units, 22
monomeric units, 23 monomeric units, 24 monomeric units, 25
monomeric units, 26 monomeric units, 27 monomeric units, 28
monomeric units, 29 monomeric units, 30 monomeric units, 31
monomeric units, 32 monomeric units, 33 monomeric units, 34
monomeric units, 35 monomeric units, 36 monomeric units, 37
monomeric units, 38 monomeric units, 39 monomeric units, 40
monomeric units, 41 monomeric units, 42 monomeric units, 43
monomeric units, 44 monomeric units, 45 monomeric units, 46
monomeric units, 47 monomeric units, 48 monomeric units, 49
monomeric units and 50 monomeric units
[0257] In some embodiments, the oligomer is selected from the group
consisting of a trimmer, a tetramer, a pentamer, a hexamer, a
heptamer, an octamer, a nonamer and a decamer. In some embodiments,
the oligomer is a tetramer.
[0258] As detailed in the Examples section that follows, novel
oligomers of DPA were successfully synthesized and tested.
[0259] As discussed hereinabove, the devitalizing activity of a DPA
oligomer, an exemplary oligomer according to some embodiments of
the invention, is demonstrated in the Examples section that
follows. Specifically, the administration of DPA oligomers was
therapeutically beneficial in the treatment of viral, benign,
premalignant and malignant skin and mucosal tumors/lesions (see,
Tables 10 and 11).
[0260] Exemplary DPA oligomers include, but are not limited to:
##STR00005##
[0261] The oligomers described herein may be synthesized via the
condensation and formation of ether and ester bonds between the
monomeric units.
[0262] Further according to embodiments of the present invention,
there are provided processes of preparing the novel oligomers
described herein. These processes are described in detail in the
Examples section that follows.
[0263] Thus, according to another aspect of some embodiments of the
present invention there is provided a process of preparing the
oligomers described herein, the process being effected by heating a
compound as described herein, in a monomer form thereof, in the
presence of an aqueous solution, at a temperature ranging from
150.degree. C. to 250.degree. C., thereby obtaining the
oligomer.
[0264] Without being bound to any particular theory, it is
speculated that the process described herein includes dehydrolysis,
caramelization and/or pyrolysis, and that the occurrence of these
reactions depend on the time and temperature at which the process
is performed.
[0265] In some embodiments, the amount of water in the aqueous
solution ranges from 0 to 50 weight percents, or from 0.1 to 50
weight percents.
[0266] In some embodiments, the heating is at a temperature that
ranges from 170.degree. C. to 220.degree. C., or from 180.degree.
C. to 200.degree. C. In some embodiments, the heating is at a
temperature of 190.degree. C.
[0267] In some embodiments, the heating is for a time period that
ranges from 0.5 to 12 hours.
[0268] The length of the oligomer is dependent on the heating time
period whereby longer oligomers (i.e. comprised of more monomeric
units) are synthesized using longer heating time periods. The
tetrameric form of DPA is synthesized by the process described
herein with a heating time period of about four hours.
[0269] In some embodiments, the heating is for a time period of at
least two hours.
[0270] In some embodiments, the heating is for a time period of at
least four hours.
[0271] In some embodiments, the heating is for a time period of at
least six hours.
[0272] The process described herein may further comprise admixing
with the oligomer an additional agent. Such an agent may be, for
example, selenium or a selenium containing compound (e.g., a
selenium oxide, a selenium salt or a selenium complex).
[0273] The present inventors have observed that the size of the
oligomer affects its devitalizing activity. Without being bound by
theory, it is speculated that neoplastic tissues are less dense,
having larger intercellular spaces between the neoplastic cells, as
compared to normal tissues. This looser structure enables the
selective penetration of larger sized oligomers into neoplastic
tissue and much less to normal tissue, thereby reducing adverse
effects associated with the undesired activity of the compound
against normal tissue.
[0274] Therefore, in some embodiments, the oligomer is selected
such that its size selectively fits an intercellular space in the
neoplastic tissue and does not fit a normal tissue in close
proximity to the neoplastic tissue.
[0275] While further analyzing the results of the clinical studies
presented hereinbelow, the inventors have surprisingly uncovered
that the administration of the tetrameric form of DPA is more
therapeutically beneficial for treating benign skin and mucosal
tumors and lesions whereas administration of lengthier oligomers is
more therapeutically beneficial for treating premalignant and
malignant skin and mucosal tumors. Without being bound by a
particular theory, it is suggested that this observed difference in
activity is due to the looser packing of premalignant and malignant
neoplastic tissue as compared to benign neoplastic tissue whereby
lengthier oligomers are less able to penetrate into benign
neoplastic tissue yet are able to penetrate into premalignant and
malignant neoplastic tissue. In contrast, monomers or tetramers,
being smaller in size, are able to penetrate benign neoplastic
tissue and thus are more suitable for treating such
tumors/lesions.
[0276] Hence, in some embodiments of the present invention, the
method described herein is for treating a medical condition
associated with benign neoplastic tissue in a subject in need
thereof, and is effected by administering to the subject a
devitalizing effective amount of a oligomeric tetramer of any of
the compounds described herein.
[0277] Accordingly, an oligomeric tetramer of the compounds
described herein is used for treating a medical condition
associated with benign neoplastic tissue in a subject in need
thereof.
[0278] In some embodiments, the oligomeric tetramer is a DPA
tetramer as described herein.
[0279] In some embodiments, the method described herein is used for
treating a medical condition associated with pre-malignant or
malignant neoplastic tissue in a subject in need thereof, and is
effected by administering to the subject a devitalizing effective
amount of an oligomeric form of a compound, as described herein,
wherein the oligomer comprises four or more monomeric units (e.g.,
the oligomer is a tetramer, pentamer or hexamer of DPA or any other
compound as described herein).
[0280] Accordingly, oligomer forms of the compounds described
herein, comprised of four or more monomeric units are used for
treating a medical condition associated with pre-malignant or
malignant neoplastic tissue in a subject in need thereof.
[0281] As exemplified in the Examples section that follows, both
the monomeric and the tetrameric forms of DPA were effectively used
to treat patients having benign tumors, viral warts or mucosal
tumor lesions while longer oligomers were used to treat patients
having malignant and pre-malignant tumors. All treatments resulted
in eradication of the tumors with very good clinical outcomes (see,
Table 10).
[0282] As discussed hereinabove, the present embodiments further
encompass any pharmaceutically acceptable salts and complexes, as
defined hereinabove, of the compounds described herein.
[0283] Without being bound by theory, it is speculated that the
formation of complexes and salts may further enhance the
devitalizing activity of the compounds described herein, possibly
by constructing larger sized forms of the compound which, as
discussed hereinabove, enable the selective penetration of the
compound to the looser packed neoplastic tissue as compared to the
penetration into the more densely packed normal tissue.
[0284] As discussed hereinabove, the beneficial therapeutic
activity of DPA and oligomers thereof, as exemplary compounds
according to embodiments of the invention, has been demonstrated in
treating medical conditions associated with viral, benign,
premalignant and malignant neoplastic tissues.
[0285] Accordingly, in any of the methods and uses described
herein, the neoplastic tissue can be a viral neoplastic tissue, a
benign neoplastic tissue, a pre-malignant neoplastic tissue and/or
a malignant neoplastic tissue.
[0286] In some embodiments of the present invention, the neoplastic
tissue is a skin or mucosal tissue.
[0287] The phrase "viral neoplastic tissue", as used herein,
describes abnormal growth of tissue cells due to a viral
infection.
[0288] The phrase "malignant neoplastic tissue", as used herein,
describes a neoplastic tissue which is not self-limited in its
growth, is capable of invading into adjacent tissues, and may be
capable of spreading to distant tissues (metastasizing).
[0289] The phrase "benign neoplastic tissue" describes a neoplastic
tissue which is not malignant (i.e. does not grow in an unlimited,
aggressive manner, does not invade surrounding tissues, and most of
them do not metastasize).
[0290] The phrase "premalignant neoplastic tissue" describes a
neoplastic tissue which is not malignant but has a higher
probability of becoming malignant as compared to normal tissue and
benign neoplastic tissues.
[0291] The term "skin tissue" describes the outer covering of a
mammalian form including, without limitation, the epidermis,
dermis, and subcutaneous tissues. Typically, skin tissue can
include other components such as hair follicles and sweat
glands.
[0292] The term "mucosal tissue" describes tissues that are
composed in part of cells of mesenchymal and epithelial origin.
Examples of mucosal tissues include, but are not limited to,
vaginal, oral, corneal, rectal, and viscero-elastic tissues.
[0293] The term "lesion" describes any abnormal tissue found on or
in an organism, usually damaged by disease or trauma. The term
"skin lesion" describes any abnormal tissue found on or in a skin
tissue. The term "mucosal lesion" describes any abnormal tissue
found on or in a mucosal tissue, as described herein.
[0294] The term "tumor" describes a swelling or lesion formed by an
abnormal growth of pathologycal cells. The term "tumor" encompasses
benign tumors (evolving from benign neoplastic tissue),
pre-malignant tumors (evolving from premalignant neoplastic tissue)
and malignant tumors which are also referred to herein as
"metastasizing malignant tumors" (evolving from malignant
neoplastic tissue).
[0295] The term "skin tumor" describes a tumor formed by an
abnormal growth of skin cells. The term "skin cells" describes
cells that make up the skin such as epidermal cells, dermal cells
or cells making up the subcutaneous tissue of the skin. Some benign
skin tumors are known to be caused by viruses (for example, warts),
systemic disease (for example, xanthelasmas or xanthomas caused by
excess fats in the blood), and environmental factors (for example,
moles (nevi) and epidermal cysts stimulated by sunlight). Other
examples of benign skin tumors are dermatofibromas;
[0296] angiomas (such as hemangiomas, port-wine stains,
lymphangiomas, and pyogenic granulomas); seborrheic keratoses; and
acrochordons, or skin tags.
[0297] The term "mucosal tumor" describes a tumor formed by an
abnormal growth of cells that make up mucosal tissue.
[0298] The term "cancer" describes a tumor formed by abnormal
growth of malignant cells. The term cancer encompasses primary or
secondary tumors. The term "primary tumor" describes a tumor that
is at the original site where it first arose and the term
"secondary tumor" describes a tumor that has spread from its
original (primary) site of growth to another site, close to or
distant from the primary site.
[0299] The term "skin cancer" describes a cancer located on or in a
skin tissue and/or originating from the abnormal growth of skin
cells. The term "mucosal cancer" describes a cancer located on or
in a mucosal tissue and/or originating from the abnormal growth of
cells that make up the mucosal tissue. There are several types of
skin cancers, the most common being basal cell carcinoma and
squamous cell carcinoma, which are both non-melanoma skin cancers.
Benign (non-cancerous) skin tumors may be present at birth or
develop later.
[0300] Accordingly, exemplary skin and mucosal neoplastic tissues
include, but are not limited to, keratoses (including, but not
limited to, actinic keratosis, hydrocarbon keratosis, keratosis
pilaris, seborrheic keratosis), nevi (including melanocytic nevi
and epidermal nevi, with exemplary nevus listed hereinunder),
archodrons, cysts, angiomas (such as hemangiomas, port-wine stains,
lymphangiomas, and pyogenic granulomas), fibromas, fibrolipomas,
condylomatas, lentigos, acanthomas, neurofibromas, hyperplasias,
fibromas, warts (caused, for example, by viruses, e.g., verrucas),
leiomyomas, syringomas, granulomas, xanthelasmas, cutaneus horns,
Juvinel pseudomelanoma, basal cell carcinomas, basaliomas, Squamous
cell carcinomas, Merkel-trabecular cell carcinomas, Nevus sebaceus
of Jadassohn with basal cell carcinoma, kaposis sarcomas, oral
visible lesions, papillomas, ibroepitheliomas, hyperplasias,
hypertrophic Lesions, polips, freckles, melasmas and melanomas.
[0301] Such neoplastic tissues are evolved from medical conditions
such as, but not limited to, a viral infection (resulting in a
viral neoplastic tissue), systemic disease (for example,
xanthelasmas or xanthomas caused by excess cholesterol and fats in
the blood), various types of skin cancers, and environmental
factors (for example, moles (nevi) and epidermal cysts stimulated
by sunlight.
[0302] Exemplary medical conditions that are associated with
neoplastic tissues such as listed hereinabove and which are
treatable by the compounds described herein include, but are not
limited to, Seborrheic keratosis, Epidermal Nevus, Linear epidermal
nevus (unius lateralis), Nevus sebaceus of Jadassohn, Intradermal
Nevus, Nevus pilosus, Skin tags and acrochordons, Epidermal
inclusion cysts, Sebaceous hyperplasia, Multiple syringomas, Clear
cell acanthoma, Compound nevus, Halo Nevi, Spindle cell (Spitz)
nevus (epitheloid), Giant Hairy Nevus, Blue Nevus, Nevus of Ota,
Dermatofibroma, Angiofibroma, Multiple cherry hemangioma, Pyogenic
granuloma, Angiokeratoma, Lymphangioma, Junctional Nevus, Nevus
Araneus (Spider telangiectasia), Reclingausen disease
(Neurofibromatisis), Steroide form Hyperkeratosis and
Papillomatosis, Nevus vasculosus, Nevus depigmentasus, Nevus
flammeus (Port-wine stain), Xanthelasma, Verruca vulgaris, Verruca
plana, Condiloma acuminatum, Molluscum contagiosum, Actinic
keratosis, Cutaneus horn, Bowens disease, Lentigo simplex and
senilis, Lentigo maligna, Keratoacanthoma, Trychoepitheliomas,
Multiple displastic Nevi, Arsenal keratosis, Juvinel
pseudomelanoma, Superficial basal cell carcinoma, Basal cell
carcinoma, Nodular basal cell carcinoma, Basal cell pigmented nevus
syndrome-Basaliomas, Squamous cell carcinoma, Merkel-trabecular
cell carcinoma, Nevus sebaceus of Jadassohn with basal cell
carcinoma, Superficial spreading melanoma in situ and stage 1a,
Nodullar malignant melanoma in situ and stage 1a, Kaposis
hemorrhagic sarcoma (Early macular lesion, non-AIDS related), oral
visible lesions, Lentigo malignant melanoma, Papillomas,
Fibroepitheliomas, Hemangiomas and Hyperplastic or Hypertrophic
Lesions, Neurofibromatosis-1 (Recklinghausen disease),
Neurofibromatosis-2, Erosionen (ectopie), Polipus,
Posthysterectomie, granuloma, Endocervicitis, cervical viral warts
such as molluscus contagious and condiloma acuminate; nabothian
cysts; Epistaxis (contact bleeding from erosion of cervix).
[0303] As discussed elaborately hereinabove, while surgical removal
of the skin or mucosal tumor/lesion is frequently the treatment of
choice, this option is non-optimal and suffers from many drawbacks
which render it not applicable in all patients.
[0304] For example, surgical treatment is problematic in treating
patients suffering from multiple tumors/lesions. In such patients,
besides the poor cosmetic result, the surgical removal of all
tumors/lesions may lead to excessive skin tension rendering
surgical wound edge closure problematic. In such cases, the topical
administration of the compounds described herein onto the multiple
tumors/lesions is particularly beneficial due to the complete
devitalization of the tumors/lesions with a very good therapeutic
as well as cosmetic result.
[0305] Hence, in some embodiments, the medical condition is
characterized by multiple skin and/or mucosal lesions.
[0306] An exemplary medical condition characterized by multiple
skin tumors is peripheral Neurofibromatosis (Recklinghausen
disease).
[0307] As further discussed hereinabove, there is an increase in
occurrence of skin disorders characterized by skin neoplasia, such
as skin lesions and skin cancer, caused by extensive exposure of
the skin to irradiation such as ultraviolet beta rays.
[0308] Hence, in some embodiments the medical condition is caused
by irradiation (e.g., sun irradiation and/or photoirradiation).
[0309] As exemplified in the Examples section that follows, the
compounds described herein are capable of devitalizing neoplastic
tissues located externally, namely skin and mucosal tissues. Since
the pathophysiology associated with neoplastic skin and mucosal
tissue is similar to the pathophysiology of all neoplastic tissues,
the compounds of the present invention can be further utilized in
the treatment of medical conditions associated with internal
neoplastic tissues.
[0310] Thus, is some embodiments, the compounds described herein
are administered for treating a medical condition associated with
neoplastic tissue wherein the neoplastic tissue is an internal
tissue.
[0311] The phrase "internal tissue" is used interchangeably herein
with the phrase "intracorporeal tissue" and describes any tissue
located in the body of a subject which is inaccessible externally.
The phrase "internal tissue" encompasses any tissue other than skin
and mucosal tissues, as described herein, that is, any tissue
within the corpus.
[0312] The phrase "internal neoplastic tissue" describes an
internal tissue, as defined herein, wherein neoplasia occurs.
Non-limiting examples of internal neoplastic tissue include liver
neoplastic tissue, thyroid neoplastic tissue, bile duct neoplastic
tissue, bladder neoplastic tissue, bone neoplastic tissue, brain
neoplastic tissue, breast neoplastic tissue, lung neoplastic
tissue, gastrointestinal neoplastic tissue, colon neoplastic
tissue, genital neoplastic tissue, epithelial neoplastic tissue,
esophageal neoplastic tissue, kidney neoplastic tissue, pancreatic
neoplastic tissue, ovarian neoplastic tissue, cervix neoplastic
tissue, uterus neoplastic tissue, testicular neoplastic tissue,
pancreatic neoplastic tissue, prostate neoplastic tissue, rectal
neoplastic tissue, stomach neoplastic tissue, sweat gland
neoplastic tissue, oral neoplastic tissue, ocular-retinal
neoplastic tissue, muscular neoplastic tissue.
[0313] Non-limiting exemplary medical conditions associated with
internal neoplastic tissue and treatable by the compounds described
herein are solid malignant tumors such as, but not limited to,
brain, ovarian, colon, prostate, kidney, bladder, breast, uterine,
cervical and lung cancers. These cancers can be further broken
down. For example, brain cancers include glioblastoma multiforme,
anaplastic astrocytoma, astrocytoma, ependyoma, oligodendroglioma,
medulloblastoma, meningioma, sarcoma, hemangioblastoma, and pineal
parenchymal.
[0314] Non-limiting examples include, but are not limited to,
acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, bile
duct carcinoma, bladder carcinoma, thyroid cancer, tracheal cancer,
bone originated tumor such as bone sarcoma, brain tumor such as
glioma and neuroblastoma; breast cancer, cervical cancer,
chondrosarcoma, chordoma, choriocarcinoma, colon carcinoma,
craniopharyngioma, cystadenocarcinoma, embryonal carcinoma,
endotheliosarcoma, ependymoma, epithelial carcinoma, esophageal
carcinoma, Ewing's tumor, fibrosarcoma, hemangioblastoma, hepatic
carcinoma, leiomyosarcoma, liposarcoma, lung carcinoma such as
bronchogenic carcinoma, small cell lung carcinoma;
lymphangioendotheliosarcoma, lymphangiosarcoma, medullary
carcinoma, medulloblastoma, mesothelioma, myxosarcoma, pancreatic
cancer, oligodendroglioma, osteogenic sarcoma, ovarian cancer,
pancreatic carcinoma, papillary carcinoma, papillary
adenocarcinoma, pinealoma, prostate cancer, rectal cancer, kidney
cancer such as renal cell carcinoma and Wilms' tumor;
retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma,
seminoma, stomach carcinoma, synovioma, sweat gland carcinoma,
testicular tumor, uterus carcinoma, and metastatic disease of the
respective primary cancer.
[0315] The administration of the compounds described herein may be
effected either locally or via systemic administration. While the
devitalizing effect of the compounds described herein may be
achieved via directly contacting the neoplastic tissue with the
compound, an indirect effect may also occur, for example, by
enhancing the response of the immune system against neoplastic
cells through a systemic route, as is detailed hereinunder.
[0316] In some embodiments, administering the compound is effected
by contacting the neoplastic tissue with the compound.
[0317] In some embodiments, the administering is effected
topically.
[0318] In some embodiments, the administering is effected
incorporeally.
[0319] The term "topically" as used herein, describes the
administration of the compounds described herein onto a surface of
the body, such as a neoplastic skin or mucosal tissue.
[0320] The term "intracorporeally", as used herein, describes an
administration which is effected within the body (as apposed to
onto the body surface, i.e., topically). An intracorporeal
administration encompasses the administration of the compounds
described herein during a surgical procedure that enables the
direct contact between the compound and internal neoplastic tissue
which is otherwise inaccessible.
[0321] Non-limiting examples of intracorporeal administration
include local, stereotactic and intravascular administration.
[0322] Local administration, as used herein, describes applying the
compound directly onto the neoplastic tissue. Intracorporeal local
administration describes applying the compound directly onto an
internal neoplastic tissue, for example, during a surgical
procedure. The term "local administration" encompasses also
administration via intratumoral injection, namely injection of the
drug directly into the tumor.
[0323] Stereotactic administration uses a computer and imaging
performed in at least two planes to localize the target neoplastic
tissue (such as a tumor) in three-dimensional space and guide the
compound to the tissue. This includes, for example, an
administration operated under "direct vision".
[0324] Intravascular administration, as used herein, describes the
administration of the compound to the blood vessels of the
neoplastic tissue.
[0325] For example, cervical and/or uterine neoplasms can be
treated by topically applying the compounds or compositions
described herein to the neoplastic tissue, by means of e.g.,
contacting the tissue with a sponge soaked with the compound.
[0326] Bladder carcinoma can be treated by administering the
compound using the direct vision technique.
[0327] Abdominal neoplasia can be treated by local administration
of the compound during a surgical procedure.
[0328] One of the important beneficial characteristics of the
compounds described herein is that while the compounds devitalize
the neoplastic tissue, the tissue is still suitable for
histological evaluation, thereby enabling the physician to assess
the specific histological characteristics of the tissue. Hence, in
some embodiments, in any of the methods and uses described herein
histologically evaluation of the neoplastic tissue is performed
subsequent to the compound administration.
[0329] In some embodiments, the compounds described herein are
utilized within a co-therapy, which further comprises surgically
removing at least a portion of the neoplastic tissue. In such
cases, the administration of the compound may be prior to, during
or subsequent to the surgical procedure.
[0330] Administering the compound prior to the surgical procedure
can be effected by any of the methods (routes of administrations)
described herein. In some embodiments, the compound is administered
locally before removal of the neoplastic tissue, yet during the
surgical procedure.
[0331] Administering the compound subsequent to the surgical
procedure can be effected either in vivo, subsequent to surgically
removing the neoplastic tissue, or ex-vivo, where the compound is
applied to the removed neoplastic tissue.
[0332] As discussed hereinabove, the surgical removal of neoplastic
tissue is one of the treatment options frequently employed in the
management of medical conditions associated with neoplastic tissue.
However, when the neoplastic tissue is malignant, during the
surgical manipulation, dissemination of malignant cells into the
blood and lymph vessels may occur, resulting in metastasis in other
body locations and postoperative recurrence. Therefore, treating
such medical conditions with the compounds described herein is
beneficial, as compared to a surgical treatment alone, since the
dissemination which may occur and the risk of a secondary tumor
evolving form metastasis is much lower. Support for such a
statement is presented in the Examples section that follows. As
shown therein, the level of malignant skin tumor recurrence
following DPA or DPA oligomer treatment, during the 2-8 year
follow-up period was negligible and furthermore, no occurrences of
regional and distant metastases of the skin tumors as well as
lethality cases were reported.
[0333] Hence, in some embodiments of the present invention, the
method described herein is for treating a medical disorder which is
associated with malignant neoplastic tissue, whereby the method
being for reducing or abolishing dissemination of malignant cells
into blood or lymph vessels. In some embodiments the dissemination
of malignant cells is associated with a surgical procedure.
[0334] Accordingly, in accordance with another aspect of some
embodiments the present invention, there is provided a method of
reducing or abolishing dissemination of malignant cells into a
blood and/or lymph vessel of a subject having a medical condition
associated with malignant neoplastic tissue and subjected to a
surgical procedure for removing at least a portion of the malignant
neoplastic tissue. The method, according to this aspect of the
invention, is effected by administering to the subject, prior to or
concomitant with the surgical procedure, a devitalizing effective
amount of a compound as described herein.
[0335] In accordance with another aspect of some embodiments of the
present invention there is provided a use of a compound as
described herein in the manufacture of a medicament for reducing or
abolishing dissemination of malignant cells into a blood and/or
lymph vessel of a subject having a medical condition associated
with malignant neoplastic tissue and subjected to a surgical
procedure for removing at least a portion of the malignant
neoplastic tissue.
[0336] In some embodiments, the malignant neoplastic tissue is a
skin or mucosal tissue. In some embodiments the malignant
neoplastic tissue is an internal tissue as defined herein.
[0337] In some embodiments, the medical condition is a
metastasizing malignant skin or mucosal tumor, as defined
herein.
[0338] Non-limiting examples of malignant skin and mucosal medical
conditions in which a surgical procedure is used for removal of the
malignant neoplastic skin or mucosal tissue and which are suitable
for treatment by the compounds described herein are Superficial
basal cell carcinoma, Basal cell carcinoma, Nodular basal cell
carcinoma, Basal cell pigmented nevus syndrome-Basaliomas, Squamous
cell carcinoma, Merkel-trabecular cell carcinoma, Nevus sebaceus of
Jadassohn with basal cell carcinoma, Superficial spreading melanoma
in situ and stage 1a, Nodullar malignant melanoma in situ and stage
1a, Kaposis hemorrhagic sarcoma (Early macular lesion, non-AIDS
related) and Lentigo malignant melanoma.
[0339] Non-limiting examples of malignant medical conditions in
which a surgical procedure is used for removal of internal
neoplastic tissue and are suitable for treatment by the compounds
described herein are solid malignant tumors as described herein,
including, but not limited to, acoustic neuroma, adenocarcinoma,
angiosarcoma, astrocytoma, bile duct carcinoma, bladder carcinoma,
thyroid cancer, tracheal cancer, bone originated tumor such as bone
sarcoma, brain tumor such as glioma and neuroblastoma; breast
cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma,
colon carcinoma, craniopharyngioma, cystadenocarcinoma, embryonal
carcinoma, endotheliosarcoma, ependymoma, epithelial carcinoma,
esophageal carcinoma, Ewing's tumor, fibrosarcoma,
hemangioblastoma, hepatic carcinoma, leiomyosarcoma, liposarcoma,
lung carcinoma such as bronchogenic carcinoma, small cell lung
carcinoma; lymphangioendotheliosarcoma, lymphangiosarcoma,
medullary carcinoma, medulloblastoma, mesothelioma, myxosarcoma,
pancreatic cancer, oligodendroglioma, osteogenic sarcoma, ovarian
cancer, pancreatic carcinoma, papillary carcinoma, papillary
adenocarcinoma, pinealoma, prostate cancer, rectal cancer, kidney
cancer such as renal cell carcinoma and Wilms' tumor;
retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma,
seminoma, stomach carcinoma, synovioma, sweat gland carcinoma,
testicular tumor, uterus carcinoma, or metastatic disease of the
respective primary cancer.
[0340] In any of the methods and uses described herein, the
compounds as defined herein can be utilized in combination with an
additional active agent. An exemplary such additional active agent
is a selenium-containing agent. The ant-cancer activity of selenium
and selenium containing compounds has been previously reported
[Clark et al. Nutr Cancer. 2008; 60(2):155-63]. For example,
SeO.sub.2 has been known to increase concentration of the endogenic
antioxidant glutathione. Selenium containing compounds such as
SeO.sub.2 have also been known to be immunostimulants, as well as
to inhibit tumor growth and dissemination. It is therefore,
suggested that the co-administration of selenium or a compound
which comprises selenium together with the halogenated aliphatic
acids described herein can achieve an enhanced devitalizing
effect.
[0341] In some embodiments, the selenium-containing is a selenium
salt, a selenium oxide, a selenium halide or a selenium acid.
Exemplary selenium-containing which are suitable for use in the
context of the present embodiments include, but are not limited to,
SeH.sub.4, SeCl.sub.4, SeF.sub.4, SeOCl.sub.2, SeH.sub.2O.sub.4 or
SeH.sub.2O.sub.3.
[0342] In some embodiments, any of the methods and uses described
herein, the compound is administered between 1 to 10 times during
the treatment period. In some embodiments, the compound is
administered once or twice during the treatment period. By
"treatment period" it is meant the time period required for
abolishing or reducing the neoplastic tissue and/or the time period
after which no recurrence of the neoplastic tissue is observed.
[0343] Without being bound by theory, it is speculated that the
compounds described herein devitalize malignant and premalignant
neoplastic tissue located in a primary tumor so as to release
antigenic components of these malignant and premalignant cells into
the blood and lymph vessels, thereby enabling the immune system to
recognize these antigens and exert a direct or indirect immune
response to these antigens. This induced immune response can
subsequently lead to the identification of similar antigens,
located on malignant cells at the primary tumor site as well as
malignant cells that have disseminated from the primary tumor into
the blood/lymph vessels, and destroy these cells, thereby
inhibiting the growth of the tumor and reducing the ability of the
malignant tumor to metastasize and create a secondary tumor.
[0344] Hence, according to another aspect of some embodiments of
the present invention, there is provided a method of inducing a
systemic immune response to malignant cells, the method comprising
administering to a subject in need thereof a therapeutically
effective amount of a compound as described herein.
[0345] Accordingly, according to another aspect of some embodiments
of the present invention there is provided a use of a compound as
described herein in the manufacture of a medicament for inducing a
systemic immune response to malignant cells.
[0346] The induction of the immune response can be further utilized
in order to reduce the capability of premalignant cells and/or
potentially malignant cells to become malignant by destroying these
cells through, the recognition of their antigenic components,
before they are transformed into malignant type cells.
[0347] Thus, according to another aspect of some embodiments of the
present invention, there is provided a method of inducing a
systemic immune response to pre-malignant, and/or potentially
malignant cells, the method comprising administering to a subject
in need thereof a therapeutically effective amount of a compound as
described herein.
[0348] Accordingly, according to another aspect of some embodiments
of the present invention there is provided a use of a compound as
described herein in the manufacture of a medicament for inducing a
systemic immune response to pre-malignant, and/or potentially
malignant cells.
[0349] The phrase "malignant cell" describes a neoplastic cell
which is not self-limited in its growth, is capable of invading
into adjacent tissues, and may be capable of spreading to distant
tissues (metastasizing).
[0350] The phrase "premalignant cell" and "potentially malignant
cell" are used interchangeably to describe a cell which is not
malignant but has a higher probability of becoming malignant as
compared to a normal cell.
[0351] The phrase "systemic immune response" describes the whole
body production and circulation, upon exposure to an antigen, of
organism specific humoral and cellular immune cells and is
characterized by organism specific immune globulin (antibodies) and
cytotoxic mononuclear cells. As used herein, an "antigen" may be
any substance which, when introduced into a mammal, will induce a
detectable immune response, both humoral and cellular. As used
herein, the term "antigen" also includes any portion of an antigen,
e.g., the epitope, which can induce an immune response.
[0352] In some embodiments the induced systemic immune response is
an innate immune response or an acquired immune response.
[0353] The immune system of higher organisms is comprised of an
adaptive (acquired) and an innate component. The innate immune
system refers to a host's antigen-nonspecific defense mechanisms
that come into action immediately or within several hours after
exposure to almost any antigen. The innate immune system represents
the initial response by the body to eliminate microbes. The innate
immune system includes phagocytic cells, which includes macrophages
and polymorphonuclear leukocytes that can engulf (phagocytose)
foreign substances. By contrast, the adaptive immune system refers
to antigen-specific defense mechanisms that emerge over several
days, and react with and remove a specific antigen. The adaptive
immune system develops throughout a lifetime. The adaptive immune
system is based on leukocytes, and is divided into two major
sections: the humoral immune system, which acts mainly via
immunoglobulins produced by B cells, and the cell-mediated immune
system, which functions mainly via T cells.
[0354] The induction of a systemic immune response may be effected
by upregulating an expression of an endogenous factor such as
TNF-.alpha., Interferon-.alpha., Interleukin-1, Interleukin-5,
Interleukin-6 and Interleukin-8 and a combination thereof. The
induction may be further effected via the activation of T helper
cells type-1. The induction may be further effected via activation
of a cytokine such as interferon, IL-10 or IL-12.
[0355] The induction of a systemic immune response by the compounds
described herein may be further enhanced by the co-administration
of the compound together with an immunostimulating agent
[0356] Hence, in some embodiments, the compounds described herein
are utilized in combination with at least one immunostimulating
agent.
[0357] The term "immunostimulating agent" describes a compound
which stimulates the immune response of a subject. Exemplary
immunostimulating properties can be manifested, for example, by an
effect on cytokines secretion, interleukins production, lymphocytes
function, and the like. In some embodiments, the immunostimulating
agent is Granulocyte-macrophage colony-stimulating factor
(GM-CSF).
[0358] Additional exemplary immunostimulants include, but are not
limited to, recombinant human interleukin 2 (rIL-2),
polysaccharides of mannose (e.g. mannans), .beta.(1,3) glucose
(e.g. glucans), .beta.(1,4) acetylated mannose (acemannans),
.beta.(1,4) N-acetyl-glucosamine (chitins), heteropolysaccharides,
such as rhamnogalacturonans (pectins), water-soluble polymers,
muramyl peptides, lipopolysaccharides (LPS) from gram-negative
bacteria and derivatives thereof, and any other of cationic
detergents, interleukins, interferons and growth factors.
[0359] The devitalizing activity of the compounds described herein
may be further due to the ability of the compounds to inhibit
angiogenesis in neoplastic tissue thereby reducing the blood supply
to the tissue. The inhibition of angiogenesis may be effected via
downregulating the expression of proangiogenic factors or/and
upregulating the expression of an endogenous angiogenesis
inhibitors such as endostatin, tumstatin, interferon, interleukin,
and/or thrombospondin.
[0360] The devitalizing activity of the compounds described herein
may be further due to the ability of the compounds to induce an
inflammatory response to pre-malignant, malignant and/or
potentially malignant cells. The inflammatory response may be
effected via upregulating the expression of inflammatory
chemoattractant proteins.
[0361] In any of the methods and uses described herein, the
compounds described herein can be utilized either per se or being
formulated into a pharmaceutical composition which may further
comprise a pharmaceutically acceptable carrier.
[0362] Thus according to some embodiment of the present invention
the compound forms a part of a pharmaceutical composition which
further comprises a pharmaceutically acceptable carrier.
[0363] According to another aspect of some embodiments of the
invention there is provided a pharmaceutical composition
comprising, as an active ingredient, any of the compounds described
herein, and a pharmaceutically acceptable carrier.
[0364] According to another aspect of some embodiments of the
present invention there is provided a use of any of the compounds
as described herein in the manufacture of a medicament.
[0365] According to another aspect of some embodiments of the
invention there is provided a pharmaceutical composition which
comprises, as an active ingredient, the oligomers described herein
(oligomer forms of a compound as described herein) and a
pharmaceutically acceptable carrier.
[0366] According to another aspect of some embodiments of the
present invention there is provided a use of an oligomer as
described herein in the manufacture of a medicament.
[0367] In some embodiments the concentration of the compound in the
composition ranges from 20 weight percents to 100 weight percents
of the total weight of the composition, and can be 20, 30, 40, 50,
60 70, 80, 90 or 100 weight percents of the composition, including
any value therebetween. In some embodiments the concentration of
the compound ranges from 70 weight percents to 90 weight percents
of the total weight of the composition.
[0368] In some embodiments, the pharmaceutical composition further
comprises at least one additional active agent, as described herein
(e.g., a selenium-containing agent). In some embodiments, the
pharmaceutical composition further comprises an immunostimulating
agent as described herein.
[0369] In some embodiments, the pharmaceutical composition is
packaged in a packaging material and identified in print, in or on
the packaging material, for use in the treatment of a medical
condition associated with a neoplastic tissue.
[0370] In some embodiments, the pharmaceutical composition is
identified for use in reducing or preventing dissemination of
malignant cells into a blood and/or lymph vessel of a subject
having a medical condition associated with malignant neoplastic
tissue and subjected to a surgical procedure for removing at least
a portion of the malignant neoplastic tissue.
[0371] As used herein a "pharmaceutical composition" refers to a
preparation of the compounds presented herein, with other chemical
components such as pharmaceutically acceptable and suitable
carriers and excipients. The purpose of a pharmaceutical
composition is to facilitate administration of a compound to an
organism.
[0372] Hereinafter, the term "pharmaceutically acceptable carrier"
refers to a carrier or a diluent that does not cause significant
irritation to an organism and does not abrogate the biological
activity and properties of the administered compound. Examples,
without limitations, of carriers are: propylene glycol, saline,
emulsions and mixtures of organic solvents with water, as well as
solid (e.g., powdered) and gaseous carriers.
[0373] Herein the term "excipient" refers to an inert substance
added to a pharmaceutical composition to further facilitate
administration of a compound. Examples, without limitation, of
excipients include calcium carbonate, calcium phosphate, various
sugars and types of starch, cellulose derivatives, gelatin,
vegetable oils and polyethylene glycols.
[0374] Techniques for formulation and administration of drugs may
be found in "Remington's Pharmaceutical Sciences" Mack Publishing
Co., Easton, Pa., latest edition, which is incorporated herein by
reference.
[0375] Pharmaceutical compositions for use in accordance with the
present invention thus may be formulated in conventional manner
using one or more pharmaceutically acceptable carriers comprising
excipients and auxiliaries, which facilitate processing of the
compounds into preparations which can be used pharmaceutically.
Proper formulation is dependent upon the route of administration
chosen. The dosage may vary depending upon the dosage form employed
and the route of administration utilized. The exact formulation,
route of administration and dosage can be chosen by the individual
physician in view of the patient's condition (see e.g., Fingl et
al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.
1).
[0376] The pharmaceutical composition may be formulated for
administration in either one or more of routes depending on whether
local or systemic treatment or administration is of choice, and on
the area to be treated. As discussed hereinabove, while the
therapeutic effect of the composition described herein may be
achieved via directly contacting the neoplastic tissue with the
compositions, an indirect effect may also occur for example, by
enhancing the response of the immune system against the neoplastic
cells through a systemic rout.
[0377] Therefore, in some embodiments the pharmaceutical
composition or the medicament is formulated for topical
administration. In some embodiments the pharmaceutical composition
or the medicament is formulated for systemic administration.
[0378] In some embodiments the pharmaceutical composition or the
medicament is formulated for incorporeal administration as defined
herein.
[0379] Administration may be done, orally, by inhalation, or
parenterally, for example by intravenous drip or intraperitoneal,
subcutaneous, intramuscular or intravenous injection,
stereotacticly, intravascular, or topically (including
ophtalmically, vaginally, rectally, intranasally).
[0380] Formulations for topical administration may include but are
not limited to lotions, ointments, gels, creams, suppositories,
drops, liquids, sprays and powders. Conventional pharmaceutical
carriers, aqueous, powder or oily bases, thickeners and the like
may be necessary or desirable.
[0381] Compositions for oral administration include powders or
granules, suspensions or solutions in water or non-aqueous media,
sachets, pills, caplets, capsules or tablets. Thickeners, diluents,
flavorings, dispersing aids, emulsifiers or binders may be
desirable.
[0382] Formulations for parenteral administration may include, but
are not limited to, sterile solutions which may also contain
buffers, diluents and other suitable additives. Slow release
compositions are envisaged for treatment.
[0383] The composition may be formulated for application on to a
neoplastic tissue during a surgical procedure. In such a case the
formulation may be formulated so as to be suitable for local
administration, intravascular administration or for use in a
stereotactic procedure.
[0384] The amount of a composition to be administered will, of
course, be dependent on the subject being treated, the severity of
the affliction, the manner of administration, the judgment of the
prescribing physician, etc.
[0385] Determination of the amount of composition to be
administered onto the neoplastic tissue is well within the
capability of those skilled in the art, especially in light of the
detailed disclosure provided herein.
[0386] In some embodiments, the amount ranges from 0.001 ml to 5 ml
of the composition per a neoplastic tissue diameter of 1 cm.
[0387] In some embodiments, the amount ranges from 0.01 ml to 1 ml
of the composition per a neoplastic tissue diameter of 1 cm.
[0388] Thus, for example, an amount of 0.1 ml can be used to treat
a neoplastic tissue having a diameter of 2-3 cm. An amount of 2 ml
of the composition can be used to treat a neoplastic tissue having
a diameter of 5-10 cm.
[0389] It is noted in this regard that, by being commonly used as a
water disinfectant, 0.2 ml of DPA are added to 1 liter of water.
Thus, it is appreciated that the above-indicated amounts are
non-toxic and are within the doses orally consumed by any person
that drinks disinfected water.
[0390] Compositions of the present invention may, if desired, be
presented in a pack or dispenser device, such as an FDA (the U.S.
Food and Drug Administration) approved kit, which may contain one
or more unit dosage forms containing the active ingredient. The
pack may, for example, comprise metal or plastic foil, such as, but
not limited to a blister pack or a pressurized container (for
inhalation). The pack or dispenser device may be accompanied by
instructions for administration. The pack or dispenser may also be
accompanied by a notice associated with the container in a form
prescribed by a governmental agency regulating the manufacture, use
or sale of pharmaceuticals, which notice is reflective of approval
by the agency of the form of the compositions for human or
veterinary administration. Such notice, for example, may be of
labeling approved by the U.S. Food and Drug Administration for
prescription drugs or of an approved product insert. Compositions
comprising the compound(s)/oligomers of the invention formulated in
a compatible pharmaceutical carrier may also be prepared, placed in
an appropriate container, and labeled for treatment of a medical
condition associated with neoplastic tissue or for reducing or
preventing dissemination of malignant cells into a blood and/or
lymph vessel of a subject having a medical condition associated
with malignant neoplastic tissue and subjected to a surgical
procedure for removing at least a portion of the malignant
neoplastic tissues as detailed hereinabove.
[0391] As used herein the term "about" refers to .+-.10%
[0392] The terms "comprises", "comprising", "includes",
"including", "having" and their conjugates mean "including but not
limited to".
[0393] The term "consisting of means "including and limited
to".
[0394] The term "consisting essentially of" means that the
composition, method or structure may include additional
ingredients, steps and/or parts, but only if the additional
ingredients, steps and/or parts do not materially alter the basic
and novel characteristics of the claimed composition, method or
structure.
[0395] The word "exemplary" is used herein to mean "serving as an
example, instance or illustration". Any embodiment described as
"exemplary" is not necessarily to be construed as preferred or
advantageous over other embodiments and/or to exclude the
incorporation of features from other embodiments.
[0396] The word "optionally" is used herein to mean "is provided in
some embodiments and not provided in other embodiments". Any
particular embodiment of the invention may include a plurality of
"optional" features unless such features conflict.
[0397] As used herein the term "method" refers to manners, means,
techniques and procedures for accomplishing a given task including,
but not limited to, those manners, means, techniques and procedures
either known to, or readily developed from known manners, means,
techniques and procedures by practitioners of the chemical,
pharmacological, biological, biochemical and medical arts.
[0398] As used herein, the term "treating" includes abrogating,
substantially inhibiting, slowing or reversing the progression of a
condition, substantially ameliorating clinical or aesthetical
symptoms of a condition or substantially preventing the appearance
of clinical or aesthetical symptoms of a condition.
[0399] As used herein, the singular form "a", "an" and "the"
include plural references unless the context clearly dictates
otherwise. For example, the term "a compound" or "at least one
compound" may include a plurality of compounds, including mixtures
thereof.
[0400] Throughout this application, various embodiments of this
invention may be presented in a range format. It should be
understood that the description in range format is merely for
convenience and brevity and should not be construed as an
inflexible limitation on the scope of the invention. Accordingly,
the description of a range should be considered to have
specifically disclosed all the possible subranges as well as
individual numerical values within that range. For example,
description of a range such as from 1 to 6 should be considered to
have specifically disclosed subranges such as from 1 to 3, from 1
to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as
well as individual numbers within that range, for example, 1, 2, 3,
4, 5, and 6. This applies regardless of the breadth of the
range.
[0401] Whenever a numerical range is indicated herein, it is meant
to include any cited numeral (fractional or integral) within the
indicated range. The phrases "ranging/ranges between" a first
indicate number and a second indicate number and "ranging/ranges
from" a first indicate number "to" a second indicate number are
used herein interchangeably and are meant to include the first and
second indicated numbers and all the fractional and integral
numerals therebetween.
[0402] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable subcombination
or as suitable in any other described embodiment of the invention.
Certain features described in the context of various embodiments
are not to be considered essential features of those embodiments,
unless the embodiment is inoperative without those elements.
[0403] Various embodiments and aspects of the present invention as
delineated hereinabove and as claimed in the claims section below
find experimental support in the following examples.
EXAMPLES
[0404] Reference is now made to the following examples, which
together with the above descriptions illustrate some embodiments of
the invention in a non limiting fashion.
Chemical Syntheses
[0405] Materials, Syntheses and Methods:
[0406] DPA was obtained from Sigma-Aldrich Ag, as a colorless,
transparent, slightly viscose, liquid substance. DPA of lower
purity was also obtained from known vendors and was successfully
used without further purification.
[0407] Selenium and Selenium Dioxide were obtained from MERCK
Ag.
[0408] DPA can be reproduced in non-limited quantities with
chemoanalytical and biological (efficacy) stability during at least
5 years, when stored in sealed brown glass containers at a
temperature of between -4.degree. C. and +50.degree. C.
[0409] Synthesis of DPA in a Form of Tetraoligomer-Polymer(s):
[0410] A 70% (v/v) solution of DPA in water was heated to a
temperature of 190.degree. C., refluxed for 2, 4 or 6 hours, and
cooled to room temperature. The obtained product was filtered,
sonicated three times (an hour every day, for three consecutive
days), using a Magnetostrictive Ultrasound Generator (USR), and
filtered once again to yield a brown colored liquid.
[0411] Elemental analysis of the obtained products indicated that
following a reflux period of 2 hours a dimmer of DPA was obtained;
following a reflux time period of 4 hours a tetramer of DPA was
obtained and following a reflux time period of 6 hours a longer
oligomer of DPA was obtained.
[0412] The obtained oligomers are identified as lipophilic, with a
tendency to form liposomes or nonvisible vesicles in aqueous
solution.
[0413] Synthesis of a DPA Oligomer Complexed with Metallic
Selenium:
[0414] Metallic Selenium (100 mg) was placed in a 250 ml pear
shaped quartz glass flask and a DPA oligomer (100 ml, synthesized
as described hereinabove) was carefully added thereto. The obtained
suspension was refluxed for 6 hours at a temperature of 195.degree.
C. and then allowed to cool to room temperature. The resulting
mixture was filtered, yielding the desired DPA oligomer-Selenium
complex as a dark brown colored liquid.
[0415] Synthesis of a DPA Oligomer Complexed with Metallic Selenium
and SiO.sub.2:
[0416] A DPA oligomer-Selenium complex, synthesized as described
hereinabove, and 10 ml of a 10% w/v aqueous solution of SeO.sub.2
were mixed together. The mixture was sonicated (an hour every day
for three consecutive days) and the product was thereafter filtered
in order to discard off solid impurities. The resulting liquid was
subjected to additional sonication cycles (an hour every day for
three consecutive days) and was thereafter further filtered,
yielding the desired product as a dark brown colored liquid.
[0417] Generally, in the Examples provided below, solutions
containing either DPA, a DPA oligomer or a DPA oligomer complexed
with selenium as described herein, were used. These are all
referred to collectively as "DPA or a DPA oligomer".
Example 1
The Therapeutic Effect of DPA in Treating Various Skin
Pathologies
[0418] Protocol:
[0419] 6938 patients suffering from various skin pathologies, from
different clinics, hospitals and private practices were recruited
prospectively, and treated with DPA or an oligomer thereof
synthesized as described hereinabove, under a common approved
protocol.
[0420] Patients suffering from benign tumors, viral warts or
mucosal membraneus tumors were administered with the tetramer form
of DPA. In some cases, DPA, as a monomer, was used. Patients
suffering from premalignant or malignant tumors were administered
with longer oligomers of DPA.
[0421] In most cases, the DPA monomer or oligomer was administered
only once and without anesthesia or other special conditions. Only
in cases of patients suffering from Recklinghausen disease (a
multiple form of peripheral Neurofibromatosis), when the number of
skin tumor lesions was more than 100, multiple treatment sessions
were performed.
[0422] Biopsy specimens of the skin tumors were taken immediately
after the DPA oligomer treatment (after the full devitalization of
the lesion tissue) by intravital fixation using
radio-electrocauterization techniques, thereby avoiding
lymphohematogenic dissemination of malignant cells from the
tumor.
Safety Studies:
[0423] The safety of DPA oligomer treatment was assessed by
evaluating the treated skin lesion appearance, local skin reaction,
vital sign measurements, adverse events and concomitant medications
taken by the patient.
Therapeutic Efficacy:
[0424] The efficacy of DPA oligomer in the treatment of the various
skin pathologies was further examined by a short and long term
follow-up.
Short Term Follow-Up:
[0425] All necessary, additional tests for further characterizing
the skin lesion/tumor and detecting regional and distant metastasis
(such as X-ray, biopsy and other laboratory tests) were performed
in the medical institutions where the patient was insured.
[0426] At the 3-week, 6-week and 12-week post-treatment visit(s), a
clinical assessment was performed to determine whether treated
lesions were visible at the target site. Pigmented lesions,
suspected of being malignant, were further evaluated
microscopically by the excision of a biopsy sample with a 3 mm
margin from the lesion, using the radioelectro technique, and
histopathologically examining the sample for evidence of residual
or recurrence of tumor.
[0427] Long Term Follow-Up:
[0428] Out of the 6,938 patients participating in the clinical
trial, long term clinical outcomes for 4,778 of the patients
(68.8%) was further obtained. The long term results were recorded
for patients treated with DPA oligomer, 4-8 years following
treatment. The 4,778 patients enrolled in the follow-up suffered
from a total of 45,474 tumor lesions. 84% (4,021) of the patients
had more than one tumor lesion and 8.4% (411) of the patients
suffered from more than 100 malignant and non-malignant tumor
lesions before treatment. 14% (6,524) of the tumor lesions were
post-treatment local recurrences (after surgery, X-ray, laser,
photo-, chemo-, immuno-manipulations, etc.).
[0429] The lesion pathology was determined microscopically in 1996
of the cases (both benign and malignant).
[0430] The long term follow-up included examination of local
recurrences or asymptomatic regional and distant metastases, as
well as the development of new primary lesions. Although no strict
guidelines regarding the number of follow-up sessions were
determined, each patient was reexamined at least 3 times per year,
with the exact number of reexaminations depending on medical
considerations such as the type of treated tumor and other risk
factors such as family history of melanoma, patient anxiety or the
patients ability to recognize signs and symptoms of the
disease.
[0431] Patients treated for pigmented tumors were also monitored by
the regional physician (in charge of routine physical and
work-related medical examinations). In some cases, for example, for
patients having malignant melanomas, histological assessment of the
presence differentiation markers of melanocytes, including
Protein-1 (TRP-1), S-100 and HMB-45, typically lacking when
malignant melanoma occurs, was performed.
[0432] A visual assessment and video-photo of the target tumor area
in each patient was performed at each follow-up meeting.
[0433] Statistical evaluation: The results of the long term
follow-up were assessed using the intention to treat (ITT) analysis
taking into account all 6938 patients.
Clinical Results
Therapeutic Efficacy:
Short-Term Follow-Up:
[0434] The short term clinical results of the DPA oligomer
treatment were similar in all treated patients.
Long-Term Follow-Up:
[0435] The results of the DPA oligomer clinical trials are
presented in Tables 1-11. Tables 1-5 present all of the 4,778
patient details subdivided according to the various types of benign
(Table 1), viral (Table 2), pre-malignant (Table 3),
non-metastazing malignant (Table 4) and visible mucosal (Table 5)
tumor lesions treated.
[0436] Table 6 presents a summary of the number of patients and
tumors in each category which were further reexamined in the long
term follow-up. Table 7 presents data regarding the age of the
patients and Table 8 presents data regarding the follow-up time
length. Table 9 presents data regarding the level of definitive
clinical diagnosis of the type of tumor using biopsy and
histological examination and/or cytological examination and/or only
clinical examination.
[0437] Table 10 presents the clinical results of the efficacy of
the DPA administration during the 2-8 years follow-up period with
very good clinical results observed in 82.1% of the tumors and a
satisfactory level of clinical results observed in 99.1% of the
tumors.
[0438] Table 11 presents data showing the level of tumor recurrence
following DPA oligomer treatment during the 2-8 years follow-up
period. The results show that the recurrent level of all tumor
types was very low with the percentage of recurrence being only
2.3%, 6.1%, 3.5%, 2.8% and 1.2% for benign, viral, pre-malignant,
non-metastizing malignant and mucosal tumors, respectively
[0439] No occurrences of regional and distant metastases of the
skin tumors as well as lethality cases were reported.
[0440] The results show that the high efficacy of DPA oligomer
treatment was observed in all treated skin tumor or lesion and was
not dependent on the type of tumor/lesion, age, skin color or
gender of the patient. The only exception was plantar and palmar
hyperkeratotic warts in which case a cure rate of only 10% was
observed. It is well-known that such lesions are highly resistant
and should be recognized that such a cure rate is significant with
respect thereto.
[0441] With regard to the safety of treatment with DPA oligomer, a
short term local allergic reaction, pain and itching were observed
in 5.8% of the patients during the treatment period, with a
possible development of visible skin hypo- or hyperpigmentation, as
well as scar and kelloid formation. No systemic toxicity was
detected in any of the patients.
[0442] In conclusion, the results show that DPA oligomer treatment
is a highly effective drug for use in the treatment of viral,
benign, premalignant and non-metastizing malignant skin and mucosal
tumors and lesions.
TABLE-US-00001 TABLE 1 Length of Follow-up Post Benign Skin No of
No of Sex Skin color (months) treatment tumors patients lesions
Male Female Fair Dark Range Mean scars (%) Seborrheic 452 3824 302
150 184 268 6-51 34 3.4 keratosis Epidermal 196 528 112 84 134 62
13-74 52 12.1 Nevus Linear epidermal 32 53 19 13 17 15 24-78 56 5.2
nevus (unius lateralis) Nevus sebaceus 58 84 33 25 40 18 15-62 41
4.9 of Jadassohn Intradermal 294 1053 157 137 188 106 3-86 59 6.7
Nevus Nevus pilosus 36 78 22 14 21 15 5-74 44 1.5 Skin tags and 114
2188 76 38 70 44 5-96 71 1.8 acrochordons Epidermal 47 158 15 92 18
29 16-72 52 0.0 inclusion cysts Sebaceous 95 884 30 65 55 40 8-64
47 0.1 hyperplasia Multiple 44 615 7 37 12 32 11-73 42 1.2
syringomas Clear cell 110 214 73 37 71 39 14-62 38 13.1 acanthoma
Compound 97 436 61 36 50 47 10-85 54 4.7 nevus Halo Nevi 27 31 18 9
8 19 11-64 47 14.2 Spindle cell 104 380 56 48 38 66 14-92 70 6.4
(Spitz) nevus (epitheloid) Giant Hairy 18 34 5 13 7 11 6-87 61 12.3
Nevus Blue Nevus 116 429 29 87 34 82 15-74 52 8.8 Nevus of Ota 5 5
2 3 1 4 7-52 34 7.1 Dermatofibroma 88 202 34 54 38 50 12-76 48 3.6
Angiofibroma 129 156 81 48 49 80 8-72 44 1.0 Multiple cherry 24 412
8 16 17 7 13-92 63 1.3 hemangioma Pyogenic 44 67 31 13 19 25 8-84
51 0.9 granuloma Angiokeratoma 184 498 80 104 97 87 6-79 52 0.1
Lymphangioma 12 36 5 7 7 5 11-68 48 0.4 Junctional 106 112 61 45 40
66 13-88 51 12.2 Nevus Nevus Araneus 23 106 13 10 16 7 6-75 46 0.1
(Spider telangiectasia) Reclingausen 28 1236 20 8 15 13 18-64 50
1.2 disease - Neurofibromatisis Steroide form 30 1158 12 18 21 9
9-76 53 2.4 Hyperkeratosis and Papillomatosis Nevus flammeus 8 8 6
2 3 5 13-82 42 0.2 (Port-wine stain) Xanthelasma 103 397 30 73 66
37 5-90 61 1.9 Total 2624 15282 1398 1286 1336 1288
TABLE-US-00002 TABLE 2 Length of No of No of Gender Follow-up pa-
Tu- Fe- Skin color (months) Viral warts tients mors Male male Fair
Dark Range Mean Verruca 104 957 60 44 74 30 6-84 60 vulgaris
Verruca 52 1017 31 21 24 28 6-71 52 plana Verruca 98 438 54 44 59
39 11-68 42 palmaris and plantaris Condiloma 78 241 60 18 54 24
6-91 59 acuminatum Molluscum 41 827 28 13 27 14 9-84 47 contagiosum
Total 373 3480 233 140 238 135
TABLE-US-00003 TABLE 3 Length of Follow-up No of No of Gender Skin
color (months) Premalignant tumors patients tumors Male Female Fair
Dark Range Mean Actinic keratosis 233 2612 181 52 199 34 5-78 52
Cutaneus horn 84 216 56 28 58 26 9-81 54 Bowens disease 51 327 32
19 37 14 6-94 42 Lentigo simplex and 102 498 68 34 71 31 3-87 50
senilis Lentigo maligna 102 232 66 36 71 31 14-92 68
Keratoacanthoma 84 114 62 22 59 25 7-83 51 Trychoepitheliomas 32
217 21 11 19 13 6-74 44 Multiple displastic 52 288 28 24 31 21 6-98
60 Nevi Arsenal keratosis 2 32 -- 2 2 -- 11-68 41 Juvinel 4 16 3 1
2 3 14-77 47 pseudomelanoma Total 746 455 517 229 549 198
TABLE-US-00004 TABLE 4 Length of Follow-up Post Malignant No of No
of Gender Skin (months) treatment skin tumors patients tumors Male
Female Fair Dark Range Mean scars (%) Superficial 148 315 88 60 111
37 3-98 67 3.7 basal cell carcinoma Basal cell 498 2024 301 197 318
180 3-81 53 8.1 carcinoma Nodular basal 102 381 73 29 60 480 6-78
47 11.2 cell carcinoma Basal cell 18 190 11 7 13 5 8-92 43 6.2
pigmented nevus syndrome- Basaliomas Squamous cell 98 422 68 30 59
1 33-90 44 14.3 carcinoma Merkel- 4 27 1 3 3 1 14-74 53 6.6
trabecular cell carcinoma Nevus 47 144 29 18 33 14 6-80 48 1.4
sebaceus of Jadassohn with basal cell carcinoma Superficial 5 11 3
2 4 1 18-75 41 2.8 spreading melanoma in situ and stage 1a Nodullar
3 3 2 1 3 -- 11-83 48 6.8 malignant melanoma in situ and stage 1a
Kaposis 15 157 8 7 11 4 13-67 35 1.4 hemorrhagic sarcoma (Early
macular lesion, non- AIDS related) Lentigo 57 85 33 24 41 16 3-92
62 8.2 malignant melanoma Total 995 3759 617 378 656 739
TABLE-US-00005 TABLE 5 Length of Follow-up Post Mucus membrane No
of No of Gender Skin color (months) treatment tumors (oral)
patients tumors Male Female Fair Dark Range Mean scars (%)
Papillomas 98 306 44 54 35 63 8-84 56 0.1 Fibroepitheliomas 16 44
12 4 8 8 6-77 49 2.3 Hemangiomas 4 13 3 1 2 2 14-82 51 1.9
Hyperplastic or 22 38 16 6 7 19 10-78 42 0.9 Hypertrophic Lesions
Total 140 401 75 65 52 88
TABLE-US-00006 TABLE 6 Number of Number of Type of lesions patients
% Tumors % Benign Tumors 2524 52.8 13,182 52 Viral warts 373 7.8
3,480 13.7 Premalignant tumors 746 15.7 4,552 17.9 Malignant skin
tumors 995 20.8 3,759 14.8 (nonmetastasizing) Mucosal membraneus
tumors 140 2.9 401 1.6 Total 4778 100 25,374 100
TABLE-US-00007 TABLE 7 Range of Age Number of patients 1-10 121
11-20 384 21-30 401 31-40 1553 41-50 528 51-60 1101 61-70 1180
71-80 342 81-90 198 Total 4778
TABLE-US-00008 TABLE 8 Months Patients 5 0 5-10 41 11-15 124 16-20
104 21-25 255 26-30 381 31-35 227 36-40 315 41-45 891 46-50 688
51-55 711 56-60 467 60 574 Total 4778
TABLE-US-00009 TABLE 9 Biopsy and histological Cytological Only
clinical Examination examination examinations Type of tumors and No
of No of No of number of patients patients % patients % patients %
Benign Tumors (2524 754 29.9 520 20.6 1,250 49.5 patients) Viral
warts (373 14 3.7 22 5.9 337 90.4 patients) Premalignant Lesions
438 44 256 34.3 208 21.7 (995 patients) Malignant Tumors 786 79 148
14.9 209 6.1 Mucosal membraneus 4 2.8 39 27.8 97 69.1 (140
patients) Total 1996 41.8 1,093 22.9 2,198 46 All together 3089
TABLE-US-00010 TABLE 10 Very good Good Satisfactory result results
results (++++) (+++) (++) Poor Type of tumor % % % results Benign
81 12.3 5.9 0.8 Viral warts 80.7 7.3 9.2 2.8 Premalignant 88.9 3.6
7.5 -- Malignant 76.0 17.2 6.7 0.1 Mucosal membraneus 82.4 11.9 5.3
0.4 Total in % 82.1 10.2 6.9 0.9%
TABLE-US-00011 TABLE 11 Number of Number of Number of recurrences
recurrent tumors = of treated tumors 25 374 tumors Retreated again
Type of tumors % % % Benign Tumors 15,282 52 315 2.3 255 80.9
Virual warts 3,480 13.7 213 6.1 202 95 Premalignant 4,552 17.9 161
3.5 155 95 lesions Malignant Tumors 3,759 14.5 107 2.8 99 92.5
Mucosal 401 1.6 5 1.2 5 100 membraneus Cure rate 98.2%
Example 2
Toxicology and Immunology Studies in Rats
[0443] Studies were conducted in order to evaluate the effect of
administration of DPA or a DPA oligomer to rats. 1% and 0.1% (by
weight) of a solution of DPA or an oligomer thereof were used, and
the solution was administered daily for several days. The obtained
data (not shown) showed that none of the rats demonstrated
morphological changes in any of the tissues that are responsible
for immunological responses nor were there abnormalities in the
generation of IgM expressed as CPP-Ig million after several days of
daily use of the tested solution.
Example 3
The Therapeutic Effect of DPA in Treating Various Skin
Pathologies
[0444] In additional clinical trials, patients suffering from
various skin pathologies were recruited, and treated with DPA or an
oligomer thereof synthesized as described hereinabove, under a
common approved protocol.
[0445] Patients suffering from benign, pre-malignant and malignant
tumors, viral warts or mucosal membraneus tumors were administered
with the tetramer form of DPA. In some cases, DPA, as a monomer,
was used.
[0446] In most cases, the DPA monomer or oligomer was administered
only once and without anesthesia or other special conditions.
[0447] The safety and efficacy of DPA oligomer treatment was
assessed by evaluating the treated skin lesion appearance, local
skin reaction, vital sign measurements, adverse events and
concomitant medications taken by the patient.
Inclusion criteria were as follows:
[0448] Sufficiently educated patients, suffering from various
superficial skin pathologies, as described in detail hereinbelow,
were enrolled. Patients included ambulatory patients older than 5
years old of both sexes and ambulatory female patients older than
18 years old without potential pregnancy or which are using an
approved contraceptive method (intrauterine apparatus,
contraceptive tablets of at least a menstrual cycle implants or
diaphragm.
The following were excluded from the study:
[0449] Lactating or pregnant women; women with a potential
pregnancy who are not using an approved method of contraception;
Patients having serious advanced diseases, such as advanced cardiac
conditions, final states of renal insufficiency, final states of
neurological diseases; patients with a history of severe allergies
of anaphylactic reactions to drugs or meals; patients with advanced
psychiatry disorders; patients that consume alcohol or illicit
drugs on a regular basis; and patients with advanced malignant skin
lesions.
[0450] Study Protocol:
[0451] Patients were requested to provide complete and
dermatological Clinical history. A dermatological evaluation of the
lesion(s) was performed and clinically diagnosed. The clinical
parameters of the afflicted tissue were measured and recorded.
Biopsy was performed in some cases.
[0452] In patients suffering from multiple lesions, the number of
lesions to be treated was determined.
[0453] All patients were treated by topically applying the tested
solution locally (less than 0.01 cc), at the skin lesion area,
using a micro-pipette. The skin lesion was photographs prior to
treatment, immediately after the topical application of the tested
solution, a week treatment and four weeks after treatment. Patients
were thereafter tested during a time period of 2 years, for
recurrence.
[0454] Clinical Results:
[0455] 453 patients participated in this study, and a total of 2201
lesions were treated. Of these, 15 cases suffered from malignant
tumors. Age distribution of the participants was as follows:
5-10 years old--20 patients; 11-20 years old--41 patients; 21-30
years old--62 patients; 41-40 years old--80 patients; 41-50--116
patients; 61-70 years old--98 patients; 71-80--31 patients; and
81-90--5 patients.
[0456] The following non-malignant lesions were treated:
TABLE-US-00012 No. Lesion (Total = 2149) Actinic Keratosis 237
Condylomata 150 Epidermoid Cyst 52 Fibrolipomas 56 Hemangiomas 12
Kerato Acanthosis 6 Lentigo 7 Molluscum contagiosum 148 Mucosal
Cysts 3 Neuro Fibromas 3 sebaceous Hyperplasia 18 Seborrheic
keratoses 358 Several types of Fibromas 560 Several types of Nevus
422 Several types of Verrucas 117
[0457] In about 98% of the above-indicated cases, the lesion was
resolved, and no recurrence was observed two years following
treatment. In the following cases recurrence was observed: Actinic
keratosis (6 patients with 6 lesions); fibrolipoma (3 cases, 3
lesions); and plantar verrucas (5 cases, 13 lesions).
[0458] In patients having a malignant skin tumor, no recurrence of
the neoplasm was observed during the indicated time period.
[0459] These results further emphasize the outstanding therapeutic
activity of DPA or oligomers thereof, in treating a variety of skin
pathologies.
Example 4
Devitalization of Malignant Tumors in Internal Tissues
[0460] General Protocols:
[0461] In one exemplary protocol, devitalization of primary tumor
and/or tumor metastases is accomplished by direct intra-tumoral
injection of DPA or oligomers thereof, as described herein, by
direct vision at the time of surgery, or by ultrasound or CT-guided
needle for devitalization of inoperable lesion or in preparation
for surgical excision prior to or at the time of operation.
[0462] DPA, or an oligomer thereof, is mixed with radiopaque
solution in order to control adequate saturation of lesions
injected with the tested compound under fluoroscopy or CT
monitoring.
[0463] Minimizing the risk of tumor cells spread in conjunction
with surgical removal of malignant lesions is accomplished by
topical application of the DPA or the oligomer thereof under direct
vision around the excised lesion and lesion bed prior to complete
removal of the lesion in order to eliminate spread of tumor cells
during the excision process itself.
[0464] In another exemplary protocol, devitalization of tumor or
tumor metastases is accomplished by injection of sub-toxic amount
of DPA or an oligomer thereof into an afferent blood vessel or
lymphatic circulation.
[0465] In another exemplary protocol, physical surgical removal of
primary tumor and/or metastases is accompanied by anti-cancer
immunization in order to minimize recurrence from minimal residual
disease using one of the following methods:
[0466] (i) Systemic immunization by subcutaneous or intradermal
administration of lysate of tumor cells modified by DPA or an
oligomer therein, chemically or by viral antigens, in order to
induce autoimmune-like reactivity against tumor cells [modified
self];
[0467] (ii) Using tumor cell lysates by pulsing patient's own
dendritic cells prepared ahead of time for immunization against
residual tumor cells modified by DPA or an oligomer thereof;
[0468] (iii) Using tumor cell lysates for loading dendritic cells
obtained from a family member sharing at least one MHC haplotype
with a patient in order to induce alloreactive response against
natural or modified tumor antigens; and
[0469] (iv) Using the primary tumor or tumor metastases devitalized
by DPA or an oligomer thereof, as an in situ tumor cell vaccine by
intra-lesional injection of autologous or allogeneic dendritic
cells without surgical excision in order to induce an immune
response in situ against local residual viable tumor cells or
against residual tumor cells elsewhere.
[0470] Taken together, a combination of local tumor devitalization,
tumor excision following blocking surgically induced tumor spread
and additional induction of anti-cancer immunotherapy by specific
local or systemic immunization provide an optimal clinical method
for improving the outcome of patients with solid tumors by
optimizing elimination of all malignant cells in primary and
metastatic cancer.
[0471] In Vivo Studies:
[0472] BALB/c mice and (BALB/cxC57BL/6)F1 mice (F1) are Modulated
with a metastatic breast cancer 4T1 cell line into the lateral
flank under the skin. This tumor grows locally and then metastases
develop in the lungs and liver.
[0473] All mice are inoculated with 4T1 subcutaneously and divided
into subgroups that are treated once a local tumor is visible as
follows:
[0474] Group I: untreated controls.
[0475] Group II: controls treated with surgical removal of
tumor.
[0476] Group III: mice treated with local injection of a DPA
oligomer in incremental doses to check role of DPA on tumor growth
and survival.
[0477] Group IV: mice treated with subtoxic doses .times.1,
.times.2, .times.3 to test the effect of cumulative subtoxic doses
of DPA on tumor growth and survival.
[0478] Group V: mice treated with DPA or subtoxic doses as in Group
IV, prior to surgical excision of tumor.
[0479] Group VI: mice treated with subtoxic doses of DPA around the
tumor bed prior to surgical excision.
[0480] Group VII: mice treated with surgical removal of tumor
followed by immunotherapy with tumor cell vaccination or with
alloreactive donor lymphocytes C57BL/6 stem cells into F1
recipients in comparison with recipients treated with tumor cell
vaccine or alloreactive lymphocytes alone.
[0481] Group VIII: mice treated with intra-lesional inoculation of
dendritic cells with and without prior devitalization with DPA.
Example 5
In Vivo Studies of Devitalization of a Primary Tumor by DPA or an
Oligomer Thereof Prior to Surgical Removal
[0482] Study Protocol:
[0483] Eight weeks old BALB/c mice were inoculated SC with
3.5.times.10.sup.6 4 T1 (a model of metastatic breast cancer). On
day +11, when tumors were visible under the skin, mice were divided
into 3 groups, 16 mice per group, as follows:
[0484] Group 1 served as untreated control; Group 2 included mice
treated with 20 microliter injections of DPA or an oligomer thereof
into the primary tumor; Group 3 included mice treated with 20
microliter saline. One hour after treatment, mice were anesthetized
and the primary tumor was surgically removed. At 3 weeks following
tumor inoculation mice were sacrificed and lungs and spleens were
tested for metastases and the weight of spleens was recorded.
[0485] Results
[0486] No cutaneous tumors were visible in mice treated with DPA or
an oligomer thereof. In the untreated control Group 1, 5 mice died.
In DPA-treated Group 2, no mice died. In group 3, 4 mice died.
[0487] Lung metastases were preset in all mice in the untreated
control Group 1, in 2 mice of Group 2 and in 5 mice of Group 3.
[0488] Spleen weight was recorded. Spleen was enlarged and full of
tumor metastases in all mice belonging to control Group 1 [average
0.477 grams]; less in mice of Group 3 [0.262 grams], and further
less in mice belonging to group 2 [0.175 grams]. The difference
between Groups 2 and 3 is significant [p=0.039] based on Levene's
Test for Equality of Variances, and borderline significant
[p=0.057] based on Multiple Comparison Graph.
[0489] The obtained results clearly show that treatment DPA or an
oligomer thereof during a surgical procedure for removing a
malignant tumor, is effective against the primary tumor. The
treatment accomplished in situ within minutes, using reasonably
well tolerated doses of a solution of DPA or an oligomer thereof.
The obtained results demonstrate that devitalization by DPA or an
oligomer thereof during surgical removal of tumors reduces the
incidence of late remote metastases, which may be caused by
systemic spread of tumor cells as a result of the trauma of surgery
through damaged blood or lymphatic vessels.
Example 6
Ex-Vivo Treatment of Human's Meningioma
[0490] A subject suffering from meningioma, as shown using CTA
3D-MPR (see, FIG. 1A), underwent surgical removal of the tumor via
LT Pterional craniotomy. On the next day, the excised meningioma
was treated with DPA and/or oligomer thereof. The results are
presented in FIGS. 1B-1D, and show excellent devitalization of the
meningioma.
[0491] Although the invention has been described in conjunction
with specific embodiments thereof, it is evident that many
alternatives, modifications and variations will be apparent to
those skilled in the art. Accordingly, it is intended to embrace
all such alternatives, modifications and variations that fall
within the spirit and broad scope of the appended claims.
[0492] All publications, patents and patent applications mentioned
in this specification are herein incorporated in their entirety by
reference into the specification, to the same extent as if each
individual publication, patent or patent application was
specifically and individually indicated to be incorporated herein
by reference. In addition, citation or identification of any
reference in this application shall not be construed as an
admission that such reference is available as prior art to the
present invention. To the extent that section headings are used,
they should not be construed as necessarily limiting.
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