U.S. patent application number 13/742865 was filed with the patent office on 2013-07-18 for pharmaceutical compositions and methods.
The applicant listed for this patent is STEVEN HOFFMAN. Invention is credited to STEVEN HOFFMAN.
Application Number | 20130183263 13/742865 |
Document ID | / |
Family ID | 48780112 |
Filed Date | 2013-07-18 |
United States Patent
Application |
20130183263 |
Kind Code |
A1 |
HOFFMAN; STEVEN |
July 18, 2013 |
PHARMACEUTICAL COMPOSITIONS AND METHODS
Abstract
Pharmaceutical compositions and kits including a tyrosine
hydroxylase inhibitor; melanin, a melanin promoter, or a
combination thereof; a p450 3A4 promoter; and a leucine
aminopeptidase inhibitor are provided. Also provided are methods of
treating cancer in a subject, comprising administering an effective
amount of a tyrosine hydroxylase inhibitor, a melanin promoter, a
p450 3A4 promoter, and a leucine aminopeptidase inhibitor to the
subject in need thereof. Also provided are methods of reducing cell
proliferation in a subject comprising administering an effective
amount of a tyrosine hydroxylase inhibitor, a melanin promoter, a
p450 3A4 promoter, and a leucine aminopeptidase inhibitor to the
subject in need thereof.
Inventors: |
HOFFMAN; STEVEN; (MAHWAH,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
HOFFMAN; STEVEN |
MAHWAH |
NJ |
US |
|
|
Family ID: |
48780112 |
Appl. No.: |
13/742865 |
Filed: |
January 16, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13371076 |
Feb 10, 2012 |
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13742865 |
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61587420 |
Jan 17, 2012 |
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Current U.S.
Class: |
424/78.32 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 31/19 20130101; A61K 31/4166 20130101; A61K 38/12 20130101;
A61K 9/10 20130101; A61K 31/366 20130101; A61K 31/787 20130101;
A61K 38/12 20130101; A61K 31/198 20130101; A61K 31/436 20130101;
A61K 31/4166 20130101; A61K 31/198 20130101; A61K 31/216 20130101;
A61K 31/55 20130101; A61K 9/0053 20130101; A61K 38/34 20130101;
A61K 9/0019 20130101; A61K 9/48 20130101; A61K 31/787 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 38/34 20130101; A61K 31/436 20130101 |
Class at
Publication: |
424/78.32 |
International
Class: |
A61K 38/12 20060101
A61K038/12; A61K 31/436 20060101 A61K031/436; A61K 31/4166 20060101
A61K031/4166; A61K 31/216 20060101 A61K031/216; A61K 31/787
20060101 A61K031/787 |
Claims
1. A pharmaceutical composition comprising a tyrosine hydroxylase
inhibitor; and melanin, a melanin promoter, or a combination
thereof.
2. The pharmaceutical composition of claim 1 wherein said tyrosine
hydroxylase inhibitor is .alpha.-methyl-DL-tyrosine.
3. The pharmaceutical composition of claim 1 comprising
melanin.
4. A pharmaceutical composition comprising a tyrosine hydroxylase
inhibitor and a p450 3A4 promoter.
5. The pharmaceutical composition of claim 4 wherein said tyrosine
hydroxylase inhibitor is .alpha.-methyl-DL-tyrosine.
6. The pharmaceutical composition of claim 4 wherein said p450 3A4
promoter is 5,5-diphenylhydantoin.
7. A pharmaceutical composition comprising a tyrosine hydroxylase
inhibitor and a leucine aminopeptidase inhibitor.
8. The pharmaceutical composition of claim 7 wherein said tyrosine
hydroxylase inhibitor is .alpha.-methyl-DL-tyrosine.
9. The pharmaceutical composition of claim 7 wherein said leucine
aminopeptidase inhibitor is rapamycin or
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine.
10. A pharmaceutical composition comprising melanin, a melanin
promoter, or a combination thereof; a p450 3A4 promoter; and a
leucine aminopeptidase inhibitor.
11. The pharmaceutical composition of claim 10 comprising melanotan
II.
12. The pharmaceutical composition of claim 10 wherein said p450
3A4 promoter is 5,5-diphenylhydantoin.
13. The pharmaceutical composition of any one of claim 10 wherein
said leucine aminopeptidase inhibitor is rapamycin or
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine.
14. A kit comprising a pharmaceutical composition of claim 1 and a
pharmaceutical composition according to claim 4.
15. The kit of claim 14 further comprising a pharmaceutical
composition of claim 7.
16. The kit of claim 15 further comprising a pharmaceutical
composition of claim 10.
17. The kit of claim 16 further comprising a pharmaceutical
composition comprising a tyrosine hydroxylase inhibitor.
18. A method for treating cancer comprising administering to a
patient in need thereof a pharmaceutical composition of claim 1, a
pharmaceutical composition of claims 7, a pharmaceutical
composition of claim 10, and a pharmaceutical composition
comprising a tyrosine hydroxylase inhibitor.
19. The method of claim 18 wherein said pharmaceutical compositions
are administered to said patient within a 24 hour period.
20. The method of claim 18 wherein said pharmaceutical compositions
are administered to said patient five days per week for six weeks.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 13/371,076, filed on Feb. 10, 2012, which
claims priority to U.S. Provisional Application No. 61/587,420,
filed on Jan. 17, 2012. This application also claims priority to
U.S. Provisional Application No. 61/702,994, filed on Sep. 19,
2012. All of the applications mentioned in this paragraph are
incorporated herein by reference in their entirety.
TECHNICAL FIELD
[0002] The present inventions relate generally to compositions,
kits and methods for the reduction of cellular proliferation as,
for example, in the treatment of cancer.
BACKGROUND
[0003] According to the U.S. National Cancer Institute's
Surveillance Epidemiology and End Results (SEER) database for the
year 2008, the most recent year for which incidence data are
available, 11,958,000 Americans have invasive cancers. Cancer is
the second most common cause of death in the United States, behind
only heart disease, and accounts for one in four deaths. It has
been estimated that approximately 1600 Americans die of cancer each
day. In addition to the medical, emotional and psychological costs
of cancer, cancer has significant financial costs to both the
individual and society. It is estimated by the National Institutes
of Health that the overall costs of cancer in 2010 was $263.8
billion. In addition, it is estimated that another $140.1 billion
is lost in productivity due to premature death.
[0004] Cancer treatments today include surgery, hormone therapy,
radiation, chemotherapy, immunotherapy, targeted therapy, and
combinations thereof. Surgical removal of cancer has advanced
significantly; however, there remains a high chance of recurrence
of the disease. Hormone therapy using drugs such as aromatase
inhibitors and luteinizing hormone-releasing hormone analogs and
inhibitors has been relatively effective in treating prostate and
breast cancers. Radiation and the related techniques of conformal
proton beam radiation therapy, stereotactic radiosurgery,
stereotactic radiation therapy, intraoperative radiation therapy,
chemical modifiers, and radio sensitizers are effective at killing
cancerous cells, but can also kill and alter surrounding normal
tissue. Chemotherapy drugs such as aminopterin, cisplatin,
methotrexate, doxorubicin, daunorubicin and others alone and in
combinations are effective at killing cancer cells, often by
altering the DNA replication process. Biological response modifier
(BRM) therapy, biologic therapy, biotherapy, or immunotherapy alter
cancer cell growth or influence the natural immune response, and
involve administering biologic agents to a patient such as an
interferons, interleukins, and other cytokines and antibodies such
as rituximab and trastuzumab and even cancer vaccines such as
Sipuleucel-T.
[0005] Recently, new targeted therapies have been developed to
fight cancer. These targeted therapies differ from chemotherapy
because chemotherapy works by killing both cancerous and normal
cells, with greater effects on the cancerous cells. Targeted
therapies work by influencing the processes that control growth,
division, and the spread of cancer cells and signals that cause
cancer cells to die naturally. One type of targeted therapy
includes growth signal inhibitors such as trastuzumab, gefitinib,
imatinib, centuximab, dasatinib and nilotinib. Another type of
targeted therapy includes angiogenesis inhibitors such as
bevacizumab that inhibit cancers from increasing surrounding
vasculature and blood supply. A final type of targeted therapy
includes apoptosis-inducing drugs that are able to induce direct
cancer cell death.
[0006] Although all of these treatments have been effective to one
degree or another, they all have drawbacks and limitations. In
addition to many of the treatments being expensive, they also are
often too imprecise or the cancers are able to adapt to them and
become resistant.
[0007] Thus, there is a great need for additional cancer
treatments. In particular, there is a need for treatments for
cancers that have become resistant to other forms of treatment.
SUMMARY
[0008] The present invention provides compositions, combination
therapies, kits, and methods for reducing undue cellular
proliferation, including that associated with the treatment of
cancer. In certain embodiments, the invention provides
pharmaceutical compositions comprising at least one tyrosine
hydroxylase inhibitor; at least one of melanin, a melanin promoter,
or a combination thereof; at least one p450 3A4 promoter; at least
one leucine aminopeptidase inhibitor; and, optionally, at least one
growth hormone inhibitor. In other embodiments, the invention
provides kits that comprise these components together with suitable
packaging. Also provided are methods of reducing cellular
proliferation and/or methods of treating cancer comprising
administering an effective amount of at least one tyrosine
hydroxylase inhibitor; at least one of melanin, a melanin promoter,
or a combination thereof; at least one p450 3A4 promoter; at least
one leucine aminopeptidase inhibitor; and, optionally, at least one
growth hormone inhibitor to the subject in need thereof.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0009] The present subject matter may be understood more readily by
reference to the following detailed description which forms a part
of this disclosure. It is to be understood that this invention is
not limited to the specific products, methods, conditions or
parameters described and/or shown herein, and that the terminology
used herein is for the purpose of describing particular embodiments
by way of example only and is not intended to be limiting of the
claimed invention.
[0010] Unless otherwise defined herein, scientific and technical
terms used in connection with the present application shall have
the meanings that are commonly understood by those of ordinary
skill in the art. Further, unless otherwise required by context,
singular terms shall include pluralities and plural terms shall
include the singular.
[0011] As employed above and throughout the disclosure, the
following terms and abbreviations, unless otherwise indicated,
shall be understood to have the following meanings.
[0012] In the present disclosure the singular forms "a," "an," and
"the" include the plural reference, and reference to a particular
numerical value includes at least that particular value, unless the
context clearly indicates otherwise. Thus, for example, a reference
to "a compound" is a reference to one or more of such compounds and
equivalents thereof known to those skilled in the art, and so
forth. The term "plurality", as used herein, means more than one.
When a range of values is expressed, another embodiment includes
from the one particular and/or to the other particular value.
Similarly, when values are expressed as approximations, by use of
the antecedent "about," it is understood that the particular value
forms another embodiment. All ranges are inclusive and
combinable.
[0013] As used herein, the terms "component," "composition,"
"composition of compounds," "compound," "drug," "pharmacologically
active agent," "active agent," "therapeutic," "therapy,"
"treatment," or "medicament" are used interchangeably herein to
refer to a compound or compounds or composition of matter which,
when administered to a subject (human or animal) induces a desired
pharmacological and/or physiologic effect by local and/or systemic
action.
[0014] As used herein, the terms "treatment" or "therapy" (as well
as different forms thereof) include preventative (e.g.,
prophylactic), curative or palliative treatment. As used herein,
the term "treating" includes alleviating or reducing at least one
adverse or negative effect or symptom of a condition, disease or
disorder. This condition, disease or disorder can be cancer.
[0015] As employed above and throughout the disclosure the term
"effective amount" refers to an amount effective, at dosages, and
for periods of time necessary, to achieve the desired result with
respect to the treatment of the relevant disorder, condition, or
side effect. It will be appreciated that the effective amount of
components of the present invention will vary from patient to
patient not only with the particular compound, component or
composition selected, the route of administration, and the ability
of the components to elicit a desired result in the individual, but
also with factors such as the disease state or severity of the
condition to be alleviated, hormone levels, age, sex, weight of the
individual, the state of being of the patient, and the severity of
the pathological condition being treated, concurrent medication or
special diets then being followed by the particular patient, and
other factors which those skilled in the art will recognize, with
the appropriate dosage being at the discretion of the attending
physician. Dosage regimes may be adjusted to provide the improved
therapeutic response. An effective amount is also one in which any
toxic or detrimental effects of the components are outweighed by
the therapeutically beneficial effects.
[0016] "Pharmaceutically acceptable" refers to those compounds,
materials, compositions, and/or dosage forms which are, within the
scope of sound medical judgment, suitable for contact with the
tissues of human beings and animals without excessive toxicity,
irritation, allergic response, or other problem complications
commensurate with a reasonable benefit/risk ratio.
[0017] Within the present invention, the disclosed compounds may be
prepared in the form of pharmaceutically acceptable salts.
"Pharmaceutically acceptable salts" refer to derivatives of the
disclosed compounds wherein the parent compound is modified by
making acid or base salts thereof. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or
organic acid salts of basic residues such as amines; alkali or
organic salts of acidic residues such as carboxylic acids; and the
like. The pharmaceutically acceptable salts include the
conventional non-toxic salts or the quaternary ammonium salts of
the parent compound formed, for example, from non-toxic inorganic
or organic acids. For example, such conventional non-toxic salts
include those derived from inorganic acids such as hydrochloric,
hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like;
and the salts prepared from organic acids such as acetic,
propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isethionic, and the like. These physiologically acceptable
salts are prepared by methods known in the art, e.g., by dissolving
the free amine bases with an excess of the acid in aqueous alcohol,
or neutralizing a free carboxylic acid with an alkali metal base
such as a hydroxide, or with an amine.
[0018] Compounds described herein can be prepared in alternate
forms. For example, many amino-containing compounds can be used or
prepared as an acid addition salt. Often such salts improve
isolation and handling properties of the compound. For example,
depending on the reagents, reaction conditions and the like,
compounds as described herein can be used or prepared, for example,
as their hydrochloride or tosylate salts. Isomorphic crystalline
forms, all chiral and racemic forms, N-oxide, hydrates, solvates,
and acid salt hydrates, are also contemplated to be within the
scope of the present invention.
[0019] Certain acidic or basic compounds of the present invention
may exist as zwitterions. All forms of the compounds, including
free acid, free base and zwitterions, are contemplated to be within
the scope of the present invention. It is well known in the art
that compounds containing both amino and carboxy groups often exist
in equilibrium with their zwitterionic forms. Thus, any of the
compounds described herein that contain, for example, both amino
and carboxy groups, also include reference to their corresponding
zwitterions.
[0020] The term "stereoisomers" refers to compounds that have
identical chemical constitution, but differ as regards the
arrangement of the atoms or groups in space.
[0021] The term "administering" means either directly administering
a compound or composition of the present invention, or
administering a prodrug, derivative or analog which will form an
equivalent amount of the active compound or substance within the
body.
[0022] The terms "subject," "individual," and "patient" are used
interchangeably herein, and refer to an animal, for example a
human, to whom treatment, including prophylactic treatment, with
the pharmaceutical composition according to the present invention,
is provided. The term "subject" as used herein refers to human and
non-human animals. The terms "non-human animals" and "non-human
mammals" are used interchangeably herein and include all
vertebrates, e.g., mammals, such as non-human primates,
(particularly higher primates), sheep, dog, rodent, (e.g. mouse or
rat), guinea pig, goat, pig, cat, rabbits, cows, horses and
non-mammals such as reptiles, amphibians, chickens, and
turkeys.
[0023] The term "inhibitor" as used herein includes compounds that
inhibit the expression or activity of a protein, polypeptide or
enzyme and does not necessarily mean complete inhibition of
expression and/or activity. Rather, the inhibition includes
inhibition of the expression and/or activity of a protein,
polypeptide or enzyme to an extent, and for a time, sufficient to
produce the desired effect.
[0024] The term "promoter" as used herein includes compounds that
promote the expression or activity of a protein, polypeptide or
enzyme and does not necessarily mean complete promotion of
expression and/or activity. Rather, the promotion includes
promotion of the expression and/or activity of a protein,
polypeptide or enzyme to an extent, and for a time, sufficient to
produce the desired effect.
[0025] In one embodiment, the present invention provides
combination therapies that alter the defenses of cancerous cells to
oxidative stress. One class of such therapies increases free
radical availability to cancerous cells. A representative subclass
of such therapies involves administration of pharmaceutical
compositions comprising a tyrosine hydroxylase inhibitor, melanin
or a melanin promoter, a p450 3A4 promoter, a leucine
aminopeptidase inhibitor, and, optionally, a growth hormone
inhibitor. Another subclass involves administration of
pharmaceutical compositions comprising melanin and either a
tyrosine hydroxylase inhibitor. Particular components of the
pharmaceutical composition are described below.
[0026] While not intending to be bound by any particular mechanism
of operation, tyrosine hydroxylase inhibitors according to the
present invention function by accumulating in cancer cells and
preventing them from forming a coating of either lipids or
hyaluronan. By preventing the cancer cells from forming a coating
of either lipids or hyaluron, the cancer cells are believed to be
made more accessible to oxidative stress. Representative tyrosine
hydroxylase inhibitors include tyrosine derivatives, which
typically are rapidly absorbed by most cancers and inflamed
tissues. Representative tyrosine derivatives include one or more of
methyl(2R)-2-amino-3-(2-chloro-4-hydroxyphenyl) propanoate,
D-tyrosine ethyl ester hydrochloride,
methyl(2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate
H-D-Tyr(TBU)-allyl ester HCl,
methyl(2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate,
methyl(2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl)methoxy]phenyl)propanoa-
te, methyl(2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl)propanoate,
diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzyl
malonate,
methyl(2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(3-chloro-4-hydroxyphenyl) propanoate,
H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl, H-D-3,5-diiodo-tyr-OME
HCl, H-D-tyr-OME HCl, D-tyrosine methyl ester hydrochloride,
D-tyrosine-ome HCl, methyl D-tyrosinate hydrochloride,
H-D-tyr-OMe.HCl, D-tyrosine methyl ester HCl, H-D-Tyr-OMe-HCl,
(2R)-2-amino-3-(4-hydroxyphenyl)propionic acid,
(2R)-2-amino-3-(4-hydroxyphenyl)methyl ester hydrochloride,
methyl(2R)-2-amino-3-(4-hydroxyphenyl)propanoate hydrochloride,
methyl(2R)-2-azanyl-3-(4-hydroxyphenyl)propanoate hydrochloride,
3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl
ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine,
Boc-Tyr(3,5-I.sub.2)-OSu, Fmoc-tyr(3-NO.sub.2)--OH, and
.alpha.-methyl-DL-tyrosine (also known as
DL-2-Methyl-3-(4-Hydroxyphenyl)alanine).
[0027] The present invention involves the use of at least one of
melanin, a melanin promoter, or a combination thereof. Thus,
melanin can be used, one or more melanin promoters can be used, and
both melanin and one or more melanin promoters can be used (either
in separate dosage forms or in the same dosage form). Melanin
promoters according to the present invention are chemical compounds
that increase the production and/or the activity of melanin.
Increased melanin levels are believed to reduce inflammation
(through, for example, suppression of TNF) and exclude the
sequestered lymph system. Melanin is a photo catalyst, and can
therefore promote chemical reactions that generate free radicals
which, in turn, can become accessible to cancer cells.
Representative melanin promoters are methoxsalen and melanotan
II.
[0028] In some instances, the tyrosine hydroxylase inhibitor is
mixed with melanin in the same dosage form. This association of
melanin with the tyrosine hydroxylase inhibitor is believed to
facilitate uptake of melanin in cancer cells because tyrosine
hydroxylase inhibitors are more readily taken up by such cells. In
certain embodiments melanin is solubilized in a solubilizing agent
and then mixed with the tyrosine hydroxylase inhibitor by methods
known in the art. The solubilizing agent may be removed by standard
techniques, such as evaporation, drying, etc. The solubilizing
agent may be a non-toxic solubilizing agent, such as hydrogen
peroxide or other solubilizing agents commonly known in the art.
The melanin and/or the pharmaceutical composition may be further
processed to optimize the pharmaceutical composition's effect on
cancer cells. In another embodiment the pharmaceutical composition
may include additional active agents and/or pharmaceutical
excipients.
[0029] The pharmaceutical compositions of the invention also
include a p450 3A4 promoter. "Cytochrome p450 3A4" (which can be
abbreviated as "p450 3A4") is a member of the cytochrome p450
superfamily of enzymes, and is a mixed-function oxidase that is
involved in the metabolism of xenobiotics in the body. It has the
widest range of substrates of all of the cytochromes. The function
of a p450 3A4 promoter in the pharmaceutical compositions of the
invention is to increase the expression and/or the activity of p450
3A4. The increased p450 3A4 expression and/or activity is believed
to reduce cortisone and estrogen levels in the patient.
Additionally, the increased p450 3A4 expression and/or activity
also slightly decreases blood pH, which is believed to help to
preserve or enhance melanin activity. Representative p450 3A4
promoters are 5,5-diphenylhydantoin (sold commercially as, for
example, Dilantin), valproic acid, and carbamazepine, which are
believed to induce expression of the p450 3A4 enzyme.
[0030] The instant pharmaceutical compositions further include
leucine aminopeptidase inhibitors (alternatively known as leucyl
aminopeptidase inhibitors). Leucine aminopeptidases are enzymes
that preferentially catalyze the hydrolysis of leucine residues at
the N-terminus of peptides and/or proteins. Inhibiting the
expression and/or activity of leucine aminopeptidases is believed
to assist in tumor reabsorption by increasing cholesterol transport
to the liver. Generally, it is believed that aminopeptidase
inhibitors, including aminopeptidase inhibitors, deplete sensitive
tumor cells of specific amino acids by preventing protein
recycling, thus generating an antiproliferative effect.
Representative leucine aminopeptidase inhibitors are
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine, and
rapamycin.
[0031] The instant pharmaceutical compositions also optionally
include a growth hormone inhibitor. Growth hormone (such as, for
example, pancreatic growth hormone) induces cell replication.
Inhibition of the expression and/or activity of growth hormone is
believed to exclude normal cells from rapid replication while
allowing cancer cells to continue to rapidly replicate and
incorporate the tyrosine derivative. Representative growth hormone
inhibitors are octreotide, somatostatin, and seglitide.
[0032] The pharmaceutical compositions of the invention can further
include D-leucine. D-leucine is a stereoisomer of the naturally
occurring L-leucine, the form of leucine incorporated into
polypeptides and proteins. D-leucine cannot be incorporated into
polypeptides and/or proteins. Along with the leucine aminopeptidase
inhibitor, the D-leucine is believed to create a physiological
environment that mimics a leucine shortage. Thus, the presence of
D-leucine permits the use of lower doses of leucine aminopeptidase
inhibitor in a pharmaceutical composition.
[0033] Also provided herein are kits including a combination
therapy that creates alterations in the defenses of cancerous cells
to oxidative stress. An intended suitable embodiment is a kit that
includes a combination therapy that increases free radical
availability to cancerous cells. Representative kits comprise a
tyrosine hydroxylase inhibitor, melanin and/or a melanin promoter,
a p450 3A4 promoter, a leucine aminopeptidase inhibitor and,
optionally, a growth hormone inhibitor of the type described above,
together with packaging for same. The kit can include one or more
separate containers, dividers or compartments and, optionally,
informational material such as instructions for administration. For
example, each inhibitor or promoter (or the various combinations
thereof) can be contained in a bottle, vial, or syringe, and the
informational material can be contained in a plastic sleeve or
packet or provided in a label. In some embodiments, the kit
includes a plurality (e.g., a pack) of individual containers, each
containing one or more unit dosage forms of a compound described
herein. For example, the kit can include a plurality of syringes,
ampules, foil packets, or blister packs, each containing a single
unit dose of a compound described herein or any of the various
combinations thereof. The containers of the kits can be air tight,
waterproof (e.g., impermeable to changes in moisture or
evaporation), and/or light-tight. The kit optionally includes a
device suitable for administration of the composition, e.g., a
syringe, inhalant, pipette, forceps, measured spoon, dropper (e.g.,
eye dropper), swab (e.g., a cotton swab or wooden swab), or any
such delivery device.
[0034] Methods of treating cancer in a subject also are provided,
as are methods of reducing undue cellular proliferation. Such
methods can include administering an effective amount of a
combination therapy that creates alterations in the defenses of
cancerous cells to oxidative stress. Representative methods of
treating cancer include administering an effective amount of a
combination therapy that increases free radical availability to
cancerous cells. Suitable embodiments are methods that include
administering an effective amount of the above-noted tyrosine
hydroxylase inhibitor, melanin and/or melanin promoter, p450 3A4
promoter, leucine aminopeptidase inhibitor and, optionally, growth
hormone inhibitor. Other suitable methods include administering an
effective amount of melanin and a tyrosine hydroxylase
inhibitor.
[0035] Suitable methods include simultaneous or at least
contemporaneous administration of at least two of the tyrosine
hydroxylase inhibitor, melanin or a melanin promoter, p450 3A4
promoter, and leucine aminopeptidase inhibitor, at least three of
them, or each of them (in each case, optionally, with a growth
hormone inhibitor). It is believed to be desirable that an
effective concentration of these moieties be in the subject's
bloodstream at the same time, and any dosing regimen that achieves
this is within the scope of the present invention. The desired
number of inhibitors and promoters can be provided in a single
dosage form or any number of desired dosage forms, including in
individual dosage forms. Representative dosage forms include
tablets, capsules, caplets, sterile aqueous or organic solutions,
reconstitutable powders, elixirs, liquids, colloidal or other types
of suspensions, emulsions, beads, beadlets, granules,
microparticles, nanoparticles, and combinations thereof. The amount
of composition administered will, of course, be dependent on the
subject being treated, the subject's weight, the severity of the
condition being treated, the manner of administration, and the
judgment of the prescribing physician.
[0036] Administration of the melanin, promoters, and/or inhibitors
can be through various routes, including orally, nasally,
subcutaneously, intravenously, intramuscularly, transdermally,
vaginally, rectally or in any combination thereof. Transdermal
administration can be effected using, for example, oleic acid,
1-methyl-2-pyrrolidone, or dodecylnonaoxyethylene glycol
monoether.
[0037] The melanin, promoters and/or inhibitors can be administered
during a cycle consisting of five to seven days of administering
the melanin, promoters and/or inhibitors and one to two days of not
administering the melanin, promoters and/or inhibitors. The
melanin, promoters and/or inhibitors can be administered over the
course of at least six of said cycles. It can be desirable to
administer these components about two hours between meals to
facilitate uptake.
[0038] The subject to which the instant compositions are
administered can be a mammal, preferably a human.
[0039] In one representative method, 60 mg of the tyrosine
derivative is administered orally and 0.25 mL of a 2 mg/mL
suspension of the tyrosine derivative is administered
subcutaneously; 10 mg of the methoxsalen is administered orally and
0.25 mL of a 1 mg/mL suspension of the methoxsalen is administered
subcutaneously; 30 mg of the 5,5-diphenylhydantoin is administered
orally; and 20 mg of the
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine is
administered orally.
[0040] In certain embodiments, the combination therapy comprises:
(i) a dosage form containing melanin (50 mcg) and
.alpha.-methyl-DL-tyrosine (75 mg); (ii) a dosage form containing
5,5-diphenylhydantoin (15 mg) and .alpha.-methyl-DL-tyrosine (75
mg); (iii) a dosage form containing
3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine (50 mcg) and
.alpha.-methyl-DL-tyrosine (75 mg); (iv) a dosage form containing
3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine (5 mcg), melanotan II
(10 mcg), and 5,5-diphenylhydantoin (2 mg); and (v) a dosage form
containing .alpha.-methyl-DL-tyrosine (5 mg) in NaCl bacteriostatic
water. In other embodiments, the combination therapy comprises: (i)
a dosage form containing melanin (50 mcg) and
.alpha.-methyl-DL-tyrosine (75 mg); (ii) a dosage form containing
5,5-diphenylhydantoin (15 mg) and .alpha.-methyl-DL-tyrosine (75
mg); (iii) a dosage form containing rapamycin (0.2 mg) and
.alpha.-methyl-DL-tyrosine (75 mg); (iv) a dosage form containing
rapamycin (0.15 mcg), melanotan II (10 mcg), and
5,5-diphenylhydantoin (2 mg); and (v) a dosage form containing
.alpha.-methyl-DL-tyrosine (5 mg) in NaCl bacteriostatic water.
Dosages that are two times greater than this, and even four times
greater than this, are believed to be both safe and
efficacious.
[0041] Representative methods include those in which the cancer is
non-small cell lung cancer. In certain embodiments, the non-small
cell lung cancer is stage 1V non-small cell lung cancer. In yet
other embodiments, the cancer is ovarian cancer, breast cancer,
cervical cancer, pancreatic cancer, stomach cancer, brain cancer,
liver cancer, or testicular cancer. The cancer can also be leukemia
or lymphoma.
[0042] In certain embodiments, one or more of the tyrosine
hydroxylase inhibitor; the melanin promoter; the p450 3A4 promoter;
and the leucine aminopeptidase inhibitor is a nucleic acid,
protein, antibody or antigen-binding fragment of an antibody.
[0043] The present methods can include not only the disclosed
administration step but also the step of assessing progression of
said cancer in said subject and/or the extent of cellular
proliferation. The assessing step can be performed before or after
the administering step.
[0044] Suitable embodiments can include a pharmaceutical
composition comprising a tyrosine hydroxylase inhibitor, melanin
and/or a melanin promoter, a p450 3A4 promoter, and a leucine
aminopeptidase inhibitor. The pharmaceutical composition can
further comprise a growth hormone inhibitor. The growth hormone can
be pancreatic growth hormone. The growth hormone inhibitor can be
octreotide or somatostatin. The tyrosine hydroxylase inhibitor can
be a tyrosine derivative. The tyrosine derivative can be one or
more of methyl(2R)-2-amino-3-(2-chloro-4 hydroxyphenyl)propanoate,
D-tyrosine ethyl ester hydrochloride,
methyl(2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl)propanoate
H-D-Tyr(TBU)-allyl ester HCl, methyl
(2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl)
methoxy]phenyl)propanoate,
methyl(2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl) propanoate,
methyl(2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl)propanoate,
diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzyl
malonate,
methyl(2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)propanoate,
H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl, H-D-3,5-diiodo-tyr-OME
HCl, H-D-tyr-OME HCl, D-tyrosine methyl ester hydrochloride,
D-tyrosine-ome HCl, methyl D-tyrosinate hydrochloride,
H-D-tyr-OMe.HCl, D-tyrosine methyl ester HCl, H-D-Tyr-OMe-HCl,
(2R)-2-amino-3-(4-hydroxyphenyl)propionic acid,
(2R)-2-amino-3-(4-hydroxyphenyl)methyl ester hydrochloride,
methyl(2R)-2-amino-3-(4-hydroxyphenyl)propanoate hydrochloride,
methyl (2R)-2-azanyl-3-(4-hydroxyphenyl)propanoate hydrochloride,
3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl
ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr
(3,5-I.sub.2)-OSu, Fmoc-tyr(3-NO.sub.2)--OH, and
.alpha.-methyl-DL-tyrosine. The melanin promoter can be methoxsalen
or melanotan II. The p450 3A4 promoter can be
5,5-diphenylhydantoin. The p450 3A4 promoter can be valproic acid
or carbamazepine. The leucine aminopeptidase inhibitor can be
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine or
rapamycin. The pharmaceutical compositions of the invention can
further comprise D-leucine.
[0045] Also provided herein are kits comprising a tyrosine
hydroxylase inhibitor, melanin and/or a melanin promoter, a p450
3A4 promoter, and a leucine aminopeptidase inhibitor, together with
packaging for same. The kit can further comprise a growth hormone
inhibitor. The growth hormone can be pancreatic growth hormone. The
growth hormone inhibitor can be octreotide or somatostatin. The
tyrosine hydroxylase inhibitor can be a tyrosine derivative. The
tyrosine derivative can be one or more of
methyl(2R)-2-amino-3-(2-chloro-4 hydroxyphenyl)propanoate,
D-tyrosine ethyl ester hydrochloride,
methyl(2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl)propanoate
H-D-Tyr(TBU)-allyl ester HCl,
methyl(2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl)
methoxy]phenyl)propanoate,
methyl(2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl) propanoate,
methyl(2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl)propanoate,
diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzyl
malonate,
methyl(2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)propanoate,
H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl, H-D-3,5-diiodo-tyr-OME
HCl, H-D-tyr-OME HCl, D-tyrosine methyl ester hydrochloride,
D-tyrosine-ome HCl, methyl D-tyrosinate hydrochloride,
H-D-tyr-OMe.HCl, D-tyrosine methyl ester HCl, H-D-Tyr-OMe.HCl,
(2R)-2-amino-3-(4-hydroxyphenyl)propionic acid,
(2R)-2-amino-3-(4-hydroxyphenyl)methyl ester hydrochloride,
methyl(2R)-2-amino-3-(4-hydroxyphenyl)propanoate hydrochloride
methyl (2R)-2-azanyl-3-(4-hydroxyphenyl)propanoate hydrochloride,
3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl
ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr
(3,5-I.sub.2)-OSu, Fmoc-tyr(3-NO.sub.2)--OH, and
.alpha.-methyl-DL-tyrosine. The melanin promoter can be methoxsalen
or melanotan II. The p450 3A4 promoter can be
5,5-diphenylhydantoin, valproic acid or carbamazepine. The leucine
aminopeptidase inhibitor can be
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine or
rapamycin. The kits of the invention can further comprise
D-leucine.
[0046] Methods of treating cancer in a subject are also provided
comprising administering an effective amount of a tyrosine
hydroxylase inhibitor, melanin and/or a melanin promoter, a p450
3A4 promoter, and a leucine aminopeptidase inhibitor to the subject
in need thereof. In a suitable embodiment, the method of treating
cancer can further comprise a growth hormone inhibitor. In certain
embodiments, at least two of the components (i.e., melanin,
promoters and/or inhibitors) are administered simultaneously. In
other embodiments, at least three of the components are
administered simultaneously. Each of the components can be
administered simultaneously. In suitable embodiments, the
components are administered orally, subcutaneously, intravenously,
transdermally, vaginally, rectally or in any combination thereof.
The transdermal administration can be done with oleic acid,
1-methyl-2-pyrrolidone, or dodecylnonaoxyethylene glycol monoether.
In other embodiments, the components are administered during a
cycle consisting of five to seven days of administering the
components and one to two days of not administering the components.
The components can be administered over the course of at least six
of said cycles. The tyrosine hydroxylase inhibitor can be a
tyrosine derivative. The tyrosine derivative can be one or more of
methyl(2R)-2-amino-3-(2-chloro-4 hydroxyphenyl)propanoate,
D-tyrosine ethyl ester hydrochloride,
methyl(2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl)propanoate
H-D-Tyr(TBU)-allyl ester HCl,
methyl(2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl)
methoxy]phenyl)propanoate,
methyl(2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl) propanoate,
methyl(2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl)propanoate,
diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzyl
malonate,
methyl(2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)propanoate,
H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl, H-D-3,5-diiodo-tyr-OME
HCl, H-D-tyr-OME HCl, D-tyrosine methyl ester hydrochloride,
D-tyrosine-ome HCl, methyl D-tyrosinate hydrochloride,
H-D-tyr-OMe.HCl, D-tyrosine methyl ester HCl, H-D-Tyr-OMe-HCl,
(2R)-2-amino-3-(4-hydroxyphenyl)propionic acid,
(2R)-2-amino-3-(4-hydroxyphenyl)methyl ester hydrochloride,
methyl(2R)-2-amino-3-(4-hydroxyphenyl)propanoate hydrochloride,
methyl(2R)-2-azanyl-3-(4-hydroxyphenyl)propanoate hydrochloride,
3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl
ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr
(3,5-I.sub.2)-OSu, Fmoc-tyr(3-NO.sub.2)--OH, and
.alpha.-methyl-DL-tyrosine. In a suitable embodiment of the method,
60 mg of the tyrosine derivative is administered orally and 0.25 mL
of a 2 mg/mL suspension of the tyrosine derivative is administered
subcutaneously. The melanin promoter can be methoxsalen. In another
suitable method, 10 mg of the methoxsalen is administered orally
and 0.25 mL of a 1 mg/mL suspension of the methoxsalen is
administered subcutaneously. The melanin promoter can also be
melanotan II. The p450 3A4 promoter can be 5,5-diphenylhydantoin.
In another suitable method, 30 mg of the 5,5-diphenylhydantoin is
administered orally. The p450 3A4 promoter can also be valproic
acid or carbamazepine. The leucine aminopeptidase inhibitor can be
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine. In another
suitable method, 20 mg of the
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine is
administered orally. The leucine aminopeptidase inhibitor can also
be rapamycin. The growth hormone can be pancreatic growth hormone.
The growth hormone inhibitor can be octreotide. The method can
further comprise administering an effective amount of D-leucine.
The subject can be a mammal and that mammal can be a human.
Representative methods include those in which the cancer is
non-small cell lung cancer. In certain embodiments, the non-small
cell lung cancer is stage IV non-small cell lung cancer. In other
embodiments, the cancer is ovarian cancer, breast cancer, cervical
cancer, pancreatic cancer, stomach cancer, brain cancer, liver
cancer, or testicular cancer. In other embodiments, the cancer is
leukemia or lymphoma. In other suitable embodiments, the tyrosine
hydroxylase inhibitor, the melanin promoter, the p450 3A4 promoter,
and the leucine aminopeptidase inhibitor is one or more of a
nucleic acid, protein, antibody or antigen-binding fragment of an
antibody. Another suitable embodiment further comprises assessing
progression of said cancer in said subject. The assessing step can
be performed before said administering step or the assessing step
can be performed after said administering step.
[0047] Methods of reducing cell proliferation in a subject are also
provided comprising administering an effective amount of a tyrosine
hydroxylase inhibitor; melanin and/or a melanin promoter; a p450
3A4 promoter; and a leucine aminopeptidase inhibitor to the subject
in need thereof. In a suitable embodiment, the method of treating
cancer can further comprise a growth hormone inhibitor. In certain
embodiments, at least two of the components (i.e., melanin,
promoters and/or inhibitors) are administered simultaneously. In
other embodiments, at least three of the components are
administered simultaneously. Each of the components can be
administered simultaneously. In suitable embodiments, components
are administered orally, subcutaneously, intravenously,
transdermally, vaginally, rectally or in any combination thereof.
The transdermal administration can be done with oleic acid,
1-methyl-2-pyrrolidone, or dodecylnonaoxyethylene glycol monoether.
In other embodiments, the components are administered during a
cycle consisting of five to seven days of administering the
components and one to two days of not administering the components.
The components can be administered over the course of at least six
of said cycles. The tyrosine hydroxylase inhibitor can be a
tyrosine derivative. The tyrosine derivative can be one or more of
methyl(2R)-2-amino-3-(2-chloro-4 hydroxyphenyl)propanoate,
D-tyrosine ethyl ester hydrochloride,
methyl(2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl)propanoate
H-D-Tyr(TBU)-allyl ester HCl,
methyl(2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl)
methoxy]phenyl)propanoate,
methyl(2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl) propanoate,
methyl(2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl)propanoate,
diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzyl
malonate,
methyl(2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl)propanoate,
methyl(2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)propanoate,
H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl, H-D-3,5-diiodo-tyr-OME
HCl, H-D-tyr-OME HCl, D-tyrosine methyl ester hydrochloride,
D-tyrosine-ome HCl, methyl D-tyrosinate hydrochloride,
H-D-tyr-OMe.HCl, D-tyrosine methyl ester HCl, H-D-Tyr-OMe-HCl,
(2R)-2-amino-3-(4-hydroxyphenyl)propionic acid,
(2R)-2-amino-3-(4-hydroxyphenyl)methyl ester hydrochloride,
methyl(2R)-2-amino-3-(4-hydroxyphenyl)propanoate hydrochloride,
methyl (2R)-2-azanyl-3-(4-hydroxyphenyl)propanoate hydrochloride,
3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl
ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr
(3,5-I.sub.2)-OSu, Fmoc-tyr(3-NO.sub.2)--OH, and
.alpha.-methyl-DL-tyrosine. In a suitable embodiment of the method,
60 mg of the tyrosine derivative is administered orally and 0.25 mL
of a 2 mg/mL suspension of the tyrosine derivative is administered
subcutaneously. The melanin promoter can be methoxsalen. In another
suitable method, 10 mg of the methoxsalen is administered orally
and 0.25 mL of a 1 mg/mL suspension of the methoxsalen is
administered subcutaneously. The melanin promoter can also be
melanotan II. The p450 3A4 promoter can be 5, 5-diphenylhydantoin.
In another suitable method, 30 mg of the 5,5-diphenylhydantoin is
administered orally. The p450 3A4 promoter can also be valproic
acid or carbamazepine. The leucine aminopeptidase inhibitor can be
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine. In another
suitable method, 20 mg of the
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine is
administered orally. The leucine aminopeptidase inhibitor can also
be rapamycin. The growth hormone can be pancreatic growth hormone.
The growth hormone inhibitor can be octreotide. The method can
further comprise administering an effective amount of D-leucine.
The subject can be a mammal and the mammal can be a human.
Representative methods include those in which the cancer is
non-small cell lung cancer. In certain embodiments, the non-small
cell lung cancer is stage 1V non-small cell lung cancer. In other
embodiments, the cancer is ovarian cancer, breast cancer, cervical
cancer, pancreatic cancer, stomach cancer, brain cancer, liver
cancer, or testicular cancer. In other embodiments, the cancer is
leukemia or lymphoma. In other suitable embodiments, the tyrosine
hydroxylase inhibitor, the melanin promoter, the p450 3A4 promoter,
and the leucine aminopeptidase inhibitor is one or more of a
nucleic acid, protein, antibody or antigen-binding fragment of an
antibody. Another suitable embodiment further comprises assessing
progression of said cancer in said subject. The assessing step can
be performed before said administering step or the assessing step
can be performed after said administering step.
[0048] The following examples of specific embodiments for carrying
out the present invention are offered for illustrative purposes
only, and are not intended to limit the scope of the present
invention in any way.
[0049] Representative methods of administration of the
pharmaceutical compositions and combination therapies also are
provided. Various embodiments of the present invention further
relate to methods of administering a pharmaceutical composition or
combination therapy to a human patient for the treatment of cancer.
The methods may comprise administering a pharmaceutical composition
or combination therapy by generally accepted routes of
administration (e.g., oral, subcutaneous, parenteral, inhalation,
topical, etc.). In some instances, a pharmaceutical composition or
combination therapy may be administered orally and/or
subcutaneously. In some instances, a pharmaceutical composition or
combination therapy may be administered to human patients between
meals.
[0050] In certain embodiments of the present invention, a
pharmaceutical composition or combination therapy may be
administered to a human patient for 5 days per week for a period of
6 weeks, creating one cycle of 30 days of treatment. Depending on
the outcome after 6 weeks or one cycle of treatment, additional
cycles of the pharmaceutical composition or combination therapy may
be administered.
[0051] The present invention also provides: [0052] pharmaceutical
compositions comprising a tyrosine hydroxylase inhibitor; and
melanin, a melanin promoter, or a combination thereof (preferably
melanin); [0053] pharmaceutical compositions comprising a tyrosine
hydroxylase inhibitor and a p450 3A4 promoter; [0054]
pharmaceutical compositions comprising a tyrosine hydroxylase
inhibitor and a leucine aminopeptidase inhibitor; and [0055]
pharmaceutical compositions comprising melanin, a melanin promoter,
or a combination thereof (preferably melanotan II); a p450 3A4
promoter; and a leucine aminopeptidase inhibitor. The tyrosine
hydroxylase inhibitor in such compositions preferably is
.alpha.-methyl-DL-tyrosine, the p450 3A4 promoter preferably is
5,5-diphenylhydantoin, and the leucine aminopeptidase inhibitor
preferably is
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine. The
invention also provides kits comprising each of these
pharmaceutical compositions, along with a pharmaceutical
composition comprising a tyrosine hydroxylase inhibitor; as well as
methods comprising administering each of the pharmaceutical
compositions to a patient along with a pharmaceutical composition
comprising a tyrosine hydroxylase inhibitor, preferably such that
they are administered to the patient within a 24 hour period.
Example 1
[0056] A clinical study was performed to evaluate the
effectiveness, safety, acceptability, and tolerability of a
combination therapy in accordance with embodiments of the present
invention as a treatment for metastatic cancer.
[0057] The combination therapy comprised the following: [0058] (a)
capsule containing melanin (50 mcg) and .alpha.-methyl-DL-tyrosine
(75 mg), administered orally; [0059] (b) capsule containing
5,5-diphenylhydantoin (15 mg) and .alpha.-methyl-DL-tyrosine (75
mg), administered orally; [0060] (c) capsule containing
5,5-diphenylhydantoin (15 mg) and .alpha.-methyl-DL-tyrosine (75
mg), administered orally; [0061] (d) capsule containing rapamycin
(0.2 mg) and .alpha.-methyl-DL-tyrosine (75 mg), administered
orally; [0062] (e) suspension containing rapamycin (0.15 mcg),
melanotan II (10 mcg), and 5,5-diphenylhydantoin (2 mg),
administered subcutaneously; and [0063] (f) suspension containing
.alpha.-methyl-DL-tyrosine (5 mg) in NaCl bacteriostatic water,
administered subcutaneously.
[0064] Each patient was administered the combination therapy five
days per week for six weeks. More than 200 patients were screened.
The criteria included patients with any metastatic cancer. Thirty
patients meeting the criteria were accepted and participated in the
study.
Treatment of Metastatic Breast Cancer
[0065] Fourteen patients in the study suffered from metastatic
breast cancer. Patient information and results are as follows in
Table 1:
TABLE-US-00001 TABLE 1 Patient Characteristics Average age 55
(40-70 years old) Female 14/14 Caucasian 13/14 Prior to Study
Declined routine treatment prior to 4/14 study enrollment Used all
available treatment and were 10/14 considered incurable Treatment
Results 1-3 point improvement in ECOG rating 11/14 1-5 point
improvement in EORTC rating 10/14 (scale 1-7) Weight Gained weight
4/14 (1-5 lbs) Remained the same weight 6/14 Lost weight 4/14 (1-2
lbs) Pain Reduction in pain level (scale of 1-10) 8/14 (1-9)
Entered study with no pain and maintained 6/14 the same level
Entered study on pain medication 6/14 No longer needed pain
medication at the 5/6 end of the cycle Evidence of Cancer Disease
free with normal physical exam, 3/14 review of systems, and imaging
Significant reduction in quantity and/or 5/14 size of the largest
tumor Reduction in quantity and/or size of the 2/14 largest tumor
No progression of the cancer 4/14 Survival Alive 14/14 33-37 wks
4/14 27-29 wks 5/14 12-19 wks 5/14 Current Status Went home 3/14
Continued treatment 11/14
One side effect of the therapy was hyperpigmentation in all of the
patients. Overall, all of the patients tolerated the combination
therapy and no adverse events were reported.
[0066] Over 200 cancer patients were screened in a clinical trial.
Thirty (30) subjects meeting the study criteria consented. The
average patient age was 56 years old with a range of 30 years old
to 70 years old. The patients in the study were administered a
treatment regimen that included a tyrosine hydroxylase inhibitor
(i.e., .alpha.-methyl-DL tyrosine), a melanin promoter (i.e.,
melanotan II), a p450 3A4 promoter (i.e., 5,5-diphenylhydantoin),
and a leucine aminopeptidase inhibitor (i.e., rapamycin). These
compounds were administered on each of five days per week for a
period of six weeks, with one or two days off between weekly
cycles.
[0067] After six weeks of treatment, 12 of the 30 patients (40%)
maintained the same rating under the Eastern Cooperative Oncology
Group (ECOG) 0-5 scale (see Oken, et al., Toxicity And Response
Criteria Of The Eastern Cooperative Oncology Group, Am. J. Clin.
Oncol., 5:649-655, 1982). Fourteen (14) of 30 (46%) had 1-3 point
improvement in their ECOG rating.
[0068] Fourteen (14) of the 30 patients (46%) maintained the same
rating under the European Organisation for the Research and
Treatment of Cancer Quality of Life Questionnaire Core (EORTC) 1-7
scale (see, e.g., Bergman, et al., The EORTC QLQ-LC13: a modular
supplement to the EORTC Core Quality of Life Questionnaire
(QLQ-C30) for use in lung cancer clinical trials, EORTC Study Group
on Quality of Life, Eur. J. Cancer, 1994. 30A(5): p. 635-42).
Sixteen (16) of 30 (54%) had 1-5 point improvement in their EORTC
rating.
[0069] Eleven (11) of the 30 patients gained weight of 1 to 9
pounds, 17 of 30 stayed the same weight, and 2 of 30 lost 1 to 2
pounds.
[0070] Thirteen (13) of 30 (43%) had a reduction in pain levels.
Seventeen (17) of 30 (57%) entered with minimal pain and maintained
the same level. Nine (9) of 30 (30%) entered the study on pain
medication and 8 of those nine (89%) no longer needed pain
medication at the end of the cycle.
[0071] No disease was detected in four (4) of 30 (13%) with normal
physical exam, review of systems, and imaging. Eight (8) of 30
(27%) had significant reduction in quantity of tumors and/or size
of the largest tumor. Eight (8) of 30 (27%) exhibited reduction in
quantity of tumors and/or size of the largest tumor. Ten (10) of 30
(33%) showed no progression of disease.
[0072] Twenty nine (29) of the 30 patients were alive with median
survival of 22 weeks. Thirteen (13) of 30 (43%) were released and
went home. Seventeen (17) of 30 (57%) continue with the treatment.
All of the subjects developed hyperpigmentation.
[0073] Overall, the above-noted treatment was well tolerated by the
subjects, with no adverse events related to the treatment, and
responses have been documented to the treatment 100%.
Example 2
[0074] In one aspect, the present invention provides methods of
inducing melanin production in vivo with one or both of methoxsalen
and melanotan and/or through administration of melanin. Without
intending to be bound by any particular theory of operation,
melanin is believed to be beneficial because of its photocatalytic
nature and its ability to convert various wavelengths of ambient or
induced electromagnetic radiation into electrical energy, thus
potentiating desirable reactions or dislocations. In some patients,
either because of genetic variation, infirmity, necessity of
expedited availability, or to realize maximum effectiveness, it has
been determined that melanin preferably is combined mechanically or
chemically with .alpha.-methyl-DL-tyrosine prior to
administration.
[0075] Melanin as a photocatalyst is believed to have polarity at
points in its physical mass. It has been determined that small
melanin particles may produce less electrical energy than larger
particles, and a plurality of melanin particles tend not to
accumulate in polarity-specific formations. An effective method to
obtain high yield of electrical energy from melanin is to form the
melanin in large, polarized particles. By implication, it is
believed that nanoparticles, regardless of quantity, are not as
desirable as larger particles for cancer treatment, and that larger
particles have a greater capacity to be accepted by cancer cell
membranes.
[0076] In accordance with certain embodiments, melanin is combined
with .alpha.-methyl-DL-tyrosine in at least three ways. [0077] 1)
Melanin, either naturally occurring or synthetic, is mechanically
mixed with compressive force to adhere the melanin, which is
non-water soluble and somewhat malleable, with the
.alpha.-methyl-DL-tyrosine. Following the initial combining of
these components, it is desirable to add additional
.alpha.-methyl-DL-tyrosine until substantial coverage of the
melanin is achieved. [0078] 2) Melanin can be solubilized by many
methods as described in U.S. Pat. No. 5,225,435, the contents of
which are incorporated herein by reference. One preferred method
involves mixing melanin with distilled water and hydrogen peroxide
to achieve a melanin concentration of at least 5 weight percent,
and then placing the resulting composition in a microwave oven
until it reaches a boiling point. The dissolved melanin that is
produced is used to infuse or saturate through the mass of
.alpha.-methyl-DL-tyrosine. The composition is then dried and the
dry powder is used. [0079] 3) .alpha.-Methyl-DL-tyrosine is placed
in distilled water with 5-benzyloxy-6-methoxy-indole and sealed for
up to a month. The L portion of the racemic
.alpha.-methyl-DL-tyrosine is believed to convert to (DOPA)
melanin. The size of the melanin particle can be controlled by
controlling the time of growth period. The powder produced is then
cleaned and dried. The ratio of the racemic mix is no longer 50/50,
but the utility of the chemically combined ingredients facilitates
penetration of the melanin even with reduced L component and
appears to offer potentially sufficient benefit.
* * * * *