U.S. patent application number 17/515530 was filed with the patent office on 2022-08-25 for use of bipolar trans carotenoids with chemotherapy and radiotherapy for treatment of cancer.
The applicant listed for this patent is DIFFUSION PHARMACEUTICALS LLC. Invention is credited to John L. GAINER.
Application Number | 20220265592 17/515530 |
Document ID | / |
Family ID | 1000006318747 |
Filed Date | 2022-08-25 |
United States Patent
Application |
20220265592 |
Kind Code |
A1 |
GAINER; John L. |
August 25, 2022 |
USE OF BIPOLAR TRANS CAROTENOIDS WITH CHEMOTHERAPY AND RADIOTHERAPY
FOR TREATMENT OF CANCER
Abstract
The subject disclosure relates to compounds and compositions
including chemotherapy agents and/or radiation therapy with bipolar
trans carotenoids, and the use of such compounds for the treatment
of various cancers including pancreatic and brain cancers.
Inventors: |
GAINER; John L.;
(Charlottesville, VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DIFFUSION PHARMACEUTICALS LLC |
Charlottesville |
VA |
US |
|
|
Family ID: |
1000006318747 |
Appl. No.: |
17/515530 |
Filed: |
October 31, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16087993 |
Sep 24, 2018 |
11185523 |
|
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PCT/US17/23844 |
Mar 23, 2017 |
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17515530 |
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62312988 |
Mar 24, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 5/1077 20130101;
A61N 2005/1098 20130101; A61K 31/704 20130101; A61K 31/202
20130101; A61K 9/19 20130101; A61K 31/7068 20130101; A61K 9/0019
20130101; A61K 31/337 20130101; A61K 45/06 20130101; A61P 35/00
20180101; A61K 47/40 20130101; A61K 47/643 20170801; A61K 33/243
20190101; A61K 31/4188 20130101; A61K 31/495 20130101 |
International
Class: |
A61K 31/202 20060101
A61K031/202; A61K 31/337 20060101 A61K031/337; A61K 31/7068
20060101 A61K031/7068; A61K 47/40 20060101 A61K047/40; A61K 9/19
20060101 A61K009/19; A61K 31/704 20060101 A61K031/704; A61K 45/06
20060101 A61K045/06; A61K 31/495 20060101 A61K031/495; A61K 9/00
20060101 A61K009/00; A61K 33/243 20060101 A61K033/243; A61K 47/64
20060101 A61K047/64; A61P 35/00 20060101 A61P035/00; A61K 31/4188
20060101 A61K031/4188; A61N 5/10 20060101 A61N005/10 |
Claims
1-24. (canceled)
25. A method of treating cancer in a human comprising: a)
administering to the human trans sodium crocetinate and b)
administering to the human radiation therapy and chemotherapy,
wherein trans sodium crocetinate is administered 45-60 minutes
prior to administration of the radiation therapy, the dose of trans
sodium crocetinate is 0.15-0.35 mg/kg, and the chemotherapy is
temozolomide.
26. A method as in claim 25, wherein trans sodium crocetinate is
administered at a dose of 0.25 mg/kg.
27. A method as in claim 25, wherein said radiation therapy is
external beam radiation therapy.
28. A method as in claim 25, wherein said radiation therapy is
administered 5 times per week for 6 weeks.
29. A method as in claim 25, wherein temozolomide is administered 7
times per week for 6 weeks.
30. A method as in claim 25, wherein said chemotherapy is
administered after said radiation therapy.
31. A method as in claim 25, wherein said cancer is brain
cancer.
32. A method as in claim 31, wherein said brain cancer is a
glioblastoma multiforme.
33. A method as in claim 25, wherein trans sodium crocetinate is in
the form of a composition with a cyclodextrin.
34. A method as in claim 25, wherein trans sodium crocetinate is in
the form of a lyophilized composition with a cyclodextrin.
35. A method of treating cancer in a human comprising: a)
administering to the human trans sodium crocetinate and b)
administering to the human chemotherapy, wherein trans sodium
crocetinate is administered 30-120 minutes prior to administration
of the chemotherapy, the dose of trans sodium crocetinate is
0.75-2.0 mg/kg, and the chemotherapy is one or more compounds
selected from the group consisting of temozolomide, gemcitabine,
5-fluorouracil (5-FU), irinotecan, oxaliplatin, nab-paclitaxel
(albumin-bound paclitaxel), capecitabine, cisplatin, elotinib,
paclitaxel, docetaxel, and irinotecan liposome.
36. A method as in claim 35, wherein trans sodium crocetinate is
administered 1-2 hours prior to administration of the
chemotherapy.
37. A method as in claim 35, wherein said cancer is a solid
tumor.
38. A method as in claim 35, wherein the cancer is selected from
the group consisting of squamous cell carcinomas, melanomas,
lymphomas, sarcomas, sarcoids, osteosarcomas, skin cancer, breast
cancer, head and neck cancer, gynecological cancer, urological and
male genital cancer, bladder cancer, prostate cancer, bone cancer,
cancers of the endocrine glands, cancers of the alimentary canal,
cancers of the major digestive glands/organs, CNS cancer, and lung
cancer.
39. A method as in claim 35, wherein the cancer is pancreatic
cancer.
40. A method as in claim 35, wherein trans sodium crocetinate is in
the form of a composition with a cyclodextrin.
41. A method as in claim 35, wherein trans sodium crocetinate is in
the form of a lyophilized composition with a cyclodextrin.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/087,993, filed Sep. 24, 2018, now issued as
U.S. Pat. No. 11,185,523, which is a U.S. National Stage
application of International Application No. PCT/US2017/023844,
filed Mar. 23, 2017, which claims the benefit of and priority to
United States Provisional Application No. 62/312,988, filed Mar.
24, 2016, the contents of which are incorporated by reference in
their entirety.
[0002] The subject disclosure relates to the use of bipolar trans
carotenoids with chemotherapy and/or radiotherapy for the treatment
of cancer including brain and pancreatic cancer.
BACKGROUND
[0003] Getting an adequate supply of oxygen to the tissues in our
body begins in the lungs, where gas exchange occurs and oxygen
enters the bloodstream while carbon dioxide exits the bloodstream
to be exhaled. The process of gas exchange occurs via diffusion,
which is the movement of molecules from an area of high
concentration to an area of low concentration. Once the oxygen
enters into the bloodstream it must diffuse through the plasma and
then enter red blood cells where it binds to hemoglobin. The oxygen
is then transported through the bloodstream, and as it enters areas
of the body with low oxygen concentration, the oxygen is off-loaded
by the red blood cells so that it can again diffuse through the
blood plasma and capillary walls to enter tissues. The oxygen then
enters the mitochondria where it is utilized for metabolic
purposes.
[0004] Each of the steps described above for the movement of oxygen
through the body results in some form of resistance, with diffusion
through the plasma being a de facto "rate-limiting" step in the
movement of oxygen through the body, accounting for 70-90% of the
overall resistance. Thus, if the movement of oxygen through plasma
could be increased, it would be possible to increase the amount of
oxygen that can make its way through the pathway at any given time
and into the various tissues in the body, including hypoxic tissues
such as tumors.
[0005] The process of diffusion follows Fick's law, which states
that the rate of oxygen diffusion through plasma is dependent upon
1) the plasma thickness; 2) the concentration gradient of oxygen;
and 3) a proportionality constant known as the diffusion
coefficient (also known as diffusivity). Thus, those are the three
factors that could potentially be altered in order to increase the
diffusion of oxygen.
[0006] The plasma thickness is set by arterial anatomy, and thus is
not readily altered. The concentration gradient of oxygen can be
altered by increasing the percentage of oxygen that a patient
breathes (air is 21% oxygen) or through the addition of
hemoglobin-like molecules into the bloodstream.
[0007] It is believed that trans sodium crocetinate (TSC) and other
bipolar trans carotenoids alter the molecular arrangement of water
molecules in the plasma (which is composed of 90% water), with the
altered structure being less dense than untreated plasma. Water is
composed of two hydrogen atoms and one oxygen atom, with a net
positive charge found on the hydrogen atoms and a net negative
charge found on the oxygen atom. This results in the formation of
hydrogen bonds, which are simply an attraction between the
net-negatively charged oxygen of one water molecule and the
net-positively charged hydrogen atoms of another water molecule.
Theoretically, one water molecule can form four hydrogen bonds with
neighboring water molecules. However, the literature indicates that
a water molecule actually forms, on average, 2 to 3.6 hydrogen
bonds.
Tumor Hypoxia
[0008] Hypoxia is a deficiency in a sufficient supply of oxygen. It
has been known for well over 50 years that tumors are specifically
susceptible to developing hypoxia, which is driven by a combination
of rapid growth, structural abnormalities of the tumor
microvessels, and disturbed circulation within the tumor. There are
a number of consequences to tumor hypoxia, including: [0009]
Increased resistance to ionizing radiation [0010] A more clinically
aggressive phenotype [0011] An increased potential for more
invasive growth [0012] Increased regional and distal tumor
spreading
Trans Sodium Crocetinate Increases Oxygenation of Hypoxic
Tumors
[0013] While first studied for the treatment of hemorrhagic shock
and ischemia, the use of TSC as an agent to increase the
oxygenation of tumors has also been studied. Tumor hypoxia is a
leading cause of resistance to both radiation and chemotherapy in a
number of solid tumors.
Glioblastoma Multiforme
[0014] Glioblastoma multiforme (GBM) is a grade IV brain tumor
characterized by a heterogeneous cell population with a number of
negative attributes. GBM cells are typically genetically unstable
(thus prone to mutation), highly infiltrative, angiogenic, and
resistant to chemotherapy. The mutations typically found in GBM
allow the tumor to grow and thrive in a hypoxic environment. Both
activating mutations and loss of tumor suppressor genes give rise
to the highly complex and difficult to treat nature of the disease.
For example, approximately 50% of GBM tumors have amplification of
the epidermal growth factor receptor (EGFR), which can then induce
activation of the PI3K signaling pathway.
[0015] GBM is classified into two major subclasses (primary or
secondary) depending upon the clinical properties as well as the
chromosomal and genetic alterations that are unique to each class.
Primary GBM arises de novo from normal glial cells and typically
occurs in those over the age of 40, while secondary GBM arises from
transformation of lower grade tumors and is usually seen in younger
patients). Primary GBM is believed to account for approximately 95%
of all GBMs.
[0016] While GBM is the most common form of primary brain tumor
involving glial cells, it is still relatively rare as approximately
24,000 people in the United States were diagnosed with some form of
malignant brain cancer in 2014. Gliomas account for approximately
80% of malignant brain cancers, with GBM accounting for
approximately 45% of gliomas. The median age of GBM diagnosis is
approximately 65 years, with the incidence of GBM in those over 65
increasing rapidly as shown by a doubling in incidence from 5.1 per
100,000 in the 1970's to 10.6 per 100,000 in the 1990's. Those
diagnosed with the disease have a very grim prognosis, with the
median survival time of untreated patients being only 4.5 months.
Current standard of care treatment only provides 12-14 months of
survival time after diagnosis.
Current Treatments for GBM
[0017] Standard of care for GBM tumors always begins with surgical
resection of the tumor, unless the tumor is deemed inoperable due
to its location near vital centers of the brain. This is performed
both to alleviate the symptoms associated with the disease as well
as to facilitate treatment of any residual tumor cells. Even with
advances in surgical technique, complete removal of the tumor with
clean margins is almost never possible, as the tumors are highly
infiltrative and typically extend into the normal brain parenchyma.
Due to this, almost all GBM patients have recurrence of the tumor,
with 90% occurring at the primary site.
[0018] Due to the invasive nature of the tumors, surgical resection
is followed by radiotherapy coupled with the use of
chemotherapeutic agents. Radiotherapy involves the administration
of irradiation to the whole brain. While nitrosoureas were the most
common chemotherapeutic agents used for a number of decades, in
1999 temozolomide (TMZ) became available and is now a part of the
standard of care. This is due to a clinical trial that showed the
addition of TMZ to surgery and radiation increased median survival
in newly diagnosed GBM patients to 14.6 months compared to 12.1
months for the surgery and radiation only group.
[0019] Most chemotherapeutic drugs have a limited ability to cross
the blood brain barrier (BBB), thus a strategy to circumvent this
was the development of dissolvable chemotherapy wafers
(Gliadel.RTM.) that could be placed in the tumor bed following
surgical resection. Gliadel.RTM. contains the nitrosourea
chemotherapeutic agent carmustine that is released for several
weeks, in contrast to systemically administered carmustine that has
a very short half-life. While Gliadel.RTM. wafers were shown to be
safe, the drugs' addition to radiation and TMZ did not result in a
statistically significant increase in survival.
[0020] GBM tumors show increased expression of VEGF, and
bevacizumab has been approved by the FDA for the treatment of
recurrent GBM. A Phase 2 study found that bevacizumab treatment in
patients with recurrent GBM increased six-month progression-free
survival from a historical 9-15% to 25% with overall six-month
survival of 54%. Another Phase 2 study showed that recurrent GBM
patients treated with bevacizumab at a lower dose but a higher
frequency had even higher six-month progression-free survival of
42.6%.
[0021] While bevacizumab has shown success in recurrent GBM, it is
not utilized in newly diagnosed patients as two separate clinical
trials showed no difference in overall survival in patients treated
with radiation, TMZ, and bevacizumab compared to patients treated
with only radiation and TMZ. Bevacizumab treatment did result in an
increase in progression free survival in both studies; however, why
the effect in progression free survival did not translate to an
increase in overall survival is unclear. In addition, it was
reported that patients treated with bevacizumab had an increased
symptom burden, a worse quality of life, and a decline in
neurocognitive function.
Pancreatic Cancer
[0022] It is estimated that in 2016 approximately 49,000 people
will be diagnosed with pancreatic cancer in the United States. More
than half of these patients will be diagnosed with metastatic
disease. The five-year survival rates for patients with pancreatic
cancer are dismal (<14%) and are particularly bad for those with
metastatic disease (.about.1%).
[0023] Pancreatic cancer is responsible for 7% of all cancer deaths
in both men and women, making it the fourth leading cause of cancer
death in the U.S. Estimates indicate that 40% of pancreatic cancer
cases are sporadic in nature, 30% are related to smoking, 20% may
be associated with dietary factors, with only 5-10% hereditary.
[0024] Pancreatic cancer is difficult to diagnose in early stages.
The reason for this is because initial symptoms of the disease are
often nonspecific and subtle in nature, and include anorexia,
malaise, nausea, fatigue, and back pain. Approximately 75% of all
pancreatic carcinomas occur within the head or neck of the
pancreas, 15-20% occur in the body of the pancreas, and 5-10% occur
in the tail.
[0025] The only potential curative therapy for pancreatic cancer is
complete surgical resection. Unfortunately, this is only possible
for approximately 20% of cases, and even of those patients whose
cancer is surgically resected, 80% will develop metastatic disease
within two to three years following surgery. Patients with
unresectable pancreatic cancer have a median overall survival of 10
to 14 months while patients diagnosed with Stage IV disease
(indicative of metastases) have a 5-year overall survival of just
1%.
[0026] Pancreatic cancers are highly hypoxic as shown by the
results of multiple studies. A study reporting the direct
measurement of oxygenation in human pancreatic tumors prior to
surgery showed dramatic differences between tumors and normal
tissue. The partial pressure of oxygen (pO2) ranged between 0-5.3
mmHg in tumors but in adjacent normal tissue it ranged from
9.3-92.7 mmHg. Hypoxic areas are also frequently found when
examining tissue from mouse models of pancreatic cancer.
[0027] The exocrine cells and endocrine cells of the pancreas form
different types of tumors. It's very important to distinguish
between exocrine and endocrine cancers of the pancreas. They have
distinct risk factors and causes, have different signs and
symptoms, are diagnosed using different tests, are treated in
different ways, and have different outlooks.
Exocrine Tumors
[0028] Exocrine tumors are by far the most common type of pancreas
cancer. When someone says that they have pancreatic cancer, they
usually mean an exocrine pancreatic cancer.
Pancreatic Adenocarcinoma
[0029] An adenocarcinoma is a cancer that starts in gland cells.
About 95% of cancers of the exocrine pancreas are adenocarcinomas.
These cancers usually begin in the ducts of the pancreas. But
sometimes they develop from the cells that make the pancreatic
enzymes, in which case they are called acinar cell carcinomas.
Less Common Types of Cancers
[0030] Other cancers of the exocrine pancreas include adenosquamous
carcinomas, squamous cell carcinomas, signet ring cell carcinomas,
undifferentiated carcinomas, and undifferentiated carcinomas with
giant cells. These types are distinguished from one another based
on how they look under the microscope.
Solid Pseudopapillary Neoplasms (SPNs)
[0031] These are rare, slow-growing tumors that almost always occur
in young women. Even though these tumors tend to grow slowly, they
can sometimes spread to other parts of the body, so they are best
treated with surgery. The outlook for people with these tumors is
usually very good.
Ampullary Cancer (Carcinoma of the Ampulla of Vater)
[0032] This cancer starts in the ampulla of Vater, which is where
the bile duct and pancreatic duct come together and empty into the
small intestine. Ampullary cancers aren't technically pancreatic
cancers, but they are included in this document because their
treatments are very similar.
[0033] Ampullary cancers often block the bile duct while they are
still small and have not spread far. This blockage causes bile to
build up in the body, which leads to yellowing of the skin and eyes
(jaundice) and can turn urine dark. Because of this, these cancers
are usually found at an earlier stage than most pancreatic cancers,
and they usually have a better prognosis (outlook) than typical
pancreatic cancers.
Endocrine Tumors
[0034] Tumors of the endocrine pancreas are uncommon, making up
less than 4% of all pancreatic cancers. As a group, they are
sometimes known as pancreatic neuroendocrine tumors (NETs) or islet
cell tumors.
[0035] Pancreatic NETs can be benign or malignant (cancer). Benign
and malignant tumors can look alike under a microscope, so it isn't
always clear whether or not a pancreatic NET is cancer. Sometimes
the diagnosis only becomes clear when the tumor spreads outside of
the pancreas. There are many types of pancreatic NETs.
Functioning Tumors
[0036] About half of pancreatic NETs make hormones that are
released into the blood and cause symptoms. These are called
functioning tumors. Each one is named for the type of
hormone-making cell it starts in. [0037] Gastrinomas come from
cells that make gastrin. About half of gastrinomas are cancers.
[0038] Insulinomas come from cells that make insulin. Most
insulinomas are benign (not cancers). [0039] Glucagonomas come from
cells that make glucagon. Most glucagonomas are cancers. [0040]
Somatostatinomas come from cells that make somatostatin. Most
somatostatinomas are cancers. [0041] VIPomas come from cells that
make vasoactive intestinal peptide (VIP). Most VIPomas are cancers.
[0042] PPomas come from cells that make pancreatic polypeptide.
Most PPomas are cancers.
[0043] The most common types of functioning NETs are gastrinomas
and insulinomas. The other types occur very rarely.
Non-Functioning Tumors
[0044] These tumors don't make enough excess hormones to cause
symptoms. They are more likely to be cancer than functioning
tumors. Because they don't make excess hormones that cause
symptoms, they can often grow quite large before they are
found.
Carcinoid Tumors
[0045] These are another type of NET that rarely can start in the
pancreas, although they are much more common in other parts of the
digestive system. These tumors often make serotonin (also called
5-HT) or its precursor, 5-HTP.
[0046] The treatment and outlook for pancreatic NETs depend on the
specific tumor type and the stage (extent) of the tumor, but the
outlook is generally better than that of pancreatic exocrine
cancers.
Current Treatment Options for Pancreatic Cancer
[0047] Surgery remains the primary mode of treatment for patients
with pancreatic cancer. However, there is an important role for
chemotherapy and/or radiation in an adjuvant (given to prevent
recurrence) or neoadjuvant (given before surgery to shrink the
tumor to make complete resection more probable) setting as well as
in patients with unresectable disease.
[0048] Since its approval in 1996, gemcitabine has been partnered
with approximately 30 different agents in late-stage clinical
trials in an attempt to improve upon the effectiveness of
gemcitabine alone in treating patients with metastatic pancreatic
cancer. Only two of these trials have led to an FDA
approval--erlotinib (Tarceva.RTM.) and nab-paclitaxel
(Abraxane.RTM.).
[0049] In patients with metastatic disease, the use of erlotinib
with gemcitabine led to a significantly higher one-year survival
rate than with the use of gemcitabine alone (23% vs. 17%, P=0.023)
as well as an increased median overall survival (6.24 months vs.
5.91 months, P=0.038). A more recent study showed that the addition
of nanoparticle albumin-bound (nab)-paclitaxel to gemcitabine
significantly improved overall survival in treatment naive patients
with metastatic cancer, as overall survival was approximately two
months longer in patients treated with combination therapy (8.5 vs.
6.7 months).
[0050] The Folfirinox
(leucovorin+5-fluorouracil+oxaliplatin+irinotecan) regimen was
shown to significantly improve overall survival compared to
treatment with gemcitabine (11.1 months vs. 6.8 months). While
dramatically improving overall survival, the Folfirinox treatment
was accompanied by serious adverse events and thus is only
recommended for patients with good performance status.
[0051] Other combinations of gemcitabine with cisplatin,
oxaliplatin, irinotecan, or docetaxel tested in Phase 3 trials have
not been of superior benefit to gemcitabine alone. The combination
therapy nab-paclitaxel and gemcitabine was recently approved by the
FDA as an additional standard of care for the treatment of patients
with untreated pancreatic adenocarcinoma. However, the improvements
were modest, and treatment of pancreatic cancer remains an intense
area of research, with 92 products in all stages of clinical
development with 14 of them in Phase 3 at this time according to
clinicaltrials.gov.
[0052] Just recently, the FDA approved Onivyde.RTM. (irinotecan
liposome injection) in combination with fluorouracil and
leucovorin, to treat patients with metastatic pancreatic cancer who
were previously treated with gemcitabine-based chemotherapy. In the
pivotal clinical trial, patients treated with Onivyde.degree. plus
fluorouracil/leucovorin lived an average of 6.1 months, compared to
4.2 months for those treated with only fluorouracil/leucovorin.
Brain Metastases
[0053] In contrast to the relative rarity of primary brain cancers,
life-threatening cancers that metastasize to the brain are much
more common and represent a serious complication in the treatment
of many cancer types. Up to 30% of adult cancer patients will
suffer from brain metastases. There are approximately 170,000 cases
of metastatic brain cancer every year in the United States.
Incidence of brain metastases varies depending upon the primary
tumor type, although lung cancer appears to carry the greatest
risk. The prognosis for patients with brain metastases is very
grim, with current treatment options only resulting in median
overall survival times of less than one year.
[0054] Treatment for brain metastases involves both controlling the
symptoms associated with the condition as well as attacking cancer
directly. Brain metastases typically result in edema that can be
controlled with the use of steroids; however, long-term use of
steroids typically results in side effects that greatly diminishes
a patient's quality of life. Approximately 25-45% of patients will
experience seizures and require the use anti-epileptic drugs.
Surgery is only utilized in patients with a solitary brain
metastatic lesion. Radiation therapy remains the standard of care
for the vast majority of patients with brain metastases. There is
very limited evidence for the use of chemotherapy, as few clinical
trials have been conducted. There are no medications approved for
the treatment of brain metastases.
Chemotherapy
[0055] Chemotherapy drugs can be grouped by how they work, their
chemical structure, and their relationships to other drugs. Some
drugs work in more than one way, and may belong to more than one
group. Knowing how the drug works is important in predicting side
effects from it. This helps doctors decide which drugs are likely
to work well together. If more than one drug will be used, this
information also helps them plan exactly when each of the drugs
should be given (in which order and how often).
Alkylating Agents
[0056] Alkylating agents keep the cell from reproducing by damaging
its DNA. These drugs work in all phases of the cell cycle and are
used to treat many different cancers, including cancers of the
lung, breast, and ovary as well as leukemia, lymphoma, Hodgkin
disease, multiple myeloma, and sarcoma.
[0057] Because these drugs damage DNA, they can affect the cells of
the bone marrow which make new blood cells. In rare cases, this can
lead to leukemia. The risk of leukemia from alkylating agents is
"dose-dependent," meaning that the risk is small with lower doses,
but goes up as the total amount of the drug used gets higher. The
risk of leukemia after getting alkylating agents is highest about 5
to 10 years after treatment.
Antimetabolites
[0058] Antimetabolites interfere with DNA and RNA growth by
substituting for the normal building blocks of RNA and DNA. These
agents damage cells during the phase when the cell's chromosomes
are being copied. They are commonly used to treat leukemias,
cancers of the breast, ovary, and the intestinal tract, as well as
other types of cancer.
Anti-Tumor Antibiotics
[0059] These drugs are not like the antibiotics used to treat
infections. They work by changing the DNA inside cancer cells to
keep them from growing and multiplying.
Topoisomerase Inhibitors
[0060] These drugs interfere with enzymes called topoisomerases,
which help separate the strands of DNA so they can be copied.
(Enzymes are proteins that cause chemical reactions in living
cells.) Topoisomerase inhibitors are used to treat certain
leukemias, as well as lung, ovarian, gastrointestinal, and other
cancers.
[0061] Topoisomerase II inhibitors can increase the risk of a
second cancer--acute myelogenous leukemia (AML)--as early as 2 to 3
years after the drug is given.
Mitotic Inhibitors
[0062] Mitotic inhibitors are compounds derived from natural
products, such as plants. They work by stopping cells from dividing
to form new cells but can damage cells in all phases by keeping
enzymes from making proteins needed for cell reproduction. They are
used to treat many different types of cancer including breast,
lung, myelomas, lymphomas, and leukemias. These drugs may cause
nerve damage, which can limit the amount that can be given.
Other Chemotherapy Drugs
[0063] Some chemotherapy drugs act in slightly different ways and
do not fit well into any of the other categories. Examples include
drugs like L-asparaginase, which is an enzyme, and the proteosome
inhibitor bortezomib (Velcade.RTM.).
[0064] U.S. Pat. No. 8,030,350 discloses the use of bipolar trans
carotenoids along with chemotherapy and radiation therapy for the
treatment of cancer.
SUMMARY
[0065] In one embodiment, the disclosure includes a method of
treating cancer (solid tumor) in a mammal (e.g. human) comprising
[0066] a) administering to the mammal a bipolar trans carotenoid
salt having the formula:
[0066] YZ-TCRO-ZY where: Y=a cation which can be the same or
different, Z=a polar group which can be the same or different and
which is associated with the cation, and TCRO=a linear trans
carotenoid skeleton with conjugated carbon-carbon double bonds and
single bonds, and having pendant groups X, wherein the pendant
groups X, which can be the same or different, are a linear or
branched hydrocarbon group having 10 or less carbon atoms, or a
halogen, [0067] b) administering to the mammal radiation therapy,
wherein said bipolar trans carotenoid salt is administered at time
and at a dose causing increased partial pressure of oxygen in the
tumor during administration of said radiation.
[0068] In a preferred embodiment, the bipolar trans carotenoid is
TSC administered at a dose of 0.15-0.35 mg/kg 45-60 minutes prior
to administration of said radiation therapy. In some embodiments,
the subject mammal is also administered chemotherapy in addition to
the radiation therapy, e.g. administering temozolomide 7 times per
week for 6 weeks.
[0069] A still further embodiment of the disclosure relates to a
method of treating cancer (solid tumor) in a mammal (e.g. human)
comprising [0070] a) administering to the mammal a bipolar trans
carotenoid salt having the formula:
[0070] YZ-TCRO-ZY where: Y=a cation which can be the same or
different, Z=a polar group which can be the same or different and
which is associated with the cation, and TCRO=a linear trans
carotenoid skeleton with conjugated carbon-carbon double bonds and
single bonds, and having pendant groups X, wherein the pendant
groups X, which can be the same or different, are a linear or
branched hydrocarbon group having 10 or less carbon atoms, or a
halogen, [0071] b) administering chemotherapy to the mammal,
wherein said bipolar trans carotenoid salt is administered at a
time and at a dose causing increased partial pressure of oxygen in
the tumor during administration of said chemotherapy.
[0072] In a preferred embodiment, TSC administered at a dose of
0.75-2.0 mg/kg 1-2 hour prior to administration of said
chemotherapy.
[0073] The cancer is selected from the group consisting of squamous
cell carcinomas, melanomas, lymphomas, sarcomas, sarcoids,
osteosarcomas, skin cancer, breast cancer, head and neck cancer,
gynecological cancer, urological and male genital cancer, bladder
cancer, prostate cancer, bone cancer, cancers of the endocrine
glands (e.g. pancreatic cancer), cancers of the alimentary canal,
cancers of the major digestive glands/organs, CNS cancer, and lung
cancer. The chemotherapy is selected from the group consisting of
alkylating agents, antimetabolites, antitumor antibiotics,
topoisomerase inhibitors, and anti-microtubule agents. In some
embodiments, the subject mammal is also administered radiation
therapy in addition to the chemotherapy.
[0074] In an advantageous embodiment, the bipolar trans carotenoid
is TSC administered at a dose of 0.75-2.0 mg/kg, 1-2 hrs. prior to
administration of said chemotherapy. The chemotherapy is one or
more compounds selected from the group consisting of gemcitabine,
5-fluorouracil (5-FU), irinotecan, oxaliplatin, nab-paclitaxel
(albumin-bound paclitaxel), capecitabine, cisplatin, elotinib,
paclitaxel, docetaxel, and irinotecan liposome.
[0075] In one embodiment, the method is administering 1.5 mg/kg TSC
45-60 minutes prior administering the chemotherapy, and
administering the chemotherapy is administering gemcitabine as an
IV infusion once per week for 3 weeks followed by a week of
rest.
[0076] In another embodiment, 1.5 mg/kg TSC is administered 45-60
minutes prior administering the chemotherapy, and administering the
chemotherapy is administering nab-paclitaxel as an IV infusion
followed by gemcitabine as an IV infusion, once per week for 3
weeks followed by a week of rest.
[0077] In another embodiment, the subject disclosure relates to a
method of treating a cancer of the pancreas in a mammal (e.g.
human) comprising: [0078] a) administering to the mammal a bipolar
trans carotenoid salt having the formula:
[0078] YZ-TCRO-ZY where: Y=a cation which can be the same or
different, Z=a polar group which can be the same or different and
which is associated with the cation, and TCRO=a linear trans
carotenoid skeleton with conjugated carbon-carbon double bonds and
single bonds, and having pendant groups X, wherein the pendant
groups X, which can be the same or different, are a linear or
branched hydrocarbon group having 10 or less carbon atoms, or a
halogen, and [0079] b) administering to the mammal chemotherapy,
wherein the bipolar trans carotenoid salt is administered at a time
and at a dose causing increased partial pressure of oxygen in the
tumor during administration of the chemotherapy.
[0080] In an advantageous embodiment, the bipolar trans carotenoid
is TSC administered at a dose of 0.75-2.0 mg/kg, 1-2 hrs. prior to
administration of said chemotherapy. The chemotherapy is one or
more compounds selected from the group consisting of gemcitabine,
5-fluorouracil (5-FU), irinotecan, oxaliplatin, nab-paclitaxel
(albumin-bound paclitaxel), capecitabine, cisplatin, elotinib,
paclitaxel, docetaxel, and irinotecan liposome.
[0081] In one embodiment, the method is administering 1.5 mg/kg TSC
45-60 minutes prior administering the chemotherapy, and
administering the chemotherapy is administering gemcitabine as an
IV infusion once per week for 3 weeks followed by a week of
rest.
[0082] In another embodiment, 1.5 mg/kg TSC is administered 45-60
minutes prior administering the chemotherapy, and administering the
chemotherapy is administering nab-paclitaxel as an IV infusion
followed by gemcitabine as an IV infusion, once per week for 3
weeks followed by a week of rest.
[0083] The disclosure also relates to a method of treating a cancer
of the brain (e.g. glioblastoma) in a mammal (e.g. human)
comprising: [0084] a) administering to the mammal a bipolar trans
carotenoid salt having the formula:
[0084] YZ-TCRO-ZY where: Y=a cation which can be the same or
different, Z=a polar group which can be the same or different and
which is associated with the cation, and TCRO=a linear trans
carotenoid skeleton with conjugated carbon-carbon double bonds and
single bonds, and having pendant groups X, wherein the pendant
groups X, which can be the same or different, are a linear or
branched hydrocarbon group having 10 or less carbon atoms, or a
halogen, and [0085] b) administering radiation therapy to the
mammal wherein the bipolar trans carotenoid salt is administered at
time and at a dose causing increased partial pressure of oxygen in
the tumor during administration of said radiation.
[0086] When the bipolar trans carotenoid is TSC, it is administered
at a dose of 0.15-0.35 mg/kg 45-60 minutes prior to said
administration, typically external beam radiation therapy. In one
embodiment, the radiation therapy is administering 5 times per week
for 6 weeks. In another embodiment, the method includes
administering chemotherapy to the mammal, e.g. administering
temozolomide 7 times per week for 6 weeks.
[0087] In all of the above embodiments, advantageously the bipolar
trans carotenoid salt is TSC is in the form of a composition with a
cyclodextrin.
BRIEF DESCRIPTION OF THE FIGURES
[0088] Certain aspects of the disclosure will be apparent with
regard to the following figures.
[0089] FIG. 1 illustrates the change in partial pressure of oxygen
of a hyperoxic rat resulting from administration of a low
efficacious dose amount compared to a high efficacious dose amount
of TSC.
[0090] FIG. 2 illustrates the observed effect that a combination
therapy of TSC and cisplatin had on tumor volume, which is
discussed in Example 1.
[0091] FIG. 3 illustrates the observed effect that a combination
therapy of TSC and gemcitabine (10 mg/kg) had on tumor volume,
which is discussed in Example 2.
[0092] FIG. 4 illustrates the observed effect that a combination
therapy of TSC and gemcitabine (5 mg/kg) had on tumor volume, which
is discussed in Example 2.
[0093] FIG. 5 illustrates the observed effect that a combination
therapy of TSC and gemcitabine (7.5 mg/kg) had on tumor volume,
which is discussed in Example 2.
[0094] FIG. 6 illustrates the observed effect that a combination
therapy of TSC and temozolomide had on tumor volume, which is
discussed in Example 3.
[0095] FIG. 7 illustrates the observed effect that a combination
therapy of TSC and doxorubicin had on tumor volume, which is
discussed in Example 4.
[0096] FIG. 8 illustrates the observed effect that a combination
therapy of TSC and paclitaxel had on tumor volume, which is
discussed in Example 5.
DETAILED DESCRIPTION
[0097] The subject disclosure relates to compounds and compositions
including chemotherapy agents and bipolar trans carotenoids, and
the use of such compounds for the treatment of various cancers
including pancreatic and brain cancers.
[0098] It is well established that tumors are hypoxic with many
tumor types being highly hypoxic. See Table 1 below:
TABLE-US-00001 TABLE 1 Oxygenation of tumors and the surrounding
normal tissue (aggregated from multiple studies) Median Tumor
pO.sub.2* Median Normal pO.sub.2* Tumor Type (number of patients)
(number of patients) Glioblastoma 4.9 (10) ND 5.6 (14) ND Head and
Neck Carcinoma 12.2 (30) 40.0 (14) 14.7 (23) 43.8 (30) 14.6 (65)
51.2 (65) Lung Cancer 7.5 (17) 38.5 (17) Breast Cancer 10.0 (15) ND
Pancreatic Cancer 2.7 (7) 51.6 (7) Cervical Cancer 5.0 (8) 51 (8)
5.0 (74) ND 3.0 (86) ND Prostate Cancer 2.4 (59) 30.0 (59) Soft
Tissue Sarcoma 6.2 (34) ND5 18 (22) ND *pO.sub.2 measured in mmHg.
Measurements were made using a commercially available oxygen
electrode (the `Eppendorf` electode). The values shown are the
median of the median values for each patient. ND, not determined;
pO.sub.2, oxygen partial pressure. Brown, JM and Wilson, WR.
"Exploiting tumour hypoxia in cancer treatment." Nat. Rev. Cancer
4(6) 2004: 437-447.
[0099] Further, it is known that hypoxic tumors are more resistant
to radiotherapy and chemotherapy.
[0100] It has been discovered that for a mammal, there are two
concentrations of a bipolar trans carotenoid, such as TSC, that
result in increased oxygen partial pressure--the "low" dose and the
"high" dose--in a tumor. For humans, the low dose range is
0.15-0.35 mg/kg and the high dose range is 0.75 to 2.0 mg/kg. Both
doses result in approximately the same maximum increase in oxygen
partial pressure. Importantly, the high dose results in a sustained
maximum oxygen partial pressure while the low dose does not. An
example of this phenomenon is shown in FIG. 1
[0101] The methods of the subject disclosure are directed to
administering a dose of a bipolar trans carotenoid at a dose and at
the proper time prior to administration of chemotherapy or
radiation therapy such that the oxygen partial pressure is elevated
inside the tumor while the chemotherapy or radiation therapy is
administered so as to obtain increased killing effect of the
chemotherapy and or radiotherapy on the cancer cells/tumor.
[0102] In one embodiment, provided is a method (Method A) of
treating cancer in a mammal (e.g. human) comprising [0103] a)
administering to the mammal a bipolar trans carotenoid salt having
the formula:
[0103] YZ-TCRO-ZY where: Y=a cation which can be the same or
different, Z=a polar group which can be the same or different and
which is associated with the cation, and TCRO=a linear trans
carotenoid skeleton with conjugated carbon-carbon double bonds and
single bonds, and having pendant groups X, wherein the pendant
groups X, which can be the same or different, are a linear or
branched hydrocarbon group having 10 or less carbon atoms, or a
halogen, [0104] b) administering to the mammal radiation therapy,
wherein said bipolar trans carotenoid salt is administered at time
and at a dose causing increased partial pressure of oxygen in the
tumor during administration of said radiation.
[0105] Further provided is Method A as follows: [0106] A.1 Method
A, wherein the bipolar trans carotenoid is TSC. [0107] A.2 Method A
or A.1, wherein the bipolar trans carotenoid is administered at a
dose of 0.05-0.5 mg/kg. [0108] A.3 Method A or A.1-A.2, wherein the
bipolar trans carotenoid is administered at a dose of 0.15-0.35
mg/kg. [0109] A.4 Method A or A.1-A.3, wherein the bipolar trans
carotenoid is administered at a dose of 0.25 mg/kg. [0110] A.5
Method A or A.1-A.4, wherein the bipolar trans carotenoid is
administered 30-120 minutes prior to administration of said
radiation therapy. [0111] A.6 Method A or A.1-A.5, wherein the
bipolar trans carotenoid is administered 45-60 minutes prior to
administration of said radiation therapy. [0112] A.7 Method A of
A.1-A.6, wherein the bipolar trans carotenoid is administered 2-5
times per week. [0113] A.8 Method A of A.1-A.7, wherein the bipolar
trans carotenoid is administered 3 times per week. [0114] A.9
Method A or A.1-A.8, wherein said radiation therapy is external
beam radiation therapy (e.g., three-dimensional conformal radiation
therapy, intensity modulated radiation therapy, proton beam
therapy, stereotactic radiation therapy). [0115] A.10 Method A or
A.1-A.8, wherein said radiation therapy is internal beam radiation
therapy. [0116] A.11 Method A or A.1-A.10, wherein said radiation
therapy is administered in an amount between 0.1 Gy and 5 Gy per
radiation therapy session. [0117] A.12 Method A or A.1-A.11,
wherein said radiation therapy is administered in an amount of 2 Gy
per radiation therapy session. [0118] A.13 Method A or A.1-A.12,
wherein said radiation therapy is administered 5 times per week for
6 weeks. [0119] A.14 Method A or A.1-A.13, further comprising
administering chemotherapy to said mammal. [0120] A.15 Method A.14,
wherein the chemotherapy is administered at least once a week for
at least three weeks. [0121] A.16 Method A.14 or A.15, wherein the
chemotherapy is administered 7 times a week for 6 weeks. [0122]
A.17 Any of Methods A.14-A.16, wherein said chemotherapy is
selected from the group consisting of alkylating agents,
antimetabolites, antitumor antibiotics, topoisomerase inhibitors,
and anti-microtubule agents. [0123] A.18 Any of Methods A.14-A.17,
wherein said chemotherapy is one or more compounds selected from
the group consisting of temozolomide, gemcitabine, 5-fluorouracil
(5-FU), irinotecan, oxaliplatin, nab-paclitaxel (albumin-bound
paclitaxel), capecitabine, cisplatin, elotinib, paclitaxel,
docetaxel, and irinotecan liposome. [0124] A.19 Any of Methods
A.14-A.18, wherein said chemotherapy is one or more compounds
selected from temozolomide, gemcitabine, irinotecan, and celecoxib.
[0125] A.20 Any of Methods A.14-A.19, wherein said chemotherapy is
one or both of gemcitabine and nab-paclitaxel. [0126] A.21 Any of
Methods A.14-A.20, wherein said chemotherapy is gemcitabine. [0127]
A.22 Any of Methods A.14-A.21, wherein said chemotherapy is
temozolomide. [0128] A.23 Any of Methods A.14-A.22 or A.22, wherein
said administering chemotherapy comprises administering
temozolomide 7 times per week for 6 weeks. [0129] A.24 Any of
Methods A.14-A.23, wherein said chemotherapy is administered after
said radiation therapy. [0130] A.25 Any of Methods A.14-A.24,
wherein said bipolar trans carotenoid salt is administered with
chemotherapy at a dose of 1.5 mg/kg. [0131] A.26 Method A or
A.1-A.25, wherein said cancer is brain cancer. [0132] A.27 Method A
or A.1-A.26, wherein said brain cancer is a glioblastoma
multiforme. [0133] A.28 Method A or A.1-A.27, wherein the bipolar
trans carotenoid salt is TSC is in the form of a composition with a
cyclodextrin. [0134] A.29 Method A or A.1-A.28, wherein the bipolar
trans carotenoid salt is TSC is in the form of a lyophilized
composition with a cyclodextrin. [0135] A.30 Method A or A.1-A.29,
wherein the bipolar trans carotenoid is synthetic TSC. [0136] A.31
Method A or A.1-A.30, wherein the absorbency of the bipolar trans
carotenoid salt (i.e., TSC) at a highest peak occurring in the
visible light wavelength range (i.e., between 380 to 470 nm)
divided by the absorbency of a peak occurring in the ultraviolet
wavelength range (i.e., between 220 to 300 nm) is greater than 7,
greater than 7.5, greater than 8.0, or greater than 8.5. [0137]
A.32 Method A.31, wherein the quotient obtained is between 7.5 and
9.0. [0138] A.33 Method A.32, wherein the quotient obtained is
between 8.0 and 8.8.
[0139] In another embodiment, provided is a method (Method B) of
treating cancer in a mammal (e.g. human) comprising [0140] a)
administering to the mammal a bipolar trans carotenoid salt having
the formula:
[0140] YZ-TCRO-ZY where: Y=a cation which can be the same or
different, Z=a polar group which can be the same or different and
which is associated with the cation, and TCRO=a linear trans
carotenoid skeleton with conjugated carbon-carbon double bonds and
single bonds, and having pendant groups X, wherein the pendant
groups X, which can be the same or different, are a linear or
branched hydrocarbon group having 10 or less carbon atoms, or a
halogen, [0141] b) administering chemotherapy to the mammal,
wherein said bipolar trans carotenoid salt is administered at a
time and at a dose causing increased partial pressure of oxygen in
the tumor during administration of said chemotherapy.
[0142] Further provided is Method B as follows: [0143] B.1 Method
B, wherein the bipolar trans carotenoid is TSC. [0144] B.2 Method B
or B.1, wherein said bipolar trans carotenoid is administered at a
dose of 0.6-2.5 mg/kg. [0145] B.3 Method B or B.1-B.2, wherein said
bipolar trans carotenoid is administered at a dose of 0.75-2.0
mg/kg. [0146] B.4 Method B or B.1-B.3, wherein said bipolar trans
carotenoid is administered at a dose of 1.5 mg/kg. [0147] B.5
Method B or B.1-B.4, wherein the bipolar trans carotenoid is
administered 30-120 minutes prior to administration of said
chemotherapy. [0148] B.6 Method B or B.1-B.5, wherein the bipolar
trans carotenoid is administered 45-60 minutes prior to
administration of said chemotherapy. [0149] B.7 Method B or
B.1-B.6, wherein the bipolar trans carotenoid is administered once
per week. [0150] B.8 Method B or B.1-B.7, wherein the bipolar trans
carotenoid is administered once per week for 3 weeks. [0151] B.9
Method B or B.1-B.8, wherein the chemotherapy is administered at
least once a week for at least three weeks. [0152] B.10 Method B or
B.1-B.9, wherein the chemotherapy is administered 7 times a week
for 6 weeks. [0153] B.11 Method B or B.1-B.10, wherein said
chemotherapy is selected from the group consisting of alkylating
agents, antimetabolites, antitumor antibiotics, topoisomerase
inhibitors, and anti-microtubule agents. [0154] B.12 Method B or
B.1-B.11, wherein said chemotherapy is one or more compounds
selected from the group consisting of temozolomide, gemcitabine,
5-fluorouracil (5-FU), irinotecan, oxaliplatin, nab-paclitaxel
(albumin-bound paclitaxel), capecitabine, cisplatin, elotinib,
paclitaxel, docetaxel, and irinotecan liposome. [0155] B.13 Method
B or B.1-B.12, wherein said chemotherapy is one or more compounds
selected from temozolomide, gemcitabine, irinotecan, and celecoxib.
[0156] B.14 Method B or B.1-B.13, wherein said chemotherapy is one
or both of gemcitabine and nab-paclitaxel. [0157] B.15 Method B or
B.1-B.14, wherein said chemotherapy is gemcitabine. [0158] B.16
Method B or B.1-B.15, wherein said chemotherapy is temozolomide.
[0159] B.17 Method B or B.1-B.16, wherein said administering
chemotherapy comprises administering temozolomide 7 times per week
for 6 weeks. [0160] B.18 Method B or B.1-B.17, wherein
administering said bipolar trans carotenoid is administering 1.5
mg/kg TSC 45-60 minutes prior administering said chemotherapy, and
administering said chemotherapy is administering gemcitabine as an
IV infusion once per week for 3 weeks followed by a week of rest.
[0161] B.19 Method B or B.1-B.18, wherein administering said
bipolar trans carotenoid is administering 1.5 mg/kg TSC 45-60
minutes prior administering said chemotherapy, and administering
said chemotherapy is administering nab-paclitaxel as an IV infusion
followed by gemcitabine as an IV infusion, once per week for 3
weeks followed by a week of rest. [0162] B.20 Method B or B.1-B.19,
wherein said cancer is a solid tumor. [0163] B.21 Method B or
B.1-B.20, wherein the cancer is selected from the group consisting
of squamous cell carcinomas, melanomas, lymphomas, sarcomas,
sarcoids, osteosarcomas, skin cancer, breast cancer, head and neck
cancer, gynecological cancer, urological and male genital cancer,
bladder cancer, prostate cancer, bone cancer, cancers of the
endocrine glands (e.g., pancreatic cancer), cancers of the
alimentary canal, cancers of the major digestive glands/organs, CNS
cancer, and lung cancer. [0164] B.22 Method B or B.1-B.21, wherein
the cancer is pancreatic cancer. [0165] B.23 Method B or B.1-B.22,
wherein the bipolar trans carotenoid salt is TSC is in the form of
a lyophilized composition with a cyclodextrin. [0166] B.24 Method B
or B.1-B.23, wherein the bipolar trans carotenoid is synthetic TSC.
[0167] B.25 Method B or B.1-B.24, wherein the absorbency of the
bipolar trans carotenoid salt (i.e., TSC) at a highest peak
occurring in the visible light wavelength range (i.e., between 380
to 470 nm) divided by the absorbency of a peak occurring in the
ultraviolet wavelength range (i.e., between 220 to 300 nm) is
greater than 7, greater than 7.5, greater than 8.0, or greater than
8.5. [0168] B.26 Method B.25, wherein the quotient obtained is
between 7.5 and 9.0. [0169] B.27 Method B.26, wherein the quotient
obtained is between 8.0 and 8.8.
[0170] In another embodiment, provided is a method (Method C) of
preventing or treating stroke in a mammal (e.g. human) comprising
administering to the mammal a bipolar trans carotenoid salt having
the formula:
YZ-TCRO-ZY where: Y=a cation which can be the same or different,
Z=a polar group which can be the same or different and which is
associated with the cation, and TCRO=a linear trans carotenoid
skeleton with conjugated carbon-carbon double bonds and single
bonds, and having pendant groups X, wherein the pendant groups X,
which can be the same or different, are a linear or branched
hydrocarbon group having 10 or less carbon atoms, or a halogen,
wherein said bipolar trans carotenoid salt is administered at a
dose effective to treat stroke.
[0171] Further provided is Method C as follows: [0172] C.1 Method
C, wherein the bipolar trans carotenoid is TSC. [0173] C.2 Method C
or C.1, wherein the bipolar trans carotenoid is administered at a
dose of 0.05-0.5 mg/kg. [0174] C.3 Method C or C.1-C.2, wherein the
bipolar trans carotenoid is administered at a dose of 0.15-0.35
mg/kg. [0175] C.4 Method C or C.1-C.3, wherein the bipolar trans
carotenoid is administered at a dose of 0.25 mg/kg. [0176] C.5
Method C or C.1-C.4, wherein said stroke is an ischemic stroke or a
hemorrhagic stroke. [0177] C.6 Method C or C.1-C.5, wherein said
stroke is an ischemic stroke. [0178] C.7 Method C or C.1-C.6,
wherein said stroke is a hemorrhagic stroke. [0179] C.8 Method C or
C.1-C.7, wherein the bipolar trans carotenoid salt is TSC is in the
form of a composition with a cyclodextrin. [0180] C.9 Method C or
C.1-C.8, wherein the bipolar trans carotenoid salt is TSC is in the
form of a lyophilized composition with a cyclodextrin. [0181] C.10
Method C or C.1-C.9, wherein the bipolar trans carotenoid is
synthetic TSC. [0182] C.11 Method C or C.1-C.10, wherein the
absorbency of the bipolar trans carotenoid salt (i.e., TSC) at a
highest peak occurring in the visible light wavelength range (i.e.,
between 380 to 470 nm) divided by the absorbency of a peak
occurring in the ultraviolet wavelength range (i.e., between 220 to
300 nm) is greater than 7, greater than 7.5, greater than 8.0, or
greater than 8.5. [0183] C.12 Method C or C.1-C.11, wherein the
quotient obtained is between 7.5 and 9.0.
[0184] C.13 Method C or C.1-C.12, wherein the quotient obtained is
between 8.0 and 8.8.
[0185] In another embodiment, provided is a bipolar trans
carotenoid salt (as defined in Method A, B or C) for use in
treating cancer in a patient receiving radiation therapy and/or
chemotherapy, e.g., for use in a method according to any of Methods
A, et seq.; Methods B, et seq.; or Methods C, et seq.
[0186] In another embodiment, provided is a use of a bipolar trans
carotenoid salt (as defined in Method A, B or C) in the manufacture
of a medicament for treating cancer in a patient receiving
radiation therapy and/or chemotherapy, e.g., in a method according
to any of Methods A, et seq.; Methods B, et seq.; or Methods C, et
seq.
[0187] In another embodiment, provided is a pharmaceutical
composition comprising an effective amount of a bipolar trans
carotenoid salt (as defined in Method A, B or C) for use in
treating cancer in a patient receiving radiation therapy and/or
chemotherapy, e.g., for use in a method according to any of Methods
A, et seq.; Methods B, et seq.; or Methods C, et seq.
Compositions
Bipolar Trans Carotenoids
[0188] The subject disclosure relates to trans carotenoids
including trans carotenoid diesters, dialcohols, diketones and
diacids, bipolar trans carotenoids (BTC), and bipolar trans
carotenoid salts (BTCS) compounds and synthesis of such compounds
having the structure:
YZ-TCRO-ZY where: [0189] Y (which can be the same or different at
the two ends)=H or a cation other than H, preferably Na.sup.+ or
K.sup.+ or Li.sup.+. Y is advantageously a monovalent metal ion. Y
can also be an organic cation, e. g., R.sub.4N.sup.+,
R.sub.3S.sup.+, where R is H, or C.sub.nH.sub.2n+1 where n is 1-10,
advantageously 1-6. For example, R can be methyl, ethyl, propyl or
butyl. [0190] Z (which can be the same or different at the two
ends)=polar group which is associated with H or the cation.
Optionally including the terminal carbon on the carotenoid (or
carotenoid related compound), this group can be a carboxyl
(COO.sup.-) group or a CO group (e.g. ester, aldehyde or ketone
group), or a hydroxyl group. This group can also be a sulfate group
(OSO.sub.3.sup.-) or a monophosphate group (OPO.sub.3.sup.-),
(OP(OH)O.sub.2.sup.-), a diphosphate group, triphosphate or
combinations thereof. This group can also be an ester group of COOR
where the R is C.sub.nH.sub.2n+1. [0191] TCRO=trans carotenoid or
carotenoid related skeleton (advantageously less than 100 carbons)
which is linear, has pendant groups (defined below), and typically
comprises "conjugated" or alternating carbon-carbon double and
single bonds (in one embodiment, the TCRO is not fully conjugated
as in a lycopene). The pendant groups (X) are typically methyl
groups but can be other groups as discussed below. In an
advantageous embodiment, the units of the skeleton are joined in
such a manner that their arrangement is reversed at the center of
the molecule. The 4 single bonds that surround a carbon-carbon
double bond all lie in the same plane. If the pendant groups are on
the same side of the carbon-carbon double bond, the groups are
designated as cis (also known as "Z"); if they are on the opposite
side of the carbon-carbon bond, they are designated as trans (also
known as "E"). Throughout this case, the isomers will be referred
to as cis and trans.
[0192] The compounds of the subject disclosure are trans. The cis
isomer typically is a detriment--and results in the diffusivity not
being increased. The placement of the pendant groups can be
symmetric relative to the central point of the molecule or can be
asymmetric so that the left side of the molecule does not look the
same as the right side of the molecule either in terms of the type
of pendant group or their spatial relationship with respect to the
center carbon.
[0193] The pendant groups X (which can be the same or different)
are hydrogen (H) atoms, or a linear or branched hydrocarbon group
having 10 or less carbons, advantageously 4 or less, (optionally
containing a halogen), or a halogen. X could also be an ester group
(COO-) or an ethoxy/methoxy group. Examples of X are a methyl group
(CH3), an ethyl group (C2H5), a phenyl or single aromatic ring
structure with or without pendant groups from the ring, a
halogen-containing alkyl group (C1-C10) such as CH2C1, or a halogen
such as Cl or Br or a methoxy (OCH3) or ethoxy (OCH2CH3). The
pendant groups can be the same or different but the pendant groups
utilized must maintain the skeleton as linear.
[0194] Although many carotenoids exist in nature, carotenoid salts
do not. Commonly-owned U.S. Pat. No. 6,060,511 hereby incorporated
by reference in its entirety, relates to trans sodium crocetinate
(TSC). The TSC was made by reacting naturally occurring saffron
with sodium hydroxide followed by extractions that selected
primarily for the trans isomer.
[0195] The presence of the cis and trans isomers of a carotenoid or
carotenoid salt can be determined by looking at the
ultraviolet-visible spectrum for the carotenoid sample dissolved in
an aqueous solution. Given the spectrum, the value of the
absorbance of the highest peak which occurs in the visible wave
length range of 380 to 470 nm (the number depending on the solvent
used and the chain length of the BTC or BTCS. The addition of
pendant groups or differing chain lengths will change this peak
absorbance but someone skilled in the art will recognize the
existence of an absorbance peak in the visible range corresponding
to the conjugated backbone structure of these molecules.) is
divided by the absorbency of the peak which occurs in the UV wave
length range of 220 to 300 nm can be used to determine the purity
level of the trans isomer. When the trans carotenoid diester (TCD)
or BTCS is dissolved in water, the highest visible wave length
range peak will be at between 380 nm to 470 nm (depending on the
exact chemical structure, backbone length and pendant groups) and
the UV wave length range peak will be between 220 to 300 nm
According to M. Craw and C. Lambert, Photochemistry and
Photobiology, Vol. 38 (2), 241-243 (1983) hereby incorporated by
reference in its entirety, the result of the calculation (in that
case crocetin was analyzed) was 3.1, which increased to 6.6 after
purification.
[0196] Performing the Craw and Lambert analysis, using a cuvette
designed for UV and visible wavelength ranges, on the trans sodium
salt of crocetin of commonly owned U.S. Pat. No. 6,060,511 (TSC
made by reacting naturally occurring saffron with sodium hydroxide
followed by extractions which selected primarily for the trans
isomer), the value obtained averages about 6.8. Performing that
test on the synthetic TSC of the subject disclosure, that ratio is
greater than 7.0 (e.g. 7.0 to 8.5, 7.0 to 8.7, or 7.0 to 9.0),
advantageously greater than 7.5 (e.g. 7.5-8.5, 7.5 to 8.7, or 7.5
to 9.0), most advantageously greater than 8. The synthesized
material is a "purer" or highly purified trans isomer.
[0197] Trans sodium crocetinate (TSC) was developed to cause
reoxygenation of hypoxic tissues. TSC can be classified as a
kosmotrope, compounds which increase the hydrogen bonding among
water molecules. This, in turn, causes the water molecules to
change from a random arrangement to one which more resembles the
structure of crystals. More structure also results in a reduction
in the density of water, allowing small molecules like oxygen or
glucose to diffuse through the liquid phase more easily.
Kosmotropes are also known to result in this structure formation at
only certain, discrete concentrations.
Formulation and Administration
[0198] In formulating trans carotenoids including BTCSs such as
trans sodium crocetinate (TSC) with other ingredients (excipients),
it is advantageous to: improve the solubility (increase the
concentration of the active agent (e.g. TSC) in solution),
stability, bioavailability and isotonic balance of the BTC,
increase the pH of an aqueous solution, and/or increase the
osmolality of an aqueous solution. The excipient should act as an
additive to prevent self aggregation of monomeric BTC units in
solution, or to prevent pre-mature precipitation of BTC. The
addition of the excipient should aid in at least one of these
aspects. Bipolar trans carotenoid (BTC) molecules can be formulated
in a variety of ways. A basic formulation is a mixture of the BTC
in sterile water, administered by intravenous injection. This
formulation can be modified through the inclusion of various
pharmaceutical excipients, including the cyclodextrins. These
formulations can also be administered by intravenous injection.
[0199] Any of the above described various liquid formulations can
be freeze-dried (lyophilized) to form a dry powder with enhanced
solubility and stability characteristics. Such powdered forms are
then reconstituted for administration. One method is to
reconstitute the powder in a liquid such as saline or sterile water
for injection and then administer it by intravenous injection. This
method can include the use of a multi-compartment syringe
containing the powder in one compartment and liquid in the other
compartment. Similarly, the product can be bottled in a vial
containing a barrier separating the powder from the liquid. Before
administration, the barrier is broken and the components mixed
before intravenous injection.
[0200] In addition to intravenous injection, routes of
administration for specially formulated trans carotenoid molecules
include intramuscular injection, delivery by inhalation, oral
administration and transdermal administration.
Cyclodextrins
[0201] In order to administer some pharmaceuticals, it is necessary
to add another compound which will aid in increasing the
absorption/solubility/concentration of the active pharmaceutical
ingredient (API). Such compounds are called excipients, and
cyclodextrins are examples of excipients. Cyclodextrins are cyclic
carbohydrate chains derived from starch. They differ from one
another by the number of glucopyranose units in their structure.
The parent cyclodextrins contain six, seven and eight glucopyranose
units, and are referred to as alpha, beta and gamma cyclodextrins
respectively. Cyclodextrins were first discovered in 1891, and have
been used as part of pharmaceutical preparations for several
years.
[0202] Cyclodextrins are cyclic (alpha-1,4)-linked oligosaccharides
of alpha-D-gluco-pyranose containing a relatively hydrophobic
central cavity and hydrophilic outer surface. In the pharmaceutical
industry, cyclodextrins have mainly been used as complexing agents
to increase the aqueous solubility of poorly water-soluble drugs,
and to increase their bioavailability and stability. In addition,
cyclodextrins are used to reduce or prevent gastrointestinal or
ocular irritation, reduce or eliminate unpleasant smells or tastes,
prevent drug-drug or drug-additive interactions, or even to convert
oils and liquid drugs into microcrystalline or amorphous
powders.
[0203] Although the BTC compounds are soluble in water, the use of
the cyclodextrins can increase that solubility even more so that a
smaller volume of drug solution can be administered for a given
dosage.
[0204] There are a number of cyclodextrins that can be used with
the Compounds of the disclosure. See for example, U.S. Pat. No.
4,727,064, hereby incorporated by reference in its entirety.
Advantageous cyclodextrins are gamma-cyclodextrin,
2-hydroxylpropyl-beta-cyclodextrin and
2-hydroxylpropyl-beta-cyclodextrin, or other cyclodextrins which
enhance the solubility of the BTC.
[0205] The use of gamma-cyclodextrin with TSC increases the
solubility of TSC in water by 3-7 times. Although this is not as
large a factor as seen in some other cases for increasing the
solubility of an active agent with a cyclodextrin, it is important
in allowing for the parenteral administration of TSC in smaller
volume dosages to humans (or animals). The incorporation of the
gamma cyclodextrin also allows for TSC to be absorbed into the
blood stream when injected intramuscularly. Absorption is quick,
and efficacious blood levels of TSC are reached quickly (as shown
in rats).
[0206] The cyclodextrin formulation can be used with other trans
carotenoids and carotenoid salts. The subject disclosure also
includes novel compositions of carotenoids which are not salts
(e.g. acid forms such as crocetin, crocin or the intermediate
compounds noted above) and a cyclodextrin. In other words, trans
carotenoids which are not salts can be formulated with a
cyclodextrin. Mannitol can be added for osmolality, or the
cyclodextrin BTC mixture can be added to isotonic saline (see
below).
[0207] The amount of the cyclodextran used is that amount which
will contain the trans carotenoid but not so much that it will not
release the trans carotenoid.
Cyclodextrin-Mannitol
[0208] A trans carotenoid such as TSC can be formulated with a
cyclodextrin as noted above and a non-metabolized sugar such as
mannitol (e.g. d-mannitol to adjust the osmotic pressure to be the
same as that of blood). Solutions containing about 20 mg TSC/ml of
solution can be made this way. This solution can be added to
isotonic saline or to other solutions in order to dilute it and
still maintain the proper osmolality. See Example 12 of U.S. Pat.
No. 8,030,350 hereby incorporated by reference in its entirety.
Mannitol/Acetic Acid
[0209] A BTCS such as TSC can be formulated with mannitol such as
d-mannitol, and a mild acid such as acetic acid or citric acid to
adjust the pH. The pH of the solution should be around 8 to 8.5. It
should be close to being an isotonic solution, and, as such, can be
injected directly into the blood stream.
Water+Saline
[0210] A BTCS such as TSC can be dissolved in water (advantageously
injectable sterile water). This solution can then be diluted with
water, normal saline, Ringer's lactate or phosphate buffer, and the
resulting mixture either infused or injected.
Buffers
[0211] A buffer such as glycine or bicarbonate can be added to the
formulation at a level of about 50 mM (in the case of glycine) for
stability of the BCT such as TSC.
TSC and Gamma-Cyclodextrin
[0212] The ratio of TSC to cyclodextrin is based on
TSC:cyclodextrin solubility data. For example, 20 mg/ml TSC, 8%
gamma cyclodextrin, 50 mM glycine, 2.33% mannitol with pH 8.2
+/-0.5, or 10 mg/ml TSC and 4% cyclodextrin, or 5 mg/ml and 2%
cyclodextrin. The ratios of these ingredients can be altered
somewhat, as is obvious to one skilled in this art.
[0213] Mannitol can be used to adjust osmolality and its
concentration varies depending on the concentration of other
ingredients. The glycine is held constant. TSC is more stable at
higher pHs. pH of around 8.2 +/-0.5 is required for stability and
is physiologically compatible. The use of glycine is compatible
with lyophilization. Alternatively, the TSC and cyclodextrin is
formulated using a 50 mM bicarbonate or other buffers, in place of
the glycine.
Endotoxin Removal of Gamma-Cyclodextrin
[0214] Commercially available pharmaceutical grade cyclodextrin has
endotoxin levels that are incompatible with intravenous injection.
The endotoxin levels must be reduced in order to use the
cyclodextrin in a BTC formulation intended for intravenous
injection.
Lyophilization
[0215] Lyophilization can be used to produce an easily
reconstituted injectable solution.
Chemotherapy Agents
[0216] It is contemplated that various chemotherapy agents can be
used in the presently disclosed treatments and/or combination
therapies. Chemotherapy agents are divided into classes. These are
sometimes listed as Alkylating Agents including Platinum based
compounds, Antimetabolites, Antitumor Antibiotics including
Anthracyclines, Topoisomerase Inhibitors, and Anti-microtubule
Agents (Mitotic Inhibitors). Other classifications also exist. It
is contemplated that any of the following classes may be used
together with the present compositions and methods of
treatment.
Alkylating Agents
[0217] Alkylating agents are the oldest group of chemotherapeutics
in use today. Originally derived from mustard gas used in World War
I, there are now many types of alkylating agents in use..sup.[1]
They are so named because of their ability to alkylate many
molecules, including proteins, RNA and DNA. This ability to bind
covalently to DNA via their alkyl group is the primary cause for
their anti-cancer effects. DNA is made of two strands and the
molecules may either bind twice to one strand of DNA (intra-strand
crosslink) or may bind once to both strands (interstrand
crosslink). If the cell tries to replicate crosslinked DNA during
cell division, or tries to repair it, the DNA strands can break.
This leads to a form of programmed cell death called apoptosis.
Alkylating agents will work at any point in the cell cycle and thus
are known as cell cycle-independent drugs. For this reason, the
effect on the cell is dose dependent; the fraction of cells that
die is directly proportional to the dose of drug.
[0218] The subtypes of alkylating agents are the nitrogen mustards,
nitrosoureas, tetrazines, aziridines, cisplatins and derivatives,
and non-classical alkylating agents. Nitrogen mustards include
mechlorethamine, cyclophosphamide, melphalan, chlorambucil,
ifosfamide and busulfan. Nitrosoureas include
N-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU)
and semustine (MeCCNU), fotemustine and streptozotocin. Tetrazines
include dacarbazine, mitozolomide and temozolomide. Aziridines
include thiotepa, mytomycin and diaziquone (AZQ). Cisplatin and
derivatives include cisplatin, carboplatin and oxaliplatin. They
impair cell function by forming covalent bonds with the amino,
carboxyl, sulfhydryl, and phosphate groups in biologically
important molecules. Non-classical alkylating agents include
procarbazine and hexamethylmelamine.
[0219] Examples of alkylating agents include: altretamine,
busulfan, carboplatin, carmustine, chlorambucil, cisplatin,
cyclophosphamide, dacarbazine, lomustine, melphalan, oxalaplatin,
temozolomide, and thiotepa.
Antimetabolites
##STR00001##
[0221] Deoxcytidine (left) and two anti-metabolite drugs (center
and right); Gemcitabine and Decitabine. The drugs are very similar
but they have subtle differences in their chemical groups.
[0222] Anti-metabolites are a group of molecules that impede DNA
and RNA synthesis. Many of them have a similar structure to the
building blocks of DNA and RNA. The building blocks are
nucleotides; a molecule comprising a nucleobase, a sugar and a
phosphate group. The nucleobases are divided into purines (guanine
and adenine) and pyrimidines (cytosine, thymine and uracil).
Anti-metabolites resemble either nucleobases or nucleosides (a
nucleotide without the phosphate group), but have altered chemical
groups. These drugs exert their effect by either blocking the
enzymes required for DNA synthesis or becoming incorporated into
DNA or RNA. By inhibiting the enzymes involved in DNA synthesis,
they prevent mitosis because the DNA cannot duplicate itself. Also,
after misincorporation of the molecules into DNA, DNA damage can
occur and programmed cell death (apoptosis) is induced. Unlike
alkylating agents, anti-metabolites are cell cycle dependent. This
means that they only work during a specific part of the cell cycle,
in this case S-phase (the DNA synthesis phase). For this reason, at
a certain dose, the effect plateaus and proportionally no more cell
death occurs with increased doses. Subtypes of the anti-metabolites
are the anti-folates, fluoropyrimidines, deoxynucleoside analogues
and thiopurines.
[0223] The anti-folates include methotrexate and pemetrexed.
Methotrexate inhibits dihydrofolate reductase (DHFR), an enzyme
that regenerates tetrahydrofolate from dihydrofolate. When the
enzyme is inhibited by methotrexate, the cellular levels of folate
coenzymes diminish. These are required for thymidylate and purine
production, which are both essential for DNA synthesis and cell
division. Pemetrexed is another anti-metabolite that affects purine
and pyrimidine production, and therefore also inhibits DNA
synthesis. It primarily inhibits the enzyme thymidylate synthase,
but also has effects on DHFR, aminoimidazole carboxamide
ribonucleotide formyltransferase and glycinamide ribonucleotide
formyltransferase. The fluoropyrimidines include fluorouracil and
capecitabine. Fluorouracil is a nucleobase analogue that is
metabolised in cells to form at least two active products;
5-fluourouridine monophosphate (FUMP) and 5-fluoro-2'-deoxyuridine
5'-phosphate (fdUMP). FUMP becomes incorporated into RNA and fdUMP
inhibits the enzyme thymidylate synthase; both of which lead to
cell death. Capecitabine is a prodrug of 5-fluorouracil that is
broken down in cells to produce the active drug. The
deoxynucleoside analogues include cytarabine, gemcitabine,
decitabine, Vidaza, fludarabine, nelarabine, cladribine,
clofarabine and pentostatin. The thiopurines include thioguanine
and mercaptopurine.
[0224] Examples of antimetabolites include: 5-fluorouracil (5-FU),
6-mercaptopurine (6-MP), capecitabine (Xeloda.RTM.), cytarabine
(Ara-C.RTM.), floxuridine, fludarabine, gemcitabine (Gemzar.RTM.),
hydroxyurea, methotrexate, and pemetrexed (Alimta.RTM.).
Anti-Microtubule Agents
[0225] Vinca alkaloids prevent the assembly of microtubules,
whereas taxanes prevent their disassembly. Both mechanisms cause
defective mitosis.
[0226] Anti-microtubule agents are plant-derived chemicals that
block cell division by preventing microtubule function.
Microtubules are an important cellular structure composed of two
proteins; .alpha.-tubulin and .beta.-tubulin. They are hollow rod
shaped structures that are required for cell division, among other
cellular functions. Microtubules are dynamic structures, which
means that they are permanently in a state of assembly and
disassembly. Vinca alkaloids and taxanes are the two main groups of
anti-microtubule agents, and although both of these groups of drugs
cause microtubule dysfunction, their mechanisms of action are
completely opposite. The vinca alkaloids prevent the formation of
the microtubules, whereas the taxanes prevent the microtubule
disassembly. By doing so, they prevent the cancer cells from
completing mitosis. Following this, cell cycle arrest occurs, which
induces programmed cell death (apoptosis). Also, these drugs can
affect blood vessel growth; an essential process that tumours
utilise in order to grow specific. They bind to the tubulin
molecules in S-phase and prevent proper microtubule formation
required for M-phase.
[0227] Taxanes are natural and semi-synthetic drugs. The first drug
of their class, paclitaxel, was originally extracted from the
Pacific Yew tree, Taxus brevifolia. This drug and another in this
class, docetaxel, are produced semi-synthetically from a chemical
found in the bark of another Yew tree; Taxus baccata. These drugs
promote microtubule stability, preventing their disassembly.
Paclitaxel prevents the cell cycle at the boundary of G2-M, whereas
docetaxel exerts its effect during S-phase. Taxanes present
difficulties in formulation as medicines because they are poorly
soluble in water.
[0228] Podophyllotoxin is an antineoplastic lignan obtained
primarily from the American Mayapple (Podophyllum peltatum) and
Himalayan Mayapple (Podophyllum hexandrum or Podophyllum emodi). It
has anti-microtubule activity, and its mechanism is similar to that
of vinca alkaloids in that they bind to tubulin, inhibiting
microtubule formation. Podophyllotoxin is used to produce two other
drugs with different mechanisms of action: etoposide and
teniposide.
[0229] Examples of mitotic inhibitors include: docetaxel,
estramustine, ixabepilone, paclitaxel, vinblastine, vincristine,
and vinorelbine.
Topoisomerase Inhibitors
[0230] Topoisomerase inhibitors are drugs that affect the activity
of two enzymes: topoisomerase I and topoisomerase II. When the DNA
double-strand helix is unwound, during DNA replication or
transcription, for example, the adjacent unopened DNA winds tighter
(supercoils), like opening the middle of a twisted rope. The stress
caused by this effect is in part aided by the topoisomerase
enzymes. They produce single- or double-strand breaks into DNA,
reducing the tension in the DNA strand. This allows the normal
unwinding of DNA to occur during replication or transcription.
Inhibition of topoisomerase I or II interferes with both of these
processes.
[0231] Two topoisomerase I inhibitors, irinotecan and topotecan,
are semi-synthetically derived from camptothecin, which is obtained
from the Chinese ornamental tree Camptotheca acuminata. Drugs that
target topoisomerase II can be divided into two groups. The
topoisomerase II poisons cause increased levels enzymes bound to
DNA. This prevents DNA replication and transcription, causes DNA
strand breaks, and leads to programmed cell death (apoptosis).
These agents include etoposide, doxorubicin, mitoxantrone and
teniposide. The second group, catalytic inhibitors, are drugs that
block the activity of topoisomerase II, and therefore prevent DNA
synthesis and translation because the DNA cannot unwind properly.
This group includes novobiocin, merbarone, and aclarubicin, which
also have other significant mechanisms of action.
[0232] Topoisomerase inhibitors are grouped according to which type
of enzyme they affect:
[0233] Topoisomerase I inhibitors include: topotecan, and
irinotecan (CPT-11).
[0234] Topoisomerase II inhibitors include: etoposide (VP-16),
teniposide, and mitoxantrone (also acts as an anti-tumor
antibiotic).
Cytotoxic Antibiotics
[0235] The cytotoxic antibiotics are a varied group of drugs that
have various mechanisms of action. The group includes the
anthracyclines and other drugs including actinomycin, bleomycin,
plicamycin, and mitomycin. Doxorubicin and daunorubicin were the
first two anthracyclines, and were obtained from the bacterium
Streptomyces peucetius. Derivatives of these compounds include
epirubicin and idarubicin. Other clinically used drugs in the
anthracyline group are pirarubicin, aclarubicin, and mitoxantrone.
The mechanisms of anthracyclines include DNA intercalation
(molecules insert between the two strands of DNA), generation of
highly reactive free radicals that damage intercellular molecules
and topoisomerase inhibition. Actinomycin is a complex molecule
that intercalates DNA and prevents RNA synthesis. Bleomycin, a
glycopeptide isolated from Streptomyces verticillus, also
intercalates DNA, but produces free radicals that damage DNA. This
occurs when bleomycin binds to a metal ion, becomes chemically
reduced and reacts with oxygen. Mitomycin is a cytotoxic antibiotic
with the ability to alkylate DNA.
[0236] Anthracyclines: Anthracyclines are anti-tumor antibiotics
that interfere with enzymes involved in copying DNA during the cell
cycle. (Enzymes are proteins that start, help, or speed up the rate
of chemical reactions in cells.) They are widely used for a variety
of cancers.
[0237] Examples of anthracyclines include: daunorubicin,
doxorubicin (Adriamycin.RTM.), epirubicin, and idarubicin.
[0238] A major concern when giving these drugs is that they can
permanently damage the heart if given in high doses. For this
reason, lifetime dose limits are often placed on these drugs.
[0239] Anti-tumor antibiotics that are not anthracyclines include:
actinomycin-D, bleomycin, mitomycin-C, and mitoxantrone (also acts
as a topoisomerase II inhibitor, see below).
Other Drugs
[0240] In another embodiment, one or more benzo[c]chromen-6-one
derivative such as SG-529, is administered prior to, during, or
after radiation therapy and/or chemotherapy. See U.S. Pat. No.
8,475,776 hereby incorporated by reference in its entirety.
Radiation Therapy
[0241] It is contemplated that radiation therapy may be used
together with a bipolar trans carotenoid salt (e.g., TSC) in the
treatment of a tumor or cancer. The following is a brief
description of types of radiation therapy that may be used with the
disclosed compositions and in the disclosed methods of
treatment.
External-Beam Radiation Therapy
[0242] This is the most common type of radiation treatment. It
delivers radiation from a machine located outside the body. It can
treat large areas of the body, if needed. The machine used to
create the radiation beam is called a linear accelerator or linac.
Computers with special software adjust the size and shape of the
beam. They also direct the beam to target the tumor while avoiding
the healthy tissue near the cancer cells. External-beam radiation
therapy does not make you radioactive.
[0243] Types of external-beam radiation therapy include: [0244]
Three-dimensional conformal radiation therapy (3D-CRT): As part of
this treatment, special computers create detailed three-dimensional
pictures of the cancer. This allows the treatment team to aim the
radiation more precisely. By doing this, they can use higher doses
of radiation while reducing the risk of damaging healthy tissue.
Studies have shown that 3D-CRT can lower the risk of side effects.
For instance, it can limit the damage to the salivary glands, which
can cause dry mouth when people with head and neck cancer have
radiation therapy. [0245] Intensity modulated radiation therapy
(IMRT): This treatment directs the radiation dose at the tumor
better than 3D-CRT by varying the intensity of the beam. IMRT
protects healthy tissues from radiation better than 3D-CRT. [0246]
Proton beam therapy: This treatment uses protons, rather than
x-rays, to treat some cancers. Protons are parts of atoms that at
high energy can destroy cancer cells. Directing protons at a tumor
decreases the amount of radiation sent to nearby healthy tissue,
reducing damage to this tissue. Because this therapy is relatively
new and requires special equipment, it is not available at every
medical center. The potential benefits of proton therapy compared
to IMRT have not been established for some cancers, such as
prostate cancer. [0247] Stereotactic radiation therapy: This
treatment delivers a large, precise radiation dose to a small tumor
area. Because of the precision involved in this type of treatment,
the patient must remain very still. Head frames or individual body
molds are used to limit movement. Although this therapy is often
given as a single treatment, some patients may need several
radiation treatments.
Internal Radiation Therapy
[0248] This type of radiation treatment is also known as
brachytherapy. Radioactive material is placed into the cancer
itself or into the tissue surrounding it. These implants may be
permanent or temporary and may require a hospital stay. Permanent
implants are tiny steel seeds about the size of a grain of rice
that contain radioactive material. These capsules are placed inside
the body at the tumor site. The seeds deliver most of the radiation
around the area of the implant. However, some radiation can be
released from the patient's body. This means the patient should
take precautions to protect others from radiation exposure while
the seeds are active. Over time, the implant loses its
radioactivity, but the inactive seeds remain in the body.
Methods of Treatment
Cancer
[0249] The subject disclosure relates to the treatment of various
tumors and/or cancers (i.e., gliobastoma, pancreatic cancer, etc.).
It is well established that tumors are hypoxic with many tumor
types being highly hypoxic. Further, it is known that hypoxic
tumors are more resistant to radiotherapy and chemotherapy. Through
HlFlalpha up-regulation, hypoxia is associated with multiple
negative effects that lead to aggressive tumor phenotypes. These
effects include increased angiogenesis, increased metastasis, as
well as increased resistance to chemotherapy and radiation therapy.
Hypoxia via HIFla affects many genes involved in cancer
progression. Bipolar trans carotenoids such as TSC alter expression
of HIF1 targeted genes in hypoxic conditions. For example, studies
have shown that the VEGF A gene which is upregulated with hypoxia
is down regulated with TSC.
[0250] The methods of the subject disclosure are directed to
administering a dose of a bipolar trans carotenoid such as TSC, at
a dose and at the proper time prior to administration of
chemotherapy or radiation therapy (as discussed above) such that
the oxygen partial pressure is elevated inside the tumor while the
chemotherapy or radiation therapy is administered so as to obtain
maximum increased killing effect of the chemotherapy and or
radiotherapy on the cancer cells/tumor. The administration of the
bipolar trans carotenoid, due to its hypoxia reducing ability, can
also decrease angiogenesis, decrease metastasis, and down regulate
HIFla production in the tumor.
[0251] Chemotherapy (chemo) uses anti-cancer drugs injected into a
vein or taken by mouth. These drugs enter the bloodstream and reach
all areas of the body, making this treatment useful for cancers
that have spread beyond the organ in which they started. [0252]
Chemotherapy can be given before surgery (sometimes along with
radiation) to shrink the tumor. This is known as neoadjuvant
treatment. [0253] Chemotherapy can be used after surgery (sometimes
along with radiation) to try to kill any cancer cells that have
been left behind (but can't be seen). This type of treatment,
called adjuvant treatment, lowers the chance that the cancer will
come back later. [0254] Chemotherapy is commonly used when the
cancer is advanced and can't be removed completely with
surgery.
[0255] When chemotherapy is given along with radiation, it is known
as chemoradiation or chemoradiotherapy. It can improve the
effectiveness of the radiation, but it also may cause more severe
side effects.
[0256] Doctors give chemotherapy in cycles, with each period of
treatment followed by a rest period to allow the body time to
recover. Each chemotherapy cycle typically lasts for a few
weeks.
[0257] With bipolar trans carotenoids such as TSC, there are
discrete concentrations that produce efficacy in causing maximum
oxygen partial pressure in animals or humans. It has been found for
all animals tested (including humans), that two such efficacious
dosages exist: a "low dose" and a "high dose." For humans, a low
dose of 0.15- 0.35 mg/kg, e.g. 0.25 mg/kg, produces the maximum
reoxygenation of hypoxic tissue 50 minutes after injection, a
change that lasts for a short time, while a high dose of 0.75-2.0
mg/kg, e.g. 1.5 mg/kg, produces the same maximum change but which
lasts for over an hour. Increasing the oxygen levels in the
cancerous tissue while administering chemotherapy or radiotherapy
results in superior cancerous tissue (tumor) killing.
[0258] In addition to enhancing the cytotoxicity of
chemotherapeutic agents in a tumor, administration of a bipolar
trans carotenoid such as TSC can reduce or treat the neurotoxicity
or neuropathy that the chemotherapy agents can cause.
Pancreatic Cancer
[0259] The various types of pancreatic cancer are discussed earlier
in this specification. Chemotherapy can be used at any stage of
these pancreatic cancers.
[0260] Pancreatic tumors are usually highly hypoxic. Hypoxia
results in impairment of the tumor response to chemotherapy agents
including antimetabolites such as gemcitabine.
[0261] Many different chemo drugs can be used to treat pancreatic
cancer, including: gemcitabine (Gemzar.RTM.), 5-fluorouracil
(5-FU), irinotecan (Camptosar.RTM.), oxaliplatin (Eloxatin.RTM.),
albumin-bound paclitaxel (nab-paclitaxel) (Abraxane.RTM.),
capecitabine (Xeloda.RTM.), cisplatin, paclitaxel (Taxol.RTM.),
docetaxel (Taxotere.RTM.), and irinotecan liposome
(Onivyde.RTM.).
[0262] In people who are healthy enough, 2 or more drugs are
usually given together. The current standard of care for patients
with metastatic pancreatic cancer includes gemcitabine combined
with either erlotinib or nab-paclitaxel. Erlotinib is approved for
the treatment of metastatic non-small cell lung cancer and
metastatic pancreatic cancer. Nab-paclitaxel is approved for the
treatment of breast cancer, non-small cell lung cancer, and
metastatic pancreatic cancer.
[0263] Other examples of combo therapies are gemcitabine and
capecitabine (Xeloda), or gemcitabine, irinotecan, and celecoxib
(an arthritis drug). Another combo regimen is the Folfirinox
(leucovorin +5-fluorouracil +oxaliplatin +irinotecan) regimen.
[0264] For people who are not healthy enough for combined
treatments, a single drug (usually gemcitabine, 5-FU, or
capecitabine) can be used.
[0265] Advantageous treatment of such tumors includes
administration of a high dose--0.75-2.0 mg/kg--of a bipolar trans
carotenoid such as TSC, 1-2 hr. prior to administration of one or
more chemotherapy agents. A typical cycle would be administration
of TSC and the chemotherapy agent (e.g. gemcitabine), or agents
(gemcitabine followed directly by nab-paclitaxel), once per week
for 3 weeks followed by a week of rest. This cycle can be repeated
the following month or months.
[0266] In an advantageous embodiment where two chemotherapy agents
(nab-paclitaxel and gemcitabine) are given sequentially, TSC (1.5
mg/kg) is given IV as a bolus 45-60 minutes before beginning
infusion of 125 mg/m2 nab-paclitaxel (30-40 min). The IV infusion
of 1000 mg/m2 gemcitabine (30-40 min.) starts soon after the IV
infusion of nab-paclitaxel. For example, once per week for three
weeks, TSC is administered IV bolus 60 minutes before start of the
IV infusion of the nab-paclitaxel, and 90 minutes prior to the
start of the IV infusion of the gemcitabine (allotting 30 minutes
for administration of each of the chemotherapeutic agents). The
effect of the TSC (increasing the oxygen partial pressure in the
tumor) will then last for the duration of both chemotherapy drugs.
The 3 weeks of the administration above is followed by a week of
rest.
[0267] Radiation therapy utilizing the 0.15-0.35 mg/kg dose of TSC
prior to administration of the RT can also be used in the treatment
of pancreatic cancer.
Gliobastoma Multiforme
[0268] Glioblastoma tumors are highly hypoxic. TSC can be used to
enhance the effects of both the radiation therapy (RT) and
chemotherapy (e.g. alkylating agent or antimetabolite such as
temozolomide (TMZ)). Advantageous treatment of GBM tumors includes
administration of a bipolar trans carotenoid such as TSC at a dose
of 0.15-0.35 mg/kg, prior to, advantageously 45-60 min. prior to,
administration of radiotherapy (optionally a chemotherapy agent
such as temozolomide is administered, usually the night preceding
RT). The TMZ is typically administered daily for the duration of
the RT sessions. The bipolar trans carotenoid, e.g. TSC, dosage
during radiation therapy is advantageously 0.25 mg/kg given 45
minutes before radiation.
[0269] The bipolar trans carotenoid, e.g. TSC dosage during
chemotherapy (without radiation) is advantageously 1.5 mg/kg given
1-2 hrs. before the chemotherapeutic agent. For temozolomide
administration (5 daily administrations during the monthly week of
chemotherapy), the bipolar trans carotenoid is typically
administered 2-5 times (advantageously 3 times) during the monthly
week. The monthly bipolar trans carotenoid and chemo cycle can
continue for 6 or more months.
[0270] In an advantageous embodiment, after surgery to remove that
portion of the GBM tumor feasibly removed, a bipolar trans
carotenoid such as TSC is infused at a dose of 0.25 mg/kg. 45-60
minutes prior to radiation therapy--(2 Gy) 5 days a week for 6
weeks. Temozolomide is administered (e.g. 75 mg/m2 temozolomide)
per day 7 days per week for the duration of RT. The TSC treatment
occurs 3 times per week for the six weeks. After a rest period of
1-4 weeks, for another 6 month period, the TSC is injected at a
dose of 1.5 mg/kg 1-2 hr. prior to chemotherapy (e.g. temozolomide
150-200 mg/m2 on 5 consecutive days for the first week of the
month). This TSC administration occurs 3 times per week for the
first week of the month for the following 6 months. For a 6-week
radiation therapy regimen followed by a 6-month chemotherapy
regimen, this results in 36 doses of TSC--18 during
radiation/chemotherapy (6 weeks), and 18 during chemotherapy (6
months).
Brain Metastases
[0271] Treatment for brain metastases involves both controlling the
symptoms associated with the condition as well as attacking the
cancer directly. Brain metastases typically result in edema that
can be controlled with the use of steroids; however, long-term use
of steroids typically results in side effects that greatly
diminishes a patient's quality of life. Approximately 25-45% of
patients will experience seizures and require the use
anti-epileptic drugs. Surgery is only utilized in patients with a
solitary brain metastatic lesion. Radiation therapy remains the
standard of care for the vast majority of patients with brain
metastases.
[0272] Brain metastases are typically hypoxic. Radiation therapy
remains the standard of care for the vast majority of patients with
brain metastases. Advantageous treatment of such tumors includes
administration of a bipolar trans carotenoid such as TSC at a dose
of 0.15-0.35 mg/kg, e.g. 0.25 mg/kg, 45-60 minutes prior to
administration of radiotherapy. In another embodiment, the methods
described above for GBM, i.e. use of a chemo agent as well as
radiation therapy, are also applicable to treatment of brain
metastases.
Other Cancers
[0273] Other cancers that can be treated according to the methods
of the subject disclosure include solid tumors such as squamous
cell carcinomas, melanomas, lymphomas, sarcomas, sarcoids,
osteosarcomas, skin cancer, breast cancer, head and neck cancer,
gynecological cancer, urological and male genital cancer, bladder
cancer, prostate cancer, bone cancer, cancers of the endocrine
glands (e.g., pancreatic cancer), cancers of the alimentary canal,
cancers of the major digestive glands/organs, CNS cancer, and lung
cancer.
[0274] Advantageous modes of treating the above cancers include the
standard of care for a given cancer indication supplemented by
administration of a bipolar trans carotenoid such as TSC at a dose
of 0.75-2.0 mg/kg, e.g. 1.5 mg/kg, prior to administration of
chemotherapy, and 0.15-0.35 mg/kg, e.g. 0.25 mg/kg, of TSC prior to
administration of radiotherapy.
Non-Cancer Uses
[0275] It has also been determined that several non-cancer
disorders are beneficially treated utilizing an administration
regimen of a bipolar trans carotenoid such as TSC, as described
below. Pre-clinical efficacy studies using TSC have demonstrated
the following:
TABLE-US-00002 Species Condition Best Dosage Rat Hemorrhagic Shock
Low Rat Ischemic Stroke Low Rat Hemorrhagic Stroke Low Rat Cancer:
Radiation Sensitizer Low Rat Cancer Chemosensitizer High Rat
Parkinson's Disease High Rat Memory Recall High Mouse Cancer:
Radiation Sensitizer Low Mouse Critical Limb Ischemia High Rabbit
Ischemic Stroke Low Pig Hemorrhagic Shock Low Pig Myocardial
Infarction Low Pig Wound Healing High
[0276] For humans, TSC at the low dosage e.g. 0.15-0.35 mg/kg, e.g.
0.25 mg/kg, is administered IV for treating cardiovascular events
including stroke, myocardial infarction or hemorrhagic shock (blood
loss). See U.S. Pat. No. 7,919,527 hereby incorporated by reference
in its entirety.
[0277] TSC at the high dose 0.75-2.0 mg/kg, e.g.1.5 mg/kg, can act
as a neuroprotective agent for humans for treating CNS conditions
(Alzheimer's, Parkinson's, memory loss), as well as for promoting
wound healing and alleviating extreme limb ischemia. See U.S. Pat.
Nos. 7,759,506 and 8,293,804 each of which is hereby incorporated
in its entirety. Advantageous administration is orally, 2-5 times
per week at a dose that achieves TSC levels equivalent to 0.75-2
mg/kg given IV. See commonly owned U.S. Pat. No. 8,974,822 hereby
incorporated by reference in its entirety.
[0278] The following Examples are illustrative, but not limiting of
the compounds, compositions and methods of the present disclosure.
Other suitable modifications and adaptations of a variety of
conditions and parameters normally encountered which are obvious to
those skilled in the art are within the spirit and scope of this
disclosure.
EXAMPLES
DMBA Tumors
[0279] Breast tumors were induced through injection of DMBA
(dimethylbenzantracene) under the mammary tissue of female rats.
The tumors usually grow in most rats and reach measurable
conditions after 10 days.
[0280] The following studies used a method in which a 3-mL syringe
is filled first with 1 ml of DMBA dissolved in sunflower seed oil
(20 mg DMBA per mL of solution). Following that, 2 mL's of air are
pulled into the syringe. The needle of the syringe is then inserted
under the mammary tissue near a hind leg and the air in the syringe
is carefully injected. The injection of the air forms a "pocket",
and then the 1 mL of DMBA solution is injected into that
pocket.
[0281] After the tumors have grown up (about 10 days), their
volumes are estimated by measuring the diameter (d) and the length
(L) of the football-shaped tumors formed. This is done using
calipers after feeling the tumor with one's fingers. To estimate
the volume of the tumor, you multiply the diameter squared times
the length and divide by 2:
Tumor volume (in mm3)={(d in mm).sup.2/2}X (L in mm)
[0282] TSC or saline (controls) was injected in the tail vein of
the rats at a volume of 0.1 mL and a dose of 0.25 mg/kg TSC about
1-2 hours before the chemotherapeutic agent was injected
intraperitoneally (IP) in the rats.
Example 1
Platinum-Containing Compounds (Cisplatin)
[0283] In order to understand which dosages are efficacious when
used with chemotherapy, a rat model of breast tumors was used. The
model involves injecting the chemical dimethylbenzanthracene (DMBA)
under the mammary gland of a female Sprague-Dawley rat. After a few
days, tumors begin to grow and can be measured by feeling the
football-shaped tumor under the skin and measured using
calipers.
[0284] In this study, a platinum based compound was used
(cisplatin). The low dose (for rats) 0.1 mg/kg of TSC given (IV) 50
minutes before chemotherapy was not effective in the study, but the
high dose (for rats) 0.25 mg/kg of TSC given 2 hours before
chemotherapy was efficacious as shown in the figure below.
[0285] High Dose of TSC given 2 hours before 1 mg/kg cisplatin.
Cisplatin (1 mg/kg) was injected IP on days 0, 4, 11, 18. As shown
in FIG. 2, rats treated with high dose TSC and cisplatin showed
significant improvement in tumor volume over the control.
Example 2
Antimetabolites (Gemcitabine)
[0286] In this study, the antimetabolite (gemcitabine) was used.
The low dose of TSC given 50 minutes before chemotherapy was not
effective in the study, but the high dose of TSC given 2 hours
before chemotherapy was efficacious as shown in FIG. 3. The
concentrations of the low dose TSC and the high dose TSC are the
same as those defined in Example 1.
[0287] High Dose of TSC given 2 hours before 10 mg/kg gemcitabine.
Gemcitabine (10 mg/kg) was injected IP on days 0, 3. As shown in
FIG. 3, rats treated with high dose TSC and gemcitabine showed a
significant decrease in tumor volume on day 3. For comparison, rats
in the control group showed only a marginal increase in tumor
volume. Most rats in both groups were dead on Day 6. Gemcitabine
dose was cut in half, and the same behavior was seen.
[0288] High dose of TSC given 2 hours before 5mg/kg gemcitabine.
Gemcitabine (5 mg/kg) was injected IP on days 0, 3: Most rats in
both groups were dead on Day 7. Results are shown in FIG. 4. Rats
given high dose TSC and gemcitabine showed substantially less tumor
growth than those in the control group. Note that % tumor growth
for both groups is greater that for gemcitabine dosage of 10
mg/kg.
[0289] Time of TSC injection relative to that of the chemotherapy
agent was tried with a gemcitabine dose of 7.5 mg/kg, but data
obtained only for Day 2 after injection of gemcitabine because of
its toxicity in rats. Dosing 2 hours before the chemotherapy is
best although all methods reduced tumor growth relative to
control.
[0290] High dose of TSC given 2 hours before 7.5 mg/kg gemcitabine.
TSC high dose given i) concurrently, ii) 1 hour before, and iii) 2
hours before gemcitabine (7.5 mg/kg, given IV). As shown in FIG. 5,
timing of TSC administration 2 hours prior to chemotherapeutic
agent gives best results in all studies.
Example 3
Alkylating Agents (Temozolomide)
[0291] A high dose of TSC as defined in Example 1 was given 2 hours
prior to chemotherapy with temozolomide. Results are summarized in
FIG. 6. Note that pseudoprogression was seen in this study, which
accounts for the increase in tumor volume in subjects administered
TSC together with temozolomide on day 7. Pseudoprogression is also
seen in human chemotherapy of glioblastoma when using temozolomide
as a radio- and chemo-sensitizer.
Example 4
Anti-tumor Antibiotics--Anthracyclines (Doxorubicin)
[0292] A high dose of TSC as defined in Example 1 was given 2 hours
prior to chemotherapy with doxorubicin. Pseudoprogression was also
seen in this study, which accounts for the increase in tumor volume
in subjects administered TSC together with doxorubicin on day 7.
The results, summarized in FIG. 7, show a marked reduction in tumor
growth in comparison with the control group.
Example 5
Mitotic Inhibitors-Taxanes (Paclitaxel)
[0293] A high dose of TSC as defined in Example 1 was given 2 hrs.
prior to chemotherapy with paclitaxel. Doses of chemotherapy and
TSC were given on Days 0, 4, 8, 14. Pseudoprogression was also seen
in this study. The results, summarized in FIG. 8, show a marked
reduction in tumor growth in comparison with the control group.
Example 6
Trans Sodium Crocetinate Phase 1/2 Clinical Trial in GBM
[0294] To date, TSC has been used in 148 human subjects inhase 1
and Phase 2 clinical trials, with no serious adverse events
reported. A Phase 1/2 clinical trial was recently completed
examining TSC in patients with GBM. The Phase 1/2 clinical trial in
GBM enrolled 59 patients with newly diagnosed disease that received
TSC in conjunction with radiation therapy (RT) and temozolomide
(TMZ). In the Phase I portion of the trial TSC was initially
administered three times per week at half-dose to three patients
prior to radiation. Six additional patients received full dose TSC
for six weeks in combination with radiation. No dose-limiting
toxicities were identified in the nine patients during the Phase I
portion of the trial. Fifty additional patients were enrolled in
the Phase II trial at full dose TSC in combination with TMZ and RT.
Four weeks after completion of RT, all patients resumed TMZ for
five days every four weeks, but no further TSC was
administered.
[0295] More specifically, fifty-nine patients with newly-diagnosed
GBM were enrolled. Patients received standard of care (SOC)
radiation therapy (RT) (2 Gy/day, 5 days/week for 6 weeks) and TMZ
(75 mg/m2) starting within 5 weeks after a surgical resection of
their tumor, if such surgery were possible. Patients receiving only
needle biopsies (i.e., no surgery) were also enrolled.
[0296] In addition to the SOC, TSC was administered 3 times per
week, 0.25 mg/kg IV, usually on Monday, Wednesday and Friday, about
45 minutes prior to the RT sessions.
[0297] Four weeks after completion of RT, patients began
chemotherapy with TMZ for 5 days of the first week of a 4 week
cycle. This continued for 6 such cycles. No TSC was administered
during this chemotherapy.
Overall Survival
[0298] Using the values reported for certain time points in the SOC
analysis (Stupp R, et al.: Radiotherapy plus concomitant and
adjuvant temozolomide for glioblastoma. N. Engl. J. Med.
352:987-996, 2005), as shown in Table 2 below, it was determined
that survival was 10% greater in the TSC trial (i.e., the present
study) at both 1 and 2 years than the rate in the historical trial,
which had established the SOC for GBM in 2005.
TABLE-US-00003 TABLE 2 Overall Survival from Kaplan-Meier Analysis
Observed Survival Rate Historical Survival Rate Time with TSC
Treatment (from Stupp study) 1 year 71.2% 61.1% 2 years 36.3%
26.5%
[0299] Both the 1- and 2-year survivals in the current trial fall
outside the Stupp confidence intervals for those time points,
suggesting statistical differences. That is, one can be 95%
confident that survival in the present trial is statistically
different from that which established the SOC.
[0300] Previous studies have shown that survival can be positively
correlated with the extent of the initial resection, which means
that those patients having inoperable tumors have a lower
probability of survival. The current trial incorporating TSC into
the SOC RT and TMZ for GBM enrolled essentially equal numbers of
patients who had undergone complete resection (14) and no resection
(15). These patients comprised approximately 50% of the 59 patients
enrolled in the trial. The other 50% were patients who had
undergone partial resection.
[0301] It would be expected that the patients who have complete
resections would have higher survivability rates than those solely
having needle biopsies (i.e., partial resections). However,
contrary to this expectation, survival at 2 years was quite similar
for both groups in the present trial. In the subgroup of patients
considered inoperable, the chance of survival at two years for
those who received TSC was increased by over 100%, as 40% in the
TSC group were alive at two years compared to less than 20 percent
in the control. For comparison, survivability of the biopsy-only
patients was observed to be 42.9% at two years. All groups of
patients administered TSC in addition to SOC treatment showed
better survival at 2 years than the overall survival rate seen with
the historical controls.
Tumor Sizes
[0302] One particularly unexpected result of the present study was
the effect that the treatment had on reduction in tumor sizes. In
the trials, 56 patients received full-dose TSC therapy. Of those
patients, 4 did not live long enough to have an MM study after
baseline, 1 patient was censored, and 14 patients underwent
complete resections. Thus, 37 patients had either partial resection
or no resection (biopsy only) and their tumors could be followed
over time. The vast majority of these 37 patients showed reduction
in tumor size, with almost 20% of the full-dose patients showing
complete elimination of tumors, which emphasizes the beneficial use
of TSC for this indication. This effect has not been documented in
humans in the art.
[0303] Thus, it is shown that TSC is effective on glioblastoma
multiforme tumors when given at a low dose (0.25 mg/kg) 45 minutes
before radiation was administered.
[0304] It will be readily apparent to those skilled in the art that
the numerous modifications and additions can be made to both the
present compounds and compositions, and the related methods without
departing from the disclosed methods and compositions.
* * * * *