U.S. patent application number 13/371076 was filed with the patent office on 2013-07-18 for pharmaceutical compositions and methods.
The applicant listed for this patent is Steven Hoffman. Invention is credited to Steven Hoffman.
Application Number | 20130184214 13/371076 |
Document ID | / |
Family ID | 48701382 |
Filed Date | 2013-07-18 |
United States Patent
Application |
20130184214 |
Kind Code |
A1 |
Hoffman; Steven |
July 18, 2013 |
PHARMACEUTICAL COMPOSITIONS AND METHODS
Abstract
Pharmaceutical compositions and kits including a tyrosine
hydroxylase inhibitor, a melanin promoter, a p450 3A4 promoter, and
a leucine aminopeptidase inhibitor are provided. Also provided are
methods of treating cancer in a subject, comprising administering
an effective amount of a tyrosine hydroxylase inhibitor, a melanin
promoter, a p450 3A4 promoter, and a leucine aminopeptidase
inhibitor to the subject in need thereof. Also provided are methods
of reducing cell proliferation in a subject comprising
administering an effective amount of a tyrosine hydroxylase
inhibitor, a melanin promoter, a p450 3A4 promoter, and a leucine
aminopeptidase inhibitor to the subject in need thereof.
Inventors: |
Hoffman; Steven; (Mahwah,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hoffman; Steven |
Mahwah |
NJ |
US |
|
|
Family ID: |
48701382 |
Appl. No.: |
13/371076 |
Filed: |
February 10, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61587420 |
Jan 17, 2012 |
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Current U.S.
Class: |
514/10.7 ;
514/11.1; 514/217; 514/291; 514/391; 514/455 |
Current CPC
Class: |
A61K 31/19 20130101;
A61K 31/37 20130101; A61K 31/55 20130101; A61K 31/216 20130101;
A61K 31/55 20130101; A61K 31/198 20130101; A61K 31/4166 20130101;
A61K 31/198 20130101; A61K 31/19 20130101; A61K 31/37 20130101;
A61K 38/34 20130101; A61K 31/436 20130101; A61K 45/06 20130101;
A61K 38/34 20130101; A61K 2300/00 20130101; A61P 35/00 20180101;
A61K 31/216 20130101; A61K 31/436 20130101; A61K 31/4166 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/10.7 ;
514/455; 514/391; 514/217; 514/291; 514/11.1 |
International
Class: |
A61K 38/31 20060101
A61K038/31; A61K 38/17 20060101 A61K038/17; A61P 35/00 20060101
A61P035/00; A61K 31/55 20060101 A61K031/55; A61K 31/436 20060101
A61K031/436; A61K 31/37 20060101 A61K031/37; A61K 31/4166 20060101
A61K031/4166 |
Claims
1. A method of treating breast cancer in a subject comprising
administering an effective amount of a tyrosine hydroxylase
inhibitor; a melanin promoter; a p450 3A4 promoter; and a leucine
aminopeptidase inhibitor to the subject in need thereof, wherein:
the melanin promoter is methoxsalen or melanotan II; the p450 3A4
promoter is 5,5-diphenylhydantoin, valproic acid, or carbamazepine;
and the leucine aminopeptidase inhibitor is
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine or
rapamycin.
2. The method of claim 1 further comprising administering a growth
hormone inhibitor.
3. The method of claim 1 wherein at least two of the promoters and
inhibitors are administered simultaneously.
4. The method of claim 1 wherein at least three of the promoters
and inhibitors are administered simultaneously.
5. The method of claim 1 wherein each of the promoters and
inhibitors is administered simultaneously.
6. The method of claim 1 wherein the promoters and inhibitors are
administered orally, subcutaneously, intravenously, transdermally,
vaginally, rectally or in any combination thereof.
7. The method of claim 6 wherein the transdermal administration is
done with oleic acid, 1-methyl-2-pyrrolidone, or
dodecylnonaoxyethylene glycol monoether.
8. The method of claim 1 wherein the promoters and inhibitors are
administered during a cycle consisting of five to seven days of
administering the promoters and inhibitors and one to two days of
not administering the promoters and inhibitors.
9. The method of claim 8 wherein the promoters and inhibitors are
administered over the course of at least six of said cycles.
10. The method of claim 1 wherein the tyrosine hydroxylase
inhibitor is a tyrosine derivative.
11. The method of claim 10 wherein the tyrosine derivative is one
or more of methyl (2R)-2-amino-3-(2-chloro-4 hydroxyphenyl)
propanoate, D-tyrosine ethyl ester hydrochloride, methyl
(2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate
H-D-Tyr(TBU)-allyl ester HCl, methyl
(2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl
(2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate,
methyl (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl) methoxy]phenyl)
propanoate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl)
propanoate, methyl
(2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate,
diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzyl
malonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)
propanoate, methyl
(2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propanoate,
methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl)
propanoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)
propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl,
H-D-3,5-diiodo-tyr-OME HCl, H-D-tyr-OME HCl, D-tyrosine methyl
ester hydrochloride, D-tyrosine-ome HCl, methyl D-tyrosinate
hydrochloride, HD-tyr-OMe.HCl, D-tyrosine methyl ester HCl,
H-D-Tyr-OMe-HCl, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid,
(2R)-2-amino-3-(4-hydroxyphenyl) methyl ester hydrochloride, methyl
(2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl
(2R)-2-azanyl-3-(4-hydroxyphenyl) propanoate hydrochloride,
3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl
ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr
(3,5-I2)-OSu, Fmoc-tyr(3-NO2)-OH, and
.alpha.-methyl-DL-tyrosine.
12. The method of claim 11 wherein 60 mg of the tyrosine derivative
is administered orally and 0.25 mL of a 2 mg/mL suspension of the
tyrosine derivative is administered subcutaneously.
13. The method of claim 1 wherein the melanin promoter is
methoxsalen.
14. The method of claim 13 wherein 10 mg of the methoxsalen is
administered orally and 0.25 mL of a 1 mg/mL suspension of the
methoxsalen is administered subcutaneously.
15. The method of claim 1 wherein the melanin promoter is melanotan
II.
16. The method of claim 1 wherein the p450 3A4 promoter is
5,5-diphenylhydantoin.
17. The method of claim 16 wherein 30 mg of the
5,5-diphenylhydantoin is administered orally.
18. The method of claim 1 wherein the p450 3A4 promoter is valproic
acid or carbamazepine.
19. The method of claim 1 wherein the leucine aminopeptidase
inhibitor is
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine.
20. The method of claim 19 wherein 20 mg of the
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine is
administered orally.
21. The method of claim 1 wherein the leucine aminopeptidase
inhibitor is rapamycin.
22. The method of claim 19 wherein the p450 3A4 promoter is
5,5-diphenylhydantoin.
23. The method of claim 22 wherein the melanin promoter is
melanotan II.
24. The method of claim 1 further comprising administering an
effective amount of D-leucine.
25. The method of claim 23 wherein the tyrosine derivative is
.alpha.-methyl-DL tyrosine.
26. The method of claim 1 wherein the melanin promoter is melanotan
II; the p450 3A4 promoter is 5,5-diphenylhydantoin; and the
tyrosine hydroxylase inhibitor is .alpha.-methyl-DL tyrosine.
27. The method of claim 26 wherein the leucine aminopeptidase
inhibitor is
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine.
28. The method of claim 26 wherein the leucine aminopeptidase
inhibitor is rapamycin.
29. The method of claim 1 further comprising assessing progression
of said cancer in said subject.
30. The method of claim 2 further comprising assessing progression
of said cancer in said subject.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/587,420, filed Jan. 17, 2012, which is
incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0002] The present inventions relate generally to compositions,
kits and methods for the reduction of cellular proliferation as,
for example, in the treatment of cancer.
BACKGROUND
[0003] According to the U.S. National Cancer Institute's
Surveillance Epidemiology and End Results (SEER) database for the
year 2008, the most recent year for which incidence data are
available, 11,958,000 Americans have invasive cancers. Cancer is
the second most common cause of death in the United States, behind
only heart disease, and accounts for one in four deaths. It has
been estimated that approximately 1600 Americans die of cancer each
day. In addition to the medical, emotional and psychological costs
of cancer, cancer has significant financial costs to both the
individual and society. It is estimated by the National Institutes
of Health that the overall costs of cancer in 2010 was $263.8
billion. In addition, it is estimated that another $140.1 billion
is lost in productivity due to premature death.
[0004] Cancer treatments today include surgery, hormone therapy,
radiation, chemotherapy, immunotherapy, targeted therapy, and
combinations thereof. Surgical removal of cancer has advanced
significantly; however, there remains a high chance of recurrence
of the disease. Hormone therapy using drugs such as aromatase
inhibitors and luteinizing hormone-releasing hormone analogs and
inhibitors has been relatively effective in treating prostate and
breast cancers. Radiation and the related techniques of conformal
proton beam radiation therapy, stereotactic radiosurgery,
stereotactic radiation therapy, intraoperative radiation therapy,
chemical modifiers, and radio sensitizers are effective at
selectively killing cancerous cells, but can also kill and alter
surrounding normal tissue. Chemotherapy drugs such as aminopterin,
cisplatin, methotrexate, doxorubicin, daunorubicin and others alone
and in combinations are effective at selectively killing cancer
cells, often by altering the DNA replication process. Biological
response modifier (BRM) therapy, biologic therapy, biotherapy, or
immunotherapy alter cancer cell growth or influence the natural
immune response, and involve administering biologic agents to a
patient such as an interferons, interleukins, and other cytokines
and antibodies such as rituximab and trastuzumab and even cancer
vaccines such as Sipuleucel-T.
[0005] Recently, new targeted therapies have been developed to
fight cancer. These targeted therapies differ from chemotherapy
because chemotherapy works by killing both cancerous and normal
cells, with greater effects on the cancerous cells. Targeted
therapies work by influencing the processes that control growth,
division, and the spread of cancer cells and signals that cause
cancer cells to die naturally. One type of targeted therapy
includes growth signal inhibitors such as trastuzumab, gefitinib,
imatinib, centuximab, dasatinib and nilotinib. Another type of
targeted therapy includes angiogenesis inhibitors such as
bevacizumab that inhibit cancers from increasing surrounding
vasculature and blood supply. A final type of targeted therapy
includes apoptosis-inducing drugs that are able to induce direct
cancer cell death.
[0006] Although all of these treatments have been effective to one
degree or another, they all have drawbacks and limitations. In
addition to many of the treatments being expensive, they also are
often too imprecise or the cancers are able to adapt to them and
become resistant.
[0007] Thus, there is a great need for additional cancer
treatments. In particular, there is a need for treatments for
cancers that have become resistant to other forms of treatment.
SUMMARY
[0008] The present invention provides compositions, kits, and
methods for reducing undue cellular proliferation, including that
associated with the treatment of cancer. In certain embodiments,
the invention provides pharmaceutical compositions comprising at
least one tyrosine hydroxylase inhibitor, at least one melanin
promoter, at least one p450 3A4 promoter, at least one leucine
aminopeptidase inhibitor, and, optionally, at least one growth
hormone inhibitor. In other embodiments, the invention provides
kits that comprise these components together with suitable
packaging. Also provided are methods of reducing cellular
proliferation and/or methods of treating cancer comprising
administering an effective amount of at least one tyrosine
hydroxylase inhibitor, at least one melanin promoter, at least one
p450 3A4 promoter, at least one leucine aminopeptidase inhibitor,
and, optionally, at least one growth hormone inhibitor to the
subject in need thereof.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0009] The present subject matter may be understood more readily by
reference to the following detailed description which forms a part
of this disclosure. It is to be understood that this invention is
not limited to the specific products, methods, conditions or
parameters described and/or shown herein, and that the terminology
used herein is for the purpose of describing particular embodiments
by way of example only and is not intended to be limiting of the
claimed invention.
[0010] Unless otherwise defined herein, scientific and technical
terms used in connection with the present application shall have
the meanings that are commonly understood by those of ordinary
skill in the art. Further, unless otherwise required by context,
singular terms shall include pluralities and plural terms shall
include the singular.
[0011] As employed above and throughout the disclosure, the
following terms and abbreviations, unless otherwise indicated,
shall be understood to have the following meanings.
[0012] In the present disclosure the singular forms "a," "an," and
"the" include the plural reference, and reference to a particular
numerical value includes at least that particular value, unless the
context clearly indicates otherwise. Thus, for example, a reference
to "a compound" is a reference to one or more of such compounds and
equivalents thereof known to those skilled in the art, and so
forth. The term "plurality", as used herein, means more than one.
When a range of values is expressed, another embodiment includes
from the one particular and/or to the other particular value.
Similarly, when values are expressed as approximations, by use of
the antecedent "about," it is understood that the particular value
forms another embodiment. All ranges are inclusive and
combinable.
[0013] As used herein, the terms "component," "composition,"
"composition of compounds," "compound," "drug," "pharmacologically
active agent," "active agent," "therapeutic," "therapy,"
"treatment," or "medicament" are used interchangeably herein to
refer to a compound or compounds or composition of matter which,
when administered to a subject (human or animal) induces a desired
pharmacological and/or physiologic effect by local and/or systemic
action.
[0014] As used herein, the terms "treatment" or "therapy" (as well
as different forms thereof) includes preventative (e.g.,
prophylactic), curative or palliative treatment. As used herein,
the term "treating" includes alleviating or reducing at least one
adverse or negative effect or symptom of a condition, disease or
disorder. This condition, disease or disorder can be cancer.
[0015] As employed above and throughout the disclosure the term
"effective amount" refers to an amount effective, at dosages, and
for periods of time necessary, to achieve the desired result with
respect to the treatment of the relevant disorder, condition, or
side effect. It will be appreciated that the effective amount of
components of the present invention will vary from patient to
patient not only with the particular compound, component or
composition selected, the route of administration, and the ability
of the components to elicit a desired result in the individual, but
also with factors such as the disease state or severity of the
condition to be alleviated, hormone levels, age, sex, weight of the
individual, the state of being of the patient, and the severity of
the pathological condition being treated, concurrent medication or
special diets then being followed by the particular patient, and
other factors which those skilled in the art will recognize, with
the appropriate dosage being at the discretion of the attending
physician. Dosage regimes may be adjusted to provide the improved
therapeutic response. An effective amount is also one in which any
toxic or detrimental effects of the components are outweighed by
the therapeutically beneficial effects.
[0016] "Pharmaceutically acceptable" refers to those compounds,
materials, compositions, and/or dosage forms which are, within the
scope of sound medical judgment, suitable for contact with the
tissues of human beings and animals without excessive toxicity,
irritation, allergic response, or other problem complications
commensurate with a reasonable benefit/risk ratio.
[0017] Within the present invention, the disclosed compounds may be
prepared in the form of pharmaceutically acceptable salts.
"Pharmaceutically acceptable salts" refer to derivatives of the
disclosed compounds wherein the parent compound is modified by
making acid or base salts thereof. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or
organic acid salts of basic residues such as amines; alkali or
organic salts of acidic residues such as carboxylic acids; and the
like. The pharmaceutically acceptable salts include the
conventional non-toxic salts or the quaternary ammonium salts of
the parent compound formed, for example, from non-toxic inorganic
or organic acids. For example, such conventional non-toxic salts
include those derived from inorganic acids such as hydrochloric,
hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like;
and the salts prepared from organic acids such as acetic,
propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isethionic, and the like. These physiologically acceptable
salts are prepared by methods known in the art, e.g., by dissolving
the free amine bases with an excess of the acid in aqueous alcohol,
or neutralizing a free carboxylic acid with an alkali metal base
such as a hydroxide, or with an amine.
[0018] Compounds described herein can be prepared in alternate
forms. For example, many amino-containing compounds can be used or
prepared as an acid addition salt. Often such salts improve
isolation and handling properties of the compound. For example,
depending on the reagents, reaction conditions and the like,
compounds as described herein can be used or prepared, for example,
as their hydrochloride or tosylate salts. Isomorphic crystalline
forms, all chiral and racemic forms, N-oxide, hydrates, solvates,
and acid salt hydrates, are also contemplated to be within the
scope of the present invention.
[0019] Certain acidic or basic compounds of the present invention
may exist as zwitterions. All forms of the compounds, including
free acid, free base and zwitterions, are contemplated to be within
the scope of the present invention. It is well known in the art
that compounds containing both amino and carboxy groups often exist
in equilibrium with their zwitterionic forms. Thus, any of the
compounds described herein that contain, for example, both amino
and carboxy groups, also include reference to their corresponding
zwitterions.
[0020] The term "stereoisomers" refers to compounds that have
identical chemical constitution, but differ as regards the
arrangement of the atoms or groups in space.
[0021] The term "administering" means either directly administering
a compound or composition of the present invention, or
administering a prodrug, derivative or analog which will form an
equivalent amount of the active compound or substance within the
body.
[0022] The terms "subject," "individual," and "patient" are used
interchangeably herein, and refer to an animal, for example a
human, to whom treatment, including prophylactic treatment, with
the pharmaceutical composition according to the present invention,
is provided. The term "subject" as used herein refers to human and
non-human animals. The terms "non-human animals" and "non-human
mammals" are used interchangeably herein and include all
vertebrates, e.g., mammals, such as non-human primates,
(particularly higher primates), sheep, dog, rodent, (e.g. mouse or
rat), guinea pig, goat, pig, cat, rabbits, cows, horses and
non-mammals such as reptiles, amphibians, chickens, and
turkeys.
[0023] The term "inhibitor" as used herein includes compounds that
inhibit the expression or activity of a protein, polypeptide or
enzyme and does not necessarily mean complete inhibition of
expression and/or activity. Rather, the inhibition includes
inhibition of the expression and/or activity of a protein,
polypeptide or enzyme to an extent, and for a time, sufficient to
produce the desired effect.
[0024] The term "promoter" as used herein includes compounds that
promote the expression or activity of a protein, polypeptide or
enzyme and does not necessarily mean complete promotion of
expression and/or activity. Rather, the promotion includes
promotion of the expression and/or activity of a protein,
polypeptide or enzyme to an extent, and for a time, sufficient to
produce the desired effect.
[0025] In one embodiment, the present invention provides
combination therapies that alter the defenses of cancerous cells to
oxidative stress. One class of such therapies increases free
radical availability to cancerous cells. A representative subclass
of such therapies involve administration of pharmaceutical
compositions comprising a tyrosine hydroxylase inhibitor, a melanin
promoter, a p450 3A4 promoter, a leucine aminopeptidase inhibitor,
and, optionally, a growth hormone inhibitor. Particular components
of the pharmaceutical composition are described below.
[0026] While not intending to be bound by any particular mechanism
of operation, tyrosine hydroxylase inhibitors according to the
present invention function by accumulating in cancer cells and
preventing them from forming a coating of either lipids or
hyaluronan. By preventing the cancer cells from forming a coating
of either lipids or hyaluron, the cancer cells are believed to be
made more accessible to oxidative stress. Representative tyrosine
hydroxylase inhibitors include tyrosine derivatives, which
typically are rapidly absorbed by most cancers and inflamed
tissues. Representative tyrosine derivatives include one or more of
methyl (2R)-2-amino-3-(2-chloro-4-hydroxyphenyl) propanoate,
D-tyrosine ethyl ester hydrochloride, methyl
(2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate
H-D-Tyr(TBU)-allyl ester HCl, methyl
(2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl
(2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate,
methyl (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl) methoxy]phenyl)
propanoate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl)
propanoate, methyl
(2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate,
diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzyl
malonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)
propanoate, methyl
(2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propanoate,
methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl)
propanoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)
propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl,
H-D-3,5-diiodo-tyr-OME HCl, H-D-tyr-OME HCl, D-tyrosine methyl
ester hydrochloride, D-tyrosine-ome HCl, methyl D-tyrosinate
hydrochloride, H-D-tyr-OMe.HCl, D-tyrosine methyl ester HCl,
H-D-Tyr-OMe-HCl, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid,
(2R)-2-amino-3-(4-hydroxyphenyl) methyl ester hydrochloride, methyl
(2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl
(2R)-2-azanyl-3-(4-hydroxyphenyl) propanoate hydrochloride,
3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl
ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr
(3,5-I.sub.2)--OSu, Fmoc-tyr(3-NO.sub.2)--OH, and
.alpha.-methyl-DL-tyrosine.
[0027] Melanin promoters according to the present invention are
chemical compounds that increase the production and/or the activity
of melanin. Increased melanin levels are believed to reduce
inflammation (through, for example, suppression of TNF) and exclude
the sequestered lymph system. Melanin also is a photo catalyst, and
can therefore promote chemical reactions that generate free
radicals which, in turn, can become accessible to cancer cells.
Representative melanin promoters are methoxsalen and melanotan
II.
[0028] The pharmaceutical compositions of the invention also
include a p450 3A4 promoter. "Cytochrome p450 3A4" (which can be
abbreviated as "p450 3A4") is a member of the cytochrome p450
superfamily of enzymes, and is a mixed-function oxidase that is
involved in the metabolism of xenobiotics in the body. It has the
widest range of substrates of all of the cytochromes. The function
of a p450 3A4 promoter in the pharmaceutical compositions of the
invention is to increase the expression and/or the activity of p450
3A4. The increased p450 3A4 expression and/or activity is believed
to reduce cortisone and estrogen levels in the patient.
Additionally, the increased p450 3A4 expression and/or activity
also slightly increases blood pH, which is believed to help to
preserve or enhance melanin activity. Representative p450 3A4
promoters are 5,5-diphenylhydantoin, valproic acid, and
carbamazepine, which are believed to induce expression of the p450
3A4 enzyme.
[0029] The instant pharmaceutical compositions further include
leucine aminopeptidase inhibitors (alternatively known as leucyl
aminopeptidase inhibitors). Leucine aminopeptidases are enzymes
that preferentially catalyze the hydrolysis of leucine residues at
the N-terminus of peptides and/or proteins. Inhibiting the
expression and/or activity of leucine aminopeptidases is believed
to assist in tumor reabsorption by increasing cholesterol transport
to the liver. Generally, it is believed that aminopeptidase
inhibitors, including aminopeptidase inhibitors, deplete sensitive
tumor cells of specific amino acids by preventing protein
recycling, thus generating an antiproliferative effect.
Representative leucine aminopeptidase inhibitors are
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine, and
rapamycin.
[0030] The suitable instant pharmaceutical compositions also
optionally includes a growth hormone inhibitor. Growth hormone
(such as, for example, pancreatic growth hormone) induces cell
replication. Inhibition of the expression and/or activity of growth
hormone is believed to exclude normal cells from rapid replication
while allowing cancer cells to continue to rapidly replicate and
incorporate the tyrosine derivative. Representative growth hormone
inhibitors are octreotide, somatostatin, and seglitide.
[0031] The pharmaceutical compositions of the invention can further
include D-leucine. D-leucine is a stereoisomer of the naturally
occurring L-leucine, the form of leucine incorporated into
polypeptides and proteins. D-leucine cannot be incorporated into
polypeptides and/or proteins. Along with the leucine aminopeptidase
inhibitor, the D-leucine is believed to create a physiological
environment that mimics a leucine shortage. Thus, the presence of
D-leucine permits the use of lower doses of leucine aminopeptidase
inhibitor in a pharmaceutical composition.
[0032] Also provided herein are kits including a combination
therapy that creates alterations in the defenses of cancerous cells
to oxidative stress. An intended suitable embodiment is a kit that
includes a combination therapy that increases free radical
availability to cancerous cells. Representative kits comprise a
tyrosine hydroxylase inhibitor, a melanin promoter, a p450 3A4
promoter, a leucine aminopeptidase inhibitor and, optionally, a
growth hormone inhibitor of the type described above, together with
packaging for same. The kit can include one or more separate
containers, dividers or compartments and, optionally, informational
material such as instructions for administration. For example, each
inhibitor or promoter (or the various combinations thereof) can be
contained in a bottle, vial, or syringe, and the informational
material can be contained in a plastic sleeve or packet or provided
in a label. In some embodiments, the kit includes a plurality
(e.g., a pack) of individual containers, each containing one or
more unit dosage forms of a compound described herein. For example,
the kit can include a plurality of syringes, ampules, foil packets,
or blister packs, each containing a single unit dose of a compound
described herein or any of the various combinations thereof. The
containers of the kits can be air tight, waterproof (e.g.,
impermeable to changes in moisture or evaporation), and/or
light-tight. The kit optionally includes a device suitable for
administration of the composition, e.g., a syringe, inhalant,
pipette, forceps, measured spoon, dropper (e.g., eye dropper), swab
(e.g., a cotton swab or wooden swab), or any such delivery
device.
[0033] Methods of treating cancer in a subject also are provided,
as are methods of reducing undue cellular proliferation. Such
methods can include administering an effective amount of a
combination therapy that creates alterations in the defenses of
cancerous cells to oxidative stress. Representative methods of
treating cancer include administering an effective amount of a
combination therapy that increases free radical availability to
cancerous cells. Suitable embodiments are methods that include
administering an effective amount of the above-noted tyrosine
hydroxylase inhibitor, melanin promoter, p450 3A4 promoter, leucine
aminopeptidase inhibitor and, optionally, growth hormone
inhibitor.
[0034] Suitable methods include simultaneous or at least
contemporaneous administration of at least two of the tyrosine
hydroxylase inhibitor, melanin promoter, p450 3A4 promoter, and
leucine aminopeptidase inhibitor, at least three of them, or each
of them (in each case, optionally, with a growth hormone
inhibitor). It is believed to be desirable that an effective
concentration of these moieties be in the subject's bloodstream at
the same time, and any dosing regimen that achieves this is within
the scope of the present invention. The desired number of
inhibitors and promoters can be provided in a single dosage form or
any number of desired dosage forms, including in individual dosage
forms. Representative dosage forms include tablets, capsules,
caplets, sterile aqueous or organic solutions, and colloidal
suspensions. The amount of composition administered will, of
course, be dependent on the subject being treated, the subject's
weight, the severity of the condition being treated, the manner of
administration, and the judgment of the prescribing physician.
[0035] Administration of the promoters and inhibitors can be
through various routes, including orally, subcutaneously,
intravenously, transdermally, vaginally, rectally or in any
combination thereof. Transdermal administration can be effected
using, for example, oleic acid, 1-methyl-2-pyrrolidone, or
dodecylnonaoxyethylene glycol monoether.
[0036] The promoters and inhibitors can be administered during a
cycle consisting of five to seven days of administering the
promoters and inhibitors and one to two days of not administering
the promoters and inhibitors. The promoters and inhibitors can be
administered over the course of at least six of said cycles.
[0037] The subject to which the instant compositions are
administered can be a mammal, preferably a human.
[0038] In one representative method, 60 mg of the tyrosine
derivative is administered orally and 0.25 mL of a 2 mg/mL
suspension of the tyrosine derivative is administered
subcutaneously; 10 mg of the methoxsalen is administered orally and
0.25 mL of a 1 mg/mL suspension of the methoxsalen is administered
subcutaneously; 30 mg of the 5,5-diphenylhydantoin is administered
orally; and 20 mg of the
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine is
administered orally.
[0039] Representative methods include those in which the cancer is
non-small cell lung cancer. In certain embodiments, the non-small
cell lung cancer is stage IV non-small cell lung cancer. In yet
other embodiments, the cancer is ovarian cancer, breast cancer,
cervical cancer, pancreatic cancer, stomach cancer, brain cancer,
liver cancer, or testicular cancer. The cancer can also be leukemia
or lymphoma.
[0040] In certain embodiments, one or more of the tyrosine
hydroxylase inhibitor; the melanin promoter; the p450 3A4 promoter;
and the leucine aminopeptidase inhibitor is a nucleic acid,
protein, antibody or antigen-binding fragment of an antibody.
[0041] The present methods can include not only the disclosed
administration step but also the step of assessing progression of
said cancer in said subject and/or the extent of cellular
proliferation. The assessing step can be performed before or after
the administering step.
[0042] Suitable embodiments can include a pharmaceutical
composition comprising a tyrosine hydroxylase inhibitor, a melanin
promoter, a p450 3A4 promoter, and a leucine aminopeptidase
inhibitor. The pharmaceutical composition can further comprise a
growth hormone inhibitor. The growth hormone can be pancreatic
growth hormone. The growth hormone inhibitor can be octreotide or
somatostatin. The tyrosine hydroxylase inhibitor can be a tyrosine
derivative. The tyrosine derivative can be one or more of methyl
(2R)-2-amino-3-(2-chloro-4 hydroxyphenyl) propanoate, D-tyrosine
ethyl ester hydrochloride, methyl
(2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate
H-D-Tyr(TBU)-allyl ester HCl, methyl
(2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl
(2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate,
methyl (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl) methoxy]phenyl)
propanoate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl)
propanoate, methyl
(2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate,
diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzyl
malonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)
propanoate, methyl
(2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propanoate,
methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl)
propanoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)
propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl,
H-D-3,5-diiodo-tyr-OME HCl, H-D-tyr-OME HCl, D-tyrosine methyl
ester hydrochloride, D-tyrosine-ome HCl, methyl D-tyrosinate
hydrochloride, H-D-tyr-OMe.HCl, D-tyrosine methyl ester HCl,
H-D-Tyr-OMe-HCl, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid,
(2R)-2-amino-3-(4-hydroxyphenyl) methyl ester hydrochloride, methyl
(2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl
(2R)-2-azanyl-3-(4-hydroxyphenyl) propanoate hydrochloride,
3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl
ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr
(3,5-I.sub.2)--OSu, Fmoc-tyr(3-NO.sub.2)--OH, and
.alpha.-methyl-DL-tyrosine. The melanin promoter can be methoxsalen
or melanotan II. The p450 3A4 promoter can be
5,5-diphenylhydantoin. The p450 3A4 promoter can be valproic acid
or carbamazepine. The leucine aminopeptidase inhibitor can be
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine or
rapamycin. The pharmaceutical compositions of the invention can
further comprise D-leucine.
[0043] Also provided herein are kits comprising a tyrosine
hydroxylase inhibitor, a melanin promoter, a p450 3A4 promoter, and
a leucine aminopeptidase inhibitor, together with packaging for
same. The kit can further comprise a growth hormone inhibitor. The
growth hormone can be pancreatic growth hormone. The growth hormone
inhibitor can be octreotide or somatostatin. The tyrosine
hydroxylase inhibitor can be a tyrosine derivative. The tyrosine
derivative can be one or more of methyl (2R)-2-amino-3-(2-chloro-4
hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride,
methyl (2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate
H-D-Tyr(TBU)-allyl ester HCl, methyl
(2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl
(2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate,
methyl (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl) methoxy]phenyl)
propanoate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl)
propanoate, methyl
(2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate,
diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzyl
malonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)
propanoate, methyl
(2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propanoate,
methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl)
propanoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)
propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl,
H-D-3,5-diiodo-tyr-OME HCl, H-D-tyr-OME HCl, D-tyrosine methyl
ester hydrochloride, D-tyrosine-ome HCl, methyl D-tyrosinate
hydrochloride, H-D-tyr-OMe.HCl, D-tyrosine methyl ester HCl,
H-D-Tyr-OMe-HCl, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid,
(2R)-2-amino-3-(4-hydroxyphenyl) methyl ester hydrochloride, methyl
(2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride methyl
(2R)-2-azanyl-3-(4-hydroxyphenyl) propanoate hydrochloride,
3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl
ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr
(3,5-I.sub.2)--OSu, Fmoc-tyr(3-NO.sub.2)--OH, and
.alpha.-methyl-DL-tyrosine. The melanin promoter can be methoxsalen
or melanotan II. The p450 3A4 promoter can be
5,5-diphenylhydantoin, valproic acid or carbamazepine. The leucine
aminopeptidase inhibitor can be
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine or
rapamycin. The kits of the invention can further comprise
D-leucine.
[0044] Methods of treating cancer in a subject are also provided
comprising administering an effective amount of a tyrosine
hydroxylase inhibitor, a melanin promoter, a p450 3A4 promoter, and
a leucine aminopeptidase inhibitor to the subject in need thereof.
In a suitable embodiment, the method of treating cancer can further
comprise a growth hormone inhibitor. In certain embodiments, at
least two of the promoters and inhibitors are administered
simultaneously. In other embodiments, at least three of the
promoters and inhibitors are administered simultaneously. Each of
the promoters and inhibitors can be administered simultaneously. In
suitable embodiments, the promoters and inhibitors are administered
orally, subcutaneously, intravenously, transdermally, vaginally,
rectally or in any combination thereof. The transdermal
administration can be done with oleic acid, 1-methyl-2-pyrrolidone,
or dodecylnonaoxyethylene glycol monoether. In other embodiments,
the promoters and inhibitors are administered during a cycle
consisting of five to seven days of administering the promoters and
inhibitors and one to two days of not administering the promoters
and inhibitors. The promoters and inhibitors can be administered
over the course of at least six of said cycles. The tyrosine
hydroxylase inhibitor can be a tyrosine derivative. The tyrosine
derivative can be one or more of methyl (2R)-2-amino-3-(2-chloro-4
hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride,
methyl (2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate
H-D-Tyr(TBU)-allyl ester HCl, methyl
(2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl
(2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate,
methyl (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl) methoxy]phenyl)
propanoate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl)
propanoate, methyl
(2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate,
diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzyl
malonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)
propanoate, methyl
(2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propanoate,
methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl)
propanoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)
propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl,
H-D-3,5-diiodo-tyr-OME HCl, H-D-tyr-OME HCl, D-tyrosine methyl
ester hydrochloride, D-tyrosine-ome HCl, methyl D-tyrosinate
hydrochloride, H-D-tyr-OMe.HCl, D-tyrosine methyl ester HCl,
H-D-Tyr-OMe-HCl, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid,
(2R)-2-amino-3-(4-hydroxyphenyl) methyl ester hydrochloride, methyl
(2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl
(2R)-2-azanyl-3-(4-hydroxyphenyl) propanoate hydrochloride,
3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl
ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr
(3,5-I.sub.2)--OSu, Fmoc-tyr(3-NO.sub.2)--OH, and
.alpha.-methyl-DL-tyrosine. In a suitable embodiment of the method,
60 mg of the tyrosine derivative is administered orally and 0.25 mL
of a 2 mg/mL suspension of the tyrosine derivative is administered
subcutaneously. The melanin promoter can be methoxsalen. In another
suitable method, 10 mg of the methoxsalen is administered orally
and 0.25 mL of a 1 mg/mL suspension of the methoxsalen is
administered subcutaneously. The melanin promoter can also be
melanotan II. The p450 3A4 promoter can be 5,5-diphenylhydantoin.
In another suitable method, 30 mg of the 5,5-diphenylhydantoin is
administered orally. The p450 3A4 promoter can also be valproic
acid or carbamazepine. The leucine aminopeptidase inhibitor can be
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine. In another
suitable method, 20 mg of the
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine is
administered orally. The leucine aminopeptidase inhibitor can also
be rapamycin. The growth hormone can be pancreatic growth hormone.
The growth hormone inhibitor can be octreotide. The method can
further comprise administering an effective amount of D-leucine.
The subject can be a mammal and that mammal can be a human.
Representative methods include those in which the cancer is
non-small cell lung cancer. In certain embodiments, the non-small
cell lung cancer is stage IV non-small cell lung cancer. In other
embodiments, the cancer is ovarian cancer, breast cancer, cervical
cancer, pancreatic cancer, stomach cancer, brain cancer, liver
cancer, or testicular cancer. In other embodiments, the cancer is
leukemia or lymphoma. In other suitable embodiments, the tyrosine
hydroxylase inhibitor, the melanin promoter, the p450 3A4 promoter,
and the leucine aminopeptidase inhibitor is one or more of a
nucleic acid, protein, antibody or antigen-binding fragment of an
antibody. Another suitable embodiment further comprises assessing
progression of said cancer in said subject. The assessing step can
be performed before said administering step or the assessing step
can be performed after said administering step.
[0045] Methods of reducing cell proliferation in a subject are also
provided comprising administering an effective amount of a tyrosine
hydroxylase inhibitor; a melanin promoter; a p450 3A4 promoter; and
a leucine aminopeptidase inhibitor to the subject in need thereof.
In a suitable embodiment, the method of treating cancer can further
comprise a growth hormone inhibitor. In certain embodiments, at
least two of the promoters and inhibitors are administered
simultaneously. In other embodiments, at least three of the
promoters and inhibitors are administered simultaneously. Each of
the promoters and inhibitors can be administered simultaneously. In
suitable embodiments, promoters and inhibitors are administered
orally, subcutaneously, intravenously, transdermally, vaginally,
rectally or in any combination thereof. The transdermal
administration can be done with oleic acid, 1-methyl-2-pyrrolidone,
or dodecylnonaoxyethylene glycol monoether. In other embodiments,
the promoters and inhibitors are administered during a cycle
consisting of five to seven days of administering the promoters and
inhibitors and one to two days of not administering the promoters
and inhibitors. The promoters and inhibitors can be administered
over the course of at least six of said cycles. The tyrosine
hydroxylase inhibitor can be a tyrosine derivative. The tyrosine
derivative can be one or more of methyl (2R)-2-amino-3-(2-chloro-4
hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride,
methyl (2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate
H-D-Tyr(TBU)-allyl ester HCl, methyl
(2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl
(2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate,
methyl (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl) methoxy]phenyl)
propanoate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl)
propanoate, methyl
(2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate,
diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzyl
malonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)
propanoate, methyl
(2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propanoate,
methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl)
propanoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)
propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl,
H-D-3,5-diiodo-tyr-OME HCl, H-D-tyr-OME HCl, D-tyrosine methyl
ester hydrochloride, D-tyrosine-ome HCl, methyl D-tyrosinate
hydrochloride, H-D-tyr-OMe.HCl, D-tyrosine methyl ester HCl,
H-D-Tyr-OMe-HCl, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid,
(2R)-2-amino-3-(4-hydroxyphenyl) methyl ester hydrochloride, methyl
(2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl
(2R)-2-azanyl-3-(4-hydroxyphenyl) propanoate hydrochloride,
3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl
ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr
(3,5-I.sub.2)--OSu, Fmoc-tyr(3-NO.sub.2)--OH, and
.alpha.-methyl-DL-tyrosine. In a suitable embodiment of the method,
60 mg of the tyrosine derivative is administered orally and 0.25 mL
of a 2 mg/mL suspension of the tyrosine derivative is administered
subcutaneously. The melanin promoter can be methoxsalen. In another
suitable method, 10 mg of the methoxsalen is administered orally
and 0.25 mL of a 1 mg/mL suspension of the methoxsalen is
administered subcutaneously. The melanin promoter can also be
melanotan II. The p450 3A4 promoter can be 5,5-diphenylhydantoin.
In another suitable method, 30 mg of the 5,5-diphenylhydantoin is
administered orally. The p450 3A4 promoter can also be valproic
acid or carbamazepine. The leucine aminopeptidase inhibitor can be
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine. In another
suitable method, 20 mg of the
N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine is
administered orally. The leucine aminopeptidase inhibitor can also
be rapamycin. The growth hormone can be pancreatic growth hormone.
The growth hormone inhibitor can be octreotide. The method can
further comprise administering an effective amount of D-leucine.
The subject can be a mammal and the mammal can be a human.
Representative methods include those in which the cancer is
non-small cell lung cancer. In certain embodiments, the non-small
cell lung cancer is stage IV non-small cell lung cancer. In other
embodiments, the cancer is ovarian cancer, breast cancer, cervical
cancer, pancreatic cancer, stomach cancer, brain cancer, liver
cancer, or testicular cancer. In other embodiments, the cancer is
leukemia or lymphoma. In other suitable embodiments, the tyrosine
hydroxylase inhibitor, the melanin promoter, the p450 3A4 promoter,
and the leucine aminopeptidase inhibitor is one or more of a
nucleic acid, protein, antibody or antigen-binding fragment of an
antibody. Another suitable embodiment further comprises assessing
progression of said cancer in said subject. The assessing step can
be performed before said administering step or the assessing step
can be performed after said administering step.
* * * * *