WO2011143590A1

WO2011143590A1 - Combination therapy compositions and methods using lipoic acid derivatives and an anti-proliferation agent

Info

Publication number: WO2011143590A1
Application number: PCT/US2011/036488
Authority: WO
Inventors: Robert J. Rodriguez; Robert G.L. Shorr
Original assignee: Cornerstone Pharmaceuticals, Inc.
Priority date: 2010-05-14
Filing date: 2011-05-13
Publication date: 2011-11-17

Abstract

The invention provides combination therapy compositions, therapeutic methods, and kits for use in treating cell proliferation disorders, such as cancer. The combination therapy involves administering a redox-modulating compound, such as a lipoic acid derivative, in combination with an anti-proliferation agent, such as gemcitabine

Description

COMBINATION THERAPY COMPOSITIONS AND METHODS USING LIPOIC ACID DERIVATIVES AND AN ANTI-PROLIFERATION AGENT

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 61/344,055, filed May 14, 2010, the contents of which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The invention provides combination therapy compositions, therapeutic methods, and kits for use in treating cell proliferation disorders, such as cancer. The combination therapy involves administering a redox-modulating compound in combination with an anti- proliferation agent, such as gemcitabine.

BACKGROUND

[0003] Cancer is a leading cause of death in many industrialized countries. Recent estimates are that 10 million Americans are currently living with cancer, and that 1.2 million Americans are newly diagnosed with cancer each year. Significant advances have been made in improving the diagnosis and treatment of cancer. However, current treatment options often suffer from severe adverse side effects and/or the treatments are not effective for all patients. For example, many clinically- accepted chemotherapeutic agents require the use of large doses of the chemotherapeutic agent that can induce profound damage to normal, proliferative host cells. Another problem associated with many chemotherapeutic treatments is that, in many tumor types, there is either inherent or acquired resistance to the therapy. In an attempt to address these and other shortcomings in current cancer therapy, researchers have investigated the mechanism of cancer cell origination and survival.

[0004] The published scientific literature does not describe a unifying theory for the origination of cancer cells. However, recent research has confirmed that cancer is a disease arising from a patient's own cells and tissue. It is also known that an individual patient may possess multiple tumor cell types, which may not be the same across patients with the same diagnosis or even in the same patient (with disease progression being a further

compounding factor).

[0005] Further, it has been observed that the vast majority of fast-growth tumor cells exhibit profound genetic, biochemical, and histological differences with respect to nontransformed cells, including a markedly-modified energy metabolism in comparison to the tissue of origin. The most notorious and well-known energy metabolism alteration in tumor cells is an increased glycolytic capacity even in the presence of a high 0₂ concentration, a phenomenon known as the Warburg effect. Consequently, glycolysis is generally believed to be the main energy pathway in solid tumors.

[0006] Transition to Warburg metabolism requires shutting down the pyruvate dehydrogenase (PDH) complex because PDH complex activity controls metabolic and malignant phenotype in cancer cells. See, J. Biol. Chem. 283: 22700-8. In this transition, there is enhanced signaling by hypoxia-inducing factor (HIF) in cancer cells, which in turn induces the overexpression of pyruvate dehydrogenase kinase (PDK) 1, which is particularly effective in maintaining an inactive PDH complex. However, alterations in

PDKl observed in cancer may be due to changes in its concentration and also to changes in its activity, and possibly in its amino acid sequence, even between one tumor type or one patient to another. Additionally, PDKl may form different complexes with various molecules associated with tumors, depending upon the tumor type presented. Recent studies suggest that forcing cancer cells into more aerobic metabolism suppresses tumor growth. Furthermore, PDH complex activation may lead to the enhanced production of reactive oxygen and nitrogen species (RONS), which may in turn lead to apoptosis. Thus, inhibition of PDK may be a potential target in generating apoptosis in tumors. However, to date, known PDKl inhibitors cause only about 60% inhibition of this isozyme.

[0007] Scientific reports have described a direct correlation between tumor progression and the activities of the glycolytic enzymes hexokinase and phosphofructokinase (PFK) 1, which are substantially increased in fast-growth tumor cells. Accordingly, it has been postulated that tumor cells that exhibit deficiencies in their oxidative capacity are more malignant than those that have an active oxidative phosphorylation. No matter whether under hypoxic or aerobic conditions, then, cancer tissue's reliance on glycolysis is associated with increased malignancy. [0008] Features of the mechanism of cancer cell origination and survival have influenced the design of cancer treatments. For example, because administration of two anti-cancer agents can have a favorable pharmacological interaction (e.g., same target but different toxicities), combination therapy using multiple therapeutic agents has been investigated. In particular, certain personalized cancer combination treatments take advantage of differing mechanistic features of the combination therapy, under which a cocktail of drugs that affect different molecular targets is directed against multiple tumor cell types. Such combination therapies are designed to prevent the emergence of treatment resistant disease and to achieve an additive or synergistic level of tumor cell kill, thereby ensuring treatment efficacy by maximizing the types, and therefore the amount, of tumor cells killed during a course of treatment.

[0009] However, despite the efforts devoted to developing combination therapies to treat cancer, a barrier to major advancements in anti-cancer combination therapy has been a lack of understanding about the intersection of critical cell signaling pathways. For example, synergy might be induced through the effect of multiple drugs either on the same signal pathway, on parallel pathways, or even on seemingly divergent pathways. Overall, because the number of drug combinations is potentially limitless, it remains difficult to identify a priori a strategy for determining the most effective anti-cancer therapeutic combinations.

[0010] Accordingly, the need exists for new therapeutic methods that provide improved efficacy and/or reduced side effects for treating cancer. The present invention addresses this need and provides other related advantages.

SUMMARY

[0011] The invention provides combination therapy compositions, therapeutic methods, and kits for use in treating cancer and other medical disorders. The combination therapy involves administering a redox-modulating compound, such as a lipoic acid derivative, in combination with an anti-proliferation agent, such as gemcitabine. The differing mechanisms of action for the redox-modulating compound compared to gemcitabine are contemplated to provide particular therapeutic advantages for patients suffering from cancer. Further, for example, the combination therapy is contemplated to provide particular advantages in treating patients suffering from a solid tumor, such as pancreatic cancer, breast cancer, or lung cancer. [0012] Accordingly, one aspect of the invention provides a method for treating cancer in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of (i) a redox-modulating compound comprising 6,8-bis-benzylthio- octanoic acid, and (ii) an anti-cancer agent selected from the group consisting of gemcitabine, a pharmaceutically acceptable salt of gemcitabine, cytarabine, and a pharmaceutically acceptable salt of cytarabine. The redox-modulating compound and anticancer agent are preferably administered to the patient in the form of a pharmaceutical composition. For example, the redox-modulating compound is preferably administered in the form of a pharmaceutical composition comprising 6,8-bis-benzylthio-octanoic acid and triethanolamine.

[0013] Another aspect of the invention provides a medical kit for treating cancer or other medical disorders using compositions described herein. For example, in certain

embodiments, the medical kit comprises (i) a redox-modulating compound comprising 6,8- bis-benzylthio-octanoic acid, and (ii) instructions for treating cancer using said redox- modulating compound in combination with an anti-cancer agent selected from the group consisting of gemcitabine, a pharmaceutically acceptable salt of gemcitabine, cytarabine, and a pharmaceutically acceptable salt of cytarabine.

[0014] Another aspect of the invention provides a pharmaceutical composition comprising one or more therapeutic agents described herein. For example, in certain embodiments, the invention provides a pharmaceutical composition comprising (i) a redox- modulating compound comprising 6,8-bis-benzylthio-octanoic acid, (ii) an anti-cancer agent selected from the group consisting of gemcitabine, a pharmaceutically acceptable salt of gemcitabine, cytarabine, and a pharmaceutically acceptable salt of cytarabine, and (iii) a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF FIGURES [0015] Figure 1 depicts graphs of data representing largest diameters derived from

Computed Tomography (CT) and Standardized Update Value (SUV) derived from Positron Emission Tomography (PET), of targeted lesions of a patient treated as described in Example 1. DETAILED DESCRIPTION

[0016] The invention provides combination therapy compositions, therapeutic methods, and kits for use in treating cancer and other medical disorders. The combination therapy involves administering a redox-modulating compound, such as a lipoic acid derivative, in combination with an anti-proliferation agent, such as gemcitabine. The differing mechanisms of action for the redox-modulating compound compared to gemcitabine are contemplated to provide particular advantages for treating patients suffering from cancer. Further, for example, the combination therapy is contemplated to provide particular advantages in treating patients suffering from a solid tumor, such as pancreatic cancer, breast cancer, or lung cancer.

[0017] The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, and biochemistry. Such techniques are explained in the literature, such as "Comprehensive Organic Synthesis" (B.M. Trost & I. Fleming, eds., 1991-1992); which is incorporated by reference. Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section.

I. DEFINITIONS

[0018] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[0019] The terms "a," "an" and "the" as used herein mean "one or more" and include the plural unless the context is inappropriate

[0020] The term "6,8-bis-benzylthio-octanoic acid" refers to the compound having the

chemical structure

[0021] The term "alkyl" is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., Q-C₃₀ for straight chain, C₃-C₃₀ for branched chain), and alternatively, about 20 or fewer. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.

[0022] The term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0023] The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group.

[0024] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0025] The term "alkylene" refers to a diradical of an alkyl group. An exemplary alkylene group is -CH₂CH₂-. The term "alkynylene" as used herein refers to an alkynyl diradical, such as -C≡C-. The term "alkenylene" as used herein refers to an alkenyl diradical, such as -CH=CH-.

[0026] The term "aryl" is art-recognized and refers to a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracenyl, and the like.

[0027] The "heteroaryl" is art-recognized and refers to aromatic groups that include at least one ring heteroatom. In certain instances, a heteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representative examples of heteroaryl groups includes pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like.

[0028] The terms "amine" and "amino" are art-recognized and refer to both

unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

wherein R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently represent a hydrogen, an alkyl, an alkenyl,

-(CH₂)_m-R⁶¹, or R⁵⁰ and R⁵¹, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R⁶¹ represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In certain embodiments, only one of R⁵⁰ or R⁵¹ may be a carbonyl, e.g., R⁵⁰, R⁵¹ and the nitrogen together do not form an imide. In other embodiments, R⁵⁰ and R 51 (and optionally R 52 ) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH₂)_m-R⁶¹. The symbol indicates a point of attachment.

[0029] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers,

(D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0030] As used herein, the term "patient" refers to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines (horses), bovines (cattle), porcines, canines, felines, and the like), and most preferably includes humans.

[0031] As used herein, the term "treating" includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. [0032] As used herein, the term "pharmaceutical composition" refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0033] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975].

[0034] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of skill in the art, "salts" of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,

ethanesulfonic, formic, benzoic, malonic, naphthalene-2- sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Examples of bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW₄ ⁺, wherein W is C_1-4 alkyl, and the like.

[0035] Further examples of salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate,

cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate,

phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Still other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na⁺, NH₄ ⁺, and NW₄ ⁺ (wherein W is a C_1-4 alkyl group), and the like.

[0036] In certain embodiments, the pharmaceutically acceptable salts are those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, palicylic, p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic, succinic, naphthalene-2- sulfonic, and benzene sulfonic. In certain other embodiments, the pharmaceutically acceptable salts are alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of a carboxylic acid group.

[0037] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0038] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0039] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

II. COMBINATION THERAPY COMPONENTS

[0040] The invention provides combination therapy using a redox-modulating compound in combination with an anti-proliferation agent. Exemplary redox-modulating compounds and exemplary anti-proliferation agents contemplated for use in the

combination therapy methods, medical kits, and pharmaceutical compositions are described below. A. Exemplary Redox-Modulating Compounds

[0041] The redox-modulating compound may be a naturally-occurring or synthetic redox-modulating compound, or an analog or derivative thereof. In certain embodiments, the redox-modulating compound is a naturally-occurring or synthetic alkyl fatty acid, such as octanoic acid, lipoic acid, or a derivative of a lipoic acid such as a compound disclosed in U.S. Patent Nos. 6,331,559 or 6,951,887, or U.S. Patent Application Nos. 12/105,096 or 12/105,100; the contents of each of which are hereby incorporated by reference.

[0042] In certain other embodiments, the redox-modulating compound is an alkyl fatty acid having the general formula:

or a derivative, congener, and salt thereof, wherein:

Ri and/or R₂ is aryl or aralkyl;

R₃ and/or R₄ is S, Se, O, N, aryl, or a metal;

P 5 is alkylene, alkenylene, or alkynylene, with a chain length of one to eighteen carbons;

R₆, is alkyl, alkenyl, alkynyl, aryl, -COOH, -OH, -COH, -NH₂OH, -CC1₃, -CF₃, -NH₂, an amino acid (such as glutamate), a carbohydrate, a nucleic acid, a lipid, and multimers thereof; and

wherein R_l5 R₂, R₅, and/or R₆ may be phosphorylated.

[0043] The alkyl fatty acid compound of Formula I may have asymmetric centers, and the R-isomer of a particular active compound may possess greater physiological activity than does the S-isomer. Consequently, all chiral, diastereomeric, and geometric isomeric forms of a compound embraced by Formula I are intended, unless the specific

stereochemistry or isomer form is specifically indicated, and the active compound should be present either solely in its R- or S-isomer form, in racemic mixtures, or various ratios of the R- and S-isomers. Additionally, where carbohydrates are co-formulated, both D and L isomers of the carbohydrates are embraced. Furthermore, to the extent a compound embraced by this general structure may be metabolized within the cell or mitochondrion to form a metabolite, such metabolites are embraced by the invention.

[0044] In certain embodiments, the redox-modulating compound is metabolized (i.e., a metabolite of unnaturally-occurring or synthetic alkyl fatty acid, such as octanoic acid, lipoic acid, or a derivative of a lipoic acid such as a compound disclosed in U.S. Patent Nos. 6,331,559 or 6,951,887, or U.S. Patent Application Nos. 12/105,096 or 12/105,100, or an alkyl fatty acid having the general formula I, described herein above.)

[0045] In embodiments where the redox-modulating compound has a stereo genie center, the redox-modulating compound may be provided as the R-isomer. In certain other embodiments, where the redox-modulating compound has a stereogenic center, the redox- modulating compound may be provided as the S-isomer. In certain other embodiments, where the redox-modulating compound has a stereogenic center, the redox-modulating compound may be provided as a racemic mixture of the R- and S-isomers.

[0046] In certain embodiments, the redox-modulating compound is conjugated to at least one solubility-enhancing polymer containing an activated linkage chemistry moiety. In certain embodiments, the solubility-enhancing polymer is polyethylene glycol. In certain embodiments, conjugation occurs at R_l5 R₂, and/or R₆ of general formula (I) of the redox- modulating alkyl fatty acid. In certain embodiments, conjugation occurs through an ionic bond, such as a salt. In certain embodiments, conjugation occurs through a hydrophobic interaction. In certain embodiments, conjugation occurs through a covalent bond. In certain embodiments, the covalent bond is reversible. In certain embodiments, the covalent bond is cleavable, such as an amide, ether, or ester linkage.

[0047] In certain other embodiments, the redox-modulating compound is lipoic acid.

Lipoic acid (6,8-dithiooctanoic acid) is a sulfur-containing antioxidant with metal-chelating and anti-glycation capabilities. Lipoic acid is the oxidized part of a redox pair, capable of being reduced to dihydrolipoic acid (DHLA). Unlike many antioxidants which are active only in either the lipid or the aqueous phase, lipoic acid is active in both lipid and aqueous phases. The anti-glycation capacity of lipoic acid combined with its capacity for hydrophobic binding enables lipoic acid to prevent glycosylation of albumin in the bloodstream. Lipoic acid is readily absorbed from the diet and is rapidly converted to DHLA by NADH or NADPH in most tissues. Additionally, both lipoic acid and DHLA are antioxidants capable of modulating intracellular signal transduction pathways which use RONS as signaling molecules.

[0048] It is uncertain whether lipoic acid is produced by cells or is an essential nutrient, as differences in intracellular concentration may exist between tissue types as well as between healthy and diseased cells or even between individuals within a species.

Mitochondrial pumps or uptake mechanisms, including binding and transport chaperones, may be important in transporting lipoic acid to mitochondria. It is already known that the expression levels and stoichiometry of the subunits comprising many of the lipoic acid- utilizing enzymes, which are linked to energy metabolism as well as growth, development and differentiation, vary with diet and exercise as well as genetics.

[0049] The role of lipoic acid as a cofactor in the PDH complex of healthy cells has been studied. The PDH complex has a central E2 (dihydrolipoyl transacetylase) subunit core surrounded by the El (pyruvate dehydrogenase) and E3 (dihydrolipoyl dehydrogenase) subunits to form the complex; the analogous alpha-ketoglutarate dehydrogenase (a-KDH) and branched chain alpha-keto acid dehydrogenase (BCAKDH) complexes also use lipoic acid as a cofactor. In the gap between the El and E3 subunits, the lipoyl domain ferries intermediates between the active sites. The lipoyl domain itself is attached by a flexible linker to the E2 core. Upon formation of a hemithioacetal by the reaction of pyruvate and thiamine pyrophosphate, this anion attacks the SI of an oxidized lipoate species that is attached to a lysine residue. Consequently, the lipoate S2 is displaced as a sulfide or sulfhydryl moiety, and subsequent collapse of the tetrahedral hemithioacetal ejects thiazole, releasing the TPP cofactor and generating a thioacetate on the SI of the lipoate. At this point, the lipoate-thioester functionality is translocated into the E2 active site, where a transacylation reaction transfers the acetyl from the "swinging arm" of lipoate to the thiol of coenzyme A. This produces acetyl-CoA, which is released from the enzyme complex and subsequently enters the TCA cycle. The dihydrolipoate, still bound to a lysine residue of the complex, then migrates to the E3 active site, where it undergoes a flavin-mediated oxidation back to its lipoate resting state, producing FAD¾ (and ultimately NADH) and regenerating the lipoate back into a competent acyl acceptor. [0050] Because lipoic acid is a cofactor of various dehydrogenase complexes which affect glycolysis, the TCA cycle, and branched-chain amino acid metabolism (e.g., the PDH, a-KDH, and BCAKDH complexes), it is expected that various lipoic acid derivatives may have the same effect in cancer cells.

[0051] In certain other embodiments, the redox-modulating compound comprises 6,8- bis-benzylthio-octanoic acid. In certain embodiments, redox-modulating compound is preferably administered in the form of a pharmaceutical composition comprising 6,8-bis- benzylthio-octanoic acid and triethanolamine. In certain embodiments, the mole ratio of triethanolamine to 6,8-bis-benzylthio-octanoic acid is in the range of about 10: 1 to about 1: 10, about 10: 1 to about 5: 1, or about 8: 1.

[0052] In certain embodiments, redox-modulating compound is an ion pair comprising 6,8-bis-benzylthio-octanoic acid and triethanolamine. In certain embodiments, the mole ratio of triethanolamine to 6,8-bis-benzylthio-octanoic acid in the ion pair is in the range of about 10: 1 to about 1: 10, about 10: 1 to about 5: 1, or about 8: 1.

B. Exemplary Anti-Proliferation Agents

[0053] The anti-proliferation agent may be any substance that inhibits cellular proliferation. Types of exemplary anti-proliferation agents include drugs, hormones, vitamins, nutrients, substances, and the like, that are useful in treatment of a disease, condition, syndrome, or symptoms thereof, characterized by cellular hyperproliferation, including cancer. The anti-proliferation agents may be uncharged or charged, nonpolar or polar, natural or synthetic, and thus include small molecule organic compounds, lipophilic polypeptides, cytotoxins, oligonucleotides, cytotoxic antineoplastic agents, antimicrotubule agents, antimetabolites, hormones, and radioactive molecules. The term "oligonucleotides" includes both antisense oligonucleotides and sense oligonucleotides (e.g., nucleic acids conventionally known as vectors). Oligonucleotides may be "natural" or "modified" with regard to subunits or bonds between subunits.

[0054] In certain embodiments, the anti-proliferation agent is an anti-cancer agent. In certain embodiments, the anti-cancer agent is selected from the group consisting of gemcitabine, a pharmaceutically acceptable salt of gemcitabine, cytarabine, and a pharmaceutically acceptable salt of cytarabine. [0055] Gemcitabine has the chemical name 2'-deoxy-2',2'-difluoro-cytidine, and has been described in U.S. Patent Nos. 4,808,614 and 5,464,826. Gemcitabine is commercially available as the monohydrochloride salt and as the β-isomer thereof. It is contemplated that a pharmaceutically acceptable salt of gemcitabine (e.g., a hydrochloride or hydrobromide salt) may be used in the pharmaceutical compositions and methods described herein. In certain embodiments, the pharmaceutical compositions or methods herein use gemcitabine hydrochloride.

[0056] The mechanism of action of gemcitabine is understood to be its replacement of cytidine during DNA replication, arresting tumor growth through the failure of attachment of new nucleosides which results in apoptosis, and in its irreversible inactivation of ribonucleotide reductase. The commercial formulation of gemcitabine hydrochloride is commonly used in patients previously treated with 5-fluorouracil and is indicated as first- line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine is also used in other carcinomas, including non-small cell lung cancer, pancreatic cancer, bladder cancer and breast cancer. It has been investigated for use in esophageal cancer, and is used

experimentally in lymphomas and other tumor types.

[0057] Gemcitabine is a hydrophilic compound and its uptake into cells is largely dependent on the activity of human equilibrative nucleoside transporters (hENTs) and human concentrative nucleoside transporters (hCNTs). While hENTs are capable of transporting pyrimidine and purine nucleosides both ways across the cell membrane and are widely distributed in most human cells, hCNTs only transport these substrates

unidirectionally into the cell and are mainly expressed in hepatic, renal, and intestinal cells. Gemcitabine is phosphorylated by deoxycytidine kinase and extensively and rapidly deaminated by cytidine deaminase in liver, kidney, and plasma to less cytotoxic

metabolites. Because of this rapid deamination, the elimination half-life of gemcitabine is often approximately 10-30 minutes.

[0058] Cytarabine has the chemical name 1-beta-D-arabinofuranosylcytosine, and has been described in U.S. Patent No. 3,116,282. It is contemplated that a pharmaceutically acceptable salt of cytarabine (e.g., a hydrochloride or hydrobromide salt) may be used in the pharmaceutical compositions and methods described herein. [0059] Cytarabine has been reported to interfere with DNA replication, both through steric hindrance caused by cytarabine's attached arabinose, which results in the inability of the molecule to rotate during DNA synthesis and through inhibition of DNA polymerase, which results in a decrease in DNA replication and repair. Cytarabine has been reported for use in the treatment of non-Hodgkin lymphoma and hematological malignancies such as acute myeloid leukemia and acute lymphocytic leukemia.

[0060] Cytarabine is a hydrophilic compound and its uptake into cells is largely dependent on the activity of human equilibrative nucleoside transporters (hENTs) and human concentrative nucleoside transporters (hCNTs). While hENTs are capable of transporting pyrimidine and purine nucleosides both ways across the cell membrane and are widely distributed in most human cells, hCNTs only transport these substrates

unidirectionally into the cell and are mainly expressed in hepatic, renal, and intestinal cells. Cytarabine is phosphorylated by deoxycytidine kinase and extensively and rapidly deaminated by cytidine deaminase in liver, kidney, and plasma to less cytotoxic

metabolites. Because of this rapid deamination, the elimination half-life of cytarabine is often approximately 10-30 minutes.

III. THERAPEUTIC APPLICATIONS OF THE COMBINATION THERAPY

[0061] The invention provides methods for treating medical disorders using a redox- modulating compound in combination with an anti-proliferation agent. The methods are contemplated to provide particular advantages in treating cancer. Various aspects of the therapeutic methods are described in detail below.

A. General Therapeutic Methods

[0062] The therapeutic methods described herein are particularly well-suited for treatment of diseases characterized by aberrant cellular metabolism, particularly cellular hyperproliferation, such as cancer. Exemplary types of cancer contemplated to be treated include a carcinoma, sarcoma, lymphoma, leukemia, germ cell tumor, and blastoma. Other types of cancer contemplated for treatment include a primary melanoma, metastatic melanoma, lung cancer (e.g., non- small cell lung cancer), liver cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, uterine cancer, cervical cancer, bladder cancer, kidney cancer, colon cancer, and adenocarcinomas such as breast cancer, prostate cancer, ovarian cancer, and pancreatic cancer. Further exemplary types of cancer include a benign tumor, malignant solid tumor, hematological malignancy, and cancer-causing stem cells, such as those exhibiting the altered energy metabolism known in the art as the Warburg effect. [0063] Non-limiting examples of other disorders characterized by cellular

hyperproliferation and contemplated for treatment include age-related macular

degeneration; Crohn's disease; cirrhosis; chronic inflammatory-related disorders; diabetic retinopathy; granulomatosis; immune hyperproliferation associated with organ or tissue transplantation; an immunoproliferative disease or disorder (e.g., inflammatory bowel disease, psoriasis, rheumatoid arthritis, or systemic lupus erythematosus); vascular hyperproliferation secondary to retinal hypoxia; and vasculitis.

[0064] Accordingly, one aspect of the invention provides a method for treating a disorder characterized by cellular hyperproliferation in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of (i) a redox-modulating compound described herein, and (ii) an anti-proliferation agent described herein.

[0065] In certain embodiments, the invention provides a method for treating cancer in a patient, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of (i) a redox-modulating compound comprising 6,8-bis- benzylthio-octanoic acid, and (ii) an anti-cancer agent selected from the group consisting of gemcitabine, a pharmaceutically acceptable salt of gemcitabine, cytarabine, and a pharmaceutically acceptable salt of cytarabine.

[0066] In certain embodiments, the cancer is a solid tumor or a hematological malignancy. In certain other embodiments the cancer is pancreatic cancer, lung cancer (e.g., non-small cell lung cancer), breast cancer, ovarian cancer, a primary melanoma, a metastatic melanoma, liver cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, uterine cancer, cervical cancer, bladder cancer, kidney cancer, colon cancer, or prostate cancer. In still other embodiments, the cancer is lung cancer or breast cancer. In yet other embodiments, the cancer is pancreatic cancer. In still other embodiments, the cancer is a lymphoma or leukemia. [0067] In certain embodiments, the redox-modulating compound is 6,8-bis-benzylthio- octanoic acid. In certain embodiments, the redox-modulating compound is administered in the form of a intravenous pharmaceutical composition comprising 6,8-bis-benzylthio- octanoic acid and triethanolamine. In certain embodiments, the intravenous pharmaceutical composition further comprises dextrose and water. In certain embodiments, the mole ratio of triethanolamine to 6,8-bis-benzylthio-octanoic acid is in the range of about 10: 1 to about 1: 10, about 10: 1 to about 5: 1, or about 8: 1.

[0068] In certain embodiments, redox-modulating compound is an ion pair comprising 6,8-bis-benzylthio-octanoic acid and triethanolamine. In certain embodiments, the mole ratio of triethanolamine to 6,8-bis-benzylthio-octanoic acid in the ion pair is in the range of about 10: 1 to about 1: 10, about 10: 1 to about 5: 1, or about 8: 1.

[0069] In certain embodiments, the redox-modulating compound is administered by intravenous administration.

[0070] In certain embodiments, the anti-cancer agent is gemcitabine or a

pharmaceutically acceptable salt thereof. In certain other embodiments, the anti-cancer agent is gemcitabine hydrochloride.

[0071] In certain embodiments, the anti-cancer agent is administered by intravenous administration.

B. Dosing Amounts & Treatment Cycles

[0072] Generally, the combination of pharmaceutical agents is delivered to the patient in an effective amount. When the medical disorder is cancer, it is preferred that active agents in the combination therapy are selectively and specifically delivered to and taken up by a tumor mass and the transformed cells within, and effectively concentrated within the mitochondria of transformed cells, thereby sparing healthy cells and tissue from the effects of the agents.

[0073] As is understood, the effective amount of a therapeutic agent may vary with the activity of the specific agent employed; the metabolic stability and length of action of that agent; the species, age, body weight, general health, dietary status, sex and diet of the subject; the mode and time of administration; rate of excretion; drug combination, if any; and extent of presentation and/or severity of the particular condition being treated. The precise dosage can be determined, may involve one or several administrations per day, in whichever order is necessary or desirable, to yield the desired results, and the dosage may be adjusted by the individual practitioner to achieve a desired effect. Preferably, the dosage amount of the agent(s) used should be sufficient to interact solely with tumor cells, leaving normal cells essentially unharmed.

[0074] For the purposes of illustration, the dosage amount of a therapeutic agent may range from about 0.3 mg/m 2 to 2000 mg/m 2 , or preferably at about 60 mg/m 2. The dosage amount may be administered in a single dose or in the form of individual divided doses, such as from one to four or more times per day. In the event that the response in a subject is insufficient at a certain dose, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent of patient tolerance. Of course, the combination of pharmaceutical agents of the present invention can be prepared in any amount desired up to the maximum amount that can be administered safely to a patient. For example, the amount of the combination of pharmaceutical agents may range from less than 0.01 mg/mL to greater than 1000 mg/mL, preferably about 50 mg/mL.

[0075] In certain embodiments, it is contemplated that the redox-modulating compound is administered at a dosage of from about 0.3 mg/m 2 to about 2000 mg/m 2. In certain embodiments, the redox-modulating compound is administered at a dosage of from about

20 mg/m 2 to about 600 mg/m 2 , about 80 mg/m 2 to about 600 mg/m 2 , about 20 mg/m 2 to about 500 mg/m 2 , about 20 mg/m 2 to about 150 mg/m 2 , about 20 mg/m 2 to about 70 mg/m 2 , or about 40 mg/m 2 to about 170 mg/m 2. In certain embodiments, the redox-modulating compound is administered at a dosage of from about 20 mg/m 2 to about 500 mg/m 2. In certain embodiments, the redox-modulating compound administered according to one of the foregoing dosages is 6,8-bis-benzylthio-octanoic acid.

[0076] In certain embodiments, it is contemplated that the anti-cancer agent is administered at a dosage of from about 0.3 mg/m 2 to about 2000 mg/m 2. In certain other embodiments, the anti-cancer agent is administered at a dosage of about 900 mg/m to about 1100 mg/m 2 , or at about 1000 mg/m 2. In certain embodiments, the anti-cancer agent administered according to one of the foregoing dosages is gemcitabine hydrochloride.

[0077] Components in the combination therapy may be administered in a particular order and/or according to a treatment cycle. For example, in certain embodiments, at least one dose of the anti-cancer agent is administered to the patient prior to administering the redox-modulating compound. In certain other embodiments, the anti-cancer agent is administered to the patient according to a treatment cycle comprising administering the anti-cancer agent once per week for a period of three weeks, followed by 1 week in which the anti-cancer agent is not administered to the patient. In certain other embodiments, the redox-modulating compound is administered to the patient according to a treatment cycle comprising administering the redox-modulating compound twice per week for a period of three weeks, followed by 1 week in which the redox-modulating compound is not administered to the patient. In certain embodiments, administration of the anti-cancer agent and the redox-modulating compound are initiated during the same week.

[0078] In certain other embodiments, active components of the combination therapy may be co-administered simultaneously. In certain other embodiments, active components of the combination therapy may be co-administered in a predetermined manner, ratio, and order of addition so as to comprise a treatment cycle. In certain other embodiments, treatment cycles may be repeated in order to maximize benefit to the patient.

[0079] Contemplated advantages of the combination therapy include (i) effective cancer therapy with minimal side effects for the patient, (ii) using active agents that incur the least possible cost and are capable of being stored for the longest possible period, (iii) novel combinations of pharmaceutically- acceptable agents to treat diseased cells which modulate tumor cell metabolism in such a way as to culminate in tumor cell death, and (iv) novel combinations of pharmaceutically- acceptable agents to be used in diseased cells which modulate the structure, function, activity, and/or expression level of the PDH, a-KDH, and/or BCAKDH complexes in such a way as to culminate in tumor cell death.

IV. MEDICAL KITS

[0080] Another aspect of the invention provides medical kits containing therapeutic agents and/or pharmaceutical compositions described herein, along with instructions for using the kits to treat a disorder characterized by cellular hyperproliferation, such as cancer.

In certain embodiments, the medical kit comprises (i) a redox-modulating compound comprising 6,8-bis-benzylthio-octanoic acid, and (ii) instructions for treating cancer using said redox-modulating compound in combination with an anti-cancer agent selected from the group consisting of gemcitabine, a pharmaceutically acceptable salt of gemcitabine, cytarabine, and a pharmaceutically acceptable salt of cytarabine. [0081] In certain other embodiments, the redox-modulating compound is 6,8-bis- benzylthio-octanoic acid. In certain other embodiments, the redox-modulating compound is provided in the form of an intravenous pharmaceutical composition comprising 6,8-bis- benzylthio-octanoic acid and triethanolamine. In certain other embodiments, the intravenous pharmaceutical composition further comprises dextrose and water. In certain embodiments, the instructions provide for administering the redox-modulating compound by intravenous administration. In certain embodiments, the mole ratio of triethanolamine to 6,8-bis-benzylthio-octanoic acid is in the range of about 10: 1 to about 1: 10, about 10: 1 to about 5: 1, or about 8: 1.

[0082] In certain embodiments, redox-modulating compound is an ion pair comprising

6,8-bis-benzylthio-octanoic acid and triethanolamine. In certain embodiments, the mole ratio of triethanolamine to 6,8-bis-benzylthio-octanoic acid in the ion pair is in the range of about 10: 1 to about 1: 10, about 10: 1 to about 5: 1, or about 8: 1.

[0083] In certain embodiments, the anti-cancer agent is gemcitabine or a

[0084] In certain embodiments, the instructions provide for administering at least one dose of the anti-cancer agent to the patient prior to administering the redox-modulating compound. In certain other embodiments, the instructions provide for administering the anti-cancer agent to the patient according to a treatment cycle comprising administering the anti-cancer agent once per week for a period of three weeks, followed by 1 week in which the anti-cancer agent is not administered to the patient. In certain other embodiments, the instructions provide for administering the redox-modulating compound to the patient according to a treatment cycle comprising administering the redox-modulating compound twice per week for a period of three weeks, followed by 1 week in which the redox- modulating compound is not administered to the patient. In certain embodiments, the instructions provide that administration of the anti-cancer agent and the redox-modulating compound are initiated during the same week.

[0085] In certain other embodiments, the instructions provide for administering the redox-modulating compound at a dosage of from about 0.3 mg/m 2 to about 2000 mg/m 2. In certain other embodiments, the instructions provide for administering the redox-modulating compound at a dosage of from about 20 mg/m 2 to about 500 mg/m 2. In certain other embodiments, the instructions provide for administering the anti-cancer agent at a dosage of from about 0.3 mg/m 2 to about 2000 mg/m 2. In certain other embodiments, the instructions provide for administering the anti-cancer agent at a dosage of about 1000 mg/m . V. PHARMACEUTICAL COMPOSITIONS

[0086] Therapeutic agents described herein may be formulated as a pharmaceutical composition comprising one or more therapeutic agents and a pharmaceutically acceptable carrier. For example, the redox-modulating compound can be formulated as a

pharmaceutical composition that, for example, optionally further contains an anti-cancer agent. A pharmaceutical composition that contains both the redox-modulating compound and the anti-cancer agent may be referred to as a co-formulated composition. Further, for example, one exemplary pharmaceutical composition comprises (i) a redox-modulating compound comprising 6,8-bis-benzylthio-octanoic acid, (ii) an anti-cancer agent selected from the group consisting of gemcitabine, a pharmaceutically acceptable salt of

gemcitabine, cytarabine, and a pharmaceutically acceptable salt of cytarabine, and (iii) a pharmaceutically acceptable carrier.

[0087] In further preferred embodiments of the present invention, the combinations of pharmaceutical agents of the present invention may be formulated as pharmaceutically- acceptable oils; liposomes; oil-water or lipid-oil-water emulsions or nanoemulsions;

liquids; or salts and crystalline forms delivered in tablets or capsules. To facilitate such formulations, the combinations of pharmaceutical agents may be combined with a pharmaceutically-acceptable carrier or excipient therefor. Examples of pharmaceutically- acceptable carriers are well known in the art and include those conventionally used in pharmaceutical compositions, such as salts, lipids, buffers, chelating agents, flavorants, colorants, preservatives, absorption promoters to enhance bioavailability, antimicrobial agents, and combinations thereof, optionally in combination with other therapeutic ingredients.

[0088] Hydrophilic pharmaceutical agents may be rendered hydrophobic for inclusion in oils, liposomes, emulsions, or nanoemulsions by chemical or ionic conjugation to lipophilicity-enhancing moieties, such as but not limited to lipids, aromatic or alkyl chains, carbohydrates, peptides, or amino acids. Such formulations may also include conjugation of the at least one redox-modulating alkyl fatty acid with solubility-enhancing polymers containing an activated linkage chemistry moiety, such as polyethylene glycol (PEG). These conjugations may occur through an ionic bond, such as a salt; a hydrophobic interaction; or through a covalent bond or a covalent reversible or cleavable bond, such as an ester linkage.

[0089] As described in detail below, the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation.

[0090] The phrase "therapeutically-effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.

[0091] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0092] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0093] Examples of pharmaceutically- acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. [0094] Methods of preparing pharmaceutical formulations or pharmaceutical compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0095] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0096] In certain embodiments, one or more of the therapeutic agents are administered by intraparenteral administration. In certain other embodiments, one or more of the therapeutic agents are formulated for inhalational, oral, topical, transdermal, nasal, ocular, pulmonary, rectal, transmucosal, intravenous, intramuscular, subcutaneous, intraperitoneal, intrathoracic, intrapleural, intrauterine, intratumoral, or infusion methodologies or administration, or combinations of any thereof, in the form of aerosols, sprays, powders, gels, lotions, creams, suppositories, ointments, and the like. As indicated above, if such a formulation is desired, other additives known in the art may be included to impart the desired consistency and other properties to the formulation.

[0097] The description above describes multiple aspects and embodiments of the invention, including therapeutic methods, pharmaceutical compositions, and medical kits. The patent application specifically contemplates all combinations and permutations of the aspects and embodiments. For example, the invention contemplates treating cancer in a human patient by administering a therapeutically effective amount of 6,8-bis-benzylthio- octanoic acid and gemcitabine hydrochloride. Further, for example, the invention contemplates a kit for treating cancer, the kit comprising 6,8-bis-benzylthio-octanoic acid and instructions for treating cancer using said 6,8-bis-benzylthio-octanoic acid in combination with gemcitabine hydrochloride. EXAMPLES

[0098] The invention now being generally described, will be more readily understood by reference to the following example, which is included merely for purposes of illustration of certain aspects and embodiments of the present invention, and is not intended to limit the invention.

EXAMPLE 1- COMB/NAT/ON THE A PF USING 6,8-B/S-BENZ FLTMO- OCTANO/CA CWAND GEMCITABINE HFDPOCHI OP WE

[0099] Patients suffering from cancer have been administered 6,8-bz^'s-benzylthio- octanoic acid in combination with gemcitabine hydrochloride. Experimental procedures and results are described below.

Part I - Experimental Procedures

[0100] Active Agents: The compound 6,8-bzs-benzylthio-octanoic acid was provided as an aqueous solution at a concentration of 50 mg/mL and containing 1M triethanolamine. Gemcitabine was provided in the form of a hydrochloride salt.

Dosing:

[0101] A treatment cycle is 2x weekly dosing of 6,8-bzs-benzylthio-octanoic acid plus lx weekly dosing of gemcitabine hydrochloride for 3 consecutive weeks, followed by 1 week of rest (i.e., 4-week cycle with 3-weeks-on-l-week-off). 6,8-5z^'i^,-benzylthio-octanoic acid was administered by IV at a rate of -0.5 mL/minute via an IV catheter with D5W (5% dextrose in water) running at a rate of about 125-150 mL/hr. The dose of gemcitabine hydrochloride is 1000 mg/m , administered by a 30-minute IV infusion. If 6, -bis- benzylthio-octanoic acid is also administered on the same day as gemcitabine

hydrochloride, 6,8-bzs-benzylthio-octanoic acid is administered -60 minutes after the administration of gemcitabine hydrochloride. When gemcitabine hydrochloride is not administered, 6,8-bzs-benzylthio-octanoic acid also is not be administered.

[0102] Patients are given one cycle of dosing. Additional dosing cycles are not intended; however, if it is beneficial to the patients according to the opinion of the investigators, additional dosing cycles with 6,8-bzs-benzylthio-octanoic acid are given at the same dose level (or at a lower dose level dependent upon toxicity), provided no toxicity is observed 1 week beyond the 4-week cycle. Part II - Results

[0103] Twenty-eight patients have been treated with 6,8-bzs-benzylthio-octanoic acid in combination with gemcitabine hydrochloride. Of these twenty-eight patients, eleven patients have completed more than one treatment cycle where the treatment resulted in the cancer being considered at least stable, and no significant adverse events were observed.

[0104] PET and CT results from one patient suffering from metastatic breast cancer are provided in Figure 1. The dosage of 6,8-bzs-benzylthio-octanoic acid administered to the patient during each cycle is listed below the cycle heading on Figure 1. Both lesion size and SUV decreased during cycles two and three, compared to lesion size and SUV during cycle 1.

[0105] Overall, the results indicate that administration of 6,8-bzs-benzylthio-octanoic acid in combination with gemcitabine hydrochloride provides an anti-cancer effect.

INCORPORATION BY REFERENCE

[0106] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.

EQUIVALENTS

[0107] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

[0108] WHAT IS CLAIMED IS :

Claims

1. A method for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of (i) a redox-modulating compound comprising 6,8-bis-benzylthio-octanoic acid, and (ii) an anti-cancer agent selected from the group consisting of gemcitabine, a pharmaceutically acceptable salt of gemcitabine, cytarabine, and a pharmaceutically acceptable salt of cytarabine.

2. The method of claim 1, wherein the cancer is a solid tumor or a hematological malignancy.

3. The method of claim 1, wherein the cancer is pancreatic cancer, lung cancer, breast cancer, ovarian cancer, a primary melanoma, a metastatic melanoma, liver cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, uterine cancer, cervical cancer, bladder cancer, kidney cancer, colon cancer, or prostate cancer.

4. The method of claim 1, wherein the cancer is lung cancer or breast cancer.

5. The method of claim 1, wherein the cancer is pancreatic cancer.

6. The method of any one of claims 1-5, wherein the redox-modulating compound is 6,8-bis- benzylthio-octanoic acid.

7. The method of any one of claims 1-5, wherein the redox-modulating compound is

administered in the form of an intravenous pharmaceutical composition comprising 6,8-bis- benzylthio-octanoic acid and triethanolamine.

8. The method of claim 7, wherein the intravenous pharmaceutical composition further

comprises dextrose and water.

9. The method of any one of claims 1-8, wherein the redox-modulating compound is

administered by intravenous administration.

10. The method of any one of claims 1-9, wherein the anti-cancer agent is gemcitabine or a pharmaceutically acceptable salt thereof.

11. The method of any one of claims 1-9, wherein the anti-cancer agent is gemcitabine

hydrochloride.

12. The method of any one of claims 1-11, wherein the anti-cancer agent is administered by intravenous administration.

13. The method of any one of claims 1-12, wherein at least one dose of the anti-cancer agent is administered to the patient prior to administering the redox-modulating compound.

14. The method of any one of claims 1-13, wherein the anti-cancer agent is administered to the patient according to a treatment cycle comprising administering the anti-cancer agent once per week for a period of three weeks, followed by 1 week in which the anti-cancer agent is not administered to the patient.

15. The method of any one of claims 1-14, wherein the redox-modulating compound is

administered to the patient according to a treatment cycle comprising administering the redox-modulating compound twice per week for a period of three weeks, followed by 1 week in which the redox-modulating compound is not administered to the patient.

16. The method of any one of claims 1-15, wherein the redox-modulating compound is

administered at a dosage of from about 0.3 mg/m 2 to about 2000 mg/m 2.

17. The method of any one of claims 1-15, wherein the redox-modulating compound is

administered at a dosage of from about 20 mg/m 2 to about 500 mg/m 2.

18. The method of any one of claims 1-17, wherein the anti-cancer agent is administered at a dosage of from about 0.3 mg/m 2 to about 2000 mg/m 2.

19. The method of any one of claims 1-17, wherein the anti-cancer agent is administered at a dosage of about 1000 mg/m .

20. A medical kit, comprising (i) a redox-modulating compound comprising 6,8-bis-benzylthio- octanoic acid, and (ii) instructions for treating cancer using said redox-modulating compound in combination with an anti-cancer agent selected from the group consisting of gemcitabine, a pharmaceutically acceptable salt of gemcitabine, cytarabine, and a pharmaceutically acceptable salt of cytarabine.

21. The medical kit of claim 20, wherein the redox-modulating compound is 6,8-bis- benzylthio-octanoic acid.

22. The medical kit of claim 20, wherein the redox-modulating compound is provided in the form of an intravenous pharmaceutical composition comprising 6,8-bis-benzylthio-octanoic acid and triethanolamine.

23. The method of claim 22, wherein the intravenous pharmaceutical composition further comprises dextrose and water.

24. The medical kit of any one of claims 20-23, wherein the instructions provide for

administering the redox-modulating compound by intravenous administration.

25. The medical kit of of any one of claims 20-24, wherein the anti-cancer agent is gemcitabine or a pharmaceutically acceptable salt thereof.

26. The medical kit of any one of claims 20-24, wherein the anti-cancer agent is gemcitabine hydrochloride.

27. The medical kit of any one of claims 20-26, wherein the instructions provide for

administering the redox-modulating compound at a dosage of from about 0.3 mg/m to about 2000 mg/m².

28. The medical kit of any one of claims 20-26, wherein the instructions provide for

administering the redox-modulating compound at a dosage of from about 20 mg/m to about 500 mg/m .

29. The medical kit of any one of claims 20-28, wherein the instructions provide for

administering the anti-cancer agent at a dosage of from about 0.3 mg/m to about 2000 mg/m².

30. The medical kit of claim 19, wherein the instructions provide for administering the anti- cancer agent at a dosage of about 1000 mg/m .

31. A pharmaceutical composition comprising (i) a redox-modulating compound comprising 6,8-bis-benzylthio-octanoic acid, (ii) an anti-cancer agent selected from the group consisting of gemcitabine, a pharmaceutically acceptable salt of gemcitabine, cytarabine, and a pharmaceutically acceptable salt of cytarabine, and (iii) a pharmaceutically acceptable carrier.