HK1168543A

HK1168543A - Compositions and methods for the treatment of cancer

Info

Publication number: HK1168543A
Application number: HK12109316.4A
Authority: HK
Inventors: Hee Ko Young
Original assignee: 高荣禧
Priority date: 2009-01-29
Filing date: 2010-01-29
Publication date: 2013-01-04

Description

Compositions and methods for cancer treatment

CROSS-REFERENCE TO RELATED APPLICATIONS AND RELATED APPLICATIONS

This application is a continuation-in-part application of U.S. patent application serial No. 11/706,868 filed on 14.2.2007, and also claims the benefit of U.S. provisional patent application serial No. 61/148,385 filed on 29.1.2009, both of which are incorporated by reference in their entireties.

Background

Each year, hundreds of thousands of men, women, and children in the united states suffer from some form of cancer. Worldwide, millions die of cancers, including bone, bladder, blood (leukemia), brain, breast, colon, cervix, esophagus, intestine, kidney, liver, lung, mouth, nose, nerve, ovary, pancreas, prostate, skin, stomach, testis, throat, thyroid, uterus, and vagina.

For many years, various approaches have been used to treat cancer, including radiation and chemotherapy. The main purpose of these treatments is to kill all cancer cells. However, in the case of cancer cell killing corneas, many healthy cells are always destroyed until eventually the patient is killed by the treatment. Even today, more metered and quantitative use of radiation and chemotherapy can still cause disease and even death in some patients. Also, in certain cancer types, malignant cells remain difficult to treat.

Therefore, research and development work related to treatment of various cancers is continuously being conducted in the field of medical technology.

Summary of The Invention

The present inventors have recognized that it would be advantageous to develop anti-cancer compositions that are effective in many cancers, safe for use in humans, and avoid or at least minimize the adverse drug experience associated with traditional cancer treatments.

Briefly, and in general terms, the present invention is directed to an anti-cancer composition comprising: a cellular energy inhibitor of formula I

Wherein X is selected from: nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, and amine oxide; r is selected from: OR ', N (R')₂C (O) R' ", C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, and alkali metal; wherein R ' represents H, an alkali metal, C1-C6 alkyl, C6-C12 aryl or C (O) R ' ", R" represents H, C1-C6 alkyl or C6-C12 aryl, and R ' "represents H, C1-C20 alkyl or C6-C12 aryl. Furthermore, the anti-cancer composition may comprise at least one sugar that stabilizes the inhibitor by significantly preventing hydrolysis of the cellular energy inhibitor. Anticancer combinationsThe composition may further comprise a glycolytic inhibitor. In addition, the anti-cancer composition may further comprise a biological buffer present in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize metabolic byproducts of the cellular energy inhibitor.

In one embodiment, a method of treating cancer may comprise administering to a subject a therapeutically effective amount of any of the anti-cancer compositions described herein.

In another embodiment, a method of minimizing the toxicity of a cellular energy inhibitor of formula (I) to a subject receiving the cellular energy inhibitor may comprise combining in the subject the cellular energy inhibitor with a biological buffer present in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize metabolic byproducts of the cellular energy inhibitor resulting from its chemical reaction and/or cellular metabolism.

In another embodiment, a method of minimizing adverse drug experiences associated with administration of any of the anti-cancer compositions described herein to a subject may comprise administering the anti-cancer composition to the subject when the subject's blood insulin/glucagon ratio is in the range of about 1 to about 10.

In another embodiment, a method for evaluating the killing efficacy of any of the anti-cancer compositions described herein in a subject may comprise measuring the lactate level in the subject prior to administration of the anti-cancer composition; administering an anti-cancer composition to a subject; measuring the lactic acid level of the subject after administration of the anti-cancer composition; and determining the effectiveness of the kill by measuring and/or correlating the difference between lactate levels as a function of treatment time.

Drawings

Other features and advantages of the present invention will be apparent from the following detailed description taken in conjunction with the accompanying drawings, which together illustrate features of the invention; wherein:

FIG. 1 is a schematic illustration of energy production by cancer cells, according to an embodiment of the present invention;

FIG. 2 is a series of photographs of cancer cells treated with 3-bromopyruvate, according to an embodiment of the invention;

FIG. 3 is a plot of cell viability of hepatocellular carcinoma versus μ M of various anti-cancer agents, in accordance with embodiments of the present invention; and

fig. 4(a) and 4(b) show a series of photographs of lungs with metastatic tumors without treatment and with 3-bromopyruvate treatment, respectively, according to embodiments of the present invention.

Reference will now be made to the illustrated exemplary embodiments, and specific language will be used herein to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended.

Detailed description of example embodiments

Before the present invention is disclosed and described, it is to be understood that this disclosure is not limited to the particular process steps and materials disclosed herein as such process steps and materials may vary somewhat. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only. The terms are not intended to be limiting because the scope of the present disclosure is intended to be limited only by the claims and the equivalents thereof.

It must be noted that, as used in the specification and the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

The compositions of the present invention may include a pharmaceutically acceptable carrier, as well as other ingredients, as determined by the particular needs of the particular dosage formulation. Such ingredients are well known to those skilled in the art. See, e.g., Gennaro, A. (Remington pharmaceutical sciences and practices)Remington：The Science and Practice of Pharmacy) 19 th edition (1995), incorporated herein by reference in its entiretyFor reference.

As used herein, "administering" refers to a method of presenting a drug to a subject. Administration can be accomplished by a variety of routes known in the art, such as oral, digestive, parenteral, transdermal, inhalation, implantation, and the like. Thus, oral administration can be achieved by drinking, swallowing, chewing, sucking an oral dosage form containing the drug. Parenteral administration can be achieved by injecting the pharmaceutical composition intravenously, intraarterially, intramuscularly, intrathecally, or subcutaneously, etc. Transdermal administration can be achieved by application of the transdermal formulation to the skin surface, pasting, rolling, adhering, pouring, pressing, rubbing, and the like. These and other methods of administration are well known in the art.

As used herein, "parenteral administration" refers to a method of administration that does not provide a pharmaceutical composition in a solid or liquid oral dosage form, which is traditionally intended to significantly release and deliver the drug into the gastrointestinal tract of the super-oral and/or buccal cavity. Such solid dosage forms include conventional tablets, capsules, caplets and the like which do not significantly release the drug in the mouth or buccal cavity.

It will be appreciated that many oral liquid dosage forms, such as solutions, suspensions, emulsions, etc., as well as some oral solid dosage forms, may release some of the drug in the mouth or buccal cavity during swallowing of these formulations. However, because of their very short transit times through the mouth and oral cavity, the release of drugs from these dosage forms into the mouth or oral cavity is considered minimal or insignificant unless otherwise indicated. Thus, for the purposes of the present invention, buccal patches, adhesive films, sublingual tablets and lozenges designed to release the drug in the mouth are non-oral compositions.

Furthermore, it is to be understood that the term "parenteral" includes parenteral, transdermal, inhalation, implantation and vaginal or rectal formulations and administrations. In addition, an implanted formulation will be encompassed by the term "non-oral," regardless of the physical location of implantation. In particular, implant formulations specifically designed for implantation and retention in the gastrointestinal tract are known. Such implants are also considered to be non-oral delivery formulations and are therefore encompassed by the term "non-oral".

As used herein, "subject" refers to a mammal that may benefit from the use of the pharmaceutical compositions or methods of the present invention. Examples of subjects include humans and other animals such as horses, pigs, cows, sheep, goats, dogs (canines), cats (felines), rabbits, rodents, primates, and aquatic mammals. In one embodiment, the subject may be a human.

As used herein, "effective amount" or "therapeutically effective amount" or similar terms refer to a non-toxic but sufficient amount of a drug to achieve a therapeutic result in the treatment of a condition for which the drug is known to be effective or has been found to be effective as disclosed herein. Various biological factors may affect the ability of the delivered substance to perform its target task or the amount of drug needed to provide a therapeutic result. Thus, an "effective amount" or a "therapeutically effective amount" may depend on these biological factors. Determination of an effective or therapeutically effective amount is well within the ordinary skill in the pharmaceutical and medical arts, based on the known art in this field and this disclosure. See, e.g., Curtis l.meinert Susan tonasitia, "clinical trials: design, execute and analyzeClinical Trials：Design，Conduct，and Analysis) Epidemiology and biometrical Monographs (monograms in Epidemiology and biostatics), vol.8 (1986).

As used herein, "drug," "active agent," "biologically active agent," "pharmaceutically active agent," "therapeutically active agent," and "pharmaceutical product" are used interchangeably to refer to an agent or substance that has a measurable designated or selected physiological activity when administered to a subject in a significant or effective amount. It is to be understood that the term "drug" is specifically encompassed by the definition of the present invention, as many drugs and prodrugs are known to have a particular physiological activity. These terms of art are well known in the pharmaceutical and pharmaceutical arts. Further, when these terms are used, or when a particular active agent is specifically referred to by name or phylum, it is to be understood that such recitation is intended to include the active agent itself, as well as its pharmaceutically acceptable salts or compounds explicitly associated therewith, including but not limited to prodrugs, active metabolites, isomers, and the like.

As used herein, "cytostatic agent" refers to a compound that inhibits glycolysis and mitochondrial function of cancer cells.

As used herein, "glycolytic inhibitor" refers to a compound that inhibits, reduces, or stops glycolysis in a cancer cell.

As used herein, "mitochondrial inhibitor" refers to a compound that inhibits, reduces, or stops mitochondrial function in cancer cells.

As used herein, the terms "dosage form," "formulation," and "composition" are used interchangeably to refer to a mixture of two or more compounds, components or molecules. In certain instances, the terms "dosage form," "formulation," and "composition" may be used to refer to a mixture of one or more active agents with a carrier or other excipient.

As used herein, "carrier" or "pharmaceutically acceptable carrier" refers to a substance with which a drug can be combined to obtain a particular dosage formulation for delivery to a subject. In certain instances of the present invention, the carrier used may or may not enhance drug delivery. As a general rule, the carrier does not react with the drug in a manner that significantly degrades the drug or otherwise adversely affects the drug, unless the carrier can react with the drug to prevent it from performing its therapeutic effect until the drug is released from the carrier. The carrier, or at least a portion thereof, must be suitable for administration with the drug to the subject.

As used herein, the terms "release," "release rate," "dissolution rate," and "dissolution rate" are used interchangeably to refer to the discharge or release of a substance, including but not limited to a drug, from a dosage form into a surrounding environment, such as an aqueous medium in vitro or in vivo.

As used herein, "controlled release," "sustained release," "modified release," "delayed release," "extended release," and "non-immediate release" are used interchangeably to refer to release of an active agent from a dosage form into a target environment or medium over a sustained period of at least 5% slower as compared to an Immediate Release (IR) formulation containing an equivalent dose. In one embodiment, a "controlled release," "sustained release," "modified release," "delayed release," "extended release," or "non-immediate release" system or composition can provide release of an active agent from a dosage form to a target environment or medium over a duration that is at least 10% slower than an equivalent dosage form containing an Immediate Release (IR) formulation.

As used herein, "release modifier," "release modifier," and "release modifier" are used interchangeably and refer to a pharmaceutically acceptable agent or device that is capable of altering, increasing or decreasing, or otherwise tailoring the release rate of at least one of the contents of a composition or dosage form thereof when exposed to an aqueous application environment.

As used herein, "blended" means that at least two components of the composition are capable of being mixed, dispersed, suspended, dissolved or emulsified with each other neat or completely. In some cases, at least a portion of the drug may be incorporated in at least one carrier substance.

As used herein, "adverse drug experience" refers to any adverse event associated with the use of a drug in a subject, including the following: adverse events that occur during drug use in professional practice; adverse events caused by accidental or intentional overdose of medication; adverse events caused by drug abuse; adverse events caused by withdrawal of medication; and any failure to anticipate a pharmacological effect. Poor drug experiences can cause significant disruption in a human's ability to perform normal vital functions. In some cases, the adverse drug experience may be severe or life threatening.

While certain adverse drug experiences may be unexpected, in certain instances such experiences may be unexpected. "unexpectedly" refers to a poor pharmaceutical experience not previously provided in current labeling of drugs and/or the classification of government agencies (e.g., the Food and Drug Administration of the United states) that have not been previously charged.

An unexpectedly adverse experience may include an event that may be related to a known event in symptoms and pathophysiology, but that is different from the event due to higher severity or specificity. For example, under this definition, hepatic necrosis would be unexpected (due to greater severity) if the known event was elevated liver enzymes or hepatitis. Likewise, cerebral thromboembolism and cerebral vasculitis would be unexpected (due to the higher specificity) if the known event was a cerebrovascular accident. For a more detailed definition and description of adverse drug experiences see 21c.f.r. § 314.80, incorporated herein by reference in its entirety.

As used herein, "substantially" or "substantial" refers to a complete or nearly complete range or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is "substantially" enclosed means that the object is completely or nearly completely enclosed. The exact degree of permissible deviation from absolute completeness depends in some cases on the particular case. However, in general, proximity to completion will be such that the overall result obtained will be the same as if absolute and full completion were achieved. The use of "substantially" is equally applicable when used in a negative sense to refer to a complete or near complete lack of an action, property, state, structure, item, or result. For example, a composition that is "substantially free" of particles will be completely devoid of particles, or very close to completely devoid of particles such that the effect will be the same as if the particles were completely absent. In other words, a composition that is "substantially free" of an ingredient or element may still contain such an item as long as it has no measurable effect. Unless otherwise indicated, reference to "substantially" preventing hydrolysis refers to the ability of the sugar to stabilize the cellular energy inhibitor for at least 1 hour while at least 50% of the cellular energy inhibitor is not hydrolyzed.

As used herein, the term "about" is used to provide flexibility to the end of a numerical range by providing a given value that may be "slightly above" or "slightly below" the end. As used herein, a plurality of items, structural elements, compositional components, and/or materials may be presented in a common list for convenience. However, these lists should be construed as if each member of the list is individually designated as a separate and unique member. Thus, each member of such a list should not be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.

As used herein, a plurality of items, structural elements, compositional components, and/or materials may be presented in a common list for convenience. However, these lists should be construed as if each member of the list is individually designated as a separate and unique member. Thus, each individual member of such a list should not be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.

Concentrations, amounts, levels, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, each value, e.g., 2, 3.5, and 4, and subranges, e.g., from 1 to 3, from 2 to 4, and from 3 to 5, etc., and 1, 2, 3, 4, and 5 individually, are included in the numerical range. The same principle applies to ranges reciting only one numerical value as either a minimum or maximum value. Moreover, such an interpretation would apply regardless of the breadth of the range or the characteristics being described.

For example, a concentration range of 0.5 to 15mM should be interpreted to include not only the explicitly recited concentration limits of 0.5mM and 15mM, but also include individual concentrations within that range, e.g., 0.5mM, 0.7mM, 1.0mM, 5.2mM, 11.6mM, 14.2mM, and sub-ranges, e.g., 0.5-2.5mM, 4.8-7.2mM, 6-14.9mM, etc. This interpretation should apply regardless of the breadth of the range or the feature being described.

The present inventors have recognized that by targeting the energy production of cancer cells, alternatives to traditional anti-cancer compositions and treatments can be obtained. Without intending to be bound by any particular theory, the inventors have discovered that certain inhibitors of cellular energy may be useful in the treatment of cancer. In general, there are two energy (ATP) production plants within the cell, glycolysis and oxidative phosphorylation by mitochondria. In normal cells, about 5% of total cellular energy (ATP) production is derived from glycolysis and about 95% is derived from mitochondria. In cancer cells, the energy produced by glycolysis can be significantly increased (up to 60%). This dramatic increase in glycolysis in cancer cells leads to a significant increase in lactate production.

Most cancers (> 90%) display this common metabolic phenotype. This is called "Warburg Effect", i.e., in cancer cells, glycolysis is significantly increased even in the presence of oxygen. The most common cancer detection method used clinically, Positron Emission Tomography (PET), is based on this metabolic phenotype, the "warburg effect". Cancer cells that exhibit the warburg effect pump out the lactic acid produced through the transporter (i.e., the monocarboxylic acid transport isoform). The number of these transporters (considered as gates or gates) is much higher in cancer cells than in normal cells.

The cellular energy inhibitors of the present disclosure, shown in fig. 1 as 3-bromopyruvate (3BP) (lactic acid analogs), are small chemical substances and can mimic the chemical structure of lactic acid; which are depicted in fig. 1 as small diamonds. Therefore, cellular energy inhibitors that pretend to be lactic acid are able to "trick" cancer cells into it like trojan horses (fig. 1). The inhibitor has little effect on normal cells, since these cells contain very little lactate transporter. Due to the highly reactive nature of the cellular energy inhibitor of the invention, it is able to disrupt two energy production plants (FIG. 1; one diamond above Hexokinase (HK) shows that 3BP is disrupting one energy production plant, i.e., glycolysis, while the other red diamond inside the mitochondria shows that 3BP is also disrupting that energy production plant). As a result, cellular energy (ATP) can be very rapidly deprived by cellular energy inhibitors; the 3BP in fig. 1 simultaneously attacks both factories, causing rapid bursting (cell membrane rupture) of the cancer cells. An example of this can be seen in fig. 2, which shows liver cancer cells treated with 3 BP. Here, healthy cancer cells are round and iridescent (left panel). However, when they were treated with 3BP, the cell membrane ruptured (middle panel) and then died (see cell debris in the far right panel).

Accordingly, the present disclosure allows for the safe administration and use of the anti-cancer compositions of the present invention comprising a cellular energy inhibitor of the structure of formula I

Wherein X is selected from: nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, and amine oxide; r is selected from: OR ', N (R')₂C (O) R' ", C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, and alkali metal; wherein R ' represents H, an alkali metal, C1-C6 alkyl, C6-C12 aryl or C (O) R ' ", R" represents H, C1-C6 alkyl or C6-C12 aryl, and R ' "represents H, C1-C20 alkyl or C6-C12 aryl. Furthermore, the anti-cancer composition may comprise at least one sugar that stabilizes the inhibitor by significantly preventing hydrolysis of the cellular energy inhibitor. The anti-cancer composition may further comprise a glycolysis inhibitor. In addition, the anti-cancer composition may further comprise a biological buffer present in an amount sufficient to render the composition fineThe cellular energy inhibitor is at least partially deacidified and neutralizes metabolic byproducts of the cellular energy inhibitor.

The present inventors have recognized the need to provide safe and effective compositions that allow the treatment of cancer. As discussed previously, the cellular energy inhibitor of the present invention may be stabilized by using at least one sugar such that the sugar substantially prevents hydrolysis of the cellular energy inhibitor. In this way, the sugar is capable of stabilizing the cellular energy inhibitor for at least 1 hour so that at least 50% of the inhibitor is not hydrolyzed. In another embodiment, the at least one sugar is capable of stabilizing the cellular energy inhibitor for at least 1 hour and preventing at least 95% of the inhibitor from hydrolyzing. In another embodiment, the at least one sugar is capable of stabilizing the inhibitor of cellular energy for at least 2 hours such that at least 95% of the inhibitor is not hydrolyzed.

The anti-cancer compositions disclosed herein generally include compounds described by formula (I). In one embodiment, R of formula (I) may be OH, and X of formula (I) may be selected from nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, and amine oxide. Further, X may be a halide selected from fluoride, bromide, chloride and iodide. In one embodiment, X may be a sulfonate selected from the group consisting of trifluoromethanesulfonate, methanesulfonate, and toluenesulfonate. In another embodiment, X may be an amine oxide. In another embodiment, the amine oxide may be dimethylamine oxide.

In one embodiment, the cellular energy inhibitor may be a 3-halopyruvate, and may be selected from the group consisting of 3-fluoropyruvate, 3-chloropropiononate, 3-bromopyruvate, 3-iodopyruvate, and combinations thereof. The anti-cancer composition may comprise the cellular energy inhibitor in a concentration of about 0.1mM to about 25.0 mM. In one embodiment, the anti-cancer composition may comprise the cellular energy inhibitor at a concentration of about 1.0mM to about 10.0 mM.

Although the anti-cancer composition generally comprises at least one sugar, in one embodiment, the anti-cancer composition may comprise other sugars, such as a second sugar. In another embodiment, the anti-cancer composition may comprise a third sugar. At least one of the sugars may be a five carbon sugar. In one embodiment, at least two of the sugars may be five carbon sugars. The five-carbon sugars can be independently selected from the group consisting of mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, sorbitol, and combinations thereof. In one embodiment, at least one of the sugars may be glycerol. In another embodiment, the sugar may be glycerol, inositol, and sorbitol. The anti-cancer composition may comprise glycerol in the range of about 0.1 wt% to about 3 wt%, inositol in the range of about 1 wt% to about 5 wt%, and sorbitol in the range of about 30 wt% to about 50 wt%. In addition, each sugar may be added in an amount up to the highest solubility of the sugar in the formulation or composition.

In one embodiment, the anti-cancer composition may comprise the at least one sugar at a concentration of about 0.1mM to about 250 mM. In another embodiment, the anti-cancer composition may comprise the at least one sugar at a concentration of about 0.5mM to about 25 mM.

In general, the anti-cancer composition may comprise a glycolysis inhibitor. In one embodiment, the glycolytic inhibitor can be 2-deoxyglucose. The anti-cancer composition can comprise the glycolytic inhibitor at a concentration of about 0.1mM to about 25.0 mM. In one embodiment, the anti-cancer composition can comprise the glycolytic inhibitor at a concentration of about 1mM to about 5 mM.

In general, the anti-cancer composition can include a biological buffer present in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize metabolic byproducts of the cellular energy inhibitor. In one embodiment, the biological buffer may be selected from citrate buffers, phosphate buffers and acetate buffers. In another embodiment, the biological buffer may be a citrate buffer. In another embodiment, the biological buffer may be sodium citrate.

As discussed herein, the cellular energy inhibitor is delivered to the cancer cells and taken up by the cells. After metabolism of the cellular energy inhibitor, the cellular energy inhibitor is capable of producing by-products. In one embodiment, the byproduct may be a hydrogen halide. Further, the hydrogen halide may be hydrogen bromide or hydrogen iodide. In one embodiment, the hydrogen halide may be hydrogen bromide.

The anti-cancer composition may comprise a biological buffer at a concentration of about 0.1mM to about 200 mM. In one embodiment, the anti-cancer composition may comprise a biological buffer at a concentration of about 1mM to about 20 mM. In addition, biological buffers are capable of maintaining a physiological pH of 4.0 to 8.5. In one embodiment, the biological buffer is capable of maintaining a physiological pH of 5.5 to 8.0. In another embodiment, the biological buffer is capable of maintaining a physiological pH of 6.8 to 7.8. In another embodiment, the biological buffer is capable of maintaining a physiological pH of 7.3 to 7.6.

In addition to the above components, the anticancer compositions described herein may also comprise a halogenated monocarboxylate compound separate from the cellular energy inhibitor. In the case where the halogenated monocarboxylate is capable of acting to inhibit glycolysis and mitochondrial function, the halogenated monocarboxylate may be considered a second cellular energy inhibitor. In one embodiment, the halogenated monocarboxylate may be a halogenated two-carbon monocarboxylate. The halo two-carbon monocarboxylate may be selected from the group consisting of 2-fluoroacetate, 2-chloroacetate, 2-bromoacetate, 2-iodoacetate, and mixtures thereof. In one embodiment, the halogenated two-carbon monocarboxylate may be a 2-bromoacetate. The anti-cancer composition may comprise the halo two-carbon monocarboxylate compound at a concentration of about 0.01mM to about 5.0 mM. In one embodiment, the anti-cancer composition may comprise halo two-carbon monocarboxylate compound at a concentration of about 0.1mM to about 0.5 mM.

Further, the halogenated monocarboxylate may be a halogenated three-carbon monocarboxylate. In one embodiment, the halogenated three carbon monocarboxylate may be selected from the group consisting of 3-fluorolactate, 3-chlorolactate, 3-bromolactate, 3-iodolactate, and mixtures thereof. The anti-cancer composition may comprise the halogenated three carbon monocarboxylate compound at a concentration of about 0.5mM to about 250 mM. In one embodiment, the anti-cancer composition may comprise a halogenated three carbon monocarboxylate compound at a concentration of about 10mM to about 50 mM.

The anti-cancer compositions described herein may also comprise an anti-fungal and/or anti-bacterial agent. In one embodiment, the anti-cancer compositions may each comprise an anti-fungal and/or anti-bacterial agent at a concentration of about 0.01mM to about 5.0 mM. In another embodiment, the anti-cancer compositions may each comprise an anti-fungal and/or anti-bacterial agent at a concentration of about 0.05mM to about 0.5 mM.

The anti-cancer compositions described herein may comprise a mitochondrial inhibitor in addition to a cellular energy inhibitor. The mitochondrial inhibitor may be selected from oligomycin, peptin, aureomycin and mixtures thereof. In one embodiment, the anti-cancer composition may comprise a mitochondrial inhibitor at a concentration of about 0.001mM to about 5.0 mM. In another embodiment, the anti-cancer composition can comprise a mitochondrial inhibitor at a concentration of about 0.01mM to about 0.5 mM.

In addition to the above concentrations, the anti-cancer composition may have various ratios of the components described herein. In one embodiment, the cellular energy inhibitor and the biological buffer may be present in a ratio in mM in the range of 1: 1 to 1: 5. In another embodiment, the cellular energy inhibitor and glycolytic inhibitor may be present in a ratio in mM in the range of 5: 1 to 1: 1. In another embodiment, the cellular energy inhibitor and the at least one sugar may be present in a ratio in mM in the range of 1: 1 to 1: 5. In another embodiment, the cellular energy inhibitor and the halogenated two-carbon monocarboxylate are present in a ratio in mM in the range of 20: 1 to 4: 1. In another embodiment, the cellular energy inhibitor and mitochondrial inhibitor may be present in a ratio in mM in the range of 20: 1 to 40: 1.

As described above, the anti-cancer composition of the present invention may comprise an antifungal agent, an antibiotic, a glycolytic inhibitor, a mitochondrial inhibitor, a sugar, and a biological buffer. Examples of such agents include, but are not limited to, amphotericin B, pepstatin, doxorubicin, 2-deoxyglucose (2DOG), analogs of 2DOG, dichloroacetic acid (or salt forms of dichloroacetic acid), oligomycin analogs, glycerol, inositol, sorbitol, ethylene glycol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, dulcitol, iditol, isomalt, maltitol, lactitol, hydrogenated glucose, sodium phosphate, sodium citrate, sodium acetate, sodium carbonate, sodium bicarbonate, sodium pyruvate, sodium lactate, oxaloacetate, isocitrate, aconitate, succinate, fumarate, malate, dilute saline solutions with various NaCl concentrations, and water. In addition to sodium ions accompanying these biological buffers, calcium and potassium cations may also accompany the biological buffers. The active agents of the anti-cancer composition can include cellular energy inhibitors, glycolysis inhibitors, mitochondrial inhibitors, halogenated monocarboxylates, antifungal agents, and antibiotic agents.

In addition to the active agent, the composition may also include a pharmaceutically acceptable carrier. The carrier may be a single composition, or a mixture of compositions. In addition, the carrier may take the form of an encapsulating coating, adsorbent, coating material, controlled release device, release modifier, surfactant, and combinations thereof. In some cases, the carrier may comprise from about 1% to about 99% by weight of the total composition. In one embodiment, the carrier may comprise from about 5% to about 95% by weight of the total dosage form. In another embodiment, the carrier may comprise from about 20% to about 80% by weight. In another embodiment, the carrier may comprise from about 30% to about 60% by weight. In one embodiment, the carrier may be mixed with the active agent. In another embodiment, the carrier may adsorb, entrap, or encapsulate at least a portion of the active agent.

Non-limiting examples of compounds that can be used as at least a part of a carrier include, but are not limited to: cetyl alcohol and esters thereof, stearic acid and glycerides thereof, polyoxyethylene alkyl esters, polyethylene glycols, polyglycolized glycerides, polyoxyethylene alkylphenols, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, polyglycerol fatty acid esters, proteins, polyoxyethylene glycerides, polyoxyethylene sterols, derivatives and analogs thereof, polyoxyethylene hydrogenated vegetable oils, reaction mixtures of polyols with at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils and sterols, tocopherol derivatives, sugar esters, sugar ethers, sucrose glycerides (sucroglyceride), waxes, shellac, pharmaceutically acceptable salts thereof and mixtures thereof.

Non-limiting examples of release modifiers include, but are not limited to: polyethylene glycols having a weight average molecular weight of about 1000 or more, carbomers, methyl methacrylate copolymers, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose acetate phthalate, ethylcellulose, methylcellulose and derivatives thereof, ion exchange resins, mono-, di-and tri-esters of fatty acids and glycerol, tocopherol and esters thereof, esters of sucrose and fatty acids, polyvinylpyrrolidone, xanthan gum, cetyl alcohol, waxes, fats and oils, proteins, alginates, polyvinyl polymers, gelatin, organic acids, derivatives thereof, and combinations thereof.

In one embodiment, the carrier may comprise at least one of: cellulose, carbomers, methacrylates, dextrins, gums, inorganic carbonates or calcium or magnesium salts or both, fatty acid esters, gelatin, lactose, maltose, mono-, di-or triesters of glycerol, oils, polyethylene glycols, polyoxyethylene copolymers, proteins, resins, shellac, silicates, starches, stearates of sugars, partially or fully hydrogenated vegetable oils, waxes, and combinations thereof.

In another embodiment, the carrier may comprise at least one of: cellulose, carbomer, methacrylate, inorganic carbonate or calcium salt, inorganic carbonate or magnesium salt, fatty acid ester, gelatin, lactose, polyethylene glycol, polyoxyethylene copolymer, silicate, partially or fully hydrogenated vegetable oil, and combinations thereof.

In another embodiment, the vector may comprise at least one of: microcrystalline cellulose, hydroxypropyl methylcellulose, ethylcellulose, silicon dioxide, magnesium aluminosilicate, lactose, xanthan gum, stearic acid, glyceryl distearate, hydrogenated vegetable oil, and combinations thereof.

The formulation, including any dosage form, may include other components and additives. Such other components or additives are optional. In one aspect, the additive may be a solid at room temperature and have a melting point or range above about 40 ℃. Non-limiting examples of additives that may be included in the system of the present invention include, but are not limited to: fillers such as lactose, starch, sugar, cellulose, calcium salts, silica, metal silicates, and the like; disintegrants such as hydroxyethyl starch, lauryl sulfate, pregelatinized starch, croscarmellose, crospovidone, and the like; binders such as pyrrolidone, methacrylate, vinyl acetate, gum arabic, tragacanth, kaolin, carrageenan, alginate, gelatin, and the like; co-solvents such as alcohols, polyethylene glycol having an average molecular weight of less than 1000, propylene glycol, and the like; surface tension modifiers such as hydrophilic or amphiphilic surfactants; taste masking agents; a sweetener; a microencapsulating agent; processing aids such as lubricants, glidants, talc, stearates, lecithin, and the like; a polymeric coating agent; a plasticizer; a buffering agent; an organic acid; an antioxidant; a flavoring agent; a colorant; an alkalizing agent; a humectant; sorbitol; mannitol; a permeable salt; a protein; a resin; a moisture resistant agent; a moisture absorbent; a desiccant; and combinations thereof.

The formulations of the present invention may be formulated into various oral dosage forms including, but not limited to, two-piece hard gelatin capsules, soft gelatin capsules, beads (beads), granules, pellets, spheres, microcapsules, microspheres, nanospheres, nanocapsules, tablets, or combinations thereof. Other forms known to those of ordinary skill in the art may also be used. In one aspect, the oral dosage form may be a capsule or tablet. In another embodiment, the oral dosage form may comprise a multicomponent dosage form, such as beads in a capsule, one or more capsules within a capsule, one or more tablets in a capsule, or a multilayer tablet. It is noteworthy that when a formulation comprises multiple dosage forms, these dosage forms need not be identical. In addition, such dosage forms may not be physically present together.

Dosage forms, such as tablets, may be coated or enrobed with hydrophilic or hydrophobic coating materials known in the art. In one embodiment, the coating may be a film coating, sugar coating, enteric coating, semipermeable coating, sustained release coating, delayed release coating, osmotic coating, or the like. In another embodiment, the coating material may be cellulose, gelatin, methacrylate, polyvinyl acetate, povidone, polyethylene glycol, polyoxyethylene, poloxamer, carbomer, shellac, phthalate, and the like, as well as derivatives thereof and combinations thereof. In another embodiment, the coating is a dry powder coating. In one embodiment, the tablet may be a matrix tablet. It is noted that when present, the coating may be considered to be part or all of the carrier component of the formulation.

IV

In addition to the compositions described herein, a method of treating cancer may comprise administering to a subject a therapeutically effective amount of an anti-cancer composition described herein. The anti-cancer composition can be administered to a subject when the subject's blood insulin/glucagon ratio is in the range of about 1 to about 10. In addition, the anti-cancer composition may be administered to the subject after fasting for at least 4 hours. In one embodiment, the anti-cancer composition may be administered to a subject after 6 hours of fasting, and in another embodiment, after 8 hours of fasting. In addition, the anti-cancer composition may be administered after the subject has fasted for 2 hours. It should be noted that such time is not intended to be limiting, and in one embodiment, the amount of time is such that the subject's blood insulin/glucagon ratio is in the range of about 2 to about 5.

Furthermore, the administration method may be selected from the group consisting of intra-arterial, intravenous, intraperitoneal, inhalation, intratumoral, oral, topical and subcutaneous administration. In one embodiment, the administration may be intraarterial. Anti-cancer compositions may also be delivered using a feeding tube. Intratumoral delivery methods may include techniques involving bronchoscopy, endoscopy and/or colonoscopy, suppositories for any opening, eye drops, nose drops and ear drops. Furthermore, if an intratumoral injection is to be performed directly on/within a tumor, ultrasound imaging (or other imaging methods) may be used to assist such injection. In addition, intravenous delivery may be combined with a hemodialysis device (i.e., a renal dialysis machine) to destroy metastatic circulating cancer cells extravascularly. In addition, a port system may be utilized to facilitate intravenous and intraperitoneal administration. In addition, the anticancer composition of the present invention may be immediate release, controlled release or time-controlled release. For time-controlled release, the compositions of the invention may be delivered by implanting chips, diamond chips (diamond chips) and other implantable devices near or on the tumor site.

In general, when the anticancer composition is administered intra-arterially or intravenously, the administration may be for a duration of about 30 minutes to about 8 hours. In one embodiment, the anti-cancer composition may be administered intra-arterially or intravenously for a duration of about 3 hours to about 5 hours. In addition, administration of the anti-cancer composition can be part of a dosing regimen. In one embodiment, administration may include a regimen that lasts for about 1 to 24 weeks. In another embodiment, the regimen may last for about 4 weeks to 8 weeks.

In general, the anti-cancer compositions of the present invention are administered in a therapeutically effective amount as defined herein. In one embodiment, a therapeutically effective amount may include a dose of about 1mM to about 10mM of the anti-cancer composition or a dose equivalent thereto in a volume of 25ml to 1000 ml.

The anti-cancer compositions described herein can be used to treat any cancer with increased glycolysis; this metabolic phenotype is referred to as the "warburg effect" as described above. In another embodiment, the anti-cancer composition can be used to treat any cancer that can be detected by Positron Emission Tomography (PET) that detects this metabolic phenotype. Human cancer cell lines against which the anticancer composition of the present invention has been shown to be effective include liver, cervix, ovary, lung, breast, colon, neuroblastoma, myeloblastoma, prostate, skin, pancreatic cancer, childhood fibrolamellar hepatocellular carcinoma (FHCC), hepatocellular carcinoma (HCC), non-small cell lung cancer. Accordingly, the cancer of the present invention that can be treated with the anticancer composition of the present invention may be selected from liver, cervix, ovary, lung, breast, colon, neuroblastoma, medulloblastoma, prostate, skin, cancer of the pancreas, childhood fibrolamellar hepatocellular carcinoma (FHCC), hepatocellular carcinoma (HCC), non-small cell lung cancer. The anti-cancer compositions of the present invention have been used to treat human cancer patients with childhood fibrolamellar hepatocellular carcinoma (FHCC), hepatocellular carcinoma (HCC), non-small cell lung cancer, colon cancer, breast cancer, and pancreatic cancer. Accordingly, the cancer that can be treated with the anticancer composition of the present invention may be selected from childhood fibrolamellar type hepatocellular carcinoma (FHCC), hepatocellular carcinoma (HCC), non-small cell lung cancer, colon cancer, breast cancer, pancreatic cancer, and a combination thereof.

In one embodiment, the anti-cancer composition can be used to treat liver cancer. In another embodiment, the anti-cancer composition can be used to treat cervical cancer. In another embodiment, the anti-cancer composition can be used to treat ovarian cancer. In another embodiment, the anti-cancer composition can be used to treat lung cancer. In another embodiment, the anti-cancer composition can be used to treat breast cancer. In another embodiment, the anti-cancer composition can be used to treat colon cancer. In another embodiment, the anti-cancer composition can be used to treat neuroblastoma. In another embodiment, the anti-cancer composition can be used to treat a myeloblastic tumor. In another embodiment, the anti-cancer composition can be used to treat prostate cancer. In another embodiment, the anti-cancer composition can be used to treat skin cancer. In another embodiment, the anti-cancer composition can be used to treat breast cancer. In another embodiment, the anti-cancer composition can be used to treat pancreatic cancer. In another embodiment, the anti-cancer composition can be used to treat fibrolamellar hepatocellular carcinoma (FHCC) in children. In another embodiment, the anti-cancer composition can be used to treat hepatocellular carcinoma (HCC). In another embodiment, the anti-cancer composition can be used to treat small cell and non-small cell lung cancer. In other embodiments, the anti-cancer composition can be used to treat vaginal, anal, testicular, nasal, throat, oral, esophageal, and brain cancers.

In addition to the cancer treatments described above, the present invention provides a method of minimizing the toxicity of a cellular energy inhibitor of formula (I) to a subject receiving the cellular energy inhibitor, the method comprising combining in the subject the cellular energy inhibitor with a biological buffer present in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize metabolic byproducts of the cellular energy inhibitor due to its chemical reactions and/or cellular metabolism:

wherein X is selected from: nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, and amine oxide; r is selected from: OR ', N (R')₂C (O) R' ", C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, and alkali metal; wherein R ' represents H, an alkali metal, C1-C6 alkyl, C6-C12 aryl or C (O) R ' ", R" represents H, C1-C6 alkyl or C6-C12 aryl, and R ' "represents H, C1-C20 alkyl or C6-C12 aryl. In one embodiment, the cellular energy inhibitor and the biological buffer may be combined prior to administration to the subject.

In addition, a method of minimizing adverse drug experiences associated with administration of an anti-cancer composition to a subject may comprise administering the anti-cancer composition to the subject when the subject's blood insulin/glucagon ratio, measured in picomolar (pM), is in the range of about 1 to about 10. The anti-cancer composition can be any anti-cancer composition described herein. In one embodiment, the insulin/glucagon ratio may be in the range of about 2 to about 5. Without intending to be bound by any particular theory, any accidental ingestion of the anticancer active agent by normal cells may be prevented by administering the anticancer composition of the present invention when the subject is low in blood glucose or low in blood insulin/glucagon ratio. In particular, such administration can protect hexokinase 2(HK-2) which is present in small amounts in normal tissues. Under hypoglycemic conditions, the HK-2 enzyme tends to enter the nucleus, rather than the cytosolic compartment, of normal cells. The nuclear localization of HK-2 provides additional protection against chemical agents such as 3-bromopyruvate, 2-bromoacetate, and 2-iodoacetate. As discussed herein, administration can include a therapeutically effective amount of an anti-cancer composition. In one embodiment, the adverse pharmaceutical experience may be cachexia. In another embodiment, the adverse drug experience may be pain.

In addition, the method for evaluating the killing efficacy of an anti-cancer composition in a subject may comprise measuring the lactic acid level of the subject prior to administration of the anti-cancer composition; administering an anti-cancer composition to a subject; measuring the lactic acid level of the subject after administration of the anti-cancer composition; and determining the effectiveness of the kill by measuring and/or correlating the difference between lactate levels as a function of treatment time. The anti-cancer composition may be any of those described herein.

Lactate levels may be measured from a biological fluid from a subject. In one embodiment, the biological fluid may be selected from the group consisting of blood and blood fractions, tears, sweat, urine, ascites, saliva, and combinations thereof. In addition, the measurement may be a colorimetric method using lactate-binding enzyme. In one embodiment, the measurement may be performed by a dipstick or dipstick method. In another embodiment, the measurement may be performed by magnetic resonance imaging.

In certain embodiments, the above-described anti-cancer compositions can comprise one or more of a cellular energy inhibitor, a glycolysis inhibitor, a mitochondrial inhibitor, a halogenated monocarboxylate, and a second chemotherapeutic agent.

The term chemotherapeutic agent includes, but is not limited to: platinum-based agents, such as carboplatin and cisplatin; a nitrogen mustard gas alkylating agent; nitrosourea alkylating agents, such as carmustine (BCNU) and other alkylating agents; antimetabolites such as methotrexate; a purine analog antimetabolite; pyrimidine analog antimetabolites such as fluorouracil (5-FU) and gemcitabine; hormonal antineoplastics such as goserelin, leuprorelin and tamoxifen; natural antitumor agents such as taxanes (e.g., docetaxel and paclitaxel), aldesleukin, interleukin-2, etoposide (VP-16), alpha-interferon, and retinoic acid (ATRA); antibiotic natural antineoplastic agents such as bleomycin, dactinomycin, daunorubicin, doxorubicin and mitomycin; and vinca alkaloid natural antineoplastic agents such as vinblastine and vincristine.

In addition, the following other drugs may also be used in combination with the antitumor agent even if they are not considered as antitumor agents by themselves: dactinomycin; daunorubicin hydrochloride; docetaxel; doxorubicin hydrochloride; alfa-eptine; etoposide (VP-16); sodium ganciclovir; gentamicin sulfate; an alpha-interferon; leuprolide acetate; meperidine hydrochloride; methadone hydrochloride; ranitidine hydrochloride; vinblastine sulfate; and Zidovudine (AZT). For example, fluorouracil has recently been formulated in combination with epinephrine and bovine collagen to form a particularly effective combination.

In addition, the amino acids, peptides, polypeptides, proteins, polysaccharides and other macromolecules listed below may also be used: interleukins 1 to 18, including mutants and analogues; interferons or cytokines such as alpha-, beta-and gamma-interferons; hormones such as Luteinizing Hormone Releasing Hormone (LHRH) and the like and gonadotropin releasing hormone (GnRH); growth factors, such as transforming growth factor-beta (TGF-beta), Fibroblast Growth Factor (FGF), Nerve Growth Factor (NGF), Growth Hormone Releasing Factor (GHRF), Epidermal Growth Factor (EGF), Fibroblast Growth Factor Homolog Factor (FGFHF), Hepatocyte Growth Factor (HGF), and Insulin Growth Factor (IGF); tumor necrosis factor-alpha and beta (TNF-alpha and beta); invasion inhibitor-2 (HF-2); bone morphogenetic protein 1-7(BMP 1-7); a somatostatin; lhygmosin-alpha-1; gamma-globulin; superoxide dismutase (SOD); a complement factor; anti-angiogenic factors; an antigenic substance; and a prodrug.

Preferred chemotherapeutic agents for use with the compositions and methods of treatment described herein include, but are not limited to, altretamine, asparaginase, BCG, bleomycin sulfate, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, 2-chlorodeoxyadenosine, cyclophosphamide, cytarabine, dacarbazine imidazole carboxamide, dactinomycin, daunorubicin-daunorubicin, dexamethasone, doxorubicin, etoposide, floxuridine, fluorouracil, fluoroxymethyltestosterone, flutamide, goserelin, hydroxyurea, idarubicin hydrochloride, ifosfamide, interferon-alpha 2a, interferon-alpha 2b, interferon-alpha n3, irinotecan, leucovorin calcium, leuprorelin, levamisole, lomustine, megestrol, melphalan, bleomycin, fludroxyverine, dactinomycin, dac, L-sarcosylin, melphalan hydrochloride, MESNA, mechlorethamine, methotrexate, mitomycin, mitoxantrone, mercaptopurine, paclitaxel, plicamycin, prednisone, procarbazine, streptozocin, tamoxifen, 6-thioguanine, thiotepa, vinblastine, vincristine, and vinorelbine tartrate.

All of the above-mentioned drugs and additives may be added singly, in combination, as long as there is no negative interaction between or among the respective drugs.

In addition, the present invention provides kits for treating cancer. The kits of the present invention provide the necessary ingredients and instructions to enable one of ordinary skill in the art to combine the ingredients into a suitable dosage form for delivery to a subject. The kit will include at least a cellular energy inhibitor component, at least one sugar component, a glycolysis inhibitor component, a biological buffer component, a container, and a set of instructions. Typically, the ingredients may be admixed such that the dosage form may be administered to a subject for the treatment of cancer. As described herein, such dosages may be part of a therapeutic regimen for the treatment of various cancers.

In one embodiment, a kit for treating cancer may comprise a) a cellular energy inhibitor component of the structure of formula I

Wherein X is selected from: nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, and amine oxide; r is selected from: OR ', N (R')₂C (O) R' ", C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, and alkali metal; wherein R ' represents H, an alkali metal, C1-C6 alkyl, C6-C12 aryl or C (O) R ' ", R" represents H, C1-C6 alkyl or C6-C12 aryl, and R ' "represents H, C1-C20 alkyl or C6-C12 aryl; b) at least one sugar component that stabilizes the cytostatic component by substantially preventing hydrolysis of the cytostatic component; c) a glycolytic inhibitor component; d) a biological buffer component present in an amount sufficient to at least partially deacidify the cellular energy inhibitor component and neutralize metabolic byproducts of the cellular energy inhibitor component; e) a container for containing the ingredient; and f) instructions for using the ingredients to prepare a dosage form and administering the dosage form to a subject.

In one embodiment, the ingredients may further be contained in separate containers within the container.

In one embodiment, the kit may further comprise a syringe filter and sterile gloves for sterilizing at least one of the ingredients.

In one embodiment, the kit may comprise the cellular energy inhibitor in powder form in an amount capable of providing a concentration of about 2.5mM to about 5.0mM when added to a solution.

In addition to the above, the components of the kit may be adjusted as described above.

In addition, the present invention provides use of a cellular energy inhibitor for the preparation of an anticancer drug for the treatment of cancer, wherein the anticancer drug comprises

a) A cellular energy inhibitor of formula I

Wherein X is selected from: nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, and amine oxide; r is selected from: OR ', N (R')₂C (O) R' ", C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, and alkali metal; wherein R ' represents H, an alkali metal, C1-C6 alkyl, C6-C12 aryl or C (O) R ' ", R" represents H, C1-C6 alkyl or C6-C12 aryl, and R ' "represents H, C1-C20 alkyl or C6-C12 aryl;

b) at least one sugar that stabilizes the inhibitor by substantially preventing hydrolysis of the cellular energy inhibitor;

c) an inhibitor of glycolysis; and

d) a biological buffer present in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize metabolic byproducts of the cellular energy inhibitor.

In one embodiment, the anti-cancer drug may be suitable for administration to a subject in a therapeutically effective amount.

In one embodiment, the anti-cancer drug may be administered to the subject when the subject's blood insulin/glucagon ratio is in the range of about 1 to about 10.

In one embodiment, the anti-cancer drug may be administered to the subject after fasting for at least 4 hours.

In one embodiment, the anticancer drug may be suitably administered by a method selected from the group consisting of intra-arterial, intravenous, intraperitoneal, inhalation, intra-tumoral, oral, topical, and subcutaneous methods.

In one embodiment, the administration may be intraarterial.

In one embodiment, the anti-cancer drug may be suitable for intra-arterial or intravenous administration for a duration of about 30 minutes to about 8 hours.

In one embodiment, the anti-cancer drug may be suitable for intra-arterial or intravenous administration for a duration of about 3 hours to about 5 hours.

In one embodiment, administration may include a regimen that lasts for about 1 to 24 weeks.

In one embodiment, a therapeutically effective amount may include a dose equivalent to about 1mM to about 10mM of the anti-cancer composition in a volume of 25ml to 1000 ml.

In one embodiment, the cancer may be selected from childhood fibrolamellar hepatocellular carcinoma (FHCC), hepatocellular carcinoma (HCC), non-small cell lung cancer, colon cancer, breast cancer, pancreatic cancer, liver cancer, and combinations thereof.

The following examples illustrate various embodiments of the compositions, systems, and methods of the present invention that are presently known. It is to be understood, however, that the following are only exemplary or illustrative of the application of the principles of the present compositions, systems, and methods. Numerous modifications and alternative compositions, methods, and systems may be devised by those skilled in the art without departing from the spirit and scope of the present systems and methods. The claims are intended to cover such modifications and arrangements. Thus, while the compositions, systems, and methods of the present invention have been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the acceptable embodiments.

Examples

Example 1Hepatocellular carcinoma study in rats

Hepatocellular carcinoma cells are treated with various anti-cancer agents including 3-bromoacetate. FIG. 3 shows a graph of cancer cell viability as a function of the amount of anti-cancer agent (μ M) over a period of 23 hours. As shown in fig. 3, the use of 3-bromopyruvate as low as 20 μ M provides little cell viability (about 5%). In fact, 3-bromopyruvate provides a 10-fold higher effect as measured by 5% versus 55% cell viability compared to the closest anticancer agent methotrexate.

Example 2Treatment of lung cancer with 3-bromopyruvate

Table 1 provides the results of cell proliferation of human lung cancer cells treated with various known anti-cancer agents compared to 3-bromopyruvate treatment.

TABLE 1

50 μ M of an anticancer agent for 24 hours	Inhibition of cell proliferation,%
		None (control)	0
3-Bromopropanesulfonate	92.5
		Carboplatin	4.5
Cyclophosphamide	0
		Doxorubicin	39.6
5-FluorouracilPyridine (I)	17.8
		Methotrexate (MTX)	28
Paclitaxel	0

As can be seen from table 1, the efficiency of 3-bromopyruvate for lung cancer cells is more than two-fold higher than that of the closest comparative known anticancer agents. Thus, the anti-cancer composition of the present invention is capable of providing at least 90% inhibition of cancer cell proliferation.

Example 3Metastatic lung cancer study

Fig. 4(a) shows a photograph of an dissected lung of a rabbit with a metastatic tumor, without treatment according to the present invention, while fig. 4(b) shows a lung of a rabbit confirmed to be free of metastatic lung cancer after treatment with 3-bromoacetated via IP port delivery. As can be seen from fig. 4(a) and 4(b), the anticancer composition of the present invention can block the metastatic lung tumor.

While the above description and examples illustrate the principles of the invention in one or more particular applications, it will be apparent to those of ordinary skill in the art that numerous modifications in form, usage and details of implementation can be made without the exercise of inventive faculty, and without departing from the principles and concepts of the invention. Accordingly, the invention is intended to be limited only by the claims set forth below.

Claims

1. An anti-cancer composition comprising:

a) a cellular energy inhibitor of formula I

Wherein X is selected from: nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, and amine oxide; and R is selected from: OR ', N (R')₂C (O) R', C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, and alkali metal; wherein R ' represents H, an alkali metal, C1-C6 alkyl, C6-C12 aryl or C (O) R ' ", R" represents H, C1-C6 alkyl or C6-C12 aryl, and R ' "represents H, C1-C20 alkyl or C6-C12 aryl;

c) an inhibitor of glycolysis; and

2. The anti-cancer composition of claim 1, wherein R of formula (I) is OH and X of formula (I) is selected from the group consisting of halides, sulfonates, carboxylates, alkoxides, and amine oxides.

3. The anti-cancer composition of claim 1, wherein X is a halide selected from the group consisting of fluoride, bromide, chloride, and iodide.

4. The anti-cancer composition of claim 1, wherein the cellular energy inhibitor is a 3-halopyruvate selected from the group consisting of 3-fluoropyruvate, 3-chloropropiononate, 3-bromopyruvate, 3-iodopyruvate, and combinations thereof.

5. The anti-cancer composition of claim 4, wherein the composition comprises the cellular energy inhibitor in a concentration from about 0.1mM to about 25.0 mM.

6. The anti-cancer composition of claim 4, wherein the composition comprises the cellular energy inhibitor in a concentration from about 1.0mM to about 10.0 mM.

7. The anti-cancer composition of claim 1, wherein X is a sulfonate selected from the group consisting of trifluoromethanesulfonate, methanesulfonate, and toluenesulfonate.

8. The anti-cancer composition of claim 1, wherein X is an amine oxide.

9. The anti-cancer composition of claim 1, wherein the amine oxide is dimethylamine oxide.

10. The anti-cancer composition of claim 1, wherein the composition comprises a second sugar.

11. The anti-cancer composition of claim 1, wherein the composition comprises a third sugar.

12. The anti-cancer composition of claim 11, wherein at least one of the sugars is a five carbon sugar.

13. The anti-cancer composition of claim 11, wherein at least two of the sugars are five carbon sugars.

14. The anti-cancer composition of claim 13, wherein the five carbon sugars are independently selected from the group consisting of mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, sorbitol, and combinations thereof.

15. The anti-cancer composition of claim 11, wherein at least one of the sugars is glycerol.

16. The anti-cancer composition of claim 11, wherein each sugar may be added in an amount up to the maximum solubility of the sugar.

17. The anti-cancer composition of claim 11, wherein the sugar is glycerol, inositol, and sorbitol.

18. The anti-cancer composition of claim 17, wherein the composition comprises glycerol in the range of about 0.1% to about 3% by weight, inositol in the range of about 1% to about 5% by weight, and sorbitol in the range of about 30% to about 50% by weight.

19. The anti-cancer composition of claim 1, wherein the composition comprises the at least one sugar at a concentration from about 0.1mM to about 250 mM.

20. The anti-cancer composition of claim 1, wherein the composition comprises the at least one sugar at a concentration from about 0.5mM to about 25 mM.

21. The anti-cancer composition of claim 1, wherein the glycolysis inhibitor is 2-deoxyglucose.

22. The anti-cancer composition of claim 1, wherein the composition comprises the glycolysis inhibitor at a concentration from about 0.1mM to about 25.0 mM.

23. The anti-cancer composition of claim 1, wherein the composition comprises the glycolysis inhibitor at a concentration from about 1mM to about 5 mM.

24. The anti-cancer composition of claim 1, wherein the biological buffer is selected from the group consisting of citrate buffer, phosphate buffer, and acetate buffer.

25. The anti-cancer composition of claim 1, wherein the biological buffer is citrate buffer.

26. The anti-cancer composition of claim 1, wherein the byproduct is hydrogen halide and the biological buffer is sodium citrate.

27. The anti-cancer composition of claim 26, wherein the hydrogen halide is hydrogen bromide.

28. The anti-cancer composition of claim 1, wherein the composition comprises the biological buffer at a concentration from about 0.1mM to about 200 mM.

29. The anti-cancer composition of claim 1, wherein the composition comprises the biological buffer at a concentration of about 1mM to about 20 mM.

30. The anti-cancer composition of claim 1, wherein the biological buffer maintains a physiological pH of 4.0 to 8.5.

31. The anti-cancer composition of claim 1, wherein the biological buffer maintains a physiological pH of 5.5 to 8.0.

32. The anti-cancer composition of claim 1, further comprising a halogenated monocarboxylate compound.

33. The anti-cancer composition of claim 32, wherein the halogenated monocarboxylate compound is a halogenated two-carbon monocarboxylate compound.

34. The anti-cancer composition of claim 33, wherein the halo two-carbon monocarboxylate compound is selected from the group consisting of 2-fluoroacetate, 2-chloroacetate, 2-bromoacetate, 2-iodoacetate, and mixtures thereof.

35. The anti-cancer composition of claim 34, wherein the halogenated two-carbon monocarboxylate compound is 2-bromoacetate.

36. The anti-cancer composition of claim 33, wherein the composition comprises the halo two-carbon monocarboxylate compound at a concentration from about 0.01mM to about 5.0 mM.

37. The anti-cancer composition of claim 33, wherein the composition comprises the halo two-carbon monocarboxylate compound at a concentration from about 0.1mM to about 0.5 mM.

38. The anti-cancer composition of claim 32, wherein the halogenated monocarboxylate compound is a halogenated three-carbon monocarboxylate compound.

39. The anti-cancer composition of claim 38, wherein the halogenated three carbon monocarboxylate compound is selected from the group consisting of 3-fluorolactate, 3-chlorolactate, 3-bromolactate, 3-iodolactate, and mixtures thereof.

40. The anti-cancer composition of claim 38, wherein the composition comprises the halo three carbon monocarboxylate compound at a concentration from about 0.5mM to about 250 mM.

41. The anti-cancer composition of claim 38, wherein the composition comprises the halo three carbon monocarboxylate compound at a concentration from about 10mM to about 50 mM.

42. The anti-cancer composition of claim 1, further comprising an anti-fungal and/or anti-bacterial agent.

43. The anti-cancer composition of claim 42, wherein the composition comprises the antifungal agent and/or antibacterial agent at a concentration of about 0.01mM to about 5.0mM, respectively.

44. The anti-cancer composition of claim 42, wherein the composition comprises the antifungal agent and/or antibacterial agent at a concentration of about 0.05mM to about 0.5mM, respectively.

45. The anti-cancer composition of claim 1, further comprising a mitochondrial inhibitor.

46. The anti-cancer composition of claim 45, wherein the mitochondrial inhibitor is selected from the group consisting of oligomycin, peptaibols, aureomycin, and mixtures thereof.

47. The anti-cancer composition of claim 45, wherein the composition comprises the mitochondrial inhibitor in a concentration from about 0.001mM to about 5.0 mM.

48. The anti-cancer composition of claim 45, wherein the composition comprises the mitochondrial inhibitor in a concentration from about 0.01mM to about 0.5 mM.

49. The anti-cancer composition of claim 1, wherein the cellular energy inhibitor and the biological buffer are present in a ratio in mM in the range of 1: 1 to 1: 5.

50. The anti-cancer composition of claim 1, wherein the cellular energy inhibitor and the glycolytic inhibitor are present in a ratio in mM in the range of 5: 1 to 1: 1.

51. The anti-cancer composition of claim 1, wherein the cytostatic agent and the at least one sugar are present in a ratio in mM in the range of 1: 1 to 1: 5.

52. The anti-cancer composition of claim 33, wherein the cytostatic agent and the halogenated two-carbon monocarboxylate compound are present in a ratio in the range of 20: 1 to 4: 1 in mM.

53. The anti-cancer composition of claim 45, wherein the cytostatic agent and the mitochondrial inhibitor are present in a ratio in mM in the range of 20: 1 to 40: 1.

54. A method for the treatment of cancer, the method comprising administering to a subject the anti-cancer composition of claim 1 in a therapeutically effective amount.

55. The method of claim 54, wherein the anti-cancer composition is administered to the subject when the subject's blood insulin/glucagon ratio is in the range of about 1 to about 10.

56. The method of claim 54, wherein the anti-cancer composition is administered to the subject after fasting for at least 4 hours.

57. The method of claim 54, wherein the administration is selected from the group consisting of intraarterial, intravenous, intraperitoneal, inhalation, intratumoral, oral, topical, and subcutaneous administration.

58. The method of claim 57, wherein the administration is intra-arterial.

59. The method of claim 57, wherein the anti-cancer composition is administered intra-arterially or intravenously for a duration of about 30 minutes to about 8 hours.

60. The method of claim 57, wherein the anti-cancer composition is administered intra-arterially or intravenously for a duration of about 3 hours to about 5 hours.

61. The method of claim 54, wherein administering comprises a regimen that lasts for about 1 week to 24 weeks.

62. The method of claim 54, wherein the therapeutically effective amount comprises a dose of about 1mM to about 10mM of the anti-cancer composition in a volume of 25ml to 1000 ml.

63. The method of claim 54, wherein the cancer is selected from the group consisting of childhood fibrolamellar hepatocellular carcinoma (FHCC), hepatocellular carcinoma (HCC), non-small cell lung cancer, colon cancer, pancreatic cancer, liver cancer, and combinations thereof.

64. A method of minimizing toxicity of a cellular energy inhibitor of formula (I) to a subject receiving the cellular energy inhibitor, the method comprising combining in the subject the cellular energy inhibitor with a biological buffer present in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize metabolic byproducts of the cellular energy inhibitor resulting from its chemical reaction and/or cellular metabolism:

wherein X is selected from: nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, and amine oxide; and R is selected from: OR ', N (R')₂C (O) R' ", C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, and alkali metal; wherein R ' represents H, an alkali metal, C1-C6 alkyl, C6-C12 aryl or C (O) R ' ", R" represents H, C1-C6 alkyl or C6-C12 aryl, and R ' "represents H, C1-C20 alkyl or C6-C12 aryl.

65. The method of claim 64, wherein the cellular energy inhibitor and the biological buffer are combined prior to administration to the subject.

66. The method of claim 64, wherein the cellular energy inhibitor is a 3-halopropionate selected from the group consisting of 3-fluoropropionate, 3-chloropropiononate, 3-bromopyruvate, 3-iodopyruvate, and combinations thereof.

67. The method of claim 64, wherein the cytostatic agent is 3-bromopyruvate.

68. The method of claim 64, wherein the biological buffer is selected from the group consisting of citrate buffers, phosphate buffers, and acetate buffers.

69. The method of claim 64, wherein the biological buffer is citrate buffer.

70. The method of claim 64, wherein the biological buffer maintains a physiological pH in the subject of 4.0 to 8.5.

71. The method of claim 64, wherein the biological buffer maintains a physiological pH of 5.5 to 8.0.

72. The method of claim 64, wherein the cellular energy inhibitor and the biological buffer are present in a ratio in mM in the range of 1: 1 to 1: 5.

73. A method of minimizing adverse pharmaceutical experience associated with administering an anti-cancer composition to a subject, the method comprising administering the anti-cancer composition to the subject when the subject's blood insulin/glucagon ratio is in the range of about 1 to about 10; the anti-cancer composition is an inhibitor of formula (I):

74. The method of claim 73, wherein the insulin to glucagon ratio is in the range of about 2 to about 5.

75. The method of claim 73, wherein the anti-cancer composition is administered to the subject after fasting for at least 4 hours.

76. The method of claim 73, wherein the administration is selected from the group consisting of intraarterial, intravenous, intraperitoneal, inhalation, intratumoral, oral, topical, and subcutaneous administration.

77. The method of claim 76, wherein the administration is intra-arterial.

78. The method of claim 73, wherein the anti-cancer composition is administered intra-arterially or intravenously for a duration of about 30 minutes to about 8 hours.

79. The method of claim 73, wherein the anti-cancer composition is administered intra-arterially or intravenously for a duration of about 3 hours to about 5 hours.

80. The method of claim 73, wherein administering comprises a regimen that lasts for about 1 week to 24 weeks.

81. The method of claim 73, wherein administering comprises a therapeutically effective amount of the anti-cancer composition.

82. The method of claim 81, wherein the therapeutically effective amount comprises a dose of about 1mM to about 10mM of the anti-cancer composition in a volume of 25ml to 1000 ml.

83. The method of claim 73, wherein the adverse pharmaceutical experience is cachexia.

84. The method of claim 73, wherein the adverse drug experience is pain.

85. A method of assessing the killing efficacy of an anti-cancer composition in a subject, the method comprising:

a) measuring the lactic acid level of the subject prior to administration of the anti-cancer composition;

b) administering an anti-cancer composition to a subject;

c) measuring the lactic acid level of the subject after administration of the anti-cancer composition; and

d) determining the killing efficacy by measuring and/or correlating the difference between lactate levels as a function of treatment time;

wherein the anticancer composition comprises

i) A cellular energy inhibitor of formula I

Wherein X is selected from: nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, and amine oxide; and R is selected from: OR ', N (R')₂C (O) R' ", C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, and alkali metal; wherein R ' represents H, an alkali metal, C1-C6 alkyl, C6-C12 aryl or C (O) R ' ", R" represents H, C1-C6 alkyl or C6-C12 aryl, and R ' "represents H, C1-C20 alkyl or C6-C12 aryl;

ii) at least one sugar that stabilizes the inhibitor by substantially preventing hydrolysis of the cellular energy inhibitor;

iii) glycolytic inhibitors; and

iv) a biological buffer present in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize metabolic by-products of the cellular energy inhibitor.

86. The method of claim 85, wherein the lactic acid level is measured from a biological fluid from the subject.

87. The method of claim 86, wherein the biological fluid is selected from the group consisting of: blood and blood fractions, tears, sweat, urine, ascites, saliva, and combinations thereof.

88. The method of claim 85, wherein the measuring is performed colorimetrically using the lactate binding enzyme.

89. The method of claim 85, wherein the measuring is performed by a dipstick or dipstick method.

90. The method of claim 85, wherein the measuring is performed by magnetic resonance imaging.

91. A kit for treating cancer, comprising:

a) a cellular energy inhibitor component of formula I

b) at least one sugar component that stabilizes the cytostatic component by substantially preventing hydrolysis of the cytostatic component;

c) a glycolytic inhibitor component;

d) a biological buffer component present in an amount sufficient to at least partially deacidify the cellular energy inhibitor component and neutralize metabolic by-products of the cellular energy inhibitor component;

e) a container for containing the ingredient; and

f) a set of instructions for using the ingredients to prepare a dosage form and administering the dosage form to a subject.

92. The kit of claim 91, wherein the components are further contained in separate containers within the container.

93. The kit of claim 91, wherein the kit further comprises a syringe filter and sterile gloves for sterilizing at least one of the ingredients.

94. The kit of claim 91, wherein the kit comprises a solution of at least one sugar in the range of about 7mM to about 14mM, a biological buffer in the range of about 7.5mM to about 15mM, and a glycolytic inhibitor in the range of about 1mM to about 2mM, such that upon addition of the cellular energy inhibitor, the solution has a biological pH, ionic strength, and bulk osmomolecular concentration that is physiologically equivalent to normal humans.

95. The kit of claim 94, wherein the kit contains the cellular energy inhibitor in powder form in an amount that provides a concentration of about 2.5mM to about 5.0mM when added to a solution.

96. The kit of claim 91, wherein R of formula (I) is OH and X of formula (I) is selected from the group consisting of halides, sulfonates, carboxylates, alkoxides, and amine oxides.

97. The kit of claim 91, wherein X is a halide selected from the group consisting of fluoride, bromide, chloride, and iodide.

98. The kit of claim 91, wherein the cellular energy inhibitor is a 3-halopropionate selected from the group consisting of 3-fluoropropionate, 3-chloropropiononate, 3-bromopyruvate, 3-iodopyruvate, and combinations thereof.

99. The kit of claim 98, wherein the composition comprises the cellular energy inhibitor in a concentration from about 0.1mM to about 25.0 mM.

100. The kit of claim 98, wherein the composition comprises the cellular energy inhibitor in a concentration from about 1.0mM to about 10.0 mM.

101. The kit of claim 91, wherein X is a sulfonate selected from the group consisting of triflate, mesylate, and tosylate.

102. The kit of claim 91, wherein X is an amine oxide.

103. The kit of claim 91 wherein the amine oxide is dimethylamine oxide.

104. The kit of claim 91, wherein the composition comprises a second saccharide.

105. The kit of claim 91, wherein the composition comprises a third saccharide.

106. The kit of claim 105, wherein at least one of the sugars is a five-carbon sugar.

107. The kit of claim 105, wherein at least two of the sugars are five-carbon sugars.

108. The kit of claim 106 wherein the five-carbon sugars are independently selected from the group consisting of mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, sorbitol, and combinations thereof.

109. The kit of claim 105, wherein at least one of the sugars is glycerol.

110. The kit of claim 105, wherein each sugar can be added in an amount up to the maximum solubility of the sugar.

111. The kit of claim 105, wherein the sugars are glycerol, inositol, and sorbitol.

112. The kit of claim 111 wherein the composition comprises glycerol in the range of about 0.1% to about 3% by weight, inositol in the range of about 1% to about 5% by weight, and sorbitol in the range of about 30% to about 50% by weight.

113. The kit of claim 105, wherein the composition comprises at least one saccharide at a concentration of about 0.1mM to about 250 mM.

114. The kit of claim 91, wherein the composition comprises at least one saccharide at a concentration of about 0.5mM to about 25 mM.

115. The kit of claim 91, wherein the glycolytic inhibitor is 2-deoxyglucose.

116. The kit of claim 91, wherein the composition comprises the glycolytic inhibitor in a concentration from about 0.1mM to about 25.0 mM.

117. The kit of claim 91, wherein the composition comprises the glycolytic inhibitor in a concentration from about 1mM to about 5 mM.

118. The kit of claim 91, wherein the biological buffer is selected from the group consisting of citrate buffer, phosphate buffer, and acetate buffer.

119. The kit of claim 91, wherein the biological buffer is citrate buffer.

120. The kit of claim 91, wherein the byproduct is hydrogen halide and the biological buffer is sodium citrate.

121. The kit of claim 120, wherein the hydrogen halide is hydrogen bromide.

122. The kit of claim 91, wherein the composition comprises the biological buffer at a concentration of about 0.1mM to about 200 mM.

123. The kit of claim 91, wherein the composition comprises the biological buffer at a concentration of about 1mM to about 20 mM.

124. The kit of claim 91, wherein the biological buffer maintains a physiological pH of 4.0 to 8.5.

125. The kit of claim 91, wherein the biological buffer maintains a physiological pH of 5.5 to 8.0.

126. The kit of claim 91, further comprising a halogenated monocarboxylate.

127. The kit of claim 126, wherein the halogenated monocarboxylate is a halogenated two-carbon monocarboxylate.

128. The kit of claim 127, wherein the halo two-carbon monocarboxylate is selected from the group consisting of 2-fluoroacetate, 2-chloroacetate, 2-bromoacetate, 2-iodoacetate, and mixtures thereof.

129. The kit of claim 128, wherein the halogenated two-carbon monocarboxylate is 2-bromoacetate.

130. The kit of claim 127, wherein the composition comprises the halo two-carbon monocarboxylate compound at a concentration from about 0.01mM to about 5.0 mM.

131. The kit of claim 127, wherein the composition comprises the halo two-carbon monocarboxylate compound at a concentration from about 0.1mM to about 0.5 mM.

132. The kit of claim 126, wherein the halogenated monocarboxylate is a halogenated three-carbon monocarboxylate.

133. The kit of claim 132, wherein the halogenated three carbon monocarboxylate compound is selected from the group consisting of 3-fluorolactate, 3-chlorolactate, 3-bromolactate, 3-iodolactate, and mixtures thereof.

134. The kit of claim 132, wherein the composition comprises the halo three carbon monocarboxylate compound at a concentration from about 0.5mM to about 250 mM.

135. The kit of claim 132, wherein the composition comprises the halo three carbon monocarboxylate compound at a concentration from about 10mM to about 50 mM.

136. The kit of claim 91, further comprising an antifungal agent and/or an antibacterial agent.

137. The kit of claim 136, wherein the composition comprises the antifungal agent and/or antibacterial agent at a concentration of about 0.01mM to about 5.0mM, respectively.

138. The kit of claim 136, wherein the composition comprises the antifungal agent and/or antibacterial agent at a concentration of about 0.05mM to about 0.5mM, respectively.

139. The kit of claim 91, further comprising a mitochondrial inhibitor.

140. The kit of claim 139 wherein the mitochondrial inhibitor is selected from the group consisting of oligomycin, peptaibols, aureomycin, and mixtures thereof.

141. The kit of claim 139, wherein the composition comprises the mitochondrial inhibitor in a concentration from about 0.001mM to about 5.0 mM.

142. The kit of claim 139, wherein the composition comprises the mitochondrial inhibitor in a concentration from about 0.01mM to about 0.5 mM.

143. The kit of claim 91, wherein the cellular energy inhibitor and the biological buffer are present in a ratio in mM in the range of 1: 1 to 1: 5.

144. The kit of claim 91, wherein the cellular energy inhibitor and the glycolytic inhibitor are present in a ratio in mM in the range of 5: 1 to 1: 1.

145. The kit of claim 91, wherein the cellular energy inhibitor and the at least one sugar are present in a ratio in mM in the range of 1: 1 to 1: 5.

146. The kit of claim 127, wherein the cytostatic agent and the halodicarbomonocarboxylate are present in a ratio in mM in the range of 20: 1 to 4: 1.

147. The kit of claim 139, wherein the cellular energy inhibitor and mitochondrial inhibitor are present in a ratio in mM in the range of 20: 1 to 40: 1.

148. Use of a cellular energy inhibitor for the preparation of an anti-cancer medicament for the treatment of cancer, wherein the anti-cancer medicament comprises

a) A cellular energy inhibitor of formula I

Wherein X is selected from: nitro, imidazole, halides, sulfonic acidsHydrides, carboxylates, alkoxides, and amine oxides; and R is selected from: OR ', N (R')₂C (O) R' ", C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, and alkali metal; wherein R ' represents H, an alkali metal, C1-C6 alkyl, C6-C12 aryl or C (O) R ' ", R" represents H, C1-C6 alkyl or C6-C12 aryl, and R ' "represents H, C1-C20 alkyl or C6-C12 aryl;

c) an inhibitor of glycolysis; and

149. The use of claim 148, wherein the anti-cancer agent is adapted for administration to a subject in a therapeutically effective amount.

150. The use of claim 148, wherein the anti-cancer medicament is administered to the subject when the subject has a blood insulin/glucagon ratio in the range of about 1 to about 10.

151. The use of claim 148, wherein the anti-cancer agent is administered to the subject after fasting for at least 4 hours.

152. The use of claim 148, wherein the anti-cancer medicament is adapted for administration by a method selected from the group consisting of intraarterial, intravenous, intraperitoneal, inhalation, intratumoral, oral, topical and subcutaneous administration.

153. The use of claim 152, wherein the administration is intra-arterial administration.

154. The use of claim 152, wherein the anti-cancer medicament is adapted for intraarterial or intravenous administration for a duration of about 30 minutes to about 8 hours.

155. The use of claim 152, wherein the anti-cancer medicament is adapted for intraarterial or intravenous administration for a duration of about 3 hours to about 5 hours.

156. The use of claim 149, wherein the administration comprises a regimen that lasts for about 1 week to 24 weeks.

157. The use of claim 149, wherein the therapeutically effective amount comprises a dose of about 1mM to about 10mM anticancer drug in a volume of 25ml to 1000 ml.

158. The use of claim 148, wherein the cancer is selected from the group consisting of childhood fibrolamellar hepatocellular carcinoma (FHCC), hepatocellular carcinoma (HCC), non-small cell lung cancer, colon cancer, pancreatic cancer, and combinations thereof.