US20110118528A1 - Methods and Nutritional Formulations to Increase the Efficacy and Reduce the Side Effects of Cancer Treatment - Google Patents

Methods and Nutritional Formulations to Increase the Efficacy and Reduce the Side Effects of Cancer Treatment Download PDF

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US20110118528A1
US20110118528A1 US12/910,508 US91050810A US2011118528A1 US 20110118528 A1 US20110118528 A1 US 20110118528A1 US 91050810 A US91050810 A US 91050810A US 2011118528 A1 US2011118528 A1 US 2011118528A1
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patient
diet
cancer
chemotherapy
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Valter D. Longo
Changhan Lee
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University of Southern California USC
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    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06Q—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES, NOT OTHERWISE PROVIDED FOR
    • G06Q10/00—Administration; Management
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L13/00—Meat products; Meat meal; Preparation or treatment thereof
    • A23L13/60—Comminuted or emulsified meat products, e.g. sausages; Reformed meat from comminuted meat product
    • A23L13/65—Sausages
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P20/00—Coating of foodstuffs; Coatings therefor; Making laminated, multi-layered, stuffed or hollow foodstuffs
    • A23P20/20—Making of laminated, multi-layered, stuffed or hollow foodstuffs, e.g. by wrapping in preformed edible dough sheets or in edible food containers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates in general to diet and cancer treatment. More specifically, the invention provides methods that may be used to sensitize cancer cells to chemotherapy drugs, while protecting normal cells.
  • Chemotherapy can extend survival in patients diagnosed with a wide range of malignancies.
  • toxic side-effects to normal cells and tissues limits chemotherapy dose intensity, frequency, and efficacy.
  • the cardiotoxicity and nephrotoxicity associated with the widely prescribed anti-cancer drugs, doxorubicin and cisplatin, respectively limit their full therapeutic potential (Rajagopalan, S. Cancer Res. 1988; Hale, J. P. Arch. Dis. Child 1994; Dobyan, D. C., J. Pharmacol. E.T 1980; Fillastre, J. P. Toxicology let 1989).
  • reduction of undesired toxicity by selective protection of normal cells without compromising the killing of malignant cells represents a promising strategy to enhance cancer treatment.
  • Calorie restriction is known to enhance stress resistance and extend life span in organisms ranging from yeast to mammals. Calorie restriction has also been shown to delay cancer growth, but its effect is small and it cannot be combined with chemotherapy nor can it be applied alone, since it requires a long-term weight loss which is detrimental to cancer patients and also very difficult to maintain.
  • the method of this embodiment includes a step in which a patient with cancer is identified and then provided with a first diet for a first predetermined period of time.
  • the first diet provides the patient with at most 50% of the patient's normal caloric intake with at least 50% of the kilocalories being derived from fat, preferably monounsaturated.
  • the patient is then provided with a second diet for a second predetermined period of time.
  • the second diet provides the patient with at most 500 kcal/day.
  • the patient is then provided with a third diet that optimizes weight regain and the replenishment of essential nutrients required for optimal recovery and health of normal cells and organs.
  • the present embodiment provides a short-term modified diet protocol that is effective in protecting normal cells and impeding and retarding cancer cell growth. The protocol and modified diet will promote these effects without causing chronic weight loss in patients,
  • a method of sensitizing cancer to chemotherapy drugs includes a step in which a patient with cancer is identified and then provided with a first diet for a first predetermined period of time.
  • the first diet provides the patient with at most 50% of the patient's normal caloric intake with at least 50% of the kilocalories being derived from fat.
  • the patient is then provided with a second diet for a second predetermined period of time.
  • the second diet provides the patient with at most 500 kcal/day.
  • the patient is then provided with a third diet that optimizes weight regain and the replenishment of essential nutrients required for optimal recovery and health of normal cells and organs.
  • the present embodiment provides a short-term modified diet protocol that is effective in protecting normal cells and sensitizing cancer from/to chemotherapy (Differential Stress Resistance). The protocol and modified diet will promote these effects without causing chronic weight loss in patients.
  • a method of sensitizing cancer to radiation therapy includes a step in which a patient with cancer is identified and then provided with a first diet for a first predetermined period of time.
  • the first diet provides the patient with at most 50% of the patient's normal caloric intake with at least 50% of the kilocalories being derived from fat.
  • the patient is then provided with a second diet for a second predetermined period of time.
  • the second diet provides the patient with at most 500 kcal/day.
  • the patient is then provided with a third diet that optimizes weight regain and the replenishment of essential nutrients required for optimal recovery and health of normal cells and organs.
  • the present embodiment provides a short-term modified diet protocol that is effective in protecting normal cells and sensitizing cancer from/to radiation therapy (Differential Stress Resistance). The protocol and modified diet will promote these effects without causing chronic weight loss in patients.
  • formulations containing specific ranges of proteins, essential amino acids, carbohydrates, fats, vitamins, minerals and essential fatty acids to delay cancer growth when administered alone or protect the host against chemotherapy and/or radiation therapy and sensitize cancer cells to chemotherapy and/or radiation therapy are provided.
  • FIG. 1 provides plots of laboratory values of blood cell counts for case 1: (A) Neutrophils; (B) Lymphocytes; (C) White blood cells, WBC; (D) Platelets; (E) Red blood cells, RBC (F) Hemoglobin, Hgb; (G) Hematocrit, Hct; (H) Body weight, filled triangle indicates day of chemotherapy; open square indicates fasting, normal ranges of laboratory values are indicated by dash lines;
  • FIG. 2 is a bar chart providing self-reported side-effects after chemotherapy for case 1, data represents the average of 2 cycles of chemo-alone Vs the average of 2 cycles of chemo-fasting treatments;
  • FIG. 3 is a bar chart providing self-reported side-effects after chemotherapy for case 2, data represents the average of 3 cycles of chemo-alone Vs the average of 5 cycles of chemo-fasting treatments;
  • FIG. 4 provides plots of laboratory values of blood cell counts for case 3: (A) Neutrophils; (B) Lymphocytes; (C) White blood cells, WBC; (D) Platelets; (E) Red blood cells, RBC (F) Hemoglobin, Hgb; (G) Hematocrit, Hct; (H) Prostate specific antigen (PSA) level, the patient was enrolled in abiraterone acetate (CYP17 inhibitor) trial for 90 days indicated by vertical dash lines, the patient also received G-CSF (Neulasta) on the day of chemotherapy except during the treatment with abiraterone acetate, filled triangle indicates day of chemotherapy; open square indicates fasting, arrow indicates testosterone application (cream 1%), normal ranges of laboratory values are indicated by horizontal dash lines;
  • G-CSF Neurogen
  • FIG. 5 is a bar chart of self-reported side-effects after chemotherapy for case 3, data represent the average of 5 cycles of chemo-alone VS the average of 7 cycles of chemo-fasting treatments;
  • FIG. 6 provides plots of laboratory values of blood cell counts for case 4: (A) Neutrophils; (B) Lymphocytes; (C) White blood cells, WBC; (D) Platelets; (E) Red blood cells, RBC (F) Hemoglobin, Hgb; (G) Hematocrit, Hct; filled triangle indicates day of chemotherapy; open square indicates fasting, normal ranges of laboratory values are indicated by dash lines;
  • FIG. 7 is a bar chart of self-reported side-effects after chemotherapy for case 4, data represent the average of 5 cycles of chemo-alone VS 1 cycle of chemo-fasting treatment;
  • FIG. 8 is a bar chart of self-reported side-effects after chemotherapy for case 5, data represent 1 cycle of chemotherapy-alone (1 st cycle) VS the average of 5 cycles of chemo-fasting treatments;
  • FIG. 9 provides plots of laboratory values of blood cell counts for case 6: (A) Neutrophils; (B) Lymphocytes; (C) White blood cells, WBC; (D) Platelets; (E) Red blood cells, RBC (F) Hemoglobin, Hgb; (G) Hematocrit, Hct; filled triangle indicates day of chemotherapy; open square indicates fasting, normal ranges of laboratory values are indicate by dash lines, the patient received red blood cell transfusion (3 units) on day 71 and also received G-CSF (Neulasta) as indicated;
  • FIG. 10 is a bar chart of self-reported side-effects after chemotherapy for case 6;
  • FIG. 11 provides plots of laboratory values of blood cell counts for case 7: (A) Neutrophils; (B) Lymphocytes; (C) White blood cells, WBC; (D) Platelets; (E) Red blood cells, RBC (F) Hemoglobin, Hgb; (G) Hematocrit, Hct; (H) Prostate specific antigen (PSA) level, filled triangle indicates day of chemotherapy; open square indicates fasting, arrow indicates abiraterone administration, normal ranges of laboratory values are indicate by dash lines, the patient also received G-CSF Neulasta) as indicated;
  • FIG. 12 is a bar chart of self-reported side-effects after chemotherapy for case 7, data represent the average of 8 cycles of chemo-fasting treatments;
  • FIG. 13 is a bar chart of self-reported side-effects after chemotherapy for case 8, data represent the average of 4 cycles of chemo-fasting treatments;
  • FIG. 14 is a bar chart of self-reported side-effects after chemotherapy for case 9, data represent the average of 4 cycles of chemo-fasting treatments;
  • FIG. 15 provides plots of laboratory values of blood cell counts for case 10: (A) Neutrophils; (B) Lymphocytes; (C) White blood cells, WBC; (D) Platelets; (E) Red blood cells, RBC (F) Hemoglobin, Hgb; (G) Hematocrit, Hct; (G) Hematocrit, Hct, filled triangle indicates day of chemotherapy; open square indicates fasting, normal ranges of laboratory values are indicated by dash lines, the patient also received G-CSF (Neulasta) as indicated;
  • FIG. 16 is a bar chart of self-reported side-effects after chemotherapy for case 10, data represent the average of 6 cycles of chemo-fasting treatments;
  • FIG. 17 is a bar chart of self-reported side-effects after chemotherapy with or without fasting.
  • A Data represent average of CTC grade reported by all the patients in this study; 18 chemotherapy cycles under ad-lib diet were compared to 46 chemo-fasting cycles;
  • B Data represent average of CTC grade from matching fasting and non-fasting cycles; 6 patients received either chemo-alone or chemofasting treatments, self-reported side effects from the closest two cycles were compared one another, statistical analysis was performed only from matching cycles, and data presented as standard error of the mean (SEM), P value was calculated with unpaired, two tail t test (*, P ⁇ 0.05);
  • FIG. 20 provides plots of an experiment in which female BALB/c mice weighing 20-25 g were subcutaneously injected with syngeneic breast cancer cells (4T1-luc; 2 ⁇ 10 ⁇ 5 cells/mouse), on day 13 the tumor progressed significantly to 300-500 mm 3 , and treatment began by fasting the mice for 48 hours prior to irradiation (IR; 5 Gy), the second cycle of STS/IR (3 Gy) was done 1 week later, and statistical analysis was done using Student's test for each day, *p ⁇ 0.05;
  • FIG. 21 provides plots of an experiment in which female C57BL/6 mice weighing 25-30 g were subcutaneously injected with syngeneic glioma cancer cells (GL26; 3 ⁇ 10 ⁇ 5 cells/mouse), on day 27 the tumor progressed significantly to 500-1000 mm 3 , and treatment began by fasting the mice for 48 hours prior to irradiation (IR; 7.5 Gy), the second cycle of STS/IR (3 Gy) was done 1 week later, and statistical analysis was done using Student's test for each day, *p ⁇ 0.05;
  • FIG. 22 provides plots showing that fasting sensitizes tumors to chemotherapy; in particular, subcutaneous tumor progression of murine (A) breast cancer (4T1), (B) melanoma (B16), and (C) glioma (GL26) is shown as percent growth together with the tumor size immediately before and after each 48-hour fasting cycle;
  • A murine
  • B melanoma
  • GL26 glioma
  • FIG. 23 provides plots showing that body weight lost during 48-60 hours of fasting was readily recovered after resuming normal feeding in (A-C) subcutaneous and (D) metastatic mouse models of cancer: (A) murine breast (4T1) cancer-bearing BALB/c mice, (B) murine melanoma (B16)- and (C) glioma (GL26)-bearing C57BL mice, and (D) murine neuroblastoma (Neuro-2a)-bearing A/J mice;
  • FIG. 24 provides plots showing that 24-48 hours of fasting enhanced the survival of metastatic murine melanoma (B16);
  • FIG. 25 is a bar chart showing metastasis of B16 melanoma cells to different organs compared to mice that received DXR under normal feeding;
  • FIG. 26 provides plots showing that fasting also sensitized tumors in 2 metastatic models of murine neuroblastoma: NXS2 (P ⁇ 0.001) resulting in long-term survival;
  • FIG. 28 provides plots showing that fasting sensitized cancer cells to chemotherapy in metastatic mourse model of breast cancer (4T1), log-rank test, P ⁇ 0.0005;
  • FIG. 29 provides plots showing that fasting retarded tumor progression of xenografted human neuroblastoma (ACN) which was subcutaneously injected into nude mice; once tumors were palpable, fasting was performed for a total of 5 cycles; one-way ANOVA with Tukey's post-test for subcutaneous models (Student's t-test for (B) day 27)), and log-rank test for metastatic models, *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001;
  • ACN xenografted human neuroblastoma
  • FIG. 30 provides a bar chart showing that serum from fasted mice sensitized breast cancer cells to doses of DXR and CP that were minimally toxic under serum from mice fed ad lib.
  • Control groups were cultured in 1.0 g/L and 2.0 g/L glucose, for human and murine cells respectively, supplemented with 10% FBS.
  • STS groups were cultured in 0.5 g/L glucose supplemented with 1% FBS. Survival was determined by MTT-reduction.
  • FIGS. 33-34 For the effects of all combinations of glucose and serum on DXR and CP, refer to FIGS. 33-34 ;
  • FIG. 31 provides a bar chart showing blood glucose levels from fasted mice
  • FIG. 32 provides plots showing the results of an experiment that STS sensitized 15 out of 17 different cancer cells to DXRin vitr, STS was applied to 4 murine cancer cells—breast cancer (4T1), melanoma (B16), glioma (GL26), and neuroblastoma (NXS2 and Neuro-2a)—and 13 different human cancer cells—prostate cancer (PC3, 22RV1), breast cancer (MCF-7, C42B), glioblastoma (U87-MG), cervical cancer (HeLa), colon cancer (LOVO), neuroblastoma (ACN, SH-SY5Y), epidermoid carcinoma (A431), melanoma (MZ-MEL) and ovarian cancer (OVCAR)—and challenged with DXR;
  • FIG. 33 provides plots showing the effects of all combinations of glucose and serum on DXR
  • FIG. 34 provides plots showing effects of all combinations of glucose and serum on CP
  • FIG. 35 provide bar charts showing that IGF-I reverses the STS-dependent sensitization of cancer cells to chemotherapy; murine breast cancer (4T1) and melanoma (B16) cells were treated with rhIGF-I (200 ⁇ M) during glucose restriction (0.5 g/L vs 2.0 g/L, under 1% FBS), followed by DXR (16 ⁇ M) treatment; Student's t-test; *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001;
  • FIG. 36 provides assay results showing that fasting and regulation of oxidative stress and DNA repair; STS was genotoxic and synergistically increased DNA damage when combined with (A) CP in breast cancer (4T1) and with DXR in (B) melanoma (B16), and (C) glioma (GL26) cells as determined by comet assay.
  • Cells in the control and STS groups were cultured in normal glucose (2.0 g/L) or low glucose (0.5 g/L), respectively, supplemented with 1% FBS. Drugs were selected for consistency with the in vivo studies in FIG. 22A-C ;
  • FIG. 37 provides results of microarray analysis on subcutaneous breast tumors (4T1) from normally fed or fasted mice show differential regulation of cellular proliferation pathways;
  • FIG. 38 provides results of microarray analysis on subcutaneous breast tumors (4T1) from normally fed or fasted mice show an increase in translational mechanisms including ribosome assembly/biogenesis;
  • FIG. 39 provides assay results showing that fasting increased Akt and S6K and reduced eIF2 ⁇ phosphorylation, consistent with increased translational components, in murine breast cancer cells (4T1) (A) in vivo and (B) in vitro;
  • FIG. 40 is a bar chart showing STS hindered cancer cell proliferation in vitro, consistent with the retarded tumor growth in mice;
  • FIG. 41 is a bar chart showing that fasting differentially regulated the expression of stress-responsive components including forkhead box O3 (FOXO3), nuclear factor kappa B (NFkB), and hemeoxygenase 1 (HO-1) by causing significant repression in the tumors, but considerable induction in the normal organs; Student's t-test; *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001;
  • FXO3 forkhead box O3
  • NFkB nuclear factor kappa B
  • HO-1 hemeoxygenase 1
  • FIG. 42 provides assay results showing that STS increased intracellular oxidative stress estimated by a superoxide marker (DHE);
  • DHE superoxide marker
  • FIG. 43 provides assay results showing that STS increases CP-induced intracellular superoxide levels; murine breast cancer cells (4T1) were fasted and treated with CP in vitro;
  • FIG. 44 provides assay results showing that fasting selectively increased the level of caspase-3 cleavage/activation in the tumors, but not in the normal organs/cells (A) in vivo and (B) in vitro;
  • FIG. 45 provides assay results showing that STS induced autophagy to sustain cellular energetics
  • FIG. 46 is a bar chart showing autophagy-blockade during STS further increases cell death
  • FIG. 47 is a plot of the results of an experiment in which murine breast cancer cells (4T1) were treated with hemin, the most common inducer of HO-1 (10 ⁇ M), in normal or low glucose under 1% FBS, then challenged with CP;
  • FIG. 48 is a plot showing that HO-1 is a major mediator of fasting-dependent DSR; murine breast cancer cells were treated with hemin, the most common inducer of HO-1, in normal or low glucose under normal (10%) or low (1%) FBS for 24 hours before and 24 during CP treatment;
  • FIG. 49 is a plot of the results of an experiment in which murine breast cancer cells (4T1) were treated with ZnPP (20 ⁇ M), a commonly used HO-1 inhibitor in normal or low glucose under 1% FBS, then challenged with CP;
  • FIG. 50 is a plot showing that HO-1 is a major mediator of fasting-dependent DSR; murine breast cancer cells were treated with ZnPP, a commonly used HO-1 inhibitor, in normal or low glucose under normal (10%) or low (1%) FBS for 24 hours before and 24 during CP treatment;
  • FIG. 51 provides a model for fasting-dependent tumor sensitization to chemotherapy in response to fasting, glucose, IGF-I and other pro-growth molecules/factors are reduced, malignant cells respond to this reduction by activating AKT/S6K and eIF2 ⁇ and attempting to increase translation but also by reducing the expression of stress resistance proteins FOXO3a, NFkB, and HO-1,these changes lead to the increase in oxidative stress and DNA damage, activation of caspase-3 and cell death;
  • FIG. 52 is a plot of the results of an experiment in which serum IGF-I levels in female CD1 mice fed with control diet (T.D.7912), fed with amino acid formula (AA-D), or starved for 2.5 days (short-term starvation, STS); modified amino acid diet reduced serum IGF-I by 50% after 5 days' feeding;
  • FIG. 53 is a plot showing that feeding of modified amino acid diet maintained low serum IGF-I level after short-term starvation (STS); female CD1 mice were starved for 2.5 days and fed with control diet (T.D.7912) or modified amino acid diet (AA-D, for 2 or 4 days;
  • STS short-term starvation
  • FIG. 54 is a plot showing blood glucose levels: (A) female CD1 mice were starved for 3 days or fed with hypocaloric (6% of normal caloric intake) VCM diet (for 3 days) or modified amino acid diet (AA-D, for 3 or 5 days); (B) female CD1 mice were starved for 2.5 days and re-fed with either control of modified amino acid diet for 4 days, glucose was measured after 4-hours of food deprivation;
  • FIG. 55 provide bar charts giving results of experiments in which serum IGF-I levels: female CD1 mice were starved for 2.5 days (STS), fed with hypo-caloric VCM-M diet (for 2 days) followed by 1-day of modified amino acid diet (M/AA), fed with hypo-caloric VCM-H diet (for 2 days) followed by 1-day of modified amino acid diet (H/AA), Tukey's test, compared to control; (B) Two-days feeding of hypocaloric VCM diets followed by 1-day of modified amino acid diet enhanced survival of mice treated with Doxorubicin (DXR, 18 mg/kg);
  • DXR Doxorubicin
  • FIG. 56 is a plot of the results of an experiment in which female CD1 mice were fed with control (TD.7912), starved, or fed with VegeGel for 2.5 days: (A) Fasting blood glucose; (B) Serum IGF-I levels; and
  • FIG. 57 is a plot of the results of an experiment in which female CD1 mice were fed with control diet (TD.7912), calorie-restricted ketogenic diet (3 days), or calorie-restricted ketogenic diet (1 days) followed with VegeGel (2 days): (A) Fasting blood glucose; (B) Serum IGF-I levels.
  • percent, “parts of,” and ratio values are by weight; the description of a group or class of materials as suitable or preferred for a given purpose in connection with the invention implies that mixtures of any two or more of the members of the group or class are equally suitable or preferred; description of constituents in chemical terms refers to the constituents at the time of addition to any combination specified in the description, and does not necessarily preclude chemical interactions among the constituents of a mixture once mixed; the first definition of an acronym or other abbreviation applies to all subsequent uses herein of the same abbreviation and applies mutatis mutandis to normal grammatical variations of the initially defined abbreviation; and, unless expressly stated to the contrary, measurement of a property is determined by the same technique as previously or later referenced for the same property.
  • essential amino acid refers to amino acids that cannot be synthesized by an organism.
  • essential amino acids include isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine.
  • the following amino acids are also essential in humans under certain conditions—histidine, tyrosine, and selenocysteine.
  • kcal kcal
  • calorie refers to the so-called small calorie.
  • patient refers to a human or animal, including all mammals such as primates (particularly higher primates), sheep, dog, rodents (e.g., mouse or rat), guinea pig, goat, pig, cat, rabbit, and cow.
  • starving means subjecting a cell or patient to reduced or no nutrients.
  • cancer refers to a disease or disorder characterized by uncontrolled division of cells and the ability of these cells to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis.
  • exemplary cancers include, but are not limited to, primary cancer, metastatic cancer, carcinoma, lymphoma, leukemia, sarcoma, mesothelioma, glioma, germinoma, choriocarcinoma, prostate cancer, lung cancer, breast cancer, colorectal cancer, gastrointestinal cancer, bladder cancer, pancreatic cancer, endometrial cancer, ovarian cancer, melanoma, brain cancer, testicular cancer, kidney cancer, skin cancer, thyroid cancer, head and neck cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, rectal cancer, myeloma, neuroblastoma, pheochromocytoma, and retinoblastoma.
  • short-term starvation selectively impedes the growth of tumors and protects normal cells from chemotherapy toxicity but sensitizes cancer cells to it.
  • Specific embodiments of methods and compositions that achieve this goal are set forth below.
  • the operation of the present invention is not limited to any particular mechanism, the protection observed in various embodiments of the present invention is due in part to modulation of the IGF-I pathway and glucose levels, without interfering with its effect on cancer cells (Differential Stress Resistance, DSR).
  • DSR Different Stress Resistance
  • long-term dietary restriction causes a much more modest reduction in IGF-I and glucose compared to fasting. Moreover, unlike fasting, long-term dietary restriction is not feasible for the great majority of cancer patients since it causes chronic weight loss and is very difficult to maintain. Instead, an average of about 62 hours of fasting prior to and 24 hours post-chemotherapy was well tolerated by cancer patients receiving a variety of toxic treatments.
  • oncogenic mutations which are generally found in pathways associated with cellular growth and stress response, prevent the switch to the high protection mode in malignant cells and continue to promote growth or a growth-associated state even during fasting.
  • Yeast and mammalian studies have suggested that the sensitization of malignant cells to toxins/oxidants may be largely independent of the type of oncogenic mutations owing to the redundancy in the pro-growth pathway in the inhibition of entry into the protected mode, indicating that the great majority of cancer cells and cancer types should not become protected in response to STS or low IGF-I.
  • a method of alleviating cancer growth or a symptom of cancer is provided.
  • a patient with cancer is identified and then provided with a first diet for a first predetermined period of time.
  • the first diet provides the patient with at most 50% of the patient's normal caloric intake with at least 50% of the kilocalories being derived from fat, preferably monounsaturated fats.
  • the patient's normal caloric intake is the number of kcal that the patient consumes to maintain his/her weight.
  • the patient's normal caloric intake may be estimated by interviewing the patient or by consideration of a patient's weight.
  • the first diet provides the patient with from 700 to 1200 kcal/day.
  • the first diet provides the male patient of average weight with about 1100 kcal/day and the female patient of average weight with 900 kcal/day.
  • the first predetermined period of time is from about 1 to 5 days. In a refinement, the first predetermined period of time is 1 day. In order to put the level of fat in the first diet in perspective, the U.S.
  • Food and Drug Administration recommends the following nutritional breakdown for a typical 2000 kilocalorie a day diet: 65 gram fat (about 585 kilocalories), 50 grams protein (about 200 kilocalories), 300 grams total carbohydrates (about 1200 kilocalories). Therefore, in one version of the first diet, a majority of the calories from carbohydrates and proteins are eliminated.
  • the first diet encompasses virtually any source of fat
  • sources high in unsaturated fat including monounsaturated and polyunsaturated fat sources are particularly useful (e.g., omega-3/6 essential fatty acids).
  • suitable examples of monounsaturated food sources include, but are not limited to, peanut butter, olives, nuts (e.g., almonds, pecans, pistachios, cashews), avocado, seeds (e.g., sesame), oils (e.g., olive, sesame, peanut, canola), etc.
  • Suitable examples of polyunsaturated food sources include, but are not limited to, walnuts, seeds (e.g., pumpkin, sunflower), flaxseed, fish (e.g., salmon, tuna, mackerel), oils (e.g., safflower, soybean, corn).
  • the first diet also includes a component selected from the group consisting of vegetable extracts, minerals, omega-3/6 essential fatty acids, and combinations thereof. In one refinement, such a vegetable extract provides the equivalent of 5 recommended daily servings of vegetable.
  • Suitable sources for the vegetable extract include, but are not limited to, bokchoy, kale, lettuce, asparagus, carrot, butternut squash, alfalfa, green peas tomato, cabbage cauliflower, beets.
  • Suitable sources for the omega-3/6 essential fatty acids include fish such as salmon, tuna, mackerel, bluefish, swordfish, and the like.
  • the patient is then provided a second diet for a second predetermined period of time.
  • the second diet provides the patient with at most 500 kcal/day.
  • the second diet provides the patient with at most 200 kcal/day.
  • the second predetermined period of time is from about 2 to 7 days.
  • the second predetermined period of time is 3 days.
  • the second diet includes a component selected from the group consisting of vegetable extracts, minerals, omega-3/6 essential fatty acids, and combinations thereof. In one refinement, such a vegetable extract provides the equivalent of 5 recommended daily servings of vegetable.
  • Suitable sources for the vegetable extract include, but are not limited to, bokchoy, kale, lettuce, asparagus, carrot, butternut squash, alfalfa, green peas tomato, cabbage cauliflower, beets.
  • Suitable sources for the omega-3/6 essential fatty acids include fish oils from salmon, tuna, mackerel, bluefish, swordfish, and the like.
  • the effectiveness of the first and second diets is monitored by measurement of a number of patient parameters. For example, it is desirable that the patient's serum concentration of IGF-I be reduced by 25-90% by the end of the second diet period. It is also desirable that the blood glucose concentration in the patient be reduced by 25-75% by the end of the second diet period.
  • the patient is provided with a third diet for a third predetermined period of time.
  • the third diet is to supplement the normal diet of the patient.
  • the replenishing composition includes essential amino acids, minerals, and essential fats.
  • the third diet will allow the patient to regain the normal weight and maximize strength.
  • the third predetermined period of time is at least 5 days.
  • the replenishing composition will also optionally include a number of additional components.
  • the replenishing composition may include a vegetable extract. In one refinement, such a vegetable extract provides the equivalent of 5 recommended daily servings of vegetable.
  • Suitable sources for the vegetable extract include, but are not limited to, bokchoy, kale, lettuce, asparagus, carrot, butternut squash, alfalfa, green peas tomato, cabbage cauliflower, beets.
  • the replenishing composition may also include omega-3/6 essential fatty acids, and non-essential amino acids. Examples of suitable non-essential amino acids include, but are not limited to, histidine, serine, taurine, tyrosine, cysteine, glutamine, and combinations thereof.
  • the replenishing composition may also include a multi-mineral tablet containing iron, zinc, copper, magnesium, and calcium and may also contain a vitamin B complex including vitamin B12.
  • a method of sensitizing cancer to chemotherapy drugs is provided.
  • a patient with cancer is identified and is then provided a first diet for a first predetermined period of time.
  • cancers that are susceptible to the present method include but are not limited to, skin cancer, colon cancer, breast cancer, esophageal cancer, prostate cancer, lung cancer, uterus cancer, ovary cancer, prostate cancer, glioma, melanoma, neuroblastoma, and pheochromocytoma.
  • the first diet provides the patient with at most 50% of the patient's normal caloric intake with at least 50% of the kilocalories being derived from fat.
  • the first predetermined period of time is from about 1 to 5 days. In a refinement, the first predetermined period of time is 1 day.
  • the first diet encompasses virtually any source of fat, with sources high in unsaturated fat, particularly monounsaturated fat sources, preferred. Suitable examples of monounsaturated food sources include, but are not limited to, peanut butter, olives, nuts (e.g., almonds, pecans, pistachios, cashews), avocado, seeds (e.g., sesame), oils (e.g., olive, sesame, peanut, canola), etc.
  • Suitable examples of polyunsaturated food sources include, but are not limited to, walnuts, seeds (e.g., pumpkin, sunflower), flaxseed, fish (e.g., salmon, tuna, mackerel), oils (e.g., safflower, soybean, corn). Additional details of the first diet are the same as those set forth above.
  • a second diet is then provided to the patient for a second predetermined period of time.
  • the second diet provides the patient with at most 500 kcal/day.
  • the second diet provides the patient with at most 200 kcal/day.
  • the second predetermined period of time is from about 2 to 7 days. In a particularly useful refinement, the second predetermined period of time is 3 days. Additional details of the second diet are the same as those set forth above.
  • a chemotherapy agent is administered to the patient during or after the patient consumes the second diet. Typically, the chemotherapy agent is administered after 48-72 hours of the second diet. It is readily appreciated that the present method is effective with virtually any chemotherapy agent.
  • useful chemotherapy agents include, but are not limited to, DNA alkylating agents, oxidants, topoisomerase inhibitors, and combinations thereof.
  • useful chemotherapeutic agents include, but are not limited to, methyl methanesulfonate, cyclophosphamide, etoposide and other topoisomerase inhibitors, doxorubicin, cisplatin, carboplatin and other platinum based drugs, gemcitabine, docetaxel, or 5-FU.
  • the patient is subsequently provided with a third diet for a third predetermined period of time.
  • the third diet supplements the patient's normal caloric intake and includes a replenishing composition.
  • the replenishing composition includes essential amino acids.
  • the replenishing composition may also include natural sources of essential fatty acids, vitamins and minerals and a multi-mineral tablet containing iron, zinc, copper, magnesium, and calcium and may also contain a vitamin B complex including vitamin B12.
  • the third diet together with the patient's normal diet will allow the patient to regain the normal weight and maximize strength.
  • the third predetermined period of time is at least 5 days and may continue indefinitely. In a refinement, the third predetermined period of time is from about 4 days to about 14 days. A week is estimated to be nearly optimal for this purpose.
  • the replenishing composition will also optionally include a number of additional components.
  • the replenishing composition may include a vegetable extract. In one refinement, such a vegetable extract provides the equivalent of 5 recommended daily servings of vegetable.
  • Suitable sources for the vegetable extract include, but are not limited to, bokchoy, kale, lettuce, asparagus, carrot, butternut squash, alfalfa, green peas tomato, cabbage cauliflower, beets.
  • the replenishing composition may also include omega-3/6 essential fatty acids, and non-essential amino acids. Examples of suitable non-essential amino acids include, but are not limited to, histidine, serine, taurine, tyrosine, cysteine, glutamine, and combinations thereof. Additional details of the third diet are the same as those set forth above.
  • the method of the present embodiment provides a number of therapeutic advantages.
  • the method allows the chemotherapy agent to be provided to the patient for a longer period of time than is standard practice for the chemotherapy agent when the patient is not provided the first diet and the second diet.
  • This increase in duration is a result of the first and second diets decreasing the toxic effects of the chemotherapy agents and/or rendering cancer cells more susceptible to the chemotherapy agents than normal (i.e., non-cancerous) cells.
  • the host protecting first and second diets allow the chemotherapy agent to be administered in a greater amount than in treatment protocols not using the first and second diets.
  • such agents can be administered in an amount that is at least 10% greater than the amounts normally tolerated by the patient.
  • doses of such agents in certain patients can increase from 10% to 40%.
  • the cancer sensitizing first and second diets allow for a lower amount of chemotherapy agent than the normal amount to be provided to the patient while maintaining a near optimal or enhanced response.
  • the chemotherapy agents can be administered in an amount that is at least 10% lower than the amounts normally administered. In some patients, doses of such agents may be lowered from 10% to 40% to reduce unwanted toxicity.
  • the present method also allows chemotherapeutic treatment of patients exhibiting unacceptable toxic side-effects to continue. In such situations, patients exhibiting a symptom of chemotherapeutic-related toxicity are identified and then provided the first, second and third diets in the manner and duration set forth above.
  • the present method also allows the continued treatment of patients that have been identified as terminal and who would otherwise discontinue therapy.
  • the first and second diets are administered during the chronic administration of chemotherapeutic agents, for example, 5 day treatment with 5-FU.
  • a method of sensitizing cancer to radiation therapy is provided.
  • a patient with cancer is identified and is then provided a first diet for a first predetermined period of time.
  • cancers that are susceptible to the present method include, but are not limited to, skin cancer, colon cancer, breast cancer, esophageal cancer, prostate cancer, lung cancer, uterus cancer, ovary cancer, prostate cancer, glioma, melanoma, neuroblastoma, and pheochromocytoma.
  • the first diet provides the patient with at most 50% of the patient's normal caloric intake with at least 50% of the kilocalories being derived from fat.
  • the first predetermined period of time is from about 1 to 5 days. In a refinement, the first predetermined period of time is 1 day.
  • the first diet encompasses virtually any source of fat, with sources high in unsaturated fat, particularly monounsaturated fat sources, preferred. Suitable examples of monounsaturated food sources include, but are not limited to, peanut butter, olives, nuts (e.g., almonds, pecans, pistachios, cashews), avocado, seeds (e.g., sesame), oils (e.g., olive, sesame, peanut, canola), etc.
  • Suitable examples of polyunsaturated food sources include, but are not limited to, walnuts, seeds (e.g., pumpkin, sunflower), flaxseed, fish (e.g., salmon, tuna, mackerel), oils (e.g., safflower, soybean, corn). Additional details of the first diet are the same as those set forth above.
  • a second diet is then provided to the patient for a second predetermined period of time.
  • the second diet provides the patient with at most 500 kcal/day.
  • the second diet provides the patient with at most 200 kcal/day.
  • the second predetermined period of time is from about 2 to 7 days. In a particularly useful refinement, the second predetermined period of time is 3 days. Additional details of the second diet are the same as those set forth above.
  • Radiation therapy is administered to the patient during or after the patient consumes the second diet. Typically, the radiation therapy is administered after 48-72 hours of the second diet.
  • the patient is subsequently provided with a third diet for a third predetermined period of time.
  • the third diet supplements the patient's normal caloric intake and includes a replenishing composition.
  • the replenishing composition includes essential amino acids.
  • the replenishing composition may also include natural sources of essential fatty acids, vitamins and minerals and a multi-mineral tablet containing iron, zinc, copper, magnesium, and calcium and may also contain a vitamin B complex including vitamin B12.
  • the third diet together with the patient normal diet, will allow the patient to regain the normal weight and maximize strength.
  • the third predetermined period of time is at least 5 days and may continue indefinitely. In a refinement, the third predetermined period of time is from about 4 days to about 14 days. A week is estimated to be nearly optimal for this purpose.
  • the replenishing composition will also optionally include a number of additional components.
  • the replenishing composition may include a vegetable extract. In one refinement, such a vegetable extract provides the equivalent of 5 recommended daily servings of vegetable.
  • Suitable sources for the vegetable extract include, but are not limited to, bokchoy, kale, lettuce, asparagus, carrot, butternut squash, alfalfa, green peas tomato, cabbage cauliflower, beets.
  • the replenishing composition may also include omega-3/6 essential fatty acids, and non-essential amino acids. Examples of suitable non-essential amino acids include, but are not limited to, histidine, serine, taurine, tyrosine, cysteine, glutamine, and combinations thereof. Additional details of the third diet are the same as those set forth above.
  • a therapeutic meal package for providing meals to a cancer patient that retards cancer growth and enhances the efficacy of chemotherapy drugs.
  • the therapeutic meal package is designed to provide the appropriate nutritional and caloric requirements of the methods set forth above.
  • the therapeutic meal package includes a first meal component, a second meal component and a replenishing composition.
  • the first meal component provides the nutritional components of the first diet set forth above.
  • the first meal component is portioned into meals that provide the cancer patient at most 50% of the patient's normal caloric intake with at least 50% of the kilocalories derived from fat.
  • the first meal component is in a sufficient amount to provide meals for a first predetermined period of time.
  • the first meal component also includes extracts equivalent to 5 serving of vegetables as well as omega-3/6 essential fatty acids.
  • the second meal component provides the nutritional components of the second diet set forth above.
  • the second meal component is portioned into meals that provide the cancer patient at most 500 kcal/day.
  • the second meal component is in a sufficient amount to provide meals for a second predetermined period of time.
  • the second meal component also includes extracts equivalent to 5 serving of vegetables as well as minerals and omega-3/6 essential fatty acids.
  • the replenishing composition at least partially provides the nutritional components of the third diet set forth above.
  • the replenishing composition is combined with the patient's normal diet in order to provide the patient with a somewhat normal caloric intake.
  • the replenishing composition includes essential amino acids.
  • the replenishing composition is in a sufficient amount to provide replenishment for a third predetermined period of time.
  • the first meal component is high in fat.
  • the first meal component encompasses virtually any source of fat, sources high in unsaturated fat, particularly monounsaturated fat sources, are preferred to minimize potentially detrimental cardiovascular side effects of fats, particularly in patients who will make frequent use of this diet.
  • monounsaturated food sources include, but are not limited to, peanut butter, olives, nuts (e.g., almonds, pecans, pistachios, cashews), avocado, seeds (e.g., sesame), oils (e.g., olive, sesame, peanut, canola), etc.
  • Suitable examples of polyunsaturated food sources include, but are not limited to, walnuts, seeds (e.g., pumpkin, sunflower), flaxseed, fish (e.g., salmon, tuna, mackerel), oils (e.g., safflower, soybean, corn).
  • the first meal component also includes a component selected from the group consisting of vegetable extracts, minerals, omega-3/6 essential fatty acids, and combinations thereof. In one refinement, such a vegetable extract provides the equivalent of 5 recommended daily servings of vegetable.
  • Suitable sources for the vegetable extract include, but are not limited to, bokchoy, kale, lettuce, asparagus, carrot, butternut squash, alfalfa, green peas tomato, cabbage cauliflower, beets.
  • Suitable sources for the omega-3/6 essential fatty acids include fish such as salmon, tuna, mackerel, bluefish, swordfish, and the like.
  • the second food component provides a very low kcal to the patient.
  • the second food component includes a component selected from the group consisting of vegetable extracts, minerals, omega-3/6 essential fatty acids, and combinations thereof.
  • a vegetable extract provides the equivalent of 5 recommended daily servings of vegetable.
  • Suitable sources for the vegetable extract include, but are not limited to, bokchoy, kale, lettuce, asparagus, carrot, butternut squash, alfalfa, green peas tomato, cabbage cauliflower, beets.
  • Suitable sources for the omega-3/6 essential fatty acids include fish such as salmon, tuna, mackerel, bluefish, swordfish, and the like.
  • the replenishing composition is designed so that the patient's normal weight and strength are maintained (or re-established if there has been a weight lost).
  • the replenishing composition further includes extracts equivalent to 5 servings of vegetables as well as minerals and omega-3/6 essential fatty acids. It should be appreciated that the replenishing composition is to be taken with a normal diet so that the weight and strength goals are achieved. Typically, the normal diet will provide about the patient's normal caloric intake as set forth above.
  • the therapeutic meal package also includes instructions for administering the first meal component, the second meal component, and the replenishing composition to the cancer patient.
  • the instruction will provide the details set forth above with respect to the methods.
  • the instructions state that the first food component is to be provided to the patient over a first predefined period of time as set forth above. Typically, the first predetermined period of time is from about 1 to 2 days. In a refinement, the first predetermined period of time is 1 day.
  • the instructions also state that the second food component is to be taken over a second predetermined period of time as set forth above. Typically, the second predetermined period of time is from about 2 to 7 days. In a particularly useful refinement, the second predetermined period of time is about 3 days.
  • the instructions also state that the replenishing composition is to be taken with the normal diet, and in particular, a sufficient amount of additional food items that the patient's weight and strength is maintained or regained.
  • the third predetermined period of time is at least 5 days. In a refinement, the third predetermined period of time is from about 4 days to about 14 days. A week is found to be nearly optimal for this purpose.
  • the therapeutic food package is packaged in a container (e.g., a box).
  • a container e.g., a box
  • each of the first meal component and the second meal component are portioned into daily servings with labeling so indicating.
  • each daily portion is further divided into three meals.
  • each meal will be a combination of solid food, a shake and a soup (day 1) and only soups and shakes for days 2, 3, and 4 (3 meals/day).
  • Each package will also contain pills with essential fatty acids, minerals and vitamins and/or vegetable extracts.
  • the box will also contain 1 week supply of the replenishment diet which will be in the form of pills. Generally, non-natural sources of any item in all components of the diet are minimized.
  • a 74-year-old Caucasian man who was diagnosed in July of 2000 with bilateral prostate adenocarcinoma, Gleason score 7 and PSA level of 5.8 ng/ml.
  • a prostatectomy performed in September of 2000 led to undetectable levels of PSA until January 2003 when it rose to 1.4 ng/ml.
  • Leuprolide acetate together with bicalutamide and finasteride were prescribed.
  • administration of these drugs had to be suspended in April 2004 due to severe side effects related to testosterone deprivation.
  • Different drugs including triptorelinpamoate, nilutamide, thalidomide, CP and ketoconazole were utilized to control the disease.
  • Platelet nadir did reach a lower level compared to previous chemo-alone treatments, which could be explained by the additive effect of three chemotherapeutic agents ( FIG. 9D ; Table 2). Nonetheless the zenith in platelet numbers and the time to recover to normal level were much pronounced and shortened, respectively, during the fasting-chemo treatments compared with chemo-alone ( FIG. 9D ; Table 2). This significant improvement and faster recovery of platelets after multiple fasting/chemotherapy not only allowed the patient to complete her chemo-treatment, but also suggests that this strategy may have protective effects on blood cells precursors, allowing a quicker repopulation of thrombocytes and granulocytes.
  • a CT scan insinuated a local progression of the disease. He started the second cycle with leuprolide acetate and also received High Dose Rate (HDR) brachytherapy and external beam radiation with Intensity Modulated Radiation Therapy (IMRT).
  • HDR High Dose Rate
  • IMRT Intensity Modulated Radiation Therapy
  • Weight loss is a major concern in cancer patients. This can be due to cancer itself, reduced appetite following chemotherapy, or gastrointestinal damage. Notably, in this case report, weight loss during fasting was rapidly recovered in most of the patients. For the patients who received chemotherapy both with and without fasting, chemotoxic side effects appeared to be attenuated during fasting-chemo cycles. Symptoms which appeared to be ameliorated by this intervention were primarily gastrointestinal and constitutional.
  • FIG. 18 fasting sensitizes malignant cells to irradiation.
  • FIG. 19 fasting sensitizes malignant cells to irradiation.
  • STS fasting sensitizes murine breast cancer cells to irradiation and enhances tumor control in mice.
  • STS fasting sensitizes murine glioma cancer cells to irradiation and enhances tumor control in mice.
  • Fasting in the glioma model was applied only once due to the unusually rapid tumor growth in the control (ad lib, no chemotherapy) group.
  • the greatest therapeutic index was observed when fasting was combined with either of the commonly used chemotherapy drugs, doxorubicin (DXR) or cyclophosphamide (CP) ( FIG. 22A-C ).
  • lung metastases were found in 100% vs65% of mice that received DXR under normal feeding and fasting, respectively.
  • metastases were not detected in the liver or spleen of fasted mice ( FIG. 25 ).
  • mice were incubated in media containing serum collected from mice either fed ad lib or fasted for 48 hours.
  • breast cancer cells (4T1) cultured in medium supplemented with serum from fasted mice were sensitized to both DXR and CP compared to the effect of incubation in serum from mice fed ad lib ( FIG. 30 ).
  • glucose and growth factor reduction e.g., the 75% reduction in the growth factor IGF-I
  • IGF-I is a key change, and that IGF-I infusion can reverse the protection of mice to chemotherapy.
  • IGF-I treatment of 4T1 and B16 cells also reverses the sensitization of cancer cells to DXR caused by glucose restriction, suggesting that STS sensitizes cancer cells, in part, by reducing IGF-I ( FIG. 35 ).
  • Glucose which is the main energy source for metazoans, is particularly important to malignant cells, a phenomenon known as the Warburg effect, and elevated blood glucose promotes increased cancer growth.
  • the effect of reduced glucose was instead additive with that of doxorubicin in the treatment of GL26 glioma cells ( FIG. 36C ).
  • heme oxygenase-1 (HO-1) is an evolutionarily conserved enzyme that is highly inducible in response to various stimuli including UVA and oxidative stress. It was found that fasting also repressed HO-1 expression in the tumors, but caused a major increase in tis expression in normal organs, consistent with those of FOXO3a and NFkB ( FIG. 41 ). Student's t-test; *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
  • HO-1 expression was induced during fasting using hemin and found that the sensitization could be partially reversed ( FIGS. 47 , 48 ).
  • ZnPP zinc protoporphyrin
  • 4T1-luc murine breast cancer cells were purchased from SibTech (Brookfield, Conn.). B16-fluc murine melanoma cells were provided by Essen Craft (UCLA). GL26 murine glioma, U87-MG human glioblastoma cells were provided by Thomas Chen (USC). PC3 and 22RV1 human prostate cancer cells were provided by Pinchas Cohen (UCLA). MCF-7 and C42B human breast cancer cells and HeLa human cervical cancer cells were provided by Amy Lee (USC). LOVO human colon cancer cells were provided by Darryl Shibata (USC).
  • NXS2 and Neuro-2a murine neuroblastoma, human ACN and SH-SY5Y neuroblastoma, OVCAR human ovarian carcinoma, MZ-MEL human melanoma, A431 epidermoid carcinoma cells were routinely cultured in the Laboratory of Oncology of Gaslini Institute. 4T1 cells were stably transfected with LC3-GFP, which was a kind gift from Jae Jung at USC, for autophagy studies. All cells were routinely maintained in DMEM 10% FBS at 37° C., 5% CO2. To inhibit autophagy cells were treated with 5 ⁇ M chloroquine (CQ) for 48 hours during in vitro STS. To modulate HO-1 activity, 4T1 cells were treated with 10 ⁇ M hemin (Sigma) or 20 ⁇ M zinc protoporphyrin (ZnPP; Sigma) for 24 hours prior to and 24 hours during chemotherapy treatment.
  • CQ chloroquine
  • Doxorubicin (DXR; Bedford Laboratories, USA) and cyclophosphamide (CP; Baxter, USA) were used in vitro and in vivo.
  • In vitro chemotherapy was performed by treating cells in medium containing chemotherapy for 24 hours. Optimum drug doses were determined for each individual cell line.
  • DXR was injected intravenously via lateral tail veins, and CP was injected intraperitoneally.
  • 12-week-old female BALB/c, 12-week-old female and male C57BL/6 mice were injected intravenously via lateral tail veins with 2 ⁇ 105 4T1, B16, GL26 cells, respectively, and 6-week-old female A/J mice were injected via lateral tail veins with 2 ⁇ 105 NXS2, and 1 ⁇ 106 Neuro-2a cells.
  • cells in log phase of growth were harvested and suspended in PBS at 2 ⁇ 106 cells/ml, and 100 uL (2 ⁇ 105 cells/mouse) were injected subcutaneously in the lower back region or intravenously via the lateral tail veins.
  • Cellular fasting was done by glucose and/or serum restriction which was based on blood glucose measurements in fasted and normally fed mice; the lower level approximated to 0.5 g/L and the upper level to 2.0 g/L.
  • normal glucose was considered as 1.0 g/L.
  • Cells were washed twice with PBS before changing to fasting medium.
  • mice were fasted for a total of 48-60 hours by complete deprivation of food but with free access to water. Mice were individually housed in a clean new cage to reduce cannibalism, coprophagy, and residual chow. Body weight was measured immediately before and after fasting.
  • MTT methylthiazolyldiphenyl-tetrazolium bromide
  • DHE dihydroethidine
  • Cells were diluted to 10 5 /ml in culture medium (DMEM/F12 with 10% FBS), and treated with 50 ⁇ M DXR for 1 hour at 37° C. Cells were then washed once with ice cold PBS and subject to CometAssay (Trevigen, Inc, Gaithersburg, Md.) according to the manufacturer's recommended procedure. Comet images were acquired with a Nikon Eclipse TE300 fluorescent microscope and analyzed with the Comet Score software (TriTek Corp., ver 1.5). 100-300 cells were scored for each genotype/treatment group.
  • mice were anesthetized with 2% inhalant isoflurane and blood was collected by left ventricular cardiac puncture. Blood was collected in tubes coated with K 2 -EDTA to process serum (BD, USA). Blood glucose was measured using the Precision Xtra blood glucose monitoring system (Abbott Laboratories, USA).
  • RNA from tissues was isolated according the procedures described by the manufacturer using the RNeasy kit from Qiagen (cat #74106). Then, RNA was hybridized to BD-202-0202 chips from IlluminaBeadchips (San Diego, Calif.). Raw data were subjected to Z normalization as described previously. Parameterized significant analysis is finished according to the SAM protocol with ANOVA filtering (ANOVA p ⁇ 0.05). Significant genes are selected for each pairwise comparison. Gene set enrichment was tested using the PAGE method as previously described. Figures were selected based on the names and descriptions provided by Gene Ontology Database and Pathway Data Set. Further gene regularly relation and canonic pathway analysis is done by the Ingenuity Pathway Analysis System (Ingenuity Systems; Redwood City, Calif.).
  • RNA from tissues was isolated according the procedures described by the manufacturer using the RNeasy kit from Qiagen (cat #74106).
  • cDNA was synthesized using the High Capacity cDNA Reverse Transcription Kit (AB Applied Biosystems cat #4368814) and RT-PCR was performed using the SYBR Green PCR master mix (AB Applied Biosystems cat #4309159). GAPDH gene was used as calibrator gene.
  • Each treatment analyzed was performed with three biological replicates and at least three reactions were used to calculate the expression. The expression ratio was calculated according to the 2 ⁇ CP method.
  • a variety of dietary formulations were tested in mouse models to validate a dietary regime for cancer patients undergoing chemotherapy.
  • the target endpoint is a 20-75% reduction in serum glucose and/or IGF-1, which has been shown to be effective in the protection of the host and sensitization of a wide variety of cancer cells.
  • the formulations are selected to provide a level of nutrients sufficient to maintain the normal body weight.
  • Daily food intake, body weight along with general health (behavior and physical appearance) is monitored.
  • blood is collected for glucose and IGF-1 determination.
  • AA-D specific amino acids
  • AA-D specific amino acids
  • glucose FIG. 54A
  • This beneficial effect is increased if used in a re-feeding paradigm ( FIGS. 53 and 54B ) where short-term starvation is followed by the AA-D formulation.
  • a diet regime consisting of 2-days on a very-low caloric diet (VCM, 6% of normal caloric intake) followed by 1-day on an amino acid deficient formulation (AA) reduced serum IGF-1 levels significantly more than short-term starvation (STS) ( FIG. 55A ). Furthermore, this diet regime protected mice from the chemotherapy drug, doxorubicin (DXR) ( FIG. 55B ). Here, DXR is injected after 2-days of VCM upon initiation of re-feeding with the amino acid deficient formulation (AA).
  • VCM very-low caloric diet
  • AA amino acid deficient formulation
  • STS short-term starvation
  • FIGS. 56A&B It was determined that a low-calorie VegeGel formulation (equivalent to recommended 5 servings of vegetables) reduces serum glucose and IGF-1 similarly to short-term starvation (STS) ( FIGS. 56A&B ). Furthermore, it was demonstrated that a caloric-restricted ketogenic diet (90% of calories fat derived) for 3 days reduces serum IGF-1 and glucose ( FIGS. 6A&B , green triangles). Importantly, 1 day of this ketogenic diet followed by 2 days on the VegeGel formulation shows a beneficial effect in reducing glucose and IGF-I over the ketogenic diet alone ( FIGS. 57A&B , red squares).

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US20170173020A1 (en) * 2014-03-28 2017-06-22 Universitá Degli Studi Di Genova Tyrosine kinase inhibitors for use in a method of treating cancer in association with a reduced caloric intake
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