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Nutritional Supplements That Support Cancer Chemotherapy

Nutritional Supplements That Support Cancer Chemotherapy. Leo Galland, M.D., F.A.C.P. Foundation for Integrated Medicine. General Overview. About 1000 drugs and fixed-drug combinations used in the U.S.: Almost 400 may deplete specific nutrients.

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Nutritional Supplements That Support Cancer Chemotherapy

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  1. Nutritional Supplements That SupportCancer Chemotherapy Leo Galland, M.D., F.A.C.P. Foundation for Integrated Medicine

  2. General Overview About 1000 drugs and fixed-drug combinations used in the U.S.: • Almost 400 may deplete specific nutrients. • Over 400 may interact with food or food components. • Over 300 have been shown to interact with dietary supplements, with adverse and beneficial interactions equally common.

  3. Types of Interactions • Pharmacodynamic: two substances exhibit pharmacologic actions that reinforce or interfere with each other’s actions. • Pharmacokinetic: the absorption, distribution, excretion or enzymatic transformation of one substance is altered by another. Most adverse interactions are of this type.

  4. Pharmacokinetic Mechanisms • Alteration of gastrointestinal or urinary pH. • Stimulation, induction or inhibition of enzymes involved in biotransformation or transport of drugs or nutrients . • Displacement of a drug from binding to plasma proteins. • Alteration of drug solubility.

  5. Effects of Interactions • Nutrient depletion: Individual nutrients may have their dietary requirement increased by specific drugs (or supplements). • Adverse: A specific supplement may undesirably decrease or increase the effect of a drug or supplement being taken. • Beneficial: Drugs (or supplements) may have their actions enhanced or side effects diminished by specific supplements.

  6. Drug-Induced Nutrient Depletion • Almost half the drugs used in clinical practice have documented nutrient depleting effects. • Co-enzyme Q10, folic acid, B2, B6, Mg, Zn are nutrients most likely to be depleted. • Mechanisms include impaired absorption or bioactivation; increased excretion, nausea, anorexia or diarrhea (common side effects of cancer therapies).

  7. Anthracyclines Deplete CoQ10 • Doxorubicin interferes with mitochondrial CoQ synthesis, inhibiting succinoxidase and NADH-oxidase, contributing to cardiotoxicity. • CoQ depletion impairs mitochondrial function, raising the serum lactate/pyruvate ratio. • Serum CoQ10 is increased by doxorubicin, due to it’s release from necrotic cardiac tissue.

  8. Doxorubicin Plus CoQ:Laboratory Studies • CoQ at 1/3 doxorubicin dose prevents mitochondrial enzyme inhibition in vitro. • Rodents: CoQ decreases several types of doxorubicin toxicity and improves survival. • No pharmacokinetic interaction. • Mice: CoQ did not impair doxorubicin efficacy against Dunn sarcoma.

  9. Anthracyclines Plus CoQ10:Human Studies • CoQ 50-90 mg/d prevented ECG changes associated with doxorubicin cardiotoxicity • In patients on doxorubicin 50 mg, 5-FU and cytoxan, Co Q 90 mg/day, prevented tachycardia and cardiac dilation (vs placebo) • Lymphoma: Co Q 1 mg/kg i.v. for 4 days decreased diarrhea, stomatitis and cardiotoxicity with no effect on remission rate or mortality.

  10. Anthracyclines Plus Carnitine • Use of L-carnitine or propionyl-L-carnitine produced an additive or superior protective effect to that of CoQ alone. • Carnitine administration does not interfere with doxorubicin's anti-tumor effect.

  11. Anthracyclines Deplete Riboflavin • Doxorubicin increases riboflavin excretion and also blocks FAD synthesis. • Erythrocyte glutathione reductase (EGR) activity measures this effect. • Providing adequate dietary riboflavin to prevent deficiency may decrease doxorubicin toxicity.

  12. Doxorubicin Plus Vitamin C:Laboratory Studies • Vit C prolongs lifespan of leukemic mice and guinea pigs receiving doxorubicin. • In vitro, vit C enhances doxorubicin cytotoxicty by reducing the Fe-doxorubicin complex that forms in cells, increasing peroxidation.

  13. Anthracyclines Plus DHA • Rats: DHA from algae increases the sensitivity of mammary tumors to epirubicin (and to radiotherapy). • DHA pretreatment decreases tumor vascularity. • Effects of DHA are reversed by vitamin E in a dose-dependent fashion.

  14. Anthracyclines Plus L-theanine(5-N-ethyl glutamine) • Rodents: L-Theanine, a unique amino acid found in green tea, enhances the efficacy and decreases toxicity of doxorubicin and idarubicin. • Theanine inhibits glutamate-mediated doxorubicin efflux, only in cancer cells. • In normal cells, theanine increases intracellular glutamate and glutathione levels and does not increase doxorubicin concentration.

  15. CISPLATIN DEPLETES Mg, K, Se, VIT E • Inhibits Mg transport proteins  renal Mg wasting, depletes muscle Mg,K before serum. • 75% incidence of hypomagnesemia, 50% lasts >3 yr. Sensory neuropathy correlates with S-Mg. • Reduces circulating vit E and numerous antioxidants, correlates with neurotoxicity. • Se in blood decreases progressively with each infusion in patients with testicular cancer.

  16. Cisplatin Toxicity:Protective Supplements • Bismuth 150 mg/kg/day X 10 days • Ginkgo biloba 100 mg/kg single dose • Glutathione 5 gm i.v. prior to infusion • MgSO4 3 gm i.v./ Mg 160 mg tid • N-acetyl cysteine 8 gm/day • Selenium 4000 mcg/day X 8 days • Vitamin C 50-200 mg/kg i.v. single dose • Vitamin E 300 IU/day till 3 months post

  17. Magnesium Diminshes Cisplatin Toxicity • Combined oral and i.v. Mg reduced nephrotoxicity in patients with testicular cancer. • Prophylactic Mg is more effective than attempted correction of a deficit. • Mg does not interfere with efficacy

  18. Cisplatin Plus Antioxidants • D-alpha-tocopherol, 300 IU/d reduced neurotoxicity when given from start of chemoRx until 3 months post. • Vits E, C and Se decreased ototoxicity, only in patients with increased blood levels of all 3. • D-alpha-tocopherol enhances cisplatin's anti-tumor effect in rodents by increasing drug concentration in tumor without increasing its concentration in healthy tissue.

  19. Cisplatin Plus Vitamin C:Laboratory Studies • Vit C enhances cisplatin antineoplastic cytotoxicity in vitro and in vivo • Vitamin C protects against cisplatin-induced oxidant stress of normal tissues • Rats: Vit C (50-200 mg/kg) 10 minutes before cisplatin decreased nephrotoxicity and markers of systemic oxidant stress.

  20. Cisplatin Plus Selenium:Rodent Studies • Se 2 mg/kg (sodium selenite) p.o. prior to cisplatin (but not post) prevented nephrotoxicity • Sodium selenite did not interfere with the therapeutic effect of cisplatin against mouse breast or plasma cell cancers in vivo. • Se 1.5 mg/kg with cisplatin prevented cisplatin resistance and enhanced efficacy in mice with human ovarian cancer explants

  21. Cisplatin Plus Glutathione:Clinical Trials • i.v. GSH (5 g) just prior to cisplatin, reduces nephrotoxicity without impairing efficacy (ovarian cancer). • GSH reduced neurotoxicity in patients with advanced gastric cancer. Dose = 3 g pre-cisplatin + 600 mg i.m. qd X 4 days.

  22. Cisplatin Plus Gingko Biloba:Rodent Studies • Ginkgo biloba extract (GBE, 100 mg/kg) prevent ototoxicity in mice and rats. • GBE as a single dose, 90 minutes before cisplatin infusion, does not impair anti-tumor efficacy.

  23. Bismuth and Cisplatin:Metallothionein Induction • Bismuth 150 mg/kg for 10 days prevents nephrotoxicity in humans by inducing metallothionein in healthy cells, not cancer cells. • Poor solubility of bismuth is overcome by dissolving it in a citric acid solution.

  24. N-acetylcysteine and Cisplatin: Diverse Protective Effects • NAC protects renal cells against cisplatin by inhibiting GGT, needed for nephrotoxic effects. • Case report: reversal of renal failure with NAC 140 mg/kg followed by 70 mg/kg q4h X 4 days • NAC 8 g/d did not block cisplatin/ifosfamide Rx • NAC enhances cisplatin cytoxocity for prostate ca cells by antagonizing cisplatin-induced increase in NFkB activity.

  25. NAC and Ifosfamide • NAC (4-8 g/day) protects against the urological side effects of ifosfamide, especially hemorrhagic cystitis, permitting the use of higher doses of ifosfamide. • NAC shows less protective effect than Mesna.

  26. Melatonin and Advanced Solid Tumors • Melatonin (20 mg HS) improved survival and reduced side effects of patients with non-small cell lung cancer being treated with cisplatin and etoposide, with doubling of one-year survival and reduction of myelosuppression, neuropathy and cachexia. • Appeared to enhance effectiveness of low-dose irinotecan in patients with colorectal cancer.

  27. Melatonin/Tamoxifen • Melatonin, 20 mg/day hs, with tamoxifen, 20 mg/day at noon, improved clinical status in 28% of patients with metastatic breast cancer unresponsive to tamoxifen alone. • Melatonin augments sensitivity of breast cancer cells to tamoxifen in tissue culture • Melatonin interferes with activation of the estrogen receptor by estradiol and also inhibits aromatase

  28. GAMMA-LINOLENIC ACID/ TAMOXIFEN • GLA (2800 mg/d) speeded the response to tamoxifen (20 mg/d) as primary treatment for postmenopausal breast ca. • GLA down-regulates estrogen receptor expression in human breast cancer xenografts in mice and in tissue culture.

  29. PSK from Coriolus versicolor:Immune Enhancing Adjuvant • PSK 1 g tid for up to 3 y enhances outcome for advanced solid tumors (over 50 clinical trials). • Various biomarkers predict response • Humans: PSK enhances PMN number and function, raises IgG and IgM levels • Mice: PSK enhances TH1 function, increases IL-12, and reverses TH2 dominance.

  30. Glutamine: Broad Protection Against Antineoplastic Side Effects • Stomatitis reduced by 4 g bid or 2 g qid glutamine powder, swish & swallow • Esophageal ca: 10 g tid ameliorated lymphopenia, enhanced lymphocyte mitogen stimulation and diminished increase in intestinal permeability due to radiochemotherapy. • Glutamine increases GSH in normal cells and reduces GSH in cancer cells.

  31. 5-FU Plus Glutamine • Oral glutamine, 18 g/day, reduced diarrhea, malabsorption and increased small intestinal permeability in patients with colorectal cancer. • Glutamine did not prevent 5-FU-induced stomatitis.

  32. MTX Plus Glutamine • Rats: oral glutamine 1 g/kg/d increases MTX uptake by breast cancer and fibrosarcoma cells, enhancing efficacy and decreasing toxicity. • Humans: Glutamine did not interfere with therapeutic effects of MTX in inflammatory breast cancer.

  33. Paclitaxel Plus Glutamine • Glutamine 4 g q4h or 10 g tid reduce muscle and joint pain, oral mucositis and peripheral neuropathy in most studies. • Oral glutamine supplementation may enhance the therapeutic index by protecting normal tissues from, and sensitizing tumor cells to chemotherapy and radiation-related injury.

  34. Prevention of chemotherapy and radiation toxicity with glutamine. Savarese et al, Cancer Treat Reviews 2003; 29:501-13 “ The available evidence suggests that glutamine supplementation may decrease the incidence and/or severity of chemotherapy-associated mucositis, irinotecan-associated diarrhea, paclitaxel-induced neuropathy, hepatic veno-occlusive disease in the setting of high dose chemotherapy and stem cell transplantation, and the cardiotoxicity that accompanies anthracycline use. Oral glutamine supplementation may enhance the therapeutic index by protecting normal tissues from, and sensitizing tumor cells to chemotherapy and radiation-related injury.”

  35. Vitamin B6 vsPalmar-Plantar Erythrodysesthesia • Vitamin B6 (50 mg t.i.d.) reverses symptoms of the palmar-plantar erythrodysesthesia syndrome (PPE) in patients receiving docetaxel and 5-FU. • This syndrome may occur with many other antineoplastic agents, although vitamin B6 therapy has not been tested for its prevention.

  36. ABC Transport Proteins • Eject xenobiotics from cells and cause backflow of some drugs from intestinal mucosa into the lumen. • Produce multi-drug resistance to cancer chemotherapy. • Inhibited by piperine, milk thistle, ginseng, curcumin, quercetin. • Stimulated by chronic use of St. John’s wort.

  37. Vitamin K InducesCell Differentiation • HCC: Vit K2 15 mg tid reduces incidence by 80% in women with cirrhosis • HCC: Vit K2 15 mg tid prolongs 3-year survival by 35% following resection. • MDS: Vit K2 induces differentiation of leukemic cell lines and blast apoptosis and improves anemia

  38. Conclusions • Adverse interactions have received extensive press coverage. • Beneficial drug-supplement interactions are at least as important and permit creative nutritional therapies. • By decreasing side effects of antineoplastic drugs, properly used supplements may prevent therapeutic failure due to under-dosing

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