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Methotrexate

Methotrexate

Drug Information

Methotrexate (MTX) is a chemotherapy drug that interferes with folic acid activation, preventing cell reproduction. Methotrexate is used to treat some forms of cancer; severe, disabling psoriasis ; and severe, active rheumatoid arthritis .

Note: Many of the interactions described below, in the text and in the Summary of Interactions, have been reported only for specific chemotherapeutic drugs, and may not apply to other chemotherapeutic drugs. There are many unknowns concerning interactions of nutrients, herbs, and chemotherapy drugs. People receiving chemotherapy who wish to supplement with vitamins, minerals, herbs, or other natural substances should always consult a physician.

Common brand names:

Rheumatrex Dose Pack, Trexall

Summary of Interactions with Vitamins, Herbs, & Foods

Types of interactions: Beneficial Adverse Check

Replenish Depleted Nutrients

  • Magnesium

    The chemotherapy drug cisplatin may cause excessive loss of magnesium and potassium in the urine.1 , 2 Preliminary reports suggest that both potassium and magnesium supplementation may be necessary to increase low potassium levels.3 , 4 Severe magnesium deficiency caused by cisplatin therapy has been reported to result in seizures.5 Severe magnesium deficiency is a potentially dangerous medical condition that should only be treated by a doctor. People receiving cisplatin chemotherapy should ask their prescribing doctor to closely monitor magnesium and potassium status.

  • Calcium

    The chemotherapy drug cisplatin may cause kidney damage, resulting in depletion of calcium and phosphate.6

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Lactobacillus GG

    In a preliminary trial, supplementation with a probiotic (Lactobacillus GG) reduced the frequency of severe diarrhea and the incidence of abdominal discomfort related to the use of 5-FU. The amount of Lactobacillus GG used was 10-20 billion organisms per day during the 24 weeks of chemotherapy.7

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • N-Acetyl Cysteine

    Chemotherapy can injure cancer cells by creating oxidative damage. As a result, some oncologists recommend that patients avoid supplementing antioxidants if they are undergoing chemotherapy. Limited test tube research occasionally does support the idea that an antioxidant can interfere with oxidative damage to cancer cells.8 However, most scientific research does not support this supposition.

    A modified form of vitamin A has been reported to work synergistically with chemotherapy in test tube research.9 Vitamin C appears to increase the effectiveness of chemotherapy in animals10 and with human breast cancer cells in test tube research.11 In a double-blind study, Japanese researchers found that the combination of vitamin E , vitamin C, and N-acetyl cysteine (NAC) —all antioxidants—protected against chemotherapy-induced heart damage without interfering with the action of the chemotherapy.12

    A comprehensive review of antioxidants and chemotherapy leaves open the question of whether supplemental antioxidants definitely help people with chemotherapy side effects, but it clearly shows that antioxidants need not be avoided for fear that the actions of chemotherapy are interfered with.13 Although research remains incomplete, the idea that people taking chemotherapy should avoid antioxidants is not supported by scientific research.

    A new formulation of selenium (Seleno-Kappacarrageenan) was found to reduce kidney damage and white blood cell–lowering effects of cisplatin in one human study. However, the level used in this study (4,000 mcg per day) is potentially toxic and should only be used under the supervision of a doctor.14

    Glutathione , the main antioxidant found within cells, is frequently depleted in individuals on chemotherapy and/or radiation. Preliminary studies have found that intravenously injected glutathione may decrease some of the adverse effects of chemotherapy and radiation, such as diarrhea .15

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Phosphate

    The chemotherapy drug cisplatin may cause kidney damage, resulting in depletion of calcium and phosphate.16

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Taurine

    Taurine has been shown to be depleted in people taking chemotherapy.17 It remains unclear how important this effect is or if people taking chemotherapy should take taurine supplements.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.

Reduce Side Effects

  • Acetyl-L-Carnitine

    Acetyl-L-carnitine in the amount of 1,000 mg three times per day for eight weeks has been shown to improve nerve damage (neuropathy) caused by the chemotherapy drug cisplatin.18

  • Melatonin

    High amounts of melatonin have been combined with a variety of chemotherapy drugs to reduce their side effects or improve drug efficacy. One study gave melatonin at night in combination with the drug triptorelin to men with metastatic prostate cancer.19 All of these men had previously become unresponsive to triptorelin. The combination decreased PSA levels—a marker of prostate cancer progression—in eight of fourteen patients, decreased some side effects of triptorelin, and helped nine of fourteen to live longer than one year. The outcome of this preliminary study suggests that melatonin may improve the efficacy of triptorelin even after the drug has apparently lost effectiveness.

  • Selenium

    Chemotherapy can injure cancer cells by creating oxidative damage. As a result, some oncologists recommend that patients avoid supplementing antioxidants if they are undergoing chemotherapy. Limited test tube research occasionally does support the idea that an antioxidant can interfere with oxidative damage to cancer cells.20 However, most scientific research does not support this supposition.

    A modified form of vitamin A has been reported to work synergistically with chemotherapy in test tube research.21 Vitamin C appears to increase the effectiveness of chemotherapy in animals22 and with human breast cancer cells in test tube research.23 In a double-blind study, Japanese researchers found that the combination of vitamin E , vitamin C, and N-acetyl cysteine (NAC) —all antioxidants—protected against chemotherapy-induced heart damage without interfering with the action of the chemotherapy.24

    A comprehensive review of antioxidants and chemotherapy leaves open the question of whether supplemental antioxidants definitely help people with chemotherapy side effects, but it clearly shows that antioxidants need not be avoided for fear that the actions of chemotherapy are interfered with.25 Although research remains incomplete, the idea that people taking chemotherapy should avoid antioxidants is not supported by scientific research.

    A new formulation of selenium (Seleno-Kappacarrageenan) was found to reduce kidney damage and white blood cell–lowering effects of cisplatin in one human study. However, the level used in this study (4,000 mcg per day) is potentially toxic and should only be used under the supervision of a doctor.26

    Glutathione , the main antioxidant found within cells, is frequently depleted in individuals on chemotherapy and/or radiation. Preliminary studies have found that intravenously injected glutathione may decrease some of the adverse effects of chemotherapy and radiation, such as diarrhea .27

  • Vitamin E

    Chemotherapy frequently causes mouth sores. In one trial, people were given approximately 400,000 IU of beta-carotene per day for three weeks and then 125,000 IU per day for an additional four weeks.28 Those taking beta-carotene still suffered mouth sores, but the mouth sores developed later and tended to be less severe than mouth sores that formed in people receiving the same chemotherapy without beta-carotene.

    In a study of chemotherapy-induced mouth sores, six of nine patients who applied vitamin E directly to their mouth sores had complete resolution of the sores compared with one of nine patients who applied placebo.29 Others have confirmed the potential for vitamin E to help people with chemotherapy-induced mouth sores.30 Applying vitamin E only once per day was helpful to only some groups of patients in another trial,31 and not all studies have found vitamin E to be effective.32 Until more is known, if vitamin E is used in an attempt to reduce chemotherapy-induced mouth sores, it should be applied topically twice per day and should probably be in the tocopherol (versus tocopheryl) form.

  • Wheat Grass

    In a preliminary trial, taking wheat grass in the amount of 60 ml (about 2 ounces) per day during chemotherapy reduced the incidence of certain chemotherapy-related side effects (including anemia and a decline in white blood cell counts) in women with breast cancer. Taking wheat grass did not appear to interfere with the anticancer effect of the chemotherapy. The chemotherapy used in this study was a combination of 5-fluorouracil, doxorubicin, and cyclophosphamide.33

  • Beta-Carotene

    Chemotherapy frequently causes mouth sores. In one trial, people were given approximately 400,000 IU of beta-carotene per day for three weeks and then 125,000 IU per day for an additional four weeks.34 Those taking beta-carotene still suffered mouth sores, but the mouth sores developed later and tended to be less severe than mouth sores that formed in people receiving the same chemotherapy without beta-carotene.

    In a study of chemotherapy-induced mouth sores, six of nine patients who applied vitamin E directly to their mouth sores had complete resolution of the sores compared with one of nine patients who applied placebo.35 Others have confirmed the potential for vitamin E to help people with chemotherapy-induced mouth sores.36 Applying vitamin E only once per day was helpful to only some groups of patients in another trial,37 and not all studies have found vitamin E to be effective.38 Until more is known, if vitamin E is used in an attempt to reduce chemotherapy-induced mouth sores, it should be applied topically twice per day and should probably be in the tocopherol (versus tocopheryl) form.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Chamomile

    A liquid preparation of German chamomile has been shown to reduce the incidence of mouth sores in people receiving radiation and systemic chemotherapy treatment in an uncontrolled study. 39

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Eleuthero

    Russian research has looked at using eleuthero with chemotherapy. One study of patients with melanoma found that chemotherapy was less toxic when eleuthero was given simultaneously. Similarly, women with inoperable breast cancer given eleuthero were reported to tolerate more chemotherapy.40 Eleuthero treatment was also associated with improved immune function in women with breast cancer treated with chemotherapy and radiation.41

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Ginger

    Ginger can be helpful in alleviating nausea and vomiting caused by chemotherapy.42 , 43 Ginger, as tablets, capsules, or liquid herbal extracts, can be taken in 500 mg amounts every two or three hours, for a total of 1 gram per day.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Spleen Peptide Extract

    Patients with inoperable head and neck cancer were treated with a spleen peptide preparation (Polyerga®) in a double-blind trial during chemotherapy with cisplatin and 5-FU.44 The spleen preparation had a significant stabilizing effect on certain white blood cells. People taking it also experienced stabilized body weight and a reduction in the fatigue and inertia that usually accompany this combination of chemotherapy agents.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Zinc

    Irradiation treatment, especially of head and neck cancers, frequently results in changes to normal taste sensation.45 , 46 Zinc supplementation may be protective against taste alterations caused or exacerbated by irradiation. A double-blind trial found that 45 mg of zinc sulfate three times daily reduced the alteration of taste sensation during radiation treatment and led to significantly greater recovery of taste sensation after treatment was concluded.47

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.

Support Medicine

  • Melatonin

    High amounts of melatonin have been combined with a variety of chemotherapy drugs to reduce their side effects or improve drug efficacy. One study gave melatonin at night in combination with the drug triptorelin to men with metastatic prostate cancer.48 All of these men had previously become unresponsive to triptorelin. The combination decreased PSA levels—a marker of prostate cancer progression—in eight of fourteen patients, decreased some side effects of triptorelin, and helped nine of fourteen to live longer than one year. The outcome of this preliminary study suggests that melatonin may improve the efficacy of triptorelin even after the drug has apparently lost effectiveness.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Milk Thistle

    Milk thistle’s major flavonoids, known collectively as silymarin, have shown synergistic actions with the chemotherapy drugs cisplatin and doxorubicin (Adriamycin®) in test tubes.49 Silymarin also offsets the kidney toxicity of cisplatin in animals.50 Silymarin has not yet been studied in humans treated with cisplatin. There is some evidence that silymarin may not interfere with some chemotherapy in humans with cancer.51

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • PSK

    The mushroom Coriolus versicolor contains an immune-stimulating substance called polysaccharide krestin, or PSK. PSK has been shown in several studies to help cancer patients undergoing chemotherapy. One study involved women with estrogen receptor-negative breast cancer. PSK combined with chemotherapy significantly prolonged survival time compared with chemotherapy alone.52 Another study followed women with breast cancer who were given chemotherapy with or without PSK. The PSK-plus-chemotherapy group had a 25% better chance of survival after ten years compared with those taking chemotherapy without PSK.53 Another study investigated people who had surgically removed colon cancer. They were given chemotherapy with or without PSK. Those given PSK had a longer disease-free period and longer survival time.54 Three grams of PSK were taken orally each day in these studies.

    Although PSK is rarely available in the United States, hot-water extract products made from Coriolus versicolor mushrooms are available. These products may have activity related to that of PSK, but their use with chemotherapy has not been studied.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.

Reduces Effectiveness

  • none

Potential Negative Interaction

  • PABA

    PABA can increase methotrexate levels, activity, and side effects.55 The incidence and severity of this interaction remains unclear.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.

Explanation Required 

  • Folic Acid

    In cancer treatment, methotrexate works by blocking activation of folic acid. Folic acid-containing supplements may interfere with methotrexate therapy in people with cancer.56 Methotrexate therapy can lead to folic acid deficiency. People using methotrexate for cancer treatment should ask their prescribing doctor before using any folic acid-containing supplements. There is no concern about folic acid supplementation for people with cancer using chemotherapy drugs other than methotrexate.

    Until recently, it was believed that methotrexate helped people with rheumatoid arthritis also by interfering with folic acid metabolism. However, this is not necessarily so, as some studies have shown that folic acid supplementation in amounts ranging from 5–50 mg per week did not alter the efficacy of methotrexate in the treatment of rheumatoid arthritis.57 , 58 , 59 Many doctors now believe that people with rheumatoid arthritis taking methotrexate should supplement large amounts of folic acid. In separate double-blind trials, 5 mg per week of folic acid and 2.5–5 mg per week of folinic acid (an activated form of folic acid) have substantially reduced side effects of methotrexate without interfering with the therapeutic action in rheumatoid patients.60 , 61 Folic or folinic acid was taken at a different time from methotrexate and sometimes only five days per week. Daily (as opposed to weekly) supplementation with folic acid (5 mg per day for 13 days) was found to reduce blood levels of methotrexate;62 however, the researchers in this study suggest that the reduction in blood methotrexate levels by folic acid does not necessarily mean that the folic acid is interfering with the therapeutic action of the drug. It is possible that the lower blood levels of methotrexate are simply an indication that the drug is being taken up more rapidly by the cells as a result of folic acid supplementation. In most of the studies cited here, folic acid supplementation was begun 24 hours after the administration of methotrexate. Because of the uncertainty regarding this interaction, persons taking methotrexate for rheumatoid arthritis who are considering supplementation with folic acid should first consult with their doctor.

    People who are prescribed methotrexate to treat severe psoriasis experience fewer side effects if they also supplement high amounts (5 mg per day) of folic acid.63 As is the case with methotrexate and rheumatoid arthritis, supplementing folic acid did not interfere with the activity of methotrexate. Such high levels of folic acid should not be taken without clinical supervision.

  • Echinacea

    Echinacea is a popular immune-boosting herb that has been investigated for use with chemotherapy. One study investigated the actions of cyclophosphamide , echinacea, and thymus gland extracts to treat advanced cancer patients. Although small and uncontrolled, this trial suggested that the combination modestly extended the life span of some patients with inoperable cancers.64 Signs of restoration of immune function were seen in these patients.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Multivitamin

    Many chemotherapy drugs can cause diarrhea , lack of appetite, vomiting, and damage to the gastrointestinal tract. Recent anti-nausea prescription medications are often effective. Nonetheless, nutritional deficiencies still occur.65 It makes sense for people undergoing chemotherapy to take a high-potency multivitamin-mineral to protect against deficiencies.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Vitamin C

    Chemotherapy can injure cancer cells by creating oxidative damage. As a result, some oncologists recommend that patients avoid supplementing antioxidants if they are undergoing chemotherapy. Limited test tube research occasionally does support the idea that an antioxidant can interfere with oxidative damage to cancer cells.66 However, most scientific research does not support this supposition.

    A modified form of vitamin A has been reported to work synergistically with chemotherapy in test tube research.67 Vitamin C appears to increase the effectiveness of chemotherapy in animals68 and with human breast cancer cells in test tube research.69 In a double-blind study, Japanese researchers found that the combination of vitamin E , vitamin C, and N-acetyl cysteine (NAC) —all antioxidants—protected against chemotherapy-induced heart damage without interfering with the action of the chemotherapy.70

    A comprehensive review of antioxidants and chemotherapy leaves open the question of whether supplemental antioxidants definitely help people with chemotherapy side effects, but it clearly shows that antioxidants need not be avoided for fear that the actions of chemotherapy are interfered with.71 Although research remains incomplete, the idea that people taking chemotherapy should avoid antioxidants is not supported by scientific research.

    A new formulation of selenium (Seleno-Kappacarrageenan) was found to reduce kidney damage and white blood cell–lowering effects of cisplatin in one human study. However, the level used in this study (4,000 mcg per day) is potentially toxic and should only be used under the supervision of a doctor.72

    Glutathione , the main antioxidant found within cells, is frequently depleted in individuals on chemotherapy and/or radiation. Preliminary studies have found that IV glutathione may decrease some of the adverse effects of chemotherapy and radiation, such as diarrhea .73

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
The Drug-Nutrient Interactions table may not include every possible interaction. Taking medicines with meals, on an empty stomach, or with alcohol may influence their effects. For details, refer to the manufacturers’ package information as these are not covered in this table. If you take medications, always discuss the potential risks and benefits of adding a new supplement with your doctor or pharmacist.

References

1. Buckley JE, Clark VL, Meyer TJ, Pearlman NW. Hypomagnesemia after cisplatin combination chemotherapy. Arch Intern Med 1984;144:2347.

2. Threlkeld DS, ed. Antineoplastics, Alkylating Agents, Cisplatin (CDDP). In Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Feb 1999, 652a–2d.

3. Rodriguez M, Solanki DL, Whang R. Refractory potassium repletion due to Cisplatin-induced magnesium depletion. Arch Intern Med 1989;149:2592–4.

4. Whang R, Whang DD, Ryan MP. Refractory potassium repletion. A consequence of magnesium deficiency. Arch Intern Med 1992;152:40–5.

5. van de Loosdrecht AA, Gietema JA, van der Graaf WT. Seizures in a patient with disseminated testicular cancer due to cisplatin-induced hypomagnesaemia. Acta Oncol 2000;39:239–40.

6. Threlkeld DS, ed. Antineoplastics, alkylating agents, cisplatin (CDDP). In Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Feb 1999, 652a–2d.

7. Osterlund P, Ruotsalainen T, Korpela R, et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer 2007;97:1028–34.

8. Witenberg B, Kalir HH, Raviv Z, et al. Inhibition by ascorbic acid of apoptosis induced by oxidative stress in HL-60 myeloid leukemia cells. Biochem Pharmacol 1999;57:823–32.

9. Sacks PG, Harris D, Chou T-C. Modulation of growth and proliferation in squamous cell carcinoma by retinoic acid: A rationale for combination therapy with chemotherapeutic agents. Int J Cancer 1995;61:409–15.

10. Taper HS et al. Non-toxic potentiation of cancer chemotherapy by combined C and K3 vitamin pre-treatment. Int J Cancer 1987;40:575–9.

11. Kurbacher CM, Wagner U, Kolster B, et al. Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro. Cancer Letters 1996:103–19.

12. Wagdi P, Fluri M, Aeschbacher B, et al. Cardioprotection in patients undergoing chemo- and/or radiotherapy for neoplastic disease. Jpn Heart J 1996;37:353–9.

13. Weijl NI, Cleton FJ, Osanto S. Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treatment Rev 1997;23:209–40 [review].

14. Hu Y-J, Chen Y, Zhang Y-Q, et al. The protective role of selenium on the toxicity of cisplatin-contained chemotherapy regimen in cancer patients. Biol Trace Elem Res 1997;56:331–41.

15. De Maria D, Falchi AM, Venturino P. Adjuvant radiotherapy of the pelvis with or without reduced glutathione: a randomized trial in patients operated on for endometrial cancer. Tumori 1992;78:374–6.

16. Threlkeld DS, ed. Antineoplastics, alkylating agents, cisplatin (CDDP). In Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Feb 1999, 652a–2d.

17. Desai TK, Maliakkal J, Kinzie JL, et al. Taurine deficiency after intensive chemotherapy and/or radiation. Am J Clin Nutr 1992;55:708–11.

18. Bianchi G, Vitali G, Caraceni A, et al. Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-L-carnitine. Eur J Cancer 2005;41:1746–50.

19. Lissoni P, Cazzaniga M, Tancini G, et al. Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin: Efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone. Eur Urol 1997;31:178–81.

20. Witenberg B, Kalir HH, Raviv Z, et al. Inhibition by ascorbic acid of apoptosis induced by oxidative stress in HL-60 myeloid leukemia cells. Biochem Pharmacol 1999;57:823–32.

21. Sacks PG, Harris D, Chou T-C. Modulation of growth and proliferation in squamous cell carcinoma by retinoic acid: A rationale for combination therapy with chemotherapeutic agents. Int J Cancer 1995;61:409–15.

22. Taper HS et al. Non-toxic potentiation of cancer chemotherapy by combined C and K3 vitamin pre-treatment. Int J Cancer 1987;40:575–9.

23. Kurbacher CM, Wagner U, Kolster B, et al. Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro. Cancer Letters 1996:103–19.

24. Wagdi P, Fluri M, Aeschbacher B, et al. Cardioprotection in patients undergoing chemo- and/or radiotherapy for neoplastic disease. Jpn Heart J 1996;37:353–9.

25. Weijl NI, Cleton FJ, Osanto S. Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treatment Rev 1997;23:209–40 [review].

26. Hu Y-J, Chen Y, Zhang Y-Q, et al. The protective role of selenium on the toxicity of cisplatin-contained chemotherapy regimen in cancer patients. Biol Trace Elem Res 1997;56:331–41.

27. De Maria D, Falchi AM, Venturino P. Adjuvant radiotherapy of the pelvis with or without reduced glutathione: a randomized trial in patients operated on for endometrial cancer. Tumori 1992;78:374–6.

28. Mills EED. The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Br J Cancer 1988;57:416–7.

29. Wadleigh RG, Redman RS, Graham ML, et al. Vitamin E in the treatment of chemotherapy-induced mucositis. Am J Med 1992;92:481–4.

30. Lopez I, Goudou C, Ribrag V, et al. Treatment of mucositis with vitamin E during administration of neutropenic antineoplastic agents. Ann Med Intern[Paris] 1994;145:405–8.

31. Lopez I, Goudou C, Ribrag V, et al. Traitement des mucites par la vitamine E lors de l’administration d’anti-neoplasiques neutropeniants. Ann Med Interne 1994;145:405–8.

32. Legha SS, Wang YM, Mackay B, et al. Clinical and pharmacologic investigation of the effects of alpha-tocopherol on Adriamycin cardiotoxicity. Ann NY Acad Sci 1982;393:411–8.

33. Bar-Sela G, Tsalic M, Fried G, Goldberg H. Wheat grass juice may improve hematological toxicity related to chemotherapy in breast cancer patients: a pilot study. Nutr Cancer 2007;58:43–8.

34. Mills EED. The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Br J Cancer 1988;57:416–7.

35. Wadleigh RG, Redman RS, Graham ML, et al. Vitamin E in the treatment of chemotherapy-induced mucositis. Am J Med 1992;92:481–4.

36. Lopez I, Goudou C, Ribrag V, et al. Treatment of mucositis with vitamin E during administration of neutropenic antineoplastic agents. Ann Med Intern[Paris] 1994;145:405–8.

37. Lopez I, Goudou C, Ribrag V, et al. Traitement des mucites par la vitamine E lors de l’administration d’anti-neoplasiques neutropeniants. Ann Med Interne 1994;145:405–8.

38. Legha SS, Wang YM, Mackay B, et al. Clinical and pharmacologic investigation of the effects of alpha-tocopherol on Adriamycin cardiotoxicity. Ann NY Acad Sci 1982;393:411–8.

39. Carl W, Emrich LS. Management of oral mucositis during local radiation and systemic chemotherapy: A study of 98 patients. J Prosthet Dent 1991;66:361–9.

40. Kupin VJ. Eleutherococcus and Other Biologically Active Modifiers in Oncology. Moscow: Medexport, 1984, 21.

41. Kupin VI, Polevaya YB, Sorokin AM. Eleutherococcus extract treatment for immunostimulation in cancer patients. Vopr Onkol 1986;32:21–6 [in Russian].

42. Meyer K, Schwartz J, Crater D, Keyes B. Zingiber officinale (ginger) used to prevent 8-Mop associated nausea. Dermatol Nurs 1995;7:242–4.

43. Pace JC. Oral ingestion of encapsulated ginger and reported self care actions for the relief of chemotherapy-associated nausea and vomiting. Dissertation Abstr Int 1987;8:3297.

44. Borghardt J, Rosien B, Gortelmeyer R, et al. Effects of a spleen peptide preparation as supportive therapy in inoperable head and neck cancer patients. Arzneimittelforschung 2000;50:178–84.

45. Henkin RI. Prevention and treatment of hypogeusia due to head and neck irradiation. JAMA 1972;220:870–1.

46. Mossman KL, Henkin RI. Radiation-induced changes in taste acuity in cancer patients. Int J Radiat Oncol Biol Phys 1978;4:663–70.

47. Ripamonti C, Zecca E, Brunelli C, et al. A randomized, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation. Cancer 1998;82:1938–45.

48. Lissoni P, Cazzaniga M, Tancini G, et al. Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin: Efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone. Eur Urol 1997;31:178–81.

49. Scambia G, De Vincenzo R, Ranelletti FO, et al. Antiproliferative effect of silybin on gynaecological malignancies: Synergism with cisplatin and doxorubicin. Eur J Cancer 1996;32A:877–82.

50. Gaedeke J, Fels LM, Bokemeyer C, et al. Cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant 1996;11:55–62.

51. Invernizzi R, Bernuzzi S, Ciani D, Ascari E. Silymarine during maintenance therapy of acute promyelocytic leukemia. Haemotologia 1993;78:340–1.

52. Toi M, Hattori T, Akagi M, et al. Randomized adjuvant trial to evaluate the addition of tamoxifen and PSK to chemotherapy in patients with primary breast cancer. Cancer 1992;70:2475–83.

53. Iino Y, Yokoe T, Maemura M, et al. Immunochemotherapies versus chemotherapy as adjuvant treatment after curative resection of operable breast cancer. Anticancer Res 1995;15:2907–12.

54. Mitomi T, Tsuchiya S, Iijima N, et al. Randomized, controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer. The Cooperative Study Group of Surgical Adjuvant Immunochemotherapy for Cancer of Colon and Rectum (Kanagawa). Dis Colon Rectum 1992;35:123–30.

55. Holt GA. Food & Drug Interactions. Chicago: Precept Press, 1998, 170.

56. Threlkeld DS, ed. Antineoplastics, Antimetabolites, Methotrexate. In Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Aug 1990, 653–4.

57. Ortiz Z, Shea B, Suarez-Almazor ME, et al. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials. J Rheumatol 1998;25:36–43.

58. Morgan SL, Baggott JE, Vaughn WH, et al. 5 mg or 50 mg/week dose of folic acid supplementation does not alter the efficacy of methotrexate treated rheumatoid arthritis patients. Arthritis Rheum 1993;36(Suppl):S79 [abstract].

59. Hendel J, Nyfors A. Nonlinear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption. Eur J Clin Pharmacol 1984;26:121–4.

60. Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med 1994;121:833–41.

61. Shiroky JB, Neville C, Esdaile JM, et al. Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. Results of a multicenter randomized, double-blind, placebo-controlled trial. Arthritis Rheum 1993;36:795–803.

62. Bressolle F, Kinowski JM, Morel J, et al. Folic acid alters methotrexate availability in patients with rheumatoid arthritis. J Rheumatol 2000;27:2110–4.

63. Duhra P. Treatment of gastrointestinal symptoms associated with methotrexate therapy for psoriasis. J Am Acad Dermatol 1993;28:466–9.

64. Lersch C, Zeuner M, Bauer A, et al. Nonspecific immunostimulation with low doses of cyclophosphamide (LDCY), thymostimulin, and Echinacea purpurea extracts (Echinacin) in patients with far advanced colorectal cancers: Preliminary results. Cancer Invest 1992;10:343–8.

65. Dreizen S et al. Nutritional deficiencies in patients receiving cancer chemotherapy. Postgrad Med 1990;87(1):163–70.

66. Witenberg B, Kalir HH, Raviv Z, et al. Inhibition by ascorbic acid of apoptosis induced by oxidative stress in HL-60 myeloid leukemia cells. Biochem Pharmacol 1999;57:823–32.

67. Sacks PG, Harris D, Chou T-C. Modulation of growth and proliferation in squamous cell carcinoma by retinoic acid: A rationale for combination therapy with chemotherapeutic agents. Int J Cancer 1995;61:409–15.

68. Taper HS et al. Non-toxic potentiation of cancer chemotherapy by combined C and K3 vitamin pre-treatment. Int J Cancer 1987;40:575–9.

69. Kurbacher CM, Wagner U, Kolster B, et al. Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro. Cancer Letters 1996:103–19.

70. Wagdi P, Fluri M, Aeschbacher B, et al. Cardioprotection in patients undergoing chemo- and/or radiotherapy for neoplastic disease. Jpn Heart J 1996;37:353–9.

71. Weijl NI, Cleton FJ, Osanto S. Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treatment Rev 1997;23:209–40 [review].

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