Cyclophosphamide

Brand Names: Cytoxan

Clinical Names: Cyclophosphamide

Summary

generic name: Cyclophosphamide

trade name: Cytoxan®

type of drug: Antineoplastic agent.

used to treat: Various forms of cancer, especially lymphomas, leukemias, neuroblastoma (in patients with disseminated disease), adenocarcinoma of the ovary, and retinoblastoma.

mechanism: Cyclophosphamide is activated by metabolism in the liver by the mixed-function oxidase system of the smooth endoplasmic reticulum.

overview of interactions:
• nutrients affecting drug performance: Vitamin A, Beta-Carotene and Vitamin E (Antioxidants)

• nutrient affecting drug performance: Vitamin C

• nutrient affected by drug: Sodium



Interactions

nutrients affecting drug performance: Vitamin A, Beta-Carotene and Vitamin E (Antioxidants)

• research: Preliminary studies on humans undergoing chemotherapy with cyclophosphamide have indicated promise of increased survival rates when supplemented with antioxidant nutrients. While antioxidants might have many benefits as supplements, evidence as to their effectiveness in patients taking cyclophosphamide are inconclusive.
(Jaakkola K, et al. Anticancer Res 1992 May;12(3):599-606; Venugopal M, et al. Life Sci 1996;59(17):1389-1400; Vinitha R, et al. Jpn J Med Sci Biol 1995 Jun;48(3):145-156.)

• nutritional concerns: Since activation of cyclophosphamide requires oxidation in the liver there has been concern that antioxidant supplementation might interfere with its effectiveness. However, at this time such concern remains speculative as no conclusive evidence as emerged to confirm an adverse interaction of this type.
(Labriola D, Livingston R. Oncology (Huntingt). 1999 Jul;13(7):1003-1008.)

nutrient affecting drug performance: Vitamin C

• research: In contrast to the concerns above, some research with mice has found a valuable synergistic effect from the combination of vitamin C and cyclophosphamide.
(Taper HS, et al. Anticancer Res 1996 Jan;16(1):499-503; Taper HS, et al. Int J Cancer 1987 Oct 15;40(4):575-579.)

• nutritional support: The relevance for humans of the conclusions from the above animal research is still largely speculative. Individuals taking cyclophosphamide might experience greater efficacy of their medication with the simultaneous use of vitamin C but such approaches should only be attempted after consultation with and under the close supervision of the prescribing physican and/or a healthcare professional trained in nutritional therapies. While the animal research does not provide precise indications for the appropriate dosage in humans using cyclophosphamide, a dosage of 1,000-2,000 mg of vitamin C 2-3 times daily could provide benefit without causing significant risk. If diarrhea results from ingestion of excessive vitamin C, the dose can simply be lowered to bowel tolerance.

nutrient affected by drug: Sodium

• mechanism: The antidiuretic effect of cyclophosphamide may induce dilutional hyponatremia and water intoxification, especially when hospitalized patients are under a concomitant overhydration protocol.
(Steele TH, et al. J Pharmacol Exp Ther. 1973 May;185(2):245-253; Bode U, et al. Med Pediatr Oncol. 1980;8(3):295-303; Spital A, Ristow S. J Rheumatol 1997 Dec;24(12):2473-2475; Chintanadilok J, et al. Geriatr Nephrol Urol. 1998;8(3):161-165; Berghmans T. Support Care Cancer. 1996 Sep;4(5):341-350; Webberley MJ, et al. Postgrad Med J. 1989 Dec;65(770):950-952.)

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References

Berghmans T. Hyponatremia related to medical anticancer treatment. Support Care Cancer. 1996 Sep;4(5):341-50. (Review)

Bode U, Seif SM, Levine AS. Studies on the antidiuretic effect of cyclophosphamide: vasopressin release and sodium excretion. Med Pediatr Oncol. 1980;8(3):295-303.

Chintanadilok J, Kallas H, Lowenthal DT. Lung cancer and drug-induced severe hyponatremia. Geriatr Nephrol Urol. 1998;8(3):161-165.

Jaakkola K, Lahteenmaki P, Laakso J, Harju E, Tykka H, Mahlberg K. Treatment with antioxidant and other nutrients in combination with chemotherapy and irradiation in patients with small-cell lung cancer. Anticancer Res 1992 May;12(3):599-606.
Abstract: Eighteen non-randomized patients with small cell lung cancer (4 women and 14 men, mean age 60.4, SD 7.8 years) received in addition to conservation small cell lung cancer treatment antioxidant treatment with vitamins, trace elements and fatty acids. All patients were out-patients who, except for one were also treated with chemotherapy and/or irradiation at regular intervals at a university of central hospital. Five patients (28%) were in an advanced stage of the disease. At the end of the follow-up period (31.7.90) the median survival time for the whole group was 505 days. Fourteen (77%) of the patients survived for more than 12 months and six patients (33%) for more than two years. One patient (5%) survived more than five years. Eight patients (44%) were still alive with a mean survival time of 32 months at the end of the study. Ten patients succumbed earlier from progression of the disease. Antioxidant treatment, in combination with chemotherapy and irradiation, prolonged the survival time of patients with small cell lung cancer compared to most published combination treatment regimens alone. We also noticed that the patients receiving antioxidants were able to tolerate chemotherapy and radiation treatment well. Surviving patients started antioxidant treatment ingeneral earlier than those who succumbed.

Labriola D, Livingston R. Possible interactions between dietary antioxidants and chemotherapy. Oncology (Huntingt). 1999 Jul;13(7):1003-1008; discussion 1008, 1011-1012.
Abstract: Many patients treat themselves with oral antioxidants and other alternative therapies during chemotherapy, frequently without advising their conventional health care provider. No definitive studies have demonstrated the long-term effects of combining chemotherapeutic agents and oral antioxidants in humans. However, there is sufficient understanding of the mechanisms of action of both chemotherapeutic agents and antioxidants to predict the obvious interactions and to suggest where caution should be exercised with respect to both clinical decisions and study interpretation. This article will describe these potential interactions and areas of concern, based on the available data. It will also suggest several potential courses of action that clinicians may take when patients indicate that they are taking or plan to use alternative therapies.

Taper HS, Keyeux A, Roberfroid M. Potentiation of radiotherapy by nontoxic pretreatment with combined vitamins C and K3 in mice bearing solid transplantable tumor. Anticancer Res 1996 Jan;16(1):499-503.
Abstract: BACKGROUND: The effect of intraperitoneal and oral pretreatment with combined vitamins C and K3 on the single dose radiotherapy of a transplantable solid mouse tumor have been investigated. MATERIALS AND METHODS: Groups of mice bearing intramuscularly transplanted liver tumors, were orally and parenterally pretreated with combined vitamins C and K3 and locally irradiated with single doses of 20, 30, or 40 Gy of X-rays. After this treatment tumor dimensions were measured twice weekly and the approximate tumor volume in groups of pretreated vitamins and irradiated mice was compared to the groups of mice only irradiated and to the absolute control groups without any therapy. RESULTS: This nontoxic pretreatment produced statistically significant potentiation of radiotherapy induced by 20 to 40 Gy of X-rays doses in groups of 11 to 20 mice. Combined vitamins C with K3 most probably constitute a redox-cycling system producing hydrogen peroxide and other active oxygen species to which cancer cells are selectively sensitive due to their frequent deficiency in enzymatic defense system against free oxyradicals agression. CONCLUSIONS: A possible introduction of such nontoxic and selective potentiation procedure into classical protocols of human cancer therapy appears to be generally accessible and without any additional risk for patients.

Spital A, Ristow S. Cyclophosphamide induced water intoxication in a woman with Sjogren's syndrome. J Rheumatol 1997 Dec;24(12):2473-2475.
Abstract: Water intoxication is a well described complication of high dose intravenous (i.v.) cyclophosphamide therapy combined with forced hydration. Less well known is that water intoxication can develop even after low dose iv cyclophosphamide. To draw attention to this potentially life threatening complication, we describe a woman who developed acute water intoxication after treatment with low dose iv cyclophosphamide for a sensory neuropathy secondary to Sjogren's syndrome. Rheumatologists should be aware of this serious adverse effect of iv cyclophosphamide because this drug is being used increasingly for treatment of a variety of rheumatological diseases. The pathogenesis, clinical characteristics, treatment, and methods for prevention of cyclophosphamide induced water intoxication are discussed.

Steele TH, Serpick AA, Block JB. Antidiuretic response to cyclophosphamide in man. J Pharmacol Exp Ther. 1973 May;185(2):245-253.

Taper HS, de Gerlache J, Lans M, Roberfroid M. Non-toxic potentiation of cancer chemotherapy by combined C and K3 vitamin pre-treatment. Int J Cancer 1987 Oct 15;40(4):575-579.
Abstract: The influence on the survival of ascitic liver tumor (TLT)-bearing mice of combined vitamins C and K3 administered before or after a single i.p. dose of 6 different cytotoxic drugs, all commonly used in human cancer therapy, was investigated. Combined i.p. administration of these vitamins produced a distinct chemotherapy-potentiating effect for all drugs examined, especially when injected before chemotherapy. This potentiating treatment did not increase the general and organ toxicity that accompanies cancer chemotherapy. The possible generation of peroxides followed by membrane lipid alteration, DNase activation and DNA destruction by combined vitamin C and K3 in catalase-deficient cancer cells might be involved in the mechanisms of this selective potentiation.

Venugopal M, Jamison JM, Gilloteaux J, Koch JA, Summers M, Giammar D, Sowick C, Summers JL. Synergistic antitumor activity of vitamins C and K3 on human urologic tumor cell lines. Life Sci 1996;59(17):1389-1400.

Vinitha R, Thangaraju M, Sachdanandam P. Effect of administering cyclophosphamide and vitamin E on the levels of tumor-marker enzymes in rats with experimentally induced fibrosarcoma. Jpn J Med Sci Biol 1995 Jun;48(3):145-156.

Webberley MJ, Murray JA. Life-threatening acute hyponatraemia induced by low dose cyclophosphamide and indomethacin. Postgrad Med J. 1989 Dec;65(770):950-952.