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The Effect of Allopurinol on Cyclophosphamide Antitumor Activity¹

Section of Hematology-Oncology, Department of Internal Medicine, College of Medicine, University of Arizona, Tucson, Arizona 85724 [D. S. A.], and The Cancer Research Institute, University of California School of Medicine, San Francisco, California 94143 [T. v. D. W.]

We have used the spleen colony assay system and survival duration studies in male DBA/2 mice with P388 leukemia to study the effects of allopurinol pretreatment on the antileukemic activity of cyclophosphamide and its bone marrow toxicity. Allopurinol drinking water (0.5 mg/ml) was given for 7 days prior to cyclophosphamide (10 to 200 mg/kg i.p.). Average daily allopurinol intake per mouse was 1.25 mg (equivalent to 4 mg/kg/day human dosage). Dose-response curves with and without allopurinol pretreatment showed an almost constant 0.9-log increase in the toxicity of cyclophosphamide to leukemic colony-forming units, whereas allopurinol had no effect on the toxicity of cyclophosphamide to normal bone marrow colony-forming units. Parallel survival studies revealed no difference in the antileukemic activity of cyclophosphamide as a result of allopurinol pretreatment. The allopurinol-induced change in the antitumor activity of cyclophosphamide as seen in the spleen colony assay was not explainable on a pharmacokinetic basis. Flow microfluorometric analysis of P388 leukemia tumor cell cycle parameters revealed no change in the blockading effects of cyclophoshamide as a result of allopurinol preexposure. Although we have failed to explain the underlying mechanism of this drug interaction, our data suggest that allopurinol may increase the antitumor activity of cyclophosphamide without increasing its bone marrow toxicity.

¹ This investigation was supported in part by Clinical Cancer Research Center Grant CA-11067 (to the University of California) and Medical Oncology Program Project Grant CA-17094 (to the University of Arizona) from the National Cancer Institute, NIH, Bethesda, Md; the Faculty Training Grant in Clinical Pharmacology from the Pharmaceutical Manufacturing Association, Washington, D. C.; and the Cancer Coordinating Committee Grant from the University of California, Berkeley, Calif. Presented in part at the 64th Annual Meeting of the American Association of Cancer Research, San Diego, Calif. May 1975 (1).

² To whom requests for reprints should be addressed.

³ Present address: Department of Microbiology, University of California, School of Medicine, San Francisco, Calif. 94143.

Received 11/ 6/75. Accepted 4/20/76.