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Synergistic Interaction between Tirapazamine and Cyclophosphamide in Human Breast Cancer Xenografts¹

SRI International, Menlo Park, California 94025

This study examined the efficacy of combining cyclophosphamide and the hypoxic cytotoxin, tirapazamine, in the treatment of human breast cancer xenografts grown in nude mice. A single dose of tirapazamine was followed 2 h later by a single dose of cyclophosphamide. As determined from tumor regrowth delay, the effectiveness of combined therapy was greater than the additive effects of each treatment given alone. Possible mechanisms of this synergistic interaction include enhancement of DNA damage, inhibition of repair of DNA damage, or induction of apoptosis. Apart from some loss in body weight, the only other toxicity of interest in mice treated with tirapazamine was necrosis of the skin on the distal tail, which appeared to be vascular in origin.

¹ Supported in part by Grant R29 CA52285 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Alza Corporation, 950 Page Mill Rd., Box 10950, Palo Alto, CA 94303-0802.

Received 2/25/94. Accepted 4/21/94.

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