Tumor-specific, schedule-dependent interaction between tirapazamine (SR 4233) and cisplatin

Tirapazamine (SR 4233), a benzotriazine di-N-oxide, a potent and selective killer of hypoxic cells, is currently in Phase I clinical trials with the expectation that it will be combined with radiation therapy. However, because of the likelihood that hypoxic tumor cells may also be resistant to some commonly used chemotherapeutic agents, we have tested tirapazamine in combination with cisplatin (c-DDP) in the mouse RIF-1 tumor. A large, schedule-dependent enhancement of tumor cell killing was observed both in vivo and in vitro, with a maximal response observed when the SR 4233 was given 2-3 h before c-DDP. Assay of serum blood urea nitrogen levels following treatment with these two drugs indicates that SR 4233 does not enhance the kidney damage which can result from high doses of c-DDP. Leukopenia induced by the two drugs in combination was equal to that predicted from an additive effect of the responses to the individual drugs. Also, there was no change in the systemic toxicity of c-DDP (as judged by 50% lethal dose) when SR 4233 was combined with c-DDP at a dose and timing that produced the maximum tumor interaction. These observations point to a promising new combination therapy with considerable therapeutic advantage.