POTENTIATION OF CISPLATIN ACTIVITY BY THE BIOREDUCTIVE AGENT TIRAPAZAMINE

Purpose: The chemosensitizing potential of the benzotriazine-N-oxide t irapazamine was determined in rodent mammary tumor cells grown as soli d tumors. Materials and methods: C3H/HeJ mice bearing i.m. transplante d 16C mammary carcinomas were treated with varying doses of either cis platin alone or cisplatin in combination with a 0.27 mmol/kg dose of t irapazamine. Tumor response to single agent or combination therapy was assessed using an in situ tumor growth delay assay. Normal tissue tox icity resulting from the tirapazamine, cisplatin, or tirapazamine plus cisplatin was determined by measuring bone marrow stem cell (CFU-GM) toxicities and blood urea nitrogen (BUN) levels. Results: Tirapazamine itself had no measurable effect on the growth of this tumor. However, when administered from 3 h before to simultaneously with a single dos e of cisplatin, the resultant tumor growth delay was significantly inc reased as compared to that seen with cisplatin alone. The administrati on of tirapazamine 3 h prior to a range of doses of cisplatin was foun d to result in a dose modifying factor (DMF) of similar to 1.7 in tumo r response compared to cisplatin alone. Tirapazamine did demonstrate s ome hematologic toxicity on its own but it did not potentiate the toxi city of cisplatin when the two agents were administered in combination . BUN analysis showed that tirapazamine had little effect on BUN level s but did suppress the BUN values of mice treated with the combination of tirapazamine and 15 mg/kg cisplatin as compared to cisplatin alone . Conclusions: The present findings suggest that the addition of tirap azamine to cisplatin therapy may lead to a therapeutic benefit. (C) 19 98 Elsevier Science Ireland Ltd. All rights reserved.