Potentiation of cisplatin activity by the bioreductive agent tirapazamine

The chemosensitizing potential of the benzotriazine-N-oxide tirapazamine was determined in rodent mammary tumor cells grown as solid tumors.

C3H/HeJ mice bearing i.m. transplanted 16C mammary carcinomas were treated with varying doses of either cisplatin alone or cisplatin in combination with a 0.27 mmol/kg dose of tirapazamine. Tumor response to single agent or combination therapy was assessed using an in situ tumor growth delay assay. Normal tissue toxicity 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.

Tirapazamine itself had no measurable effect on the growth of this tumor. However, when administered from 3 h before to simultaneously with a single dose of cisplatin, the resultant tumor growth delay was significantly increased as compared to that seen with cisplatin alone. The administration of tirapazamine 3 h prior to a range of doses of cisplatin was found to result in a dose modifying factor (DMF) of approximately 1.7 in tumor response compared to cisplatin alone. Tirapazamine did demonstrate some hematologic toxicity on its own but it did not potentiate the toxicity of cisplatin when the two agents were administered in combination. BUN analysis showed that tirapazamine had little effect on BUN levels but did suppress the BUN values of mice treated with the combination of tirapazamine and 15 mg/kg cisplatin as compared to cisplatin alone.

The present findings suggest that the addition of tirapazamine to cisplatin therapy may lead to a therapeutic benefit.