Enhancement of the anti-tumour effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine

摘要

The ability of the bioreductive drugs AQ4N and tirapazamine to enhance the anti-tumour effect of cyclophosphamide was assessed in three murine tumour models. In male BDF mice implanted with the T50/80 mammary carcinoma, AQ4N (50–150 mg kg⁻¹) in combination with cyclophosphamide (100 mg kg⁻¹) produced an effect equivalent to a single 200 mg kg⁻¹dose of cyclophosphamide. Tirapazamine (25 mg kg⁻¹) in combination with cyclophosphamide (100 mg kg⁻¹) produced an effect equivalent to a single 150 mg kg⁻¹dose of cyclophosphamide. In C3H mice implanted with the SCCVII or RIF-1 tumours, enhancement of tumour cell killing was found with both drugs in combination with cyclophosphamide (50–200 mg kg⁻¹); AQ4N (50–200 mg kg⁻¹) produced a more effective combination than tirapazamine (12.5–50 mg kg⁻¹). Unlike tirapazamine, which showed a significant increase in toxicity to bone marrow cells, the combination of AQ4N (100 mg kg⁻¹) 6 h prior to cyclophosphamide (100 mg kg⁻¹) resulted in no additional toxicity towards bone marrow cells compared to that caused by cyclophosphamide alone. In conclusion, AQ4N gave a superior anti-tumour effect compared to tirapazamine when administered with a single dose of cyclophosphamide (100 mg kg⁻¹). © 2000 Cancer Research Campaign