Potentiation of combination chemotherapy by nitroheterocyclics

The effect of including a nitroimidazole in a treatment regimen combining two alkylating chemotherapeutic agents was evaluated in a mouse tumor model. KHT sarcoma-bearing female C3H/HeJ mice were treated with a single dose of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) either alone or in combination with the radiosensitizer misonidazole (MISO) prior to a range of cyclophosphamide (CY) doses. CCNU (5 mg/kg) preceded CY treatment by 3 hr. MISO (1 mmol/kg) was given 1 hr after CCNU (2 hr prior to CY). Tumor response was assessed using either an in vitro to in vivo clonogenic cell survival assay 22-24 hr after treatment or an in situ delay of tumor regrowth assay. The results demonstrated that the inclusion of MISO at a dose of 1.0 mmol/kg increased tumor cell kill resulting from the combination of CCNU-CY by a factor of 1.4-1.5 compared to that seen in the absence of the nitroimidazole. Normal tissue toxicity resulting from the CCNU-CY or CCNU-MISO-CY combinations was determined by measuring bone marrow stem cell (CFU-S or CFU-GM) toxicity. Compared to CCNU-CY alone, the addition of MISO did not enhance this normal tissue toxicity. These findings indicate that the inclusion of MISO in a combination chemotherapy protocol may yield a significant therapeutic benefit.