Therapeutic advantage from combining 5-fluorouracil with the hypoxia-selective cytotoxin NLCQ-1 in vivo; comparison with tirapazamine.

ABSTRACT

PURPOSE: The antitumor effect and bone marrow toxicity of 5-fluorouracil (5FU) in combination with the hypoxia-selective cytotoxins NLCQ-1 or tirapazamine (TPZ) were investigated in vivo. METHODS: Using appropriate intraperitoneal administration schedules for optimal synergistic interactions, the antitumor effect and the bone marrow toxicity of combinations of NLCQ-1 or TPZ and 5FU were determined in EMT6/BALB/c and SCCVII/C3H models in terms of dose modification factors (DMF) using the in vivo-in vitro clonogenic assay as endpoint. Bone marrow toxicity studies were performed in parallel using a modified CFU-GM assay. The antitumor efficacies of each combination treatment under optimal administration conditions were evaluated in the SCCVII/C3H model using also the tumor regrowth assay as endpoint. RESULTS: A schedule-dependent and tumor-specific synergistic interaction was observed for NLCQ-1 plus 5FU and DMFs of 2.0-2.3 and 1.0 were obtained for the antitumor effect and bone marrow toxicity, respectively, in both tumor models. The antitumor effect of 5FU was slightly potentiated (DMF 1.2) by TPZ in the EMT6/BALB/c model but not in the SCCVII/C3H model when the in vivo-in vitro assay was used as the endpoint. Significant additional tumor regrowth delays (about 11 and 6 days for NLCQ-1 and TPZ, respectively) were observed, compared to the effect of 5FU alone, when an equitoxic dose of NLCQ-1 (10 mg/kg) or TPZ (23 mg/kg) was administered 1 h before 5FU (50 mg/kg) twice a day at 4-h intervals on days 0 and 9. CONCLUSIONS: These results corroborate the therapeutic advantage of combining hypoxia-selective cytotoxins such as NLCQ-1 and TPZ with chemotherapy.