Schedule-dependent potentiation of chemotherapeutic drugs by the bioreductive compounds NLCQ-1 and tirapazamine against EMT6 tumors in mice

Abstract.

Purpose: Comparisons of schedule-dependent interactions between the hypoxic cytotoxins NLCQ-1/tirapazamine (TPZ) and various chemotherapeutic drugs in BALB/c mice bearing EMT6 tumors. Methods: The antitumor effects of the single or combined drugs were assessed with various administration time intervals using the in vivo-in vitro clonogenic assay as the endpoint. The chemotherapeutic drugs tested were cisplatin (cisDDP), melphalan (L-PAM), cyclophosphamide (CPM), 5-fluorouracil (5-FU), doxorubicin (Doxo), etoposide (VP-16) and Taxol at doses of 8, 5, 100, 150, 12, 35 and 20 mg/kg, respectively. NLCQ-1 was given at 10 mg/kg (28% of its single LD₅₀ value) and TPZ was given at 30 mg/kg (38% of its single LD₅₀ value). All drugs were given by i.p. injection in saline or as commercially available pharmaceutical solutions. Results: Schedule-dependent synergistic interactions with different patterns for each bioreductive drug were observed with almost all of the chemotherapeutic agents examined. Potentiation accounting for more than 25% of the total tumor cell killing was observed with NLCQ-1/TPZ and cisDDP, L-PAM, CPM, 5-FU and Taxol at the optimal administration intervals. Potentiation accounting for 70% of the total tumor cell killing was found with NLCQ-1 and CPM. Conclusions: These results suggest a potential clinical use of NLCQ-1/TPZ as adjuvants to certain chemotherapeutic agents.