melphalan and 4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-chloroquinoline-hydrochloride

To investigate potential synergistic interactions between bioreductive agents, either NLCQ-1 or tirapazamine (TPZ) and two alkylating chemotherapeutic drugs, and how such interactions compare in vitro and in vivo.. V79 cells (in vitro studies) and the SCCVII/C3H murine tumor model (in vivo studies) were used. The alkylating chemotherapeutic agents examined were cisplatin (cisDDP) and melphalan (L-PAM). In vivo, all agents were administered by i.p. injection wherein NLCQ-1 and TPZ were given at equitoxic doses of 10 and 23 mg/kg, respectively. Optimal administration schedules and dose modification factors (DMF) were determined in vivo for the antitumor effect or bone marrow toxicity by using the in vivo-in vitro clonogenic assay as the endpoint.. A schedule-dependent synergistic interaction was observed between NLCQ-1/TPZ and each alkylating agent, both in vitro and in vivo, and an optimal potentiation was obtained when each bioreductive agent was administered prior to each chemotherapeutic drug. However, significant DMF values and an in vivo therapeutic index (TI) was obtained only with NLCQ-1. Limited mechanistic studies in V79 cells by using the alkaline comet assay demonstrated that hypoxic preincubation with NLCQ-1 increases the cross-links induced by subsequent aerobic exposure to cisDDP.. These results verify our previous observations in EMT6 tumors and suggest a potential clinical use of NLCQ-1 as a synergistic adjuvant to chemotherapy with alkylating agents against solid tumors possessing hypoxic regions.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Cisplatin; Comet Assay; Cricetinae; Drug Synergism; Female; Hypoxia; Imidazoles; In Vitro Techniques; Melphalan; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Quinolines; Tirapazamine; Triazines

Comparisons of schedule-dependent interactions between the hypoxic cytotoxins NLCQ-1/ tirapazamine (TPZ) and various chemotherapeutic drugs in BALB/c mice bearing EMT6 tumors.. 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.. 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.. These results suggest a potential clinical use of NLCQ-1/TPZ as adjuvants to certain chemotherapeutic agents.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Synergism; Etoposide; Female; Fluorouracil; Imidazoles; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred BALB C; Paclitaxel; Quinolines; Tirapazamine; Triazines; Tumor Cells, Cultured