Potentiation of alkylating agents by NLCQ-1 or TPZ in vitro and in vivo.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Papadopoulou
Maria V
MV
Department of Radiation Medicine at Evanston Northwestern Healthcare, IL 60201, USA. m-papadopoulou@northwestern.edu
Ji
Xinhai
X
Bloomer
William D
WD
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D020552:Comet Assay; D006224:Cricetinae; D004357:Drug Synergism; D005260:Female; D000860:Hypoxia; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D011804:Quinolines / Q000494:pharmacology*; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology*
C434187:4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-chloroquinoline hydrochloride; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D007093:Imidazoles; D011804:Quinolines; D014227:Triazines; D000077704:Tirapazamine; D002945:Cisplatin; D008558:Melphalan