9-[3-(2-Nitro-1-imidazolyl)propylamino]-cyclopenteno[b]quinoline hydrochloride (NLCPQ-1): a novel DNA-affinic bioreductive agent as chemosensitizer. I.
9-(3-(2-Nitro-1-imidazolyl)propylamino]-cyclopentano[b]quinoline hydrochloride (NLCPQ-1) is one member of a limited series of 2-nitroimidazole-linked derivatized quinolines we have synthesized to be weak DNA binding compounds. On a concentration basis, NLCPQ-1 is the most potent analogue of the series as a radiosensitizer and cytotoxin of hypoxic cells in vitro and in vivo. This improved efficacy compared to untargeted nitroimidazolic bioreductive compounds has been mainly attributed to its weak DNA binding. In the present study, we investigated the ability of NLCPQ-1 to act synergistically with 4-[bis(2-chloroethyl)amino]-L-phenylalanine (L-PAM, melphalan) or cis-diamminedichloroplatinum (cis-DDP, cisplatin) against tumor cells in vitro and in vivo. We demonstrated that 7 microM NLCPQ-1 potentiated the toxic effect of cis-DDP and L-PAM against V79 cells under hypoxic pretreatment conditions with dose modification factors (DMF) of 2.6 and 2.4, respectively, measured at 0.1 survival. Potentiation was dependent on the concentrations of both the chemotherapeutic agent and NLCPQ-1 as well as on the duration of the hypoxic pretreatment with NLCPQ-1. No potentiation was observed under aerobic cotreatment conditions in vitro. Significant synergism was observed when 15 mg/kg NLCPQ-1 was administered IP at various time intervals before a single dose of L-PAM (5 mg/kg) or cis-DDP (5 mg/kg) in Balb/c mice bearing EMT6 tumors. The in vivo/in vitro assay was used as the investigational endpoint and either the fractional product or isobologramic analysis was used to determine synergistic interactions.
Papadopoulou
M V
MV
Radiation Medicine Institute, Evanston Hospital Corporation, IL 60201, USA. mvp499@anima.nums.nwu.edu
Ji
M
M
Rao
M K
MK
Bloomer
W D
WD
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D006224:Cricetinae; D003412:Cricetulus; D018736:DNA Adducts / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D008558:Melphalan / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009593:Nitroimidazoles / Q000378:metabolism / Q000494:pharmacology*; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
C106788:9-(3-(2-nitro-1-imidazolyl)-propylamino)cycopenteno(b)quinoline; D000970:Antineoplastic Agents; D018736:DNA Adducts; D004273:DNA, Neoplasm; D009593:Nitroimidazoles; D011804:Quinolines; D002945:Cisplatin; D008558:Melphalan