9-[3-(2-Nitro-1-imidazolyl)propylamino]-cyclopenteno[b]quinoline hydrochloride (NLCPQ-1). A novel DNA-affinic bioreductive agent as chemosensitizer: mechanistic studies. II.
NLCPQ-1 is a novel, weak, DNA-affinic bioreductive compound with enhanced chemosensitizing ability for commonly used chemotherapeutic agents, both in vitro and in vivo. In the present report we investigated possible mechanisms involved in the potentiation of cis-DDP and L-PAM in V79 cells. Potentiation was observed when cells were pretreated under hypoxic conditions with NLCPQ-1 prior to their aerobic exposure to each chemotherapeutic agent studied and in the presence of NLCPQ-1. The dominant mechanisms, under hypoxic pretreatment conditions, participating in the potentiation were: a) extensive DNA damage, as measured by the comet and alkaline elution assays, b) DNA, RNA, and protein synthesis inhibition, c) significant delay in the traverse through the S phase, as observed by flow cytometry, and possibly d) suppression of PLD repair. Apoptosis was also detected 36 h posttreatment in the chemotherapeutic drug-treated as well as the combination drug-treated cells. Glutathione depletion by NLCPQ-1 metabolites under hypoxic conditions was also involved in the potentiation process, but its contribution in potentiation was minimal.
Papadopoulou
M V
MV
Radiation Medicine Institute, Evanston Northwestern Healthcare, IL 60201, USA. mvp499@anima.nums.nwu.edu
Rosenzweig
H S
HS
Ji
M
M
Khan
S H
SH
Bloomer
W D
WD
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009593:Nitroimidazoles / Q000378:metabolism* / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000378:metabolism / Q000494:pharmacology; D011804:Quinolines / Q000378:metabolism* / Q000494:pharmacology; D012313:RNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis
C106788:9-(3-(2-nitro-1-imidazolyl)-propylamino)cycopenteno(b)quinoline; D000477:Alkylating Agents; D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D011500:Protein Synthesis Inhibitors; D011804:Quinolines; D012313:RNA; D004247:DNA; D005978:Glutathione