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 enhan ced chemosensitizing ability for commonly used chemotherapeutic agents , both in vitro and in vivo. In the present report we investigated pos sible 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 eac h chemotherapeutic agent studied and In the presence of NLCPQ-1. The d ominant mechanisms, under hypoxic pretreatment conditions, participati ng in the potentiation were: a) extensive DNA damage, as measured by t he comet and alkaline elution assays, b) DNA, RNA, and protein synthes is inhibition, c) significant delay in the traverse through the S phas e, as observed by Bow cytometry, and possibly d) suppression of PLD re pair. Apoptosis was also detected 36 h posttreatment in the chemothera peutic drug-treated as well as the combination drug-treated cells. Glu tathione depletion by NLCPQ-1 metabolites under hypoxic conditions was also involved in the potentiation process, but its contribution in po tentiation was minimal.