Likelihood of the new antitumoral drug 10-[gamma-diethylaminopropylamino]-6-methyl-5H-pyrido[3',4':4,5]pyrrolo [2,3-g]isoquinoline (BD-40), a pyridopyrroloisoquinoline derivative, to induce DNA strand breaks in vivo and its nonmutagenicity in yeast.
BD-40, a pyridopyrroloisoquinoline analogue of ellipticines, has dose-dependent cytostatic and cytotoxic effects on cultures of Saccharomyces cerevisiae. These inhibitory effects take place only in growing cells and are enhanced in the presence of oxygen. Among the different repair-deficient mutants examined, a mutant defective in DNA strand break repair (rad52-1) was found to be the most sensitive to such a toxic effect. A triple mutant blocked in the excision (rad2), the mutagenic (rad6), and the recombinogenic (rad52) repair pathways demonstrated the same sensitivity as the single rad52 mutant. Nuclear reversion and forward mutations as well as mitochondrial "petite" mutation were not induced by BD-40. These results indicate that: (a) the lesions induced in vivo by BD-40 are likely to be DNA strand breaks; (b) such damage is repairable in the wild type and is not of the mutagenic type; and (c) the excision pathway is not involved in such a repair of BD-40-induced lesions, and the mutagenic pathway plays a minor role. Since DNA strand breaks were not detected in vitro whether exposure of DNA to BD-40 was achieved in the presence or the absence of microsomal S-9 mix, it is suggested that an oxygen-dependent enzymatic processing, not linked to the microsomal monooxygenase complex, is required for the development of the cytotoxic activity of BD-40.
D000332:Aerobiosis; D000693:Anaerobiosis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002417:Cattle; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology*; D007546:Isoquinolines; D009152:Mutagenicity Tests; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000254:growth & development / Q000528:radiation effects
D000970:Antineoplastic Agents; D007211:Indoles; D007546:Isoquinolines; C024256:pazelliptine; D004247:DNA