LIKELIHOOD OF THE NEW ANTI-TUMORAL 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 INVIVO AND ITS NONMUTAGENICITY IN YEAST

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (8) , 3700-3706
Abstract
BD-40, a pyridopyrroloisoquinoline analog of ellipticines, has dose-dependent cytostatic and cytotoxic effects on cultures of S. cerevisiae. These inhibitory effects take place only in growing cells and are enhanced in the presence of O2. Among the different repair-deficient mutants examined, a mutant defective in DNA strand break repair (rad52-1) was 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 the lesions induced in vivo by BD-40 are likely to be DNA strand breaks; such damage is repairable in the wild type and is not of the mutagenic type; and 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, an O2-dependent enzymatic processing, not linked to the microsomal monooxygenase complex, may be required for the development of the cytotoxic activity of BD-40.

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