Sites and Extents of Alkylation in Tumour Cell DNA and their Relation to Antitumour Effects of Dibromodulcitol and Dianhydrogalactitol

Abstract

It has been revealed that dibromodulcitol (DBD) and one of its conversion products dianhydrogalactitol (DAG) alkylate DNA in vivo yielding 3-alkyladenine, 7-alkylguanine and di(guanin-7-yl)-galactitol. The doses of the two drugs which produced nearly equal tumour inhibitory effects on Yoshida sarcoma cells resulted in the same amount of diguaninyl moieties in the tumour cell DNA but DBD produced six times as much monoalkylpurines as the DAG did. The persistence of monoalkylguanine and diguaninyl-galactitol in DNA was followed as a function of time. There was no significant loss of either monoalkylguanine or diguaninyl derivatives during the observation period i.e. 7–36hr, whereas the physical measurements of the amount of renaturable DNA showed a rapid opening of cross-links in the same period. The removal of cross-linking is proceeded by a two-step mechanism. In the first step, one arm of the cross-links is removed, leaving the DNA non- renaturable. While the other arm of cross-link is still attached covalently to the DNA molecule rendering possible the detection of the diguaninyl moiety in DNA. In the second step the other arm of the cross-link will be excised more later, probably at the same rate as it is in the case of monoalkylguanine.