Studies on the Cytotoxicity of Myleran and Dimethyl Myleran

Abstract

Myleran and dimethyl Myleran (DMM) are two potentially bifunctional alkylating agents which might be expected to form cross-links between guanine residues on the same or opposite strands of native DNA. When L cells were treated with these agents DMM was considerably more toxic than Myleran. When DNA, RNA, and protein were subsequently isolated and analyzed it was found that both agents reacted with DNA to the same extent, the degree of labelling being linear with the concentration of the agents. RNA and protein were labelled to a rather greater extent. When DNA was analyzed chromatographically, no evidence was found for the formation of alkylated guanine residues after treatment with DMM. With Myleran, a product corresponding to the N-7 alkylated monoguaninyl derivative was formed, but no diguaninyl product was detected. Similar results were obtained when DNA was treated in vitro. No evidence of cross-linking by either agent was found when DNA treated in vitro was subjected to alkaline denaturation and subsequent renaturation, and then analyzed by cesium chloride density gradient centrifugation. It is concluded that neither Myleran nor DMM causes cross-linking of DNA strands, nor do they form links between adjacent guanine residues in one strand of DNA.