THE ROLE OF FORMALDEHYDE IN METHYLENE DIMETHANESULFONATE-INDUCED DNA CROSS-LINKS AND ITS RELEVANCE TO CYTO-TOXICITY

The interaction of the antitumor dialkanesulfonate ester, methylene dimethanesulfonate (MDMS), with the DNA of [rat] Yoshida sarcoma cells was studied using the technique of alkaline elution. A marked retention which was reversed by proteolytic treatment indicated the presence of DNA-protein cross-links. A small proteinase-resistant retention was also observed which indicated that a low leve of DNA-DNA interstrand cross-links also occurred. Treatment of cells with the amounts of formaldehyde expected by hydrolysis of the drug showed proteinase-reversible DNA-protein cross-linking which on proteolytic removal revealed a small number of single-strand breaks. Thus, MDMS causes both DNA-protein and DNA-DNA interstrand cross-links, the former component being attributed totally to the formaldehyde produced on the drug''s hydrolysis. Cell survival data showed formaldehyde to be comparatively non-cytotoxic, providing evidence that DNA-DNA cross-links observable by this technique may be associated with the cytotoxicity of MDMS.