Cytogenetic Analysis of the Action of Carcinogens and Tumour Inhibitors in Drosophila Melanogaster. X. the Nature of the Mutations Induced by the Mesyloxy Esters in Relation to Molecular Cross-linkage

N efforts to establish a correlation between the chemical structure of “nitrogen Imustards” and their tumour inhibitory activity, it was noted that the presence of two active groups per molecule was more favourable (HADDOW, KON and Ross 1948). Seeking an explanation for this difunctional requirement, the cross-linkage hypothesis was postulated ( GOLDACRE, LOVELESS and Ross 1949). This suggested that two active groups might be required to permit the molecule to react at two distinct points lying either on a single fibre, or more especially on two contiguous fibres. Mutagenesis studies did not support the cross-linkage hypothesis. The monofunctional compound ethylene oxide proved to be decisively mutagenic ( BIRD 1952), though at the same molar dose it was still far less effective than the corresponding difunctional compound diepoxybutane ( FAHMY and FAHMY 1956). More significant in this connection is the situation with the mesyloxy esters, where it was found that the monofunctional compounds (the methyl and ethyI derivatives) were highly active mutagens (FAHMY and FAHMY 1957). At the same molar dose, the above monosulphonates were considerably more mutagenic on mature sperm than the majority of the difunctional derivatives (FAHMY and FAHMY 1956 and unpublished). Recent physicochemical studies on the in uitro reactions of alkylating agents on model macromolecules, as well as on deoxyribonucleic acid (DNA) have revived interest in cross-linkage (ALEXANDER, COUSENS and STACEY 195 7; STACEY, COBB, COUSENS and ALEXANDER 1958). Evidence was available for the occurrence of interand intramolecular cross-linkage under difunctional compounds, which resulted in marked alterations of the physical characteristics of the DNA molecules (changes in molecular weight and viscosity). In contrast, it was possible to demonstrate that monofunctional compounds produce separate and independent esterification of the phosphate groups of DNA. While it is now certain that cross-linkage under the alkylating agents cannot be the reason for their mutagenicity, yet it was thought feasible that this phenomenon might somehow influence the molecular basis of the induced mutations. Accordingly a detailed comparative study of the mutagenic properties of a series