The influence of radiomimetic substances on deoxyribonucleic acid synthesis and function studied in Escherichia coli /phage systems - I. The nature of the inactivation of T 2 phage in vitro by certain alkylating agents

Abstract

Nucleophilic alkylating agents such as bis-chloroethylamines and sulphides (‘mustards’), bis-epoxides and others, and their monofunctional analogues, have been found to elicit characteristic responses when administered to suitable biological systems. These include inhibition of cellular proliferation, the production of abnormal chromosome configurations and mutations, and the initiation of malignant transformation. From these observations and allied chemical investigations it has been supposed that deoxyribonucleic acids are the primary sites of attack by such reagents. The present communication reports the results of a study of the inactivation of T 2 bacteriophage by a representative group of mono- and bifunctional alkylating agents con­ducted as a preliminary to an investigation of their effects upon the host/virus complexes. It was found that, with both mono- and bifunctional compounds, inactivation continued after removal of the agent. In the case of monofunctional compounds this was due to a dose-dependent and acid-catalyzed breakdown of the alkylated particles. With bifunctional compounds the delay in inactivation was occasioned largely by the necessity for reaction of the second functional groups of the attached residues. Some evidence was obtained suggesting a subsequent breakdown of the phage material though, if this occurred, it was more rapid than in the case of monofunctional compounds. The dose/survival curves were revealed as exponential, and thus similar to those obtained with radiations, when these reactions were allowed to go to completion. The interpretation of these results is discussed and their possible relevance to the biological response to alkylating agents in other systems considered.