CELLULAR AND ANTIVIRAL EFFECTS OF HALOGENATED DEOXYRIBONUCLEOSIDES *

A study has been in progress of the effect of 5-iodo-2’-deoxyuridine (IUDR) and its phosphorylated derivatives on the enzymes concerned with the formation of precursors of DNA-thymine in a cell-free extract of herpes simplex virusinfected and noninfected cells. The problem is to determine whether the enzymes concerned with these biotransformations in the virus-infected cells are more sensitive to inhibition by the iodinated analog or its phosphorylated derivatives than are the corresponding enzymes of the noninfected cells. Such a difference in susceptibility to inhibition could account for the virus being inhibited under conditions that are noninhibitory to the host cell. That a difference might exist in the enzymes of the normal host cell and the cell infected with animal virus is supported by observations in phage-infected bacterial cells that indicate the formation of a new phage-specific DNA polymerase’ and a deoxynucleotide kinase.24 Whereas the polymerase present normally in Escherichiu coli utilizes native DNA as a primer, that induced by infection with Tz phage functions best with denatured DNA and is inert with native DNA. The formation of enzymes induced by bacteriophage in bacterial cells has been reviewed by Cohens and Schmidt.s Increases in the activities of enzymes concerned with the formation of precursors of DNA-thymine, as well as with the polymerization of have been reported to occur upon infection of mammalian cells with certain animal viruses. This, however, is neither a general finding nor applicable to all enzyme~. *,~J~ Physical differences between enzymes induced by animal viruses and their counterpart in the noninfected cell have been observed recently. Nohara and KaplanZ2 have demonstrated that thymidine monophosphate kinase induced by infection of rabbit kidney cells with pseudorabies virus has a markedly greater thermostability than the enzyme present in the noninfected cells. Rogers and Moore23 reported that the enzyme, arginase, induced by Shope papilloma virus differed from the normal enzyme of the host animal in several physicochemical characteristics as well as metal requirements. McAuslanZ4 found thymidine kinase induced by pox virus to have a higher thermostability and a lower Michaelis constant than the corresponding enzyme present normally. Such findings support the possibility that a difference between an enzyme present normally in mammalian cells and the corresponding virus-induced enzyme may be found that will permit preferential inhibition of the latter by a drug and hence selective toxicity. Indeed, IUDR has been reported to inhibit the replication of several DNA-containing viruses under conditions that exert no apparent inhibition of the host cells. The present report is an evaluation of the inhibitory effect of IUDR and its monophosphate derivative on the thymidine kinase and thymidylic * This investigation was supported by U.S. Public Health Research Grant CA-526245 and US. National Science Foundation Grant GB-2805. t Support from the James Hudson Brown Memorial Fund (1962-1963) and the Anna Fuller Fund (1963-1964) is gratefully acknowledged (Y. S. Bakhle).