The metabolism of α-2′ -deoxythioguanosine in murine tumor cells

Abstract

Preparations of [alpha]-2[image]-deoxythioguanosine ([alpha]-TGdR) completely free of [beta]-2[image]-deoxythioguanosine ([beta]-TGdR) were made and labeled with radiosulfur. A purified preparation of nucleoside phosphorylase obtained from human blood cells was found to be active on the [beta]-anomer but completely inactive on the [alpha]-anomer. This property of the enzyme was used to characterize metabolites of [alpha]-TGdR. [alpha]-TGdR and [beta]-TGdR were both converted to the corresponding mono-, di-, and tri-phosphates and incorporated into the nucleic acids of Mecca lymphosarcoma cells in vivo. [alpha]-TGdR appeared predominantly in the terminal nucleoside positions of RNA and DNA. [beta]-TGdR appeared predominantly in the nucleotide chain. Both Mecca lymphosarcoma and Ehrlich carcinoma cells formed significant quantities of analog nucleotides at all 3 levels of phosphorylation, probably exceeding the levels of guanine nucleotides in the cells for an appreciable time. The findings further support a correlation reported earlier between the incorporation of 6-thioguanine into DNA and the inhibition of cell growth.