EFFECT OF 9-BENZYL-9-DEAZAGUANINE, A POTENT INHIBITOR OF PURINE NUCLEOSIDE PHOSPHORYLASE, ON THE CYTOTOXICITY AND METABOLISM OF 6-THIO-2'-DEOXYGUANOSINE

6-Thio-2'-deoxyguanosine (T-dGuo) has been reported to be both phospho rylated by deoxycytidine kinase and converted to 6-thioguanine by puri ne nucleoside phosphorylase (PNP). Combination of T-dGuo with an inhib itor of PNP would be expected to generate the 5'-triphosphate of T-dGu o and limit or prevent the formation of 6-thioguanosine triphosphate. Because the incorporation of 6-thioguanine into DNA is believed to be primarily responsible for the antitumor activity of the thiopurines, t his treatment might result in enhanced activity against certain tumors , particularly those of T-cell origin. We have evaluated the metabolic basis of this strategy by examining the effects of 9-benzyl-9-deazagu anine (BDG), a potent inhibitor of PNP, on the metabolism of T-dGuo in CEM cells. The concentration of T-dGuo required to inhibit cell growt h by 50% was approximately 50-fold greater in the presence of 8.0 muM BDG than in its absence. As expected, the addition of BDG to cells tre ated with T-dGuo prevented the metabolism of T-dGuo to 6-thio-guanine- containing ribonucleotides, but, unexpectedly, no 6-thio-2'-deoxyguano sine 5'-triphosphate was detected. In cells treated with T-dGuo plus B DG, the major phosphorylated metabolite was T-dGMP. These results indi cated that even in the absence of PNP activity, T-dGuo cannot be phosp horylated directly to 6-thio-2'-deoxyguanosine 5'-triphosphate due to the inability of guanylate kinase to utilize T-dGMP as a substrate.