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 phosphorylated by deoxycytidine kinase and converted to 6-thioguanine by purine nucleoside phosphorylase (PNP). Combination of T-dGuo with an inhibitor of PNP would be expected to generate the 5'-triphosphate of T-dGuo 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, this 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-deazaguanine (BDG), a potent inhibitor of PNP, on the metabolism of T-dGuo in CEM cells. The concentration of T-dGuo required to inhibit cell growth by 50% was approximately 50-fold greater in the presence of 8.0 microM BDG than in its absence. As expected, the addition of BDG to cells treated with T-dGuo prevented the metabolism of T-dGuo to 6-thio-guanine-containing ribo-nucleotides, but, unexpectedly, no 6-thio-2'-deoxyguanosine 5'-triphosphate was detected. In cells treated with T-dGuo plus BDG, the major phosphorylated metabolite was T-dGMP. These results indicated that even in the absence of PNP activity, T-dGuo cannot be phosphorylated directly to 6-thio-2'-deoxyguanosine 5'-triphosphate due to the inability of guanylate kinase to utilize T-dGMP as a substrate.
Parker
W B
WB
Southern Research Institute, Birmingham, Alabama 35205.
Allan
P W
PW
Niwas
S
S
Montgomery
J A
JA
Bennett
L L
LL
D001593:Benzyl Compounds / Q000494:pharmacology*; D001711:Biotransformation; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D013872:Thionucleosides / Q000378:metabolism / Q000633:toxicity*
D001593:Benzyl Compounds; D013872:Thionucleosides; C082660:9-benzyl-9-deazaguanine; C002062:alpha-2'-deoxythioguanosine; D006147:Guanine; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine