The metabolism of 3'-azido-2',3'-dideoxyguanosine in CEM cells.
When CEM cells were incubated with [3H]-labeled 3'-azido-2',3'-dideoxyguanosine (AzddGuo), the isotope was largely recovered as ribo- and deoxyribonucleotides in the acid soluble fraction of CEM cells, due to extensive catabolism of AzddGuo and recycling of the guanine formed by purine nucleoside phosphorylase. Only 10% was found as the AzddGuo nucleotides, with the diphosphate of AzddGuo as the dominating nucleotide at all time points. Thus nucleoside diphosphate kinase was rate limiting for the formation of AzddGuo triphosphate, responsible for the toxic and antiviral activity of the nucleoside. Inhibition of de novo deoxyribonucleotide synthesis with hydroxyurea increased the phosphorylation of AzddGuo twofold.
Department of Biochemistry 1, Medical Nobel Institute, Karolinska Institute, Stockholm, Sweden.
A
A
Karlsson
P
P
Reichard
F
F
Eckstein
D000998:Antiviral Agents / Q000378:metabolism*; D002460:Cell Line; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003854:Deoxyribonucleotides / Q000378:metabolism; D015224:Dideoxynucleosides / Q000378:metabolism*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D007700:Kinetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011865:Radioisotope Dilution Technique; D014316:Tritium; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism*
D000998:Antiviral Agents; D004273:DNA, Neoplasm; D003854:Deoxyribonucleotides; D015224:Dideoxynucleosides; D012334:RNA, Neoplasm; D014316:Tritium; C051073:3'-azido-2',3'-dideoxyguanosine; D006918:Hydroxyurea