Cytotoxicity of tiazofurin and its arabinose and xylose analogues in K562 cells.
2-beta-D-Arabinofuranosylthiazole-4-carboxamide and 2-beta-D-xylofuranosyl-thiazole-4-carboxamide are sugar modified analogues of tiazofurin, a C-glycosyl nucleoside which after anabolism to the dinucleotide, TAD (thiazole-4-carboxamide adenine dinucleotide), exhibits antitumor activity. However, ara-T and xylo-T did not exhibit cytotoxicity. Compared to tiazofurin, only 12.5% of the ara-T and 8.8% of the xylo-T were metabolized to TAD derivatives by human myelogenous leukemia K562 cells. This was reflected in the finding that guanylate pools were not depressed after treatment with either tiazofurin derivative. These results provide evidence that the ribose moiety is essential for the metabolism and cytotoxicity of tiazofurin. This investigation should be helpful in the design of new analogues of tiazofurin for future clinical trials.
Zhen
W
W
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200.
Jayaram
H N
HN
Marquez
V E
VE
Goldstein
B M
BM
Cooney
D A
DA
Weber
G
G
D000227:Adenine Nucleotides / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001087:Arabinonucleosides / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D009705:Nucleosides / Q000494:pharmacology*; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000494:pharmacology
D000227:Adenine Nucleotides; D000964:Antimetabolites, Antineoplastic; D001087:Arabinonucleosides; D009705:Nucleosides; D012254:Ribavirin; C038167:thiazole-4-carboxamide adenine dinucleotide; C071386:2-beta-arabinofuranosylthiazole-4-carboxamide; C071387:2-beta-xylofuranosylthiazole-4-carboxamide; D007168:IMP Dehydrogenase; C033706:tiazofurin