ACTIVITY AND METABOLISM OF 2-BETA-D-RIBOFURANOSYLTHIAZOLE-4-CARBOXAMIDE IN HUMAN LYMPHOID TUMOR-CELLS IN CULTURE

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (1) , 133-137
Abstract
The antitumor activity of the C-nucleoside, 2-.beta.-D-ribofuranosylthiazole-4-carboxamide (TR), was investigated in 4 human lymphoid tumor cell lines in culture. Exposure of the cell lines CCRF-CEM (T cell leukemia), HUT-78 (cutaneous T cell lymphoma), NALM-1 (B cell leukemia), and MOLT-4 (T cell leukemia) for 72 h to TR resulted in 50% inhibitory concentration [IC50] of 30, 27, 7 and 6 .mu.M, respectively. Maximum inhibition of DNA and RNA synthesis occurred 6 h after drug treatment. The IC50 of TR among the 4 cell lines varied from 5-8 .mu.M for RNA synthesis and from 4-8 .mu.M for DNA synthesis. Nucleotide analyses in MOLT-4 cells after 6 h of drug exposure to 10 and 100 .mu.M TR revealed increased IMP concentrations which were 18- to 20-fold greater than control levels and a parallel reduction of 82 and 100% in GMP concentrations. Growth inhibition of MOLT-4 cells by 6 h exposure to TR was almost fully reversible by addition of 50 .mu.M guanosine to the medium for 18 h. Analyses by high-pressure liquid chromatography revealed 2 metabolites of TR in all 4 cell lines, namely, thiazolecarboxamide riboside 5''-monophosphate and thiazolecarboxamide adenine dinucleotide, the latter of which is a potent inhibitor of IMP dehydrogenase. These results suggest that the antitumor effects of TR in human tumor cell lines may relate to guanine nucleotide depletion.