Activity and metabolism of 2-beta-D-ribofuranosylthiazole-4-carboxamide in human lymphoid tumor cells in culture.

The antitumor activity of the C-nucleoside, 2-beta-D-ribofuranosylthiazole-4-carboxamide (TR), was investigated in four 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 hr to TR resulted in 50% inhibitory concentration of 30, 27, 7, and 6 microM, respectively. Maximum inhibition of DNA and RNA synthesis occurred 6 hr after drug treatment. The 50% inhibitory concentration of TR among the four cell lines varied from 5 to 8 microM for RNA synthesis and from 4 to 8 microM for DNA synthesis. Nucleotide analyses in MOLT-4 cells after 6 hr of drug exposure to 10 and 100 microM TR revealed increased inosine 5'-monophosphate concentrations which were 18- to 20-fold greater than control levels and a parallel reduction of 82 and 100% in guanosine 5'-monophosphate concentrations. Growth inhibition of MOLT-4 cells by 6 hr exposure to TR was almost fully reversible by addition of 50 microM guanosine to the medium for 18 hr. Analyses by high-pressure liquid chromatography revealed two metabolites of TR in all four cell lines, namely, thiazolecarboxamide riboside 5'-monophosphate and thiazolecarboxamide adenine dinucleotide, the latter of which is a potent inhibitor of inosine-5-'-monophosphate dehydrogenase. These results suggest that the antitumor effects of TR in human tumor cell lines may relate to guanine nucleotide depletion.