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Activity and Metabolism of 2-ß-D-Ribofuranosylthiazole-4-carboxamide in Human Lymphoid Tumor Cells in Culture

Applied Pharmacology Section, Laboratory of Medicinal Chemistry and Biology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205

The antitumor activity of the C-nucleoside, 2-ß-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 µM, 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 µM for RNA synthesis and from 4 to 8 µM for DNA synthesis. Nucleotide analyses in MOLT-4 cells after 6 hr of drug exposure to 10 and 100 µM 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 µM guanosine to the medium for 18 hr. Analyses by highpressure 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.

¹ To whom requests for reprints should be addressed, at National Cancer Institute, Building 37, Room 6D28, Bethesda, Md. 20205.

Received 7/ 6/82. Accepted 10/12/82.

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