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RL Blakley, FC Harwood and KD Huff
Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101.
The 2',3'-dideoxy analogues of cytidine, guanosine, adenosine, inosine, and thymidine have been compared for their cytostatic effects on 14 cell lines that include B lymphoblastic, T lymphoblastic, and myeloblastic lines. In all cases 2',3'-dideoxycytidine (ddCyd) was the most toxic nucleoside, with dideoxyguanosine (ddGuo) next, and little cytostatic action by the analogues of thymidine, adenosine, or inosine. The cytostatic action of ddCyd was examined in more detail. The concentration for 50% inhibition of growth over 4 days (IC50) was 0.2 to 3 microM for five T lymphoblastic lines. Although most B lymphoblastic and myeloblastic lines were less sensitive (IC50, 16-70 microM), some were as sensitive as the T lymphoblastic lines. The four lines most sensitive to ddGuo (three T lymphoblastic and one B lymphoblastic) had IC50 values of 47-80 microM. Two lines with high sensitivity to ddCyd had levels of ddCyd triphosphate about 4-7 times higher than those found in the two least sensitive after 1-, 3-, or 24- hr exposure to 3 microM [3H]ddCyd. This was associated with a much higher ratio of the diphosphate to the triphosphate in the least sensitive cells, an observation suggesting slow nucleoside diphosphate kinase action on the diphosphate of ddCyd in the resistant cells. Catabolism of the mono-, di-, and triphosphate was very slow in all cell lines, and in lines of low sensitivity disappearance of the triphosphate had a half life (approximately 19 hr) about twice as long as in sensitive lines. This may be due to continuing slow conversion of diphosphate to triphosphate after removal of nucleoside from the medium.
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