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Studies with 8-azainosine, a cytotoxic nucleoside with antitumor activity.

1973; National Institutes of Health; Volume: 33; Issue: 3 Linguagem: Inglês

L. Lee Bennett, Margaret H. Vail, Paula W. Allan, W R Laster,

Adenosine and Purinergic Signaling

8-Azainosine (8-azaHR) inhibited the growth of H. Ep. No. 2 cells in culture and also inhibited the growth of a subline (H. Ep. No. 2/MP) that was selected for resistance to 6-mercaptopurine (MP) and that was resistant also to 8-azahypoxanthine (8-azaH). In mice, 8-azaHR was more toxic than 8-azaH; it inhibited the growth of solid Adenocarcinoma 755 to 25% of that of controls and prolonged by about 50% the life-span of mice bearing lymphoid leukemia L1210 or a subline of this leukemia resistant to both MP and 8-azaH. The inhibition of growth of Adenocarcinoma 755 cells in culture by 8-azaHR was reversed partially by inosine, hypoxanthine, or guanine but not by adenine or 4-amino-5-imidazolecarboxamide. At concentrations of 1 to 2 µm 8-azaHR inhibited, by 50%, colony formation by the following lines of H. Ep. No. 2 cells that were selected for resistance to the indicated inhibitors and that had lost activities of the indicated enzymes: ( a ) H. Ep. No. 2/MeMPR, 6-methylthiopurine ribonucleoside [adenosine kinase (EC 2.7.1.20)]; ( b ) H. Ep. No. 2/FA, 2-fluoroadenine [adenine phosphoribosyltransferase (EC 2.4.2.7)]; and ( c ) H. Ep. No. 2/FA/FAR, 2-fluoroadenine and 2-fluoroadenosine (adenine phosphoribosyltransferase and adenosine kinase). It did not inhibit H. Ep. No. 2/MP/MeMPR cells that were selected for resistance to MP and 6-methylthiopurine ribonucleoside and that were deficient in both hypoxanthine (guanine) phosphoribosyltransferase (EC 2.4.2.8) and adenosine kinase. In H. Ep. No. 2 cells in culture, resistance to 8-azaHR developed rapidly, was stable when the cells were cultured in the absence of 8-azaHR, and was not associated with decreases in the activities of adenine or hypoxanthine phosphoribosyltransferases or adenosine kinase or with any marked change in capacity to convert 8-azaHR to 8-azainosine monophosphate of 8-AzaH. This resistant subline was highly resistant to 8-azaH and 2-azahypoxanthine, was slightly resistant (up to 10-fold) to several other analogs of hypoxanthine or guanine, and was not at all resistant to analogs of adenine or adenosine. These results suggest that to be biologically active, 8-azaHR must be converted to 8-azainosine monophosphate and that this conversion may occur either by direct phosphorylation or via 8-azaH.