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The mechanism of action of the cyclopentenyl analogue of 3-deazaadenosine (3-deazaneplanocin A or c3Nep) was investigated in the human colon carcinoma cell line HT-29. Upon exposure of cells for 24 hr to 3-deazaneplanocin A (c3Nep), neplanocin A (Nep) or 3-deazaaristeromycin (c3Ari), significant toxicity was noted only for Nep, wherein an 87% reduction in viability was produced at a 100 microM concentration. c3Nep and c3Ari at 100 microM reduced viability by 34 and 21%, respectively. Intracellular levels of S-adenosylhomocysteine (AdoHcy) were elevated by a 24-hr exposure to 100 microM c3Nep, Nep and c3Ari and were 120, 75 and 25 pmoles/10(6) cells respectively. Only Nep was metabolized to an S-adenosylmethionine-like metabolite, and its formation was dose-related to its cytotoxicity. The t1/2 for the disappearance of elevated levels of AdoHcy following drug removal was 1.6 to 2.5 hr for all drugs. rRNA and tRNA methylation was inhibited significantly by Nep, but c3Nep and c3Ari inhibited tRNA methylation but not rRNA methylation to a lesser degree. These results demonstrate that c3Nep is a potent inhibitor of AdoHcy synthesis with a low degree of cytotoxicity.

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