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  • Title: Antitumor activity and novel DNA-self-strand-breaking mechanism of CNDAC (1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl) cytosine) and its N4-palmitoyl derivative (CS-682).
    Author: Hanaoka K, Suzuki M, Kobayashi T, Tanzawa F, Tanaka K, Shibayama T, Miura S, Ikeda T, Iwabuchi H, Nakagawa A, Mitsuhashi Y, Hisaoka M, Kaneko M, Tomida A, Wataya Y, Nomura T, Sasaki T, Matsuda A, Tsuruo T, Kurakata S.
    Journal: Int J Cancer; 1999 Jul 19; 82(2):226-36. PubMed ID: 10389757.
    Abstract:
    We have studied the antitumor activity and the novel DNA-self-strand-breaking mechanism of CNDAC (1-(2-Ccyano-2-deoxy-beta-D-arabino-pentofuranosyl)cytosine) and its N4-palmitoyl derivative (CS-682). In vitro, CS-682 showed strong cytotoxicity against human tumor cells comparable with that of CNDAC; both compounds displayed a similar broad spectrum. In vivo, however, orally administered CS-682 showed a more potent activity against human tumor xenografts than CNDAC, 5'-deoxy-5-fluorouridine, 5-fluorouracil and 2',2'-difluorodeoxycytidine. Moreover, CS-682 was effective against various human organ tumor xenografts at a wide dose range and with low toxicity, and was effective against P388 leukemic cells resistant to mitomycin-C, vincristine, 5-fluorouracil or cisplatin in syngeneic mice. CNDAC, an active metabolite of CS-682, had a prolonged plasma half-life after repeated oral administrations of CS-682 but not after oral administrations of CNDAC itself. This difference may partially explain the higher antitumor activity of CS-682 relative to CNDAC. In both CNDAC- and CS-682-treated carcinoma cells, CNDAC 5'-triphosphate (CNDACTP) was generated and incorporated into a DNA strand. High performance liquid chromatography (HPLC) and mass spectrometric analysis of the nucleosides prepared by digestion of the DNA from the CNDAC-treated cells detected ddCNC (2'-Ccyano-2',3 '-didehydro-2',3 '-dideoxycytidine), which was shown to be generated only when the self-strand-breakage of CNDACTP-incorporated DNA occurred. The cytotoxicity of CNDAC was completely abrogated by the addition of 2'-deoxycytidine and was low against cells with decreased deoxycytidine kinase. Our results suggest that CNDAC is converted to CNDACMP by deoxycytidine kinase and that the resulting CNDACTP incorporated into a DNA strand as CNDACMP may induce DNA-self-strand-breakage. This novel DNA-self-strand-breaking mechanism may contribute to the potent antitumor activity of CS-682.
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