Antitumor activity and novel DNA-self-strand-breaking mechanism of CNDAC (1-(2-C-cyano-2-deoxy-?-d-ARABINO-Pentofuranosyl) cytosine) and itsN4-palmitoyl derivative (CS-682)

Abstract

We have studied the antitumor activity and the novel DNA‐self‐strand‐breaking mechanism of CNDAC (1‐(2‐C‐cyano‐2‐deoxy‐β‐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′‐C‐cyano‐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. Int. J. Cancer 82:226–236, 1999. © 1999 Wiley‐Liss, Inc.

Antiproliferative effects of sapacitabine (CYC682), a novel 2′-deoxycytidine-derivative, in human cancer cells

“…Other authors have demonstrated that sapacitabine also had cytotoxic activity against a broad spectrum of human tumour cells, and although the average cytotoxicities were comparable with CNDAC, sapacitabine was more potent (Hanaoka et al, 1999). In gastric, lung, mammary, colon, ovary and epidermoid cell lines, the IC 50 values for sapacitabine ranged from 0.1 to 11 mM, whereas for CNDAC they ranged from 0.1 to 4350 mM (Azuma et al, 1993;Hanaoka et al, 1999;Matsuda and Sasaki, 2004). Figure 5 Correlation between mRNA levels and sensitivity to deoxycytidine analogues.…”

“…Furthermore, data have suggested that the sapacitabine cytotoxicity profile may differ from that of other nucleoside analogues (Kaneko et al, 1997;Faivre et al, 1999;Hanaoka et al, 1999;Zhang et al, 1999;Wu et al, 2003;Matsuda and Sasaki, 2004). Therefore, further investigations are required to ascertain the exact mechanism of action of sapacitabine, to evaluate the toxicity of combinations with other compounds and to screen the range of its activity in various tumour systems that may eventually lead to clinical application.…”

Survival Efficacy of Adjuvant Cytosine-Analogue CS-682 in a Fluorescent Orthotopic Model of Human Pancreatic Cancer

“…This 2Ј-deoxycytidine analogue (22) has been shown to inhibit tumor growth by both inhibiting DNA polymerase and by inducing DNA self-strand breakage through incorporation of an active metabolite into the strands (23). Oral CS-682 has been shown to possess potent cytotoxic activity against several tumor cell lines in vitro and in vivo (23) and has been demonstrated to inhibit the development of liver metastasis (24).…”

“…This 2Ј-deoxycytidine analogue (22) has been shown to inhibit tumor growth by both inhibiting DNA polymerase and by inducing DNA self-strand breakage through incorporation of an active metabolite into the strands (23). Oral CS-682 has been shown to possess potent cytotoxic activity against several tumor cell lines in vitro and in vivo (23) and has been demonstrated to inhibit the development of liver metastasis (24). We have reported the efficacy of this agent in inhibiting growth and dissemination of pancreatic cancer in an orthotopic model and demonstrated that this ability may be caused by a direct inhibitory effect on the development of metastases (13).…”

Improvement of the Antitumor Activity of Poorly Soluble Sapacitabine (CS-682) by Using Soluplus® as a Surfactant

“…Transportation within cells and hydrolysis of sapacitabine lead to the formation of the active compound 1-[2-C-cyano-2-deoxy-β-D-arabino-pentafuranosyl]cytosine) (CNDAC). [1][2][3] Among antimetabolite drugs, CNDAC has a unique antitumor mechanism, in that it causes DNA singlestrand breaks through a β-elimination rearrangement after incorporation into the DNA during the first replication. 4,5) A preclinical study showed that both CNDAC and sapacitabine were effective antitumor nucleosides against various solid tumors such as those of the stomach, colon, and lung.…”