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).
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.
Hanaoka
K
K
Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. hanaok@shina.sankyo.co.jp
Suzuki
M
M
Kobayashi
T
T
Tanzawa
F
F
Tanaka
K
K
Shibayama
T
T
Miura
S
S
Ikeda
T
T
Iwabuchi
H
H
Nakagawa
A
A
Mitsuhashi
Y
Y
Hisaoka
M
M
Kaneko
M
M
Tomida
A
A
Wataya
Y
Y
Nomura
T
T
Sasaki
T
T
Matsuda
A
A
Tsuruo
T
T
Kurakata
S
S
D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D001087:Arabinonucleosides / Q000494:pharmacology* / Q000627:therapeutic use; D001711:Biotransformation; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D003841:Deoxycytidine / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D007624:KB Cells / Q000187:drug effects; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D016685:Mitomycin / Q000494:pharmacology; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D051381:Rats; D011923:Rats, Nude; D013047:Specific Pathogen-Free Organisms; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D001087:Arabinonucleosides; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D003561:Cytarabine; D003841:Deoxycytidine; C070279:2'-cyano-2'-deoxyarabinofuranosylcytosine; D016685:Mitomycin; D014750:Vincristine; D003596:Cytosine; D003842:Deoxycytidine Kinase; D002945:Cisplatin; D005472:Fluorouracil; C117959:sapacitabine