[Design of a new antitumor nucleoside CNDAC, against solid tumors].
The design, antitumor activity in vitro as well as in vivo, and mechanism of CNDAC have been described. CNDAC had potent antitumor effects against various solid tumors in vitro as well as in vivo. CNDAC was phosphorylated by deoxycytidine kinase, followed by certain nucleotide kinases to afford its 5'-triphosphate (CNDACTP), which was a potent inhibitor of DNA polymerase alpha. Using a chain-extension method with Vent (exo-) DNA polymerase and a short primer/template system, we found that CNDACTP was incorporated into the primer. After further chain-extension reaction of the primer containing CNDAC at the 3'-terminus, chain elongation was not observed. Therefore, CNDACTP appeared to act as a chain-terminator. Analyses of the structure of the 3'terminus in the primer revealed the presence of ddCNC together with CNDAC and CNDC. The existence of ddCNC in the 3'-end of the primer would be due to the self-strand-break by the nucleotide incorporated next to CNDAC.
Matsuda
A
A
Faculty of Pharmaceutical Sciences, Hokkaido University, Japan.
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004249:DNA Damage; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D003561:Cytarabine; C070279:2'-cyano-2'-deoxyarabinofuranosylcytosine; D004257:DNA Polymerase II