Antitumor mechanisms of zinostatin stimalamer (YM881).
The mechanism of antitumor action of zinostatin stimalamer (YM881) was studied. YM881 suppressed colony formation of HeLa cells dose-dependently, and showed cytocidal activity. The compound inhibited DNA synthesis, but neither RNA nor protein synthesis in L1210 cells, and induced cellular DNA strand breaks in HeLa cells and DNA cleavage of PM2 phage supercoiled DNA. The compound was also shown to cause typical G2/M phase arrest in the L1210 cell cycle, and inhibited activity of DNA polymerase alpha of HeLa cells, but only at a high concentration. These results suggest that the antitumor and cytotoxic mechanisms of YM881 are identical to those of neocarzinostatin (NCS), and were due to cellular DNA strand breaks induced by direct DNA-cleaving activity and the subsequent inhibition of DNA synthesis.
Tanaka
S
S
Pharmacology Dept., Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan.
Yamamoto
M
M
Numasaki
Y
Y
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000378:metabolism; D004278:DNA, Superhelical / Q000096:biosynthesis / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism; D008299:Maleic Anhydrides / Q000494:pharmacology*; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011137:Polystyrenes / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D009353:Zinostatin / Q000031:analogs & derivatives* / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D008299:Maleic Anhydrides; D009363:Neoplasm Proteins; D011137:Polystyrenes; D012334:RNA, Neoplasm; C035755:poly(maleic acid-styrene)neocarzinostatin; D009353:Zinostatin; D004256:DNA Polymerase I; D004257:DNA Polymerase II