[Mechanism of antitumor effect of a benzoylphenylurea derivative, HO-221].
HO-221, N-[4-(5-Bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2-nitrobenzoyl ) urea is a novel benzoylphenylurea derivative. We previously reported HO-221 showed significant antitumor activities against various experimental tumor models, and was especially effective against the solid tumor. In this report we studied the mechanism of action of the compound. The inhibitory activity of HO-221 and 6 kinds of antitumor agents on DNA polymerase alpha was examined in vitro. HO-221 inhibited DNA polymerase alpha activity strongly. From the comparison with IC50 values of individual agents, the inhibitory activity of HO-221 was almost equivalent to aphidicolin and ara-CTP. By double reciprocal plot analysis, the inhibition of HO-221 was found to be non-competitive with the dCTP unlike that of aphidicolin and ara-CTP. Furthermore, HO-221 showed almost no effect on RNA polymerase activity and the protein synthesis. The effect of HO-221 on cell cycle progression of HL-60 cells was examined by flow cytometry analysis. The compound accumulated cells at S phase at a low concentration. The compound showed accumulation of cells in G1, G1-S and G2 + M phases. At higher concentrations, HO-221 increased the G1 phase of tumor cells, stopping the cell cycle progression. Therefore, G1 and S phase accumulation by HO-221 was considered to be correlated with the inhibition of DNA polymerase alpha dependent DNA synthesis. These results suggest that HO-221 is a novel antitumor agent with different mechanism of action from the known antitumor agents.
Nakajima
T
T
Research Division, Green Cross Corporation, Osaka, Japan.
Okamoto
T
T
Masuda
H
H
Watanabe
M
M
Yokoyama
K
K
Yamada
N
N
Tsukagoshi
S
S
Taguchi
T
T
D000818:Animals; D000970:Antineoplastic Agents; D001549:Benzamides / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D003864:Depression, Chemical; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009578:Nitrobenzenes / Q000494:pharmacology*; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D001549:Benzamides; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D009578:Nitrobenzenes; D012334:RNA, Neoplasm; C066688:N-(4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl)-N'-(2-nitrobenzoyl)urea; D012319:RNA Polymerase II; D004257:DNA Polymerase II