Cellular responses to methyl-N-[4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride, an analogue of amsacrine active against non-proliferating cells

被引:10
作者
Moreland, N
Finlay, GJ
Dragunow, M
Holdaway, KM
Baguley, BC
机构
[1] UNIV AUCKLAND,SCH MED,CANC RES LAB,AUCKLAND 1000,NEW ZEALAND
[2] UNIV AUCKLAND,SCH MED,DEPT PHARMACOL,AUCKLAND 1000,NEW ZEALAND
[3] COULTER ELECT PTY LTD,BROOKVALE,NSW 2100,AUSTRALIA
关键词
topoisomerase; p53; poly(ADP)ribose polymerase; amsacrine and cell cycle;
D O I
10.1016/S0959-8049(97)00165-2
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The acridine derivative m-AMCA (methyl-N-C4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride), a carbamate analogue of the toposiomerase II poison amsacrine, is distinguished by its high cytotoxicity against non-cycling tumour cells. We compared the response of cultured Lewis lung carcinoma cells to m-AMCA, amsacrine and the topoisomerase I poison camptothecin. The DNA polymerase inhibitor aphidicolin reversed the cytotoxicity of camptothecin fully, that of amsacrine partially, and that of m-AMCA minimally. The ability of m-AMCA to induce the enzyme poly(ADP-ribose)polymerase (PARP) was markedly lower than that of camptothecin or amsacrine. Cell cycle responses to m-AMCA and amsacrine were similar, with slowing of progress through S-phase and arrest in G(2)-phase. These cell cycle changes were also observed when plateau phase cultures were exposed to drug for Ih, washed free of drug and cultured in fresh medium, with m-AMCA having a more pronounced effect than amsacrine and camptothecin having no effect. We also examined the role of p53 protein in the response using cultured human H460 cells. Both m-AMCA and amsacrine induced p53 protein expression in proliferating but not in non-proliferating H460 cells, and induced p21(WAF1) regardless of proliferation status. Both induced G(1)-phase cell cycle arrest. It is suggested that two cytotoxicity mechanisms can be distinguished using these drugs. The first is specific for S-phase cells, is reversed by aphidicolin and induces PARP activity. The second is cell cycle non-specific, does not induce PARP and is unaffected by aphidicolin. Camptothecin activates only the first, m-AMCA primarily the second and amsacrine activates both. (C) 1997 Elsevier Science Ltd.
引用
收藏
页码:1668 / 1676
页数:9
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