CELLULAR-RESPONSES TO -N-[4-(9-ACRIDINYLAMINO)-2-METHOXYPHENYL]CARBAMATE HYDROCHLORIDE, AN ANALOG OF AMSACRINE ACTIVE AGAINST NONPROLIFERATING CELLS

The acridine derivative m-AMCA -N-C4-(9-acridinylamino)-2-methoxypheny l]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 pois on 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 p oly(ADP-ribose)polymerase (PARP) was markedly lower than that of campt othecin or amsacrine. Cell cycle responses to m-AMCA and amsacrine wer e 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 culture d in fresh medium, with m-AMCA having a more pronounced effect than am sacrine and camptothecin having no effect. We also examined the role o f 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. I t is suggested that two cytotoxicity mechanisms can be distinguished u sing these drugs. The first is specific for S-phase cells, is reversed by aphidicolin and induces PARP activity. The second is cell cycle no n-specific, does not induce PARP and is unaffected by aphidicolin. Cam ptothecin activates only the first, m-AMCA primarily the second and am sacrine activates both. (C) 1997 Elsevier Science Ltd.