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Cellular Responses to methyl-N-[4-9-acridinylamino)-2-methoxyphenyl] Carbamate Hydrochloride, an Analogue of Amsacrine Active Against Non-Proliferating Cells

Cellular Responses to methyl-N-[4-9-acridinylamino)-2-methoxyphenyl] Carbamate Hydrochloride, an Analogue of Amsacrine Active Against Non-Proliferating Cells

N Moreland, G J Finlay, M Dragunow, K M Holdaway, B C Baguley

Eur J Cancer. 1997 Sep;33(10):1668-76.

PMID: 9389932

Abstract:

The acridine derivative m-AMCA (methyl-N-[4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride), a carbamate analogue of the topoisomerase 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 G2-phase. These cell cycle changes were also observed when plateau phase cultures were exposed to drug for 1 h, 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 p21WAF1 regardless of proliferation status. Both induced G1-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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP54301154	Amsacrine hydrochloride		54301-15-4	Price

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