Cytotoxicity of carcinogenic aromatic amides in normal and xeroderma pigmentosum fibroblasts with different DNA repair capabilities.

The effect of exposure to UV irradiation or to the N-acetoxy-ester derivatives of four carcinogenic aromatic amides, 4-acetylaminobiphenyl (AABP), 2-acetylaminofluorene (AAF), 2-acetylaminophenanthrene, and 4-acetylaminostilbene, on cell survival was compared in strains of cultured human fibroblasts possessing normal rates of excision repair of DNA and in three strains of xeroderma pigmentosum (XP) cells, each differing in its rate of excision repair. The survival of each strain after exposure to UV reflected its capacity to repair DNA. Thus the slope of the survival curve for the XP strain with the poorest capacity for excision repair (XP12BE complementation group A) was 5.8-fold steeper than the exponential portion of the curve for the normally repairing strains; that of XP2BE (complementation group C) was 1.95-fold; and that of XP4BE (a variant capable of a normal rate of dimer excision) was only 1.3-fold steeper. The slope of the survival curves after exposure to each N-acetoxy ester derivative for these same XP strains averaged 6.4, 2.0, and 1.4 times steeper, respectively, than that of the normal strains tested. The excision repair capacity of these lines after exposure to N-acetoxy-AAF (50 muM/ml) was tested with alkaline cesium chloride density gradient centrifugation to detect incorporation of tritiated thymidine into nonreplicated DNA. The normal strains and XP4BE exhibited DNA excision repair by this method, whereas XP patients 2 and 12 did not. The cytotoxic effect of the four parent aromatic amide carcinogens, their N-hydroxy derivatives, as well as the N-acetoxy ester of each of the four N-hydroxy compounds and the N-sulfate ester of N-hydroxy-AAF and N-hydroxy-AABP in the XP2BE strain, was compared with their effect on the normal fibroblasts. The parent amides proved to be noncytotoxic at all doses tested. In contrast, the N-hydroxy derivatives of each aromatic amide were highly cytotoxic, as were the ester compounds. For each active derivative, the slope of the survival curve for XP2BE was 2-2.k times steeper than that of the normally repairing strain.