Lack of correlation between hypersensitivity to cell killing and impaired inhibition of DNA synthesis in ataxia telangiectasia fibroblasts treated with 4-nitroquinoline 1-oxide

Abstract

Compared to normal controls from healthy subjects, cells cultured from patients with the autosomal recessive, cancer-prone disorder ataxia telangiectasia (AT) uniformly display impaired clonogenic survival, in concert with decreased inhibition of DNA synthesis, on exposure to ionizing radiation. In this study we have determined the effects of 4-nitroquinoline 1-oxide (4NQO), a partially radiomimetic chemical carcinogen, on colony-forming ability and rate of DNA synthesis in non-transformed skin fibroblasts strains derived from clinically normal volunteers and AT patients. Strain AT3BI, belonging to AT complementation group A, displayed substantial hypersensitivity to the lethal action of 4NQO, whereas the survival response of strain AT5BI (group D) did not differ significantly from that of the three normal controls. The 4NQO-hypersensitive AT3BI cells exhibited normal inhibition of DNA synthesis when treated with the chemical, as manifested by both dose-response and time-course measurements. However, 4NQO treatment decreased the rate of DNA synthesis to a much lesser degree in AT5BI than in normal strains. Hence, our data demonstrate unequivocally that, unlike that universally observed following exposure of AT cells to ionizing radiation, carcinogen-resistant DNA synthesis does not segregate with elevated cytotoxicity when cultured fibroblasts representing at least some genetic forms of AT (i.e. groups A and D) are damaged by 4NQO.