The response of ataxia-telangiectasia homozygous and heterozygous skin fibroblasts to neocarzinostatin

Abstract

Skin fibroblast strains from patients with ataxia-telangiectasia (A-T) were recently reported to be hypersensitive to the antitumor antibiotic neocarzinostatin (NCS). The distinct intermediate degree of NCS sensitivity previously shown with 2 strains of A-T heterozygous fibroblasts was extended and confirmed in an additional 8 strains. A sensitivity baseline for A-T heterozygous cells were established and may serve for the laboratory diagnosis of A-T heterozygotes, a cancer-prone population. The response of A-T homozygous and heterozygous cells to NCS was further characterized by 2 molecular parameters, DNA repair synthesis and inhibition of DNA replication. The pattern of dose response with regard to DNA repair synthesis, as assayed by the benzoylated naphthoylated DEAE cellulose chromatography method, was similar in normal, A-T homozygous and A-T heterozygous cells, although certain variability between strains was observed with regard to the amount of repair incorporation. This finding correlates with a similar observation made with the same cell strains following .gamma.-irradiation. Inhibition of DNA synthesis following NCS treatment was reduced in A-T homozygous cells, as compared to normal cells, but the inhibition resistant component of DNA synthesis typically observed following treatment with low doses of X-rays or bleomycin was not observed with NCS. A-T heterozygous cells showed somewhat less inhibition of DNA synthesis than normal cells following NCS treatment, although this difference was small and was not significant enough to serve as an additional laboratory diagnostic aid. The reduced inhibition of DNA synthesis, rather than reduced extent of DNA repair synthesis, correlates with the cellular hypersensitivity of A-T homozygous cells. This hypersensitivity seems to be observed primarily, if not exclusively, with DNA breaking agents.