Inhibition of mammalian deoxyribonucleic acid synthesis by neocarzinostatin: selective effect on replicon initiation in CHO cells and resistant synthesis in ataxia telangiectasia fibroblasts.

Treatment of CHO cells with low doses of the protein antibiotic neocarzinostatin severely inhibited DNA replicon initiation but had no effect on chain elongation. The selectivity of the effect on initiation, which was greater than that seen with other chemical agents and comparable to that seen with X-rays, explains the biphasic dose response seen for DNA synthesis inhibition by this drug. Parallel experiments employing the nucleoid sedimentation technique indicated that half-maximal relaxation of domains of DNA supercoiling and half-maximal inhibition of replicon initiation required the same dose of neocarzinostatin, approximately 0.03 micrograms/mL. These results, similar results obtained with the protein antibiotic auromomycin, and previous results obtained with X-rays suggest a quantitative correlation between inhibition of replicon initiation and induction of sufficient strand breakage to relax domains of supercoiling in DNA of mammalian cells. Results in human ataxia telangiectasia fibroblasts indicated that neocarzinostatin, like X-rays, is much less effective in inhibiting DNA synthesis in these cells than in normal human fibroblasts. This finding is consistent with the hypothesis that the genetic defect in ataxia telangiectasia involves a failure to recognize the presence of strand breaks in cellular DNA.