Abnormal response of ataxia-telangiectasia cells to agents that break the deoxyribose moiety of DNA via a targeted free radical mechanism.
A defect in DNA repair coupled to anomalous DNA synthesis after induction of certain radiogenic DNA damage is suspected to underlie the radiosensitivity of cells from patients with ataxia-telangiectasia (A-T). The response of cultured skin fibroblasts from A-T patients and A-T heterozygotes to six agents inducing various levels of DNA strand breakage by different mechanisms was studied to obtain further information on the nature of the 'A-T critical DNA lesion'. The A-T cells showed varying degrees of hypersensitivity to the cytotoxic action of the quinone-containing anti-tumor antibiotics streptonigrin and adriamycin and to hydrogen peroxide. This hypersensitivity was accompanied by reduced inhibition of DNA synthesis compared to normal cells after treatment with these agents. A limited degree of cellular hypersensitivity that was not sufficient to allow for definition of a separate sensitivity range was shown by A-T heterozygous cells. On the other hand, the A-T cells showed a normal response to paraquat, saframycin A and ellipticine. Taken together with previous results showing hypersensitivity of A-T cells to ionizing radiation, bleomycin and neocarzinostatin, these data indicate that the critical DNA lesion in A-T cells is a strand break caused by deoxyribose destruction following the action of free radicals targeted into the DNA.
D001260:Ataxia Telangiectasia / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D003855:Deoxyribose / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004611:Ellipticines / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005609:Free Radicals; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D010269:Paraquat / Q000494:pharmacology; D013308:Streptonigrin / Q000494:pharmacology
D004611:Ellipticines; D005609:Free Radicals; D007546:Isoquinolines; C034192:ellipticine; D013308:Streptonigrin; D003855:Deoxyribose; D004317:Doxorubicin; D004247:DNA; D006861:Hydrogen Peroxide; C026925:saframycin A; D010269:Paraquat