Hypersensitivity to Clinically Useful Alkylating Agents and Radiation in Poly(ADP-ribose) Polymerase-Deficient Cell Lines

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Abstract
Mutant V79 Chinese hamster cell lines, deficient in poly (ADP-ribose) polymerase activity, were previously shown to be significantly resistant to etoposide, a topoisomerase II inhibitor, and hypersensitive to camptothecin, a topoisomerase I inhibitor (Chatterjee, S.; Trivedi, D.; Petzold, S. J.; Berler, N. A. Mechanism of epipophyllotoxin- induced cell death in poly (adenosine diphosphate-ribose) synthesis-deficient V79 Chinese hamster cell lines. Cancer Res. 50:2713–2718,1990 and Chatterjee, S.; Cheng, M. F.; Trivedi, D.; Petzold, S. J.; Berger, N. A. Camptothecin hypersensitivity in poly(adenosine diphosphate-ribose) polymerase-deficient cell lines. Cancer Commun. 1:389–394; 1990). We have now demonstrated hypersensitivity of these mutant cell lines, designated ADPRT 54 and ADPRT 351, to a variety of antitumor agents including melphalan, BCNU, mitomycin, and bleomycin. They are also hypersensitive to UV- and x-irradiation. These mutants, however, are significantly resistant to the topoisomerase II-targeted DNA intercalators, Adriamycin™ and m-AMSA. Our results strongly suggest that inhibition of poly( ADP-ribose) polymerase could be useful to potentiate the cytotoxicity of a variety of currently available antitumor drugs.