Hypersensitivity to clinically useful alkylating agents and radiation in poly(ADP-ribose) polymerase-deficient cell lines.
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.
Department of Medicine, University Hospitals of Cleveland, Ohio.
S
S
Chatterjee
M F
MF
Cheng
N A
NA
Berger
D000477:Alkylating Agents / Q000494:pharmacology*; D000677:Amsacrine / Q000494:pharmacology; D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D006531:HEPES / Q000494:pharmacology; D066298:In Vitro Techniques; D008558:Melphalan / Q000494:pharmacology; D008937:Mitomycins / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D011878:Radiotherapy; D014466:Ultraviolet Rays
D000477:Alkylating Agents; D008937:Mitomycins; D000677:Amsacrine; D001761:Bleomycin; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; D008558:Melphalan; D006531:HEPES; D002330:Carmustine; D004121:Dimethyl Sulfoxide