Alkylating agent hypersensitivity in poly(adenosine diphosphate-ribose) polymerase deficient cell lines.
Starting with the V79 cell line, two poly(ADP-ribose) polymerase deficient mutants, designated ADPRT 54 and ADPRT 351, had been shown to be hypersensitive to x- and UV-irradiation and to topoisomerase I inhibitors but to be resistant to topoisomerase II inhibitors (Chatterjee, S.; Cheng, M. F.; Berger, N. A. Hypersensitivity to clinically useful alkylating agents and radiation in poly(ADP-ribose) polymerase-deficient cell lines. Cancer Commun. 2:401-407;1990). We now report that these mutants were hypersensitive to a series of different alkylating agents, including alkylsufonates, alkylnitrosoureas, and nitrosoguanidine. In addition, they were hypersensitive to the UV-mimetic agent 4-nitroquinoline-1-oxide. Our findings provide strong evidence that poly(ADP-ribose) polymerase was involved in the repair of alkylating agent induced DNA damage as well as in the damage induced by UV- and x-irradiation and radiomimetic agents. The poly(ADP-ribose) polymerase deficient cell lines showed a marked decrease in the shoulder region of their survival curves, suggesting that poly(ADP-ribose) polymerase was involved in the repair of alkylating agent induced sublethal damage.
Chatterjee
S
S
Department of Medicine, University Hospitals of Cleveland, Case Western Reserve University, Ohio 44106.
Cheng
M F
MF
Berger
S J
SJ
Berger
N A
NA
D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D006224:Cricetinae; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005020:Ethyl Methanesulfonate / Q000494:pharmacology; D005038:Ethylnitrosourea / Q000494:pharmacology; D007928:Lethal Dose 50; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency*; D013463:Sulfuric Acid Esters / Q000494:pharmacology
D000477:Alkylating Agents; D013463:Sulfuric Acid Esters; D008769:Methylnitronitrosoguanidine; D015112:4-Nitroquinoline-1-oxide; D005020:Ethyl Methanesulfonate; D008741:Methyl Methanesulfonate; D011065:Poly(ADP-ribose) Polymerases; C007482:dimethyl sulfate; D005038:Ethylnitrosourea