Sensitization to radiation and alkylating agents by inhibitors of poly(ADP-ribose) polymerase is enhanced in cells deficient in DNA double-strand break repair.
As single agents, chemical inhibitors of poly(ADP-ribose) polymerase (PARP) are nontoxic and have clinical efficacy against BRCA1- and BRCA2-deficient tumors. PARP inhibitors also enhance the cytotoxicity of ionizing radiation and alkylating agents but will only improve clinical outcomes if tumor sensitization exceeds effects on normal tissues. It is unclear how tumor DNA repair proficiency affects the degree of sensitization. We have previously shown that the radiosensitizing effect of PARP inhibition requires DNA replication and will therefore affect rapidly proliferating tumors more than normal tissues. Because many tumors exhibit defective DNA repair, we investigated the impact of double-strand break (DSB) repair integrity on the sensitizing effects of the PARP inhibitor olaparib. Sensitization to ionizing radiation and the alkylating agent methylmethane sulfonate was enhanced in DSB repair-deficient cells. In Artemis(-/-) and ATM(-/-) mouse embryo fibroblasts, sensitization was replication dependent and associated with defective repair of replication-associated damage. Radiosensitization of Ligase IV(-/-) mouse embryo fibroblasts was independent of DNA replication and is explained by inhibition of "alternative" end joining. After methylmethane sulfonate treatment, PARP inhibition promoted replication-independent accumulation of DSB, repair of which required Ligase IV. Our findings predict that the sensitizing effects of PARP inhibitors will be more pronounced in rapidly dividing and/or DNA repair defective tumors than normal tissues and show their potential to enhance the therapeutic ratio achieved by conventional DNA-damaging agents.
Genome Damage and Stability Centre, University of Sussex, Falmer, United Kingdom.
Dana A
DA
Löser
Atsushi
A
Shibata
Akiko K
AK
Shibata
Lisa J
LJ
Woodbine
Penny A
PA
Jeggo
Anthony J
AJ
Chalmers
D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000172:deficiency / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004720:Endonucleases; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D051379:Mice; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011995:Recombination, Genetic / Q000187:drug effects / Q000235:genetics; D016196:S Phase / Q000187:drug effects; D019098:Telomerase / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000477:Alkylating Agents; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D000072481:DNA Ligase ATP; D011088:DNA Ligases; D004268:DNA-Binding Proteins; D004720:Endonucleases; D006657:Histones; D008741:Methyl Methanesulfonate; D009687:Nuclear Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011838:Radiation-Sensitizing Agents; D019098:Telomerase; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576325:Atm protein, mouse; C509187:Tert protein, mouse; C473337:Dclre1c protein, mouse; C475961:gamma-H2AX protein, mouse