Tyrosyl-DNA phosphodiesterase 1 targeting for modulation of camptothecin-based treatment.
The targeting of specific DNA repair mechanisms may be a promising strategy to improve the efficacy of antitumor therapy. The cytotoxic effects of the clinically relevant topoisomerase 1 (Top1) poison camptothecins are related to the generation of DNA lesions and tumor cells may be resistant to DNA damaging agents due to increased repair. Tyrosyl- DNA phosphodiesterase 1 (TDP1) is implicated in the repair of strand breaks by removing abortive Top1/DNA complexes. Thus, a role for TDP1 in counteracting DNA damage induced by camptothecins has been proposed. Here, we review the role of TDP1 in DNA repair with particular reference to TDP1 function, its cooperation with other pathways and the development of pharmacological inhibitors.
Beretta
G L
GL
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, viaVenezian 1, 20133 Milan, Italy.
Cossa
G
G
Gatti
L
L
Zunino
F
F
Perego
P
P
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry* / Q000627:therapeutic use; D002166:Camptothecin / Q000627:therapeutic use*; D004249:DNA Damage; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D006801:Humans; D009422:Nervous System Diseases / Q000188:drug therapy; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*
D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin