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PolyADP-ribosylation and Cancer > Basic Studies
of Therapeutic Strategies for Cancer by Targeting PolyADP-ribosylation Reaction
Basic Studies of Therapeutic Strategies for Cancer by Targeting PolyADP-ribosylation Reaction
Enhancement of cytotoxic effects of bleomycin against tumors by PARP inhibitors was shown in 1980s (J. Pharmacobiodyn., 1982, 5: 900-904). Potent and specific PARP inhibitors have been developed and they are now subjected to phase II clinical trials with anti-cancer drug, temozolomide (reference 1). PARP inhibitors alone show anti-tumor effect on the BRCA2 mutated tumors (reference 2). Mechanistic studies on the effective sensitization of chemotherapeutic agents by PARP inhibitors are undertaken.
Increased lethality of Parg knockout ES cells after treatment with alkylating agents and γ-irradiation suggests that inhibition of Parg might sensitize chemo- and radiotherapy.
Search for Parg inhibitors is ongoing since only a few Parg inhibitors are available to date. We reported cyclic peptide antibiotic pargamicin containing piperadic acid residues has inhibitory activity against Parg (Proc. Japan Acad., 2002, 78 Ser. B:15-17) .
The Poly(etheno ADP-ribose) (poly(εADP-ribose)) prepared by converting the adenine moiety of poly(ADP-ribose) to 1-N6-etheno adenine residues was shown to be highly resistant to digestion by Parg (Biochem. Biophys. Res. Commun., 2007, 355:451-456). Poly(εADP-ribose) inhibited Parg activity to hydrolyse ribose-ribose bonds of poly(ADP-ribose). This study also suggests the possibility that poly(εADP-ribose) might be a useful tool for studying the poly(ADP-ribose) dynamics and function of Parg.
References
1. Calabrese C.R. et al., J. Natl. Cancer Inst., 2004, 96:56-67.
2. Bryant H. E. et al., Nature, 2005, 434: 913-917.