DNA repair inhibition and cancer therapy.
The DNA repair process in mammalian cells is a multi-pathway mechanism that protects cells from the plethora of DNA damaging agents that are known to attack nuclear DNA. Moreover, the majority of current anticancer therapies (e.g. ionising radiation and chemotoxic therapies) rely on this ability to create DNA lesions, leading to apoptosis/cell death. A cells natural ability to repair such DNA damage is a major cause of resistance to these existing antitumour agents. It seems logical, therefore, that by modulating these repair mechanisms, greater killing effect to anticancer agents would occur. Experimental data support this, either through knockout studies or by the use of pharmacological inhibitors which target some of the key regulatory proteins involved in the DNA repair process. Several of these key DNA repair proteins which are actively under investigation as novel sites for intervention in cancer biology are discussed.
Martin
N M
NM
KuDOS Pharmaceuticals Ltd, 327 Cambridge Science Park, Milton Road, Cambridge, Cambs. CB4 4WG, UK. nmartin@kudospharma.co.uk
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D009687:Nuclear Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase; D011065:Poly(ADP-ribose) Polymerases; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases