Interrogation of nucleotide excision repair capacity: impact on platinum-based cancer therapy.
DNA repair is essential for routine monitoring and repair of damage imparted to our genetic material by exposure to endogenous and exogenous carcinogens, including reactive oxygen species, UV light, and chemicals such as those found in cigarette smoke. Without DNA repair pathways, the continual assault on our DNA would be highly mutagenic and the risk of cancer increased. Paradoxically, the same pathways that help prevent cancer development are detrimental to the efficacy of DNA-damaging cancer therapeutics such as cisplatin. Recent studies demonstrate the inverse relationship between DNA repair capacity and efficacy of platinum-based chemotherapeutics: increased DNA repair capacity leads to resistance, while decreased capacity leads to increased sensitivities. Cisplatin's cytotoxic effects are mediated by formation of intrastrand DNA crosslinks, which are predominantly repaired via the nucleotide excision repair (NER) pathway. In an effort to personalize the treatment of cancers based on DNA repair capacity, we developed an ELISA-based assay to measure NER activity accurately and reproducibly as a prognostic for platinum-based treatments. Here we present an overview of DNA repair and its link to cancer and therapeutics. We also present data demonstrating the ability to detect the proteins of the pre-incision complex within the NER pathway from cell and tissue extracts.
Earley
Jennifer N
JN
Department of Medicine/Hematology and Oncology, Indiana University School of Medicine, 980 W. Walnut Street, Indianapolis, IN 46202, USA.
Turchi
John J
JJ
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010984:Platinum / Q000494:pharmacology / Q000627:therapeutic use; D051716:Replication Protein A / Q000235:genetics / Q000378:metabolism; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D051716:Replication Protein A; D051760:Xeroderma Pigmentosum Group A Protein; D010984:Platinum; D002945:Cisplatin
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