Nucleotide excision repair pathways involved in Cisplatin resistance in non-small-cell lung cancer.
BACKGROUND
In spite of the growing list of genetic abnormalities identified as being involved in DNA repair pathways that alter chemosensitivity in non-small-cell lung cancer (NSCLC) patients, translational assays have not yet been developed for use in individualized chemotherapy.


METHODS
In metastatic NSCLC, no single cisplatin-based chemotherapy regimen has been shown to be superior to any other. Although these studies show a small survival tail at 3 years, the majority of patients had a median survival of 8 to 10 months. We review the principal mechanisms of cisplatin resistance, particularly those involved in the nucleotide excision repair (NER) pathways (transcription-coupled repair and global genomic repair).


RESULTS
ERCC1 is a single-stranded DNA endonuclease that forms a tight heterodimer with xeroderma pigmentosum complementation group F. It incises DNA on the 5' side of a lesion such as cisplatin-DNA adduct. Therefore, overexpression of ERCC1 and other NER enzymes during ovarian cancer chemotherapy with cisplatin appears to be implicated in the formation of cellular and clinical drug resistance. Recently, baseline ERCC1 mRNA overexpression has been related to poor response and survival in cisplatin-treated NSCLC patients.


CONCLUSIONS
The level of evidence for many assays is limited, and only ERCC1 mRNA levels have been analyzed extensively. The impact of ERCC1 should be fully validated in prospective clinical trials.
Rosell
Rafael
R
Medical Oncology Service, Hospital Germans Trias i Pujol, Barcelona, Spain. rrosell@ns.hugtip.scs.es
Taron
Miguel
M
Barnadas
Agusti
A
Scagliotti
Giorgio
G
Sarries
Carme
C
Roig
Barbara
B
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D002945:Cisplatin / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004260:DNA Repair; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004720:Endonucleases; D015870:Gene Expression; D005819:Genetic Markers; D006801:Humans; D008175:Lung Neoplasms; D011506:Proteins / Q000235:genetics / Q000502:physiology
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D011506:Proteins; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin