Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cisplatin-based chemotherapy has long been the cornerstone of non-small cell lung cancer (NSCLC) management. However, median survival rarely exceeds 1 year. The identification of molecular markers can help to predict response, leading to a broad implementation of the new concept of customized chemotherapy. ERCC1 is an excision nuclease within the nucleotide excision repair pathway that forms a heterodimer with XPE As a unit, they execute the 5' incision into the DNA strand relative to the site of DNA damage. The 5' excision is the last of several steps that are specific to excision of a platinum DNA lesion. In mouse models, normal ERCC1 function is critical to normal aging and brain development. Numerous studies indicate that ERCC1 influences the repair of platinum DNA damage. We report here our accumulated experience of ERCC1 mRNA expression and outcome in cisplatin-treated NSCLC patients and the preliminary confirmatory data on a prospective ERCC1 mRNA customized docetaxel-cisplatin trial, in which low ERCC1 mRNA levels in the tumor correlate with significantly better response. ERCC1 is one of several proteins involved in the repairosome, where other DNA repair genes, such as BRCA1, are also central to cisplatin resistance.
Lung Cancer 2005 Dec
PMID:Applications of genomics in NSCLC. 1655 21

Trivalent antimony is a known genotoxic agent classified as a possible human carcinogen by the International Agency for Research on Cancer (IARC) and as an animal carcinogen by the German MAK Commission. Nevertheless, the underlying mechanism for its genotoxicity remains elusive. Because of the similarities between antimony and arsenic, the inhibition of DNA repair has been a promising hypothesis. Investigations on the removal of DNA lesions now revealed a damage specific impairment of nucleotide excision repair (NER). After irradiation of A549 human lung carcinoma cells with UVC, a higher number of cyclobutane pyrimidine dimers (CPD) remained in the presence of SbCl(3), whereas processing of the 6-4 photoproducts (6-4PP) and benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts was not impaired. Nevertheless, cell viability was reduced in a more than additive mode after combined treatment of SbCl(3) with UVC as well as with BPDE. In search of the molecular targets, a decrease in gene expression and protein level of XPE was found, which is known to be indispensable for the recognition of CPD. Moreover, trivalent antimony was shown to interact with the zinc finger domain of XPA, another NER protein, since SbCl(3) mediated a concentration dependent release of zinc from a peptide consistent with this domain. In the cellular system, association of XPA to and dissociation from damaged DNA was diminished in the presence of SbCl(3). These results show for the first time that trivalent antimony interferes with proteins involved in nucleotide excision repair and partly impairs this pathway, pointing to an indirect mechanism in the genotoxicity of trivalent antimony.
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PMID:Antimony impairs nucleotide excision repair: XPA and XPE as potential molecular targets. 2050 21