Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular profiling of markers involved in the activity of chemotherapeutic agents can shed light on the successes and failures of treatment in patients and can also provide a basis for individualization of therapy. Toward those ends, we have used reverse-phase protein lysate microarrays to evaluate expression of protein components of the nucleotide excision repair (NER) pathways. Those pathways strongly influence the anticancer activities of numerous drugs, including those that are the focus here, cisplatin and ecteinascidin 743 (Et-743; Yondelis, Trabectedin). Cisplatin is generally more active in cell types deficient in NER, whereas Et-743 tends to be less active in those cells. We measured protein expression and sensitivity to those drugs in 17 human ovarian and colon cancer cell lines (13 of them from the NCI-60 panel) and five xeroderma pigmentosum (XP) patient cell types, each containing a different NER defect. Of the NER proteins giving reliable signals, XPF and XPG showed the highest correlations of protein expression with drug activity across all three tissue-of-origin groups. When we compared protein expression data with mRNA expression data from Affymetrix U133A chips, we found no consistent correlation between the two across the cell lines studied, which reinforces the conclusion that protein measurements can give more interpretable mechanistic information than can transcript measurements. The work reported here provides motivation for larger proteomic studies with more cell types focused on potential biomarkers in additional pharmacologically pertinent pathways.
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PMID:Predicting cisplatin and trabectedin drug sensitivity in ovarian and colon cancers. 1818 10

XPG, a structure-specific DNA endonuclease responsible for the 3' incision of DNA lesions during nucleotide excision repair (NER), is associated with high risk of skin cancer as well as skeletal, neurological and developmental abnormalities when functionally defective. These observations have led to the model wherein the endonuclease activity of XPG is important for NER. Herein, we first demonstrate a sensitive assay of XPG cleavage activity using direct nuclear extracts as an XPG source. This method provided quantitative evaluation of the activity of endogenous XPG endonuclease derived from cells with high reproducibility. Our new assay takes advantage of 3'-end oligolabeling of the bubble-shaped substrate. Our results demonstrate efficient cleavage of the model substrate in two XPG wild-type cell lines (human fibroblasts and RKO colon cancer cells) in a time- and dose-dependent manner. In addition, XPG-deficient cells manifested lower cleavage activity relative to normal XPG cells, indicating that the incision activity of XPG was intrinsic in our methodology. It was also found that 7 mM MgCl2 and buffer pH 6.8 resulted in optimal endonucleolytic activity. Based on these results, our modified methodology has potential for quantitative monitoring of XPG cleavage activity in any cell type or tissue of interest.
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PMID:Development of quantitative DNA cleavage assay for XPG endonuclease activity using endogenous nuclear proteins in human cell lines. 2187 51