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|Title:||Increased γ-H2AX and Rad51 DNA repair biomarker expression in human cell lines resistant to the chemotherapeutic agents nitrogen mustard and cisplatin.|
|Citation:||Chemotherapy, 60(5-6): pp. 310 - 320, (2015)|
|Abstract:||Chemotherapeutic anticancer drugs mediate cytotoxicity by a number of mechanisms. However, alkylating agents which induce DNA interstrand cross links (ICL) are amongst the most effective anticancer agents and often form the mainstay of many anticancer therapies. The effectiveness of these drugs can be limited by the development of drug resistance in cancer cells and many studies have demonstrated that alterations in DNA repair kinetics are responsible for drug resistance. In this study we developed two cell lines resistant to the alkylating agents nitrogen mustard (HN2) and cisplatin (Pt). To determine if drug resistance was associated with enhanced ICL DNA repair we used immunocytochemistry and imaging flow cytometry to quantitate the number of gamma-H2AX and Rad51 foci in the nuclei of cells post drug exposure. Gamma-H2AX was used to evaluate DNA strand breaks caused by repair incision nucleases and Rad51 was used to measure the activity of homologous recombination (HR) in the repair of ICL. In the drug resistant derivative cell lines, overall there was a significant increase in the number and persistence of both gamma-H2AX and Rad51 foci in the nuclei of cells over a 72 hr period, when compared to the non-resistant parental cell lines (ANOVA P < 0.0001). In a cisplatin resistant ovarian cancer cell line (A2780cisR) a similar enhancement of DNA repair was observed when compared to the non-drug resistant wild type ovarian cancer cells (A2780) following exposure to nitrogen mustard. Our data suggest that using DNA repair biomarkers to evaluate mechanisms of resistance in cancer cell lines and human tumours may be of experimental and clinical benefit. We concede however, that examination of a larger population of cell lines and tumours is required to fully evaluate the validity of this approach.|
|Appears in Collections:||Dept of Life Sciences Research Papers|
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