Combined evaluation of Rad51 and ERCC1 expressions for sensitivity to platinum agents in non-small cell lung cancer (NSCLC)
Ichiro YoshinoTomoyoshi TakenakaHidenori KosoT. OhbaTomofumi YohenaAtsushi OsoegawaFumihiro ShojiYoshihiko Maehara
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Abstract:
18085 Background: DNA repair enzyme expression in tumor cells possibly affects sensitivity to anti-cancer agents. The aim of this study was to determine the relationship between expression status of DNA repair proteins and chemosensitivity in patients with NSCLC. Rad51 and ERCC1 play important roles in repair of double and single strand breaks of DNA, respectively, and may protect cells from cytotoxic effect of platinum agents. Methods: NSCLC tissues prepared from the surgical specimens of 41 patients were subjected to an immunohistochemical analysis for Rad51 and ERCC1 proteins and to a chemosensitivity test using the MTT assay. The relationships between the expression status of the DNA repair enzymes and ex vivo chemosensitivity to various agents were evaluated. Results: A positive expression for Rad51 and ERCC1 was observed in 17 cases (41%) and 20 cases (49%), respectively. The positivity of Rad51 was closely related to a certain histologic type of squamous cell carcinoma and poor differentiation, and the positivity of ERCC1 tended to be related to squamous cell carcinoma. In chemosensitivity tests, sensitivities to CDDP and CBDCA were significantly lower when both two enzymes were positive (p = 0.012 and 0.04 in CDDP, 0.014 and 0.03 in CBDCA), but not when either or neither of them was positive. Both Rad51 and ERCC1 expressions showed no significant relationship with sensitivities to paclitaxel, etoposide, vinorelbine, gemcitabine, 5-FU, or irinotecan. Conclusions: Combined expression of Rad51 and ERCC1 is associated with resistance to platinum agents in the ex vivo study of clinical NSCLC, and evaluation of expression status of both DNA repair enzymes would be a predictor for clinical response to platinum-based chemotherapies. No significant financial relationships to disclose.Keywords:
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Vinorelbine
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Background and purpose: Excision repair cross-complementing 1(ERCC1) has been associated with cisplatin resistance.The study aimed to explore the role and clinical significance of detection of ERCC1 protein in individualized therapy of advanced non-small cell lung cancer(NSCLC) patients.Methods: From Aug.2006 to Jul.2009,222 stage ⅢB/Ⅳ NSCLC patients were enrolled.The expressions of ERCC1 protein in advanced stage NSCLC tissues were qualitatively detected by immunohistochemical methods.Patients were randomly assigned in a 2∶1 ratio to either the individualized treatment group or the standard treatment group before ERCC1 assessment.Patients in the control arm received gemcitabine plus cisplatin or vinorelbine plus cisplatin.In the genotypic arm,patients with low ERCC1 levels received gemcitabine plus cisplatin or vinorelbine plus cisplatin,and those with high levels received gemcitabine plus vinorelbine.Main outcome measures include response rate,overall survival and time to progression.Differences between the groups were statistically analyzed by chi-square test.Survival differences were analyzed by temporal inspection and Kaplan-Meier survival curves.Results: Follow-up data was up to Sep.30,2012.Objective response was obtained by 20 patients(26.6%) in the standard treatment group and 40 patients(27.2%) in the individualized treatment group(P=0.931).One year survival rate was 40.0% in the standard treatment group and 48.3% in the genotypic arm(P=0.24).The median survival time was 10.2 months(95%CI was 8.67 months to 11.73 months) in the standard treatment group and 13.3 months(95%CI was 12.46 months to 14.14 months) in the individualized treatment group(P=0.041).The time to progression was 4.8 months(95%CI was 4.12 months to 5.48 months) in the standard treatment group and 4.7 months(95%CI was 3.88 months to 5.52 months) in the individualized treatment group(P=0.395).Conclusion: The median survival time has extended in the individualized treatment group.But individualized therapy in advanced NSCLC guiding by detection of ERCC1 protein has not reflected advantage in response rate,overall survival and time to progression.Additional studies are warranted to optimize detections of biomarkers in guiding rational clinical chemotherapy regimens.
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The standard first-line treatment for around 80% of newly-diagnosed advanced non-small cell lung cancer (NSCLC) is chemotherapy. Currently, patients are allocated to chemotherapy on the basis of clinical conditions, comorbidities and histology. If feasible, platinum-based chemotherapy is considered as the most efficacious option. Due to the heterogeneity in terms of platinum-sensitivity among patients with NSCLC, great efforts have been made in order to identify molecular predictive markers of platinum resistance. Based on the mechanism of action of platinum, several components of DNA repair pathways have been investigated as potential predictive markers. The main DNA repair pathways involved in the repair of platinum-induced DNA damage are nucleotide excision repair and homologous recombination. The most studied potential predictive markers of platinum-sensitivity are Excision Repair Cross Complementing-1 (ERCC1) and Brest Cancer Type-I Susceptibility protein (BRCA1); however, increasing biological knowledge about DNA repair pathways suggests the potential clinical usefulness of integrated analysis of multiple DNA repair components.
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Objective:To observe the efficacy,toxicity and side effects of gemcitable or vinorelbine cominld with cisplation in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Methods: Total of 80 patients with advanced NSCLC diagnosed by pathology or cytology were enrolled into two groups randomly, 40 in each group . Group gemcitabine with 40 patients received gemcitabine 1200 mg/m2 on d1,8 and cisplatin 80mg/m2 on d1,d3; group vinorelbine received vinorelbine 25 mg/m2 on d1,8 and cisplatin 80 mg/m2 on d1,d3. Both regiments had 21 days for each cycle, three weeks repeated and the efficacy was observed after 3 periods. Results: The effective rates of group gemcitabine and vinorelbine were 47.5% (19/40) and 45.0%(18/40) respectively, there was no significant difference (P0.05) between two groups. The median ailment development time were 4.9 and 4.1 months for group gemcitabine and vinorelbine ,respectively and there was sfafastic difference (P0.05). The 1-year survival rates were 42.5% for group gemcitabine and 40.0% for group vinorelbine, no significant difference (P0.05).Thrombocytopenia with group gemcitabine was higher than that of group vinorelbine but the leucopenian and alopecia and phlebitis in group gemcitabine were apparently lower than that in group vinorelbine. Conclusion: There was no significant difference between group gemcitabine and vinorelbine on efficacy ,median survival time and 1-year survival rate ,but there was a little advantage in group gemcitabine on median ailment development time. Both regimens are effective and well tolerated for patients with advanced non-small cell lung cancer.
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The ERCC1–XPF complex is a structure-specific endonuclease essential for the repair of DNA damage by the nucleotide excision repair pathway. It is also involved in other key cellular processes, including DNA interstrand crosslink (ICL) repair and DNA double-strand break (DSB) repair. New evidence has recently emerged, increasing our understanding of its requirement in these additional roles. In this review, we focus on the protein–protein and protein–DNA interactions made by the ERCC1 and XPF proteins and discuss how these coordinate ERCC1–XPF in its various roles. In a number of different cancers, high expression of ERCC1 has been linked to a poor response to platinum-based chemotherapy. We discuss prospects for the development of DNA repair inhibitors that target the activity, stability or protein interactions of the ERCC1–XPF complex as a novel therapeutic strategy to overcome chemoresistance.
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Alternative splicing is a common natural tool for the inhibition of function of full length gene products. We explored whether there was evidence that alternative splicing of ERCC1 may serve such a function for nucleotide excision repair. The ratio of alternatively spliced species to full length species was assessed for the protein and/or for the mRNA, for a series of human cell lines and tissues. This ratio was plotted against the amount of cisplatin-DNA adduct repair in each cell line (n=9), as measured by atomic absorbance spectrometry. As the percentage of alternatively spliced protein and/or mRNA increased, the amount of cisplatin-DNA adduct that was repaired was reduced. This inverse relationship was associated with a substantial amount of scatter (r=0.635), particularly at low levels of repair. These data demonstrate an association between alternative splicing of ERCC1, and reduction in cellular capability to repair cisplatin-DNA adduct.
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