Cisplatin, carboplatin and oxaliplatin are some of the most widely used anti-cancer agents in solid tumours. The cytotoxicity of platinating agents is directly related to their ability to cause DNA intra-strand crosslinks that trigger a series of intracellular events that ultimately result in cell death. DNA intra-strand crosslinks are processed and repaired by the nucleotide excision repair pathway. It is now clear that nucleotide excision repair (NER) capacity may have a major impact on the emergence of resistance, normal tissue tolerance and patient outcomes. ERCC1 is a key player in NER. In this review, we provide an overview of mammalian NER and then focus on biochemical, structural and pre-clinical aspects of ERCC1. We then present current clinical evidence implicating ERCC1 as a predictive and prognostic marker in cancer. Early evidence also suggests that ERCC1 or the pathways involved in the regulation of ERCC1 expression may be attractive anti-cancer targets. Such agents are expected to potentiate the cytotoxicity of platinating agents and could have a major impact on cancer therapy.
"Nucleotide excision repair pathway involves a number of genes, including excision repair cross-complementation group 1 (ERCC1). This protein forms a heterodimer with xeroderma pigmentosum group F to execute the incision into the DNA strand (Raymond et al, 2002; Goodisman et al, 2006; Gossage and Madhusudan, 2007; Rabik and Dolan, 2007; Martin et al, 2008). "
[Show abstract][Hide abstract] ABSTRACT: Background:
Excision repair cross-complementation group 1 (ERCC1) expression status has been identified as a candidate marker for predicting efficacy of oxaliplatin (OX) treatment for metastatic colorectal cancer (CRC) in several trials. Also, an association between expression of mismatch repair (MMR) genes and favourable postoperative survival in stage II CRC receiving 5-FU chemotherapy has been identified. It is unknown if the expression of ERCC1 protein and MMR status are associated with survival of stage III colon cancer receiving OX-based chemotherapy.
Immunohistochemistry (IHC) analysis of the expression of MMR and ERCC1 was performed on tumour tissue of 255 patients with stage III colon cancer. In all, 95 patients received fluoropyrimidine-based chemotherapy and 160 patients received OX-based chemotherapy. A predictive model for 5-year disease-free survival (DFS) and overall survival (OS) was constructed using Kaplan–Meier analysis, logistic and Cox regression.
Patients who were treated with OX-based therapy with positive ERCC1 tumours had lower 5-year DFS (54%) and OS (60%) than those with negative ERCC1 tumours (72% and 78%, respectively; DFS HR: 1.98, 95% confidence interval (CI): 1.19–3.31, P=0.009; OS HR: 2.44, 95% CI: 1.37–4.34, P=0.02). Excision repair cross-complementation group 1 status did not impact DFS or OS in fluorouracil group (DFS HR: 1.16, 95% CI: 0.63–2.14, P=0.62; OS HR: 1.16, 95% CI: 0.63–2.14, P=0.63), whereas MMR status had no impact on DFS or OS in either group.
Excision repair cross-complementation group 1 status is highly predictive of which patients will benefit from the addition of OX to 5-FU for stage III colon cancer. Mismatch repair status had no predictive value in this setting.
British Journal of Cancer 03/2013; 108(6). DOI:10.1038/bjc.2013.83 · 4.84 Impact Factor
"ERCC1 expression has been studied as a predictive or prognostic marker in various human cancers. Many studies have demonstrated its correlation with resistance to cisplatin or oxaliplatin and with survival outcome in lung, colorectal, gastric, and ovarian cancer . However, no study has focused on ERCC1 expression in BDC, even though platinum agents such as cisplatin or oxaliplatin are commonly used for treatment of advanced BDC. "
[Show abstract][Hide abstract] ABSTRACT: There are three types of bile duct cancer, intrahepatic cholangiocarcinoma (ICC), hilar cholangiocarcinoma (HC), and extrahepatic cholangiocarcinoma (EHC). Despite different clinical presentation, the same protocol has been used in treatment of patients with these cancers. We analyzed clinicopathologic findings and protein expression in order to investigate the difference and the specific prognostic factors among these three types of cancers.
We conducted a retrospective review of 104 patients diagnosed with bile duct cancer at Seoul St. Mary's Hospital between January 1994 and May 2004. We performed immunohistochemical staining for p53, cyclin D1, thymidine phosphorylase, survivin, and excision repair cross-complementing group 1 (ERCC1).
Of the 104 patients, EHC was most common (44.2%). In pathologic findings, perineural invasion was significantly less common in ICC. Overall survival was similar among the three types of cancer. Lymph node invasion, lymphatic, and venous invasion showed a significant association with survival outcome in ICC, however, the differentiation of histologic grade had prognostic significance in HC and EHC. No difference in protein expression was observed among these types of cancer, however, ERCC1 showed a significant association with survival outcome in HC and EHC, not in ICC.
Based on our data, ICC showed different characteristics and prognostic factors, separate from the other two types of bile duct cancer. Conduct of further studies with a large sample size is required in order to confirm these data.
Cancer Research and Treatment 03/2013; 45(1):63-9. DOI:10.4143/crt.2013.45.1.63 · 3.32 Impact Factor
"DNA repair pathways that may result in platinum-based chemotherapeutic resistance include mismatch repair (MMR) and nucleotide excision repair (NER) [12,13]. Excision repair cross-complementation group 1 (ERCC1) is the initial enzyme in the NER pathway of DNA repair, and reports have shown that increased mRNA levels of ERCC1 are associated with clinical resistance to platinum-based chemotherapy in human lung, gastric, ovarian, cervical, and colorectal carcinomas and impact with the survival rate of cancer patients [14,15,16,17,18]. In addition, thymidine phosphorylase (TP), a key enzyme in the pyrimidine nucleoside salvage pathway, is known to catalyze the reversible conversion of thymidine to thymine and 2-deoxy-D-ribose-1-phosphate . "
[Show abstract][Hide abstract] ABSTRACT: Cisplain, a platinum-containing anticancer drug, has been shown to enhance DNA repair and to inhibit cell apoptosis, leading to drug resistance. Thus, the combination of anticancer drugs with nutritional factors is a potential strategy for improving the efficacy of cisplatin chemotherapy. In this study, we investigated the anti-proliferative effects of a combination of fucoxanthin, the major non-provitamin A carotenoid found in Undaria Pinnatifida, and cisplatin in human hepatoma HepG2 cells. We found that fucoxanthin (1-10 μΜ) pretreatment for 24 h followed by cisplatin (10 μΜ) for 24 h significantly decreased cell proliferation, as compared with cisplatin treatment alone. Mechanistically, we showed that fucoxanthin attenuated cisplatin-induced NFκB expression and enhanced the NFκB-regulated Bax/Bcl-2 mRNA ratio. Cisplatin alone induced mRNA expression of excision repair cross complementation 1 (ERCC1) and thymidine phosphorylase (TP) through phosphorylation of ERK, p38 and PI3K/AKT pathways. However, fucoxanthin pretreatment significantly attenuated cisplatin-induced ERCC1 and TP mRNA expression, leading to improvement of chemotherapeutic efficacy of cisplatin. The results suggest that a combined treatment with fucoxanthin and cisplatin could lead to a potentially important new therapeutic strategy against human hepatoma cells.
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