Internal ID
DOH98-HO-2038
Principal Investigator
Start Date
January 1, 2009
End Date
December 31, 2009
Organizations
Partner Organizations
Ministry of Health and Welfare
The roles of DNA repair protein Rad51 and ERCC1 in overcoming drug resistance to epidermal growth factor receptor (EGFR) inhibitor and chemotherapeutic agents in human small-cell lung cancer cells = 核酸修補蛋白Rad51及ERCC1在克服人類小細胞肺癌產生對表皮生長因子受體抑制劑及化療藥物抗藥性之角色探討
Keywords
小細胞肺癌
表皮生長因子
ERCC1蛋白質
Rad51蛋白質
Description
Lung cancer is one of the most commonly occurring malignancies, second to prostate cancer among men and breast cancer among women in the U. S. However, lung cancer has the highest mortality rate for all cancers among both men and women .Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers (Landis, 1999 #1383)(Silvestri, 2006 #266). Lung cancer is the leading cause of cancer-related death in the world. Recent epidemiological data suggest that the incidence of small-cell lung cancer (SCLC) is falling and that the proportion of lung cancer patients with small-cell histology is now 13% (compared with 20–25% previously) (Govindan, 2006 #5640). Characterisation of patients with SCLC into limited-stage disease (LD) and extensive-stage disease (ED) based on Veterans Administration Lung Study Group (VALG) staging system has been the basis of treatment choice for a number of years (Zelen, 1973 #5641), and revised by the consensus report of the International Association of Lung Cancer (IASLC) which had greater power in predicting survival (Micke, 2002 #5642). At the time of presentation, two-thirds of patients will have disseminated disease which means systemic chemotherapy will be the cornerstone of treatment. SCLC is exquisitely sensitive to chemotherapy. Sixty percent of patients with extensive-stage disease may achieve an objective response with combination chemotherapy but, despite high responses, the mean survival remains dismal a 9-11 months. If left untreated patients rarely survive beyond a few months (Albain, 1991 #5643). With the introduction of cisplatin into the treatment of SCLC, PE (cisplatin and etoposide) became a popular regimen because it was associated with fewer toxicities and was equally as effective as CAV (cyclophosphamide, doxorubicin, and vincristine) in randomized trials (Fukuoka, 1991 #5647)(Roth, 1992 #5646). When compared PE to CEV (cyclophosphamide, epirubicin, and vincristine) in 436 patients with SCLC, there was a survival benefit for patients receiving PE. PE produced a median survival of 14.5 months, a 2-year survival rate of 25%, and a 5-year survival rate of 10% (Sundstrom, 2002 #5644). A meta-analysis of 36 trials showed that regimens containing cisplatin or etoposide offered a significant survival advantage to patients with SCLC (Mascaux, 2000 #5645). Although considerable progress has been achieved in the overall management of SCLC, such as having a far greater understanding of the optimum chemotherapy, the importance of appropriate and timely radiotherapy, the importance of prognostic factors and the impact of co-existing morbidity, nonetheless, cure remaons elusive for most patients. Considering that fewer than 10% of extensive-stage SCLC patients survive beyond 2 years, new therapeutic approaches are clearly needed. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib ("Iressa", ZD1839) has demonstrated anti-tumor activity in non-small cell lung cancer (NSCLC) (Silvestri, 2005 #265). NSCLC has been reported to express high levels of EGFR. However, gefitinib appears to be more effective against adenocarcinoma than squamous cell carcinoma (Perng, 2008 #5576). Recent reports have identified specific mutant versions of EGFR in NSCLC cells that seem to determine response to treatment with gefitinib (Lynch, 2004 #1029)(Paez, 2004 #254)(Rosell, 2006 #262). The role of EGFR tyrosine kinase inhibitor in treating SCLC is still not suggested and remains to be elucidated. Recent study has evaluated the effect of gefitinib against the SCLC cell lines. SCLC expressed a low to undetectable level of EGFR. Gefitinib could inhibit the phosphorylation of ERK1/2 by EGF addition in cell lines with detectable and undetectable EGFR expression. These results suggest that gefitinib is potentially effective against SCLC with low EGFR expression (Tanno, 2004 #1350). The mechanism for tolerance to the EGFR tyrosine kinase inhibitor in SCLC is rare mutations occurred in SCLC (Tatematsu, 2008 #5648), other mechanism is EGFR expression in the SCLC was at a very low or undetectable levels (Cerny, 1986 #5649)(Kaseda, 1989 #5650)(Sobol, 1987 #5651). To date, no targeted therapy has been approved for use in the treatment of patients with SCLC (Rossi, 2008 #5599). Novel approaches employing targeted therapies are under evaluation for the treatment of SCLC. The role of these novel biological agents, including bcl-2 antisense oligonuclide, proteasome inhibitor bortezomib, inhibitors of matrix metalloproteinases (MMPs), tyrosine kinase inhibitors and anti-angiogenic strategies, has recently been reviewed in detail and is still under investigation (Board, 2006 #5602) (Ferraldeschi, 2007 #5621)(Rossi, 2008 #5599). Rad51 is a DNA repair nuclear protein that is involved in homologous recombination (Shinohara, 1992 #107)(Haaf, 1995 #7). When cells are exposed to genotoxic treatments, the Rad51 protein relocalizes and concentrates in nuclear foci (Haaf, 1995 #7). The foci are believed to be sites of repair, either at DNA lesions or at stalled replication forks (Haaf, 1995 #7)(Tashiro, 1996 #1297). Abnormal expression of Rad51 has been reported in various carcinomas (Maacke, 2000 #8)(Yoshikawa, 2000 #9). Overexpression of Rad51 can enhance spontaneous recombination frequency and increase resistance to ionizing radiation treatment and chemotherapy in mammalian cells (Vispe, 1998 #1305)(Arnaudeau, 1999 #1157)(Schneider, 2006 #1344). Moreover, high level of Rad51 expression in tumor tissue is associated with an unfavorable prognosis in lung cancer (Qiao, 2005 #1332)(Takenaka, 2007 #1321), and recent study has shown that Rad51 protein protects NSCLC from synergistic cytotoxic effects induced by gefitinib and chemotherapeutic agents. Suppression of Rad51 expression may be a novel therapeutic modality to overcome drug resistance to EGFR inhibitors and chemotherapeutic agents in NSCLC (Ko, 2008 #5652). Excision repair cross-complementation group 1 (ERCC1) is the lead enzyme in the nucleotide excision repair (NER) pathway of DNA repair (de Laat, 1998 #5653). ERCC1 forms a heterodimer with xeroderma pigmentosum- F (XPF), and the ERCC1/XPF complex is responsible for the incision to cleave the damaged strand at the 5’ end of the lesion (de Laat, 1998 #5653)(Sijbers, 1996 #5654). Increased ERCC1 mRNA levels are related to clinical resistance to platinum-based chemotherapy in human gastric, ovarian, cervical, colorectal carcinomas and NSCLC (Britten, 2000 #5661). Two polymorphisms of ERCC1, codon 118 C/T and C8092A, are associated with altered ERCC1 mRNA levels, and overall survival in advanced NSCLC (Zhou, 2004 #5657). Recently, increased expression of ERCC1 mRNA was proven to be a significant and independent predictor of improved survival in resected patients with NSCLC (Simon, 2005 #5659). Patients with completely resected non-small-cell lung cancer and ERCC1-negative tumors appear to benefit from adjuvant cisplatin-based chemotherapy, whereas patients with ERCC1-positive tumors do not (Olaussen, 2006 #5660). Expression of Rad51 and ERCC1 can be linked to resistance of chemosensitivity, especially in relation to treatment causing DNA damage which requires NER or HR for DNA repair (Ito, 2005 #1346). Combined expression of Rad51 and ERCC1 expression 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 (Takenaka, 2007 #1321). However, the role of DNA repair proteins in resistance to chemotherapeutic agents and EGFR inhibitors in small cell lung cancer is unclear. This study will evaluate the roles of protein Rad51 and ERCC1 in overcoming the drug resistance to epidermal growth factor receptor (EGFR) inhibitor (gefitinib) and chemotherapeutic agents (etoposide and cisplatin) in human small-cell lung cancer cells. This study may provide a novel therapeutic modality to improve the the therapeutic response and outcome in SCLC in the future.