Significance of thymidylate synthase expression for resistance to pemetrexed in pulmonary adenocarcinoma.

Pemetrexed (PEM), a multi-targeted antifolate, has promising clinical activity in non-squamous non-small cell lung cancer. However, the majority of patients eventually acquire resistance to PEM. To evaluate the resistant mechanisms, the A549 lung adenocarcinoma cell line was exposed to stepwise increasing PEM concentrations of 1.6, 6.4 and 16 µM to establish three PEM-resistant lung cancer cell lines, A549/PEM-1.6, -6.4 and -16. Growth inhibition was determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Expression of the genes encoding thymidylate synthase (TS), reduced folate carrier (RFC) and folypoly-γ-glutamate synthetase (FPGS) were analyzed by quantitative real-time reverse transcription polymerase chain reaction. The three A549 cell lines showed more resistance to PEM (3.7-, 17.3- and 38.0-fold, respectively) compared with that of the parental cell line, which also showed cross-resistance to cisplatin, but not to docetaxel, vinorelbine and 5-Fluorouracil (5-FU). TS gene expression was significantly increased in three PEM-resistant cells, relative to that of the parental cells, in a PEM dose-dependent manner. Knockdown of TS expression with siRNA enhanced the cytotoxicity of PEM in A549/PEM-16 cells. By contrast, the levels of RFC and FPGS gene expression in A549/PEM-1.6 and -6.4 cells were significantly decreased, whereas the levels of the two genes were restored in A549/PEM-16 cells. In summary, PEM-resistant A549 cells remained sensitive to docetaxel, vinorelbine and 5-FU. TS expression appeared to be associated with resistance to PEM, which may be a predictive marker for PEM sensitivity in lung adenocarcinoma.

Prognostic value of survivin in patients with non-small cell lung carcinoma: a systematic review with meta-analysis.

PURPOSE: The potential prognostic value of survivin in resected non-small cell lung carcinoma (NSCLC) is variably reported. The objective of this study was to conduct a systematic review of literatures evaluating survivin expression in resected NSCLC as a prognostic indicator. METHODS: Relevant literatures were identified using PubMed, EMBASE and Chinese Biomedicine Databases. We present the results of a meta-analysis of the association between survivin expression and overall survival (OS) in NSCLC patients. Studies were pooled and summary hazard ratios (HR) were calculated. Subgroup analyses and publication bias were also conducted. RESULTS: We performed a final analysis of 2703 patients from 28 evaluable studies. Combined HRs suggested that survivin overexpression had an unfavorable impact on NSCLC patients' survival with no evidence of any significant publication bias (HR = 2.03, 95%CI: 1.78-2.33, Egger's test, P = 0.24) and no severe heterogeneity between studies (I²  =  26.9%). Its effect also appeared significant when stratified according to the studies categorized by histological type, HR estimate, patient race, cutoff point (5%, 10%), detection methods and literature written language except for disease stage. Survivin was identified as a prognostic marker of advanced-stage NSCLC (HR = 1.93, 95%CI: 1.49-2.51), but not early-stage NSCLC (HR = 1.97, 95%CI: 0.76-5.14), in spite of the combined data being relatively small. CONCLUSION: This study shows that survivin expression appears to be a pejorative prognostic factor in terms of overall survival in surgically treated NSCLC. Large prospective studies are now needed to confirm the clinical utility of survivin as an independent prognostic marker.

Evaluation of oral chemotherapy with capecitabine and cyclophosphamide plus thalidomide and prednisone in prostate cancer patients.

PURPOSE: The aim of this study was to evaluate clinical outcomes of second-line chemotherapy with capecitabine and cyclophosphamide (CTX) plus thalidomide and prednisone in refractory advanced castrate-resistant prostate cancer (CRPC) patients. METHODS: We retrospectively reviewed patients with advanced CRPC who had previously progressed to first-line docetaxel-based chemotherapy. Patients were given second-line chemotherapy with capecitabine and CTX plus thalidomide and prednisone throughout the course. Patients were evaluated for response and toxicity, and treatment was continued until the disease progression or excessive toxicity was noted. RESULTS: From April 2007 to February 2010, a total of 28 patients (median age, 72.8 ± 2.9 years) received second-line chemotherapy. The median cycle and duration of metronomic chemotherapy were six (range: 1-12) cycles and 6.3 (range 1.5-20.5) months, respectively. Prostatic-specific antigen was decreased by more than 50% in 10 (35.7%) of the 28 patients. All patients had bone metastases, and 8 patients (28.6%) had measurable soft tissue lesions. Among the 8 patients, 1 patient achieved partial response, and 3 patients had stabilized disease. With a median follow-up time of 29.5 (95% CI, 26.4-33.4) months, median composite progression-free survival and overall survival were 4.7 (95% CI, 3.4-5.7) months and 19.5 (95% CI, 18.9-25.5) months, respectively. No grade 3-4 toxicity was observed, and none of the patients experienced grade 3-4 hematological and nonhematological toxicities. CONCLUSIONS: These data suggested that oral combination second-line chemotherapy with capecitabine and CTX plus thalidomide and prednisone offers promising activity with an excellent safety profile for patients with advanced CRPC.

Cyclin D1 G870A polymorphism and colorectal cancer susceptibility: a meta-analysis of 20 populations.

PURPOSE: Studies investigating the association between genetic polymorphism of cyclin D1 (CCND1) G870A and risk of colorectal cancer (CRC) reported conflicting results. In order to derive a more precise estimation of the relationship, a meta-analysis was performed. MATERIALS AND METHODS: We performed an extensive search of relevant studies and carried out a meta-analysis, including 20 studies with 5,975 cases and 8,333 controls, to obtain a more precise estimate. RESULTS: Overall, significantly elevated colorectal cancer risk was associated with variant allele 870A when all studies were pooled (AA vs. GG: OR = 1.23, 95% CI = 1.04-1.44; GA vs. GG: OR = 1.13, 95% CI = 1.01-1.26; dominant model: OR = 1.16, 95% CI = 1.03-1.31). In the subgroup analysis by ethnicity, significantly increased risks were detected among Caucasians (AA vs. GG: OR = 1.27, 95% CI = 1.04-1.44; dominant model: OR = 1.17, 95% CI = 1.02-1.34).We also observed sporadic CRC with an increased cancer susceptibility (AA vs. GG: OR = 1.24, 95% CI = 1.04-1.48; dominant model: OR = 1.17, 95% CI = 1.04-1.33), when colorectal cancer was stratified into sporadic CRC and hereditary nonpolyposis colorectal cancer (HNPCC). However, no significant associations were found in both Asians and HNPCC patients for all genetic models. CONCLUSION: Result suggests that the cyclin D1 870A allele is a low-penetrant risk factor for developing sporadic colorectal cancer, especially among Caucasians.

The cyclin D1 G870A polymorphism and colorectal cancer susceptibility: a meta-analysis of 20 populations.

PURPOSE: Studies of the association between the cyclin D1 (CCND1) G870A genetic polymorphism and risk of colorectal cancer (CRC) have generated conflicting results. In order to derive a more precise estimation, a meta-analysis was here performed. MATERIALS AND METHODS: An extensive search of relevant studies was carried out as a meta-analysis of twenty studies with 5,975 cases and 8,333 controls. RESULTS: Overall, a significantly elevated colorectal cancer risk was associated with variant allele 870A when all studies were pooled (AA vs. GG: OR = 1.23, 95%CI = 1.04-1.44; GA vs. GG: OR = 1.13, 95% CI = 1.01-1.26; dominant model: OR = 1.16, 95%CI = 1.03-1.31). In the subgroup analysis by ethnicity, significantly increased risks were detected among Caucasians (AA vs. GG: OR = 1.27, 95%CI = 1.04-1.44; and dominant model: OR = 1.17, 95%CI = 1.02-1.34). With stratification into sporadic CRC and hereditary nonpolyposis colorectal cancer (HNPCC), the former demonstrated increased cancer susceptibility (AA vs. GG: OR = 1.24, 95%CI = 1.04-1.48; dominant model: OR = 1.17, 95%CI = 1.04-1.33). However, no significant associations were found in either Asians or HNPCC patients for any genetic model. CONCLUSION: The results suggest that the cyclin D1 870A allele is a low-penetrant risk factor for development of sporadic colorectal cancer, especially among Caucasians.