Apoptosis ; Caspase 3/genetics* ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Pentacyclic Triterpenes ; Stomach Neoplasms/drug therapy*

OBJECTIVE: To analyze the impact of β-tubulin-III (TUBB3), thymidylate synthase (TS) and excision repair cross complementation group 1 (ERCC1) mRNA expression on chemoresponse and clinical outcome of patients with advanced gastric cancer treated with TXT/CDDP/FU (DCF) regimen chemotherapy. METHODS: The study population consisted of 48 patients with advanced gastric cancer. All patients were treated with DCF regimen palliative chemotherapy. The mRNA expressions of TUBB3, TS and ERCC1 of primary tumors were examined by multiplex branched-DNA liquid chip technology. RESULTS: The patients with low TUBB3 mRNA expression had higher response rate to chemotherapy than patients with high TUBB3 expression (P=0.011). There were no significant differences between response rate and TS or ERCC1 expression pattern. Median overall survival (OS) and median time to progression (TTP) were significantly longer in patients with low TUBB3 mRNA expression (P=0.002, P<0.001). TS or ERCC1 expression was not correlated with TTP and OS. In the combined analysis including TUBB3, TS and ERCC1, the patients with 0 or 1 high expression gene had better response rate, TTP and OS than the remaining patients (all P<0.001). Multivariate analysis revealed that ECOG (Eastern Cooperative Oncology Group)≥2 (HR=2.42, P=0.009) and TUBB3 (HR=2.34, P=0.036) mRNA expression significantly impacted on OS. CONCLUSION High TUBB3 mRNA expression is correlated with resistance to DCF regimen chemotherapy. TUBB3 might be a predictive and prognostic factor in patients with advanced gastric cancer treated with TXT-based chemotherapy. The combined evaluation of TUBB3, TS and ERCC1 expression can promote the individual treatment in advanced gastric cancer.
Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Biomarkers, Tumor ; metabolism ; DNA-Binding Proteins ; genetics ; metabolism ; Drug Resistance, Neoplasm ; Endonucleases ; genetics ; metabolism ; Humans ; RNA, Messenger ; genetics ; metabolism ; Stomach Neoplasms ; drug therapy ; genetics ; Thymidylate Synthase ; genetics ; metabolism ; Treatment Outcome ; Tubulin ; genetics ; metabolism

OBJECTIVETo investigate whether CK20 mRNA expression level could be considered as an effective molecular indicator for evaluation of chemotherapy sensitivity.

METHODSAll samples of peripheral blood were taken from 31 gastric cancer patients undergone radical operation a week before postoperative chemotherapy, at the first day of chemotherapy point, and after the first cycle of chemotherapy respectively, and subjected to FQ RT-PCR assay for CK20 mRNA. The chemotherapy scheme was FOLFOX 4. The control group was 15 healthy volunteers.

RESULTSAomng the 31 gastric cancer patients, the value of CK20 mRNA before postoperative chemotherapy was increased (2.96+/-2.27 vs 2.22+/-2.12, t=2.10, P<0.05) in 25 positive cases, and then declined after chemotherapy(2.05+/-1.86 vs 2.96+/-2.27, t=2.50, P<0.05) in 24 positive cases. The expression level of CK20 mRNA in patients before chemotherapy was increased in 16 cases(51.6%), declined in 9 cases(29.0%) and stabilized as negative in 6 cases(19.4%). After chemotherapy the level of CK20 mRNA was increased in 7 cases(22.6%), declined in 17 cases (54.8%) and stabilized as negative in 7 cases(22.6%), there was significant difference between the two groups(chi(2)=6.06, P<0.05).

CONCLUSIONSThe expression level of CK20 mRNA in the peripheral blood detected by FQ RT-PCR in patients with gastric cancer declines after postoperative adjuvant chemotherapy. Different individuals have different sensitivity to chemotherapeutics. Dynamic monitoring CK20 mRNA should be considered as an effective index to evaluate the efficacy of postoperative adjuvant chemotherapy.

Aged ; Antineoplastic Combined Chemotherapy Protocols ; Female ; Humans ; Keratin-20 ; genetics ; metabolism ; Male ; Middle Aged ; Postoperative Period ; Prognosis ; RNA, Messenger ; genetics ; Stomach Neoplasms ; blood ; drug therapy ; metabolism

The aim of the present study was to accurately evaluate the association of Sox2 expression with the survival of patients with digestive tract cancers. Relevant literatures were identified by comprehensively searching databases including the Pubmed, Embase, CBMdisc, and Wanfang (up to October 2014). A meta-analysis was performed to clarify the association between Sox2 expression and overall survival or clinicopathological parameters of patients with digestive tract cancers (esophageal, gastric, and colorectal cancers). The results showed a significant association between high Sox2 expression and poor overall survival in patients with digestive tract carcinomas (HR=1.55, 95% CI=1.04-2.31), especially for patients with esophageal cancer (HR=2.04, 95%CI=1.30-3.22), colorectal cancer (HR=1.40, 95% CI=1.04-1.89), and digestive tract adenocarcinoma (HR=1.80, 95% CI=1.12-2.89), for Europeans (HR=1.98, 95% CI=1.44-2.71) or patients who did not receive neoadjuvant treatment (HR=1.73, 95% CI=1.10-2.72). Furthermore, Sox2 over-expression was highly correlated with vascular invasion (OR=1.86, 95% CI=1.25-2.77) and poor differentiation (OR=1.88, 95% CI=1.14-3.08), especially in esophageal and colorectal cancers. In conclusion, Sox2 expression may serve as a novel prognostic factor for patients with digestive tract cancers. Over-expression of Sox2 that is correlated with vascular invasion and poor differentiation suggests poor outcomes of patients with digestive tract cancers.
Antineoplastic Agents ; therapeutic use ; Biomarkers, Tumor ; genetics ; metabolism ; Colorectal Neoplasms ; diagnosis ; drug therapy ; mortality ; pathology ; Esophageal Neoplasms ; diagnosis ; drug therapy ; mortality ; pathology ; Gastrointestinal Tract ; metabolism ; pathology ; Gene Expression ; Humans ; Neoadjuvant Therapy ; methods ; Neoplasm Grading ; Neoplasms, Vascular Tissue ; diagnosis ; drug therapy ; mortality ; secondary ; Prognosis ; SOXB1 Transcription Factors ; genetics ; metabolism ; Stomach Neoplasms ; diagnosis ; drug therapy ; mortality ; pathology ; Survival Analysis

OBJECTIVETo investigate the effect of replication-competent adenovirus-mediated interleukin-12 gene to chemotherapeutic sensitivity on gastric cancer cell.

METHODSReplication-competent adenovirus and replication-competent adenovirus- mediated interleukin- 12 gene was constructed and expanded separately. The mortality of gastric cancer cell caused by the CNHK200- mIL- 12, Onyx- 015 in combination with different dosages of chemotherapeutic agents were evaluated by MTT assay at the same viral titer with a series of different dosages of chemotherapeutic agent,or at a series of different viral titers with the same dosage of chemotherapeutic agent. The curative effect to the xenografts gastric tumor in nude mouse was also observed by two viruses solely or together with 5-Fu.

RESULTSThe lytic activity of replication-competent adenovirus to gastric cancer cell line SGC-7901 was relatively poor at MOI value of 0.5, but it could be improved significantly when combined with chemotherapeutic agents of ADM, 5-Fu or CAP compared to the simple chemical therapy (P< 0.05). Chemotherapeutic agent 5- Fu could not effectively kill SGC-7901 when used at a relatively low dosage of 10microg/ml,whereas its activity could be improved when combined with a replication-competent adenovirus,and the killing rate was much higher than that with replication-competent adenovirus solely (P< 0.05). The gastric tumor xenografts was prevented and killed by replication adenovirus solely or combined with 5-Fu.

CONCLUSIONThe replication- competent adenovirus- mediated interleukin- 12 gene can increase the chemotherapeutic sensitivity on gastric cancer cell. There is synergetic effect between the replication adenovirus and the chemotherapeutic agents in killing gastric cancer cell.

Adenoviridae ; genetics ; Animals ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Genetic Therapy ; Humans ; Interleukin-12 ; genetics ; Male ; Mice ; Mice, Inbred BALB C ; Stomach Neoplasms ; drug therapy ; Viral Vaccines ; Virus Replication

BACKGROUND/AIMS: Thymidylate synthase (TS) is a target enzyme of 5-fluorouracil (5-FU) and has a polymorphic 28 bp tandem repeated sequence. TS enhancer region (TSER) polymorphism has been associated with the efficacy of 5-FU-based chemotherapy in colon cancer. Methylenetetrahydrofolate reductase (MTHFR) plays a central role in converting folate to methyl donor for DNA methylation. The aim of this study was to determine the clinical value of TSER and MTHFR polymorphism in gastric cancer. METHODS: From October, 1995 to February, 2002, 40 gastric cancer patients underwent operation and 25 patients among those patients have received postoperative 5-FU-based chemotherapy (5-FU (+) group). Peripherial blood were sampled for TSER and MTHFR genotype analysis by PCR amplification of genomic DNA. The survival of patients according to TSER and MTHFR polymorphism were compared. RESULTS: We observed a longer survival in stage II than stage III of the patients (p=0.0037). However, the TSER and MTHFR C677T polymorphisms were not associated with better survival of gastric cancer patients as well as combined TSER and MTHFR genotypes with 5-FU chemotherapy. CONCLUSIONS: The TSER and MTHFR genotypes are not effective markers for tumor sensitivity to 5-FU-based chemotherapy in Korean gastric cancer patients after curative resection. These results may suggest further large-scale study about TSER and MTHFR polymorphism for the prediction of efficacy of 5-FU-based chemotherapy in gastric cancer in Korea.
Aged ; Antimetabolites, Antineoplastic/*therapeutic use ; Drug Screening Assays, Antitumor ; Female ; Fluorouracil/*therapeutic use ; Humans ; Male ; Methylenetetrahydrofolate Reductase (NADPH2)/*genetics ; Middle Aged ; *Polymorphism, Genetic ; Stomach Neoplasms/*drug therapy/genetics/mortality ; Survival Rate ; Thymidylate Synthase/*genetics

Cancer is a collection of complex diseases in which cell proliferation and apoptosis are dysregulated due to the acquisition of genetic changes in cancer cells. These genetic changes, combined with the interrelated physiologic adaptations of neo-angiogenesis, recruitment of stromal support tissues, and suppression of immune recognition, are measurable characteristics in tumor gene expression profiles and biochemical pathways. These measures can lead to identification of disease drivers and, ultimately, can be used to assign therapy. With advances in RNA sequencing technologies, the ability to simultaneously measure all genetic and gene expression changes with a single technology is now possible. The ability to create a comprehensive catalog of genotypic and phenotypic changes in a collection of histologically similar but otherwise distinct tumors should allow for a more precise positioning of existing targeted therapies and identification of new targets for intervention.
Animals ; Asian Continental Ancestry Group ; Cell Transformation, Neoplastic ; genetics ; Disease Models, Animal ; Drug Discovery ; Genes, Tumor Suppressor ; Helicobacter pylori ; Humans ; Neoplasms ; genetics ; Oncogenes ; Signal Transduction ; Stomach Neoplasms ; genetics ; microbiology ; therapy

Evodiamine is one of the most important antitumor alkaloid from evodiamine. This study focused on the mechanism of evodiamine in inducing apoptosis of gastric cancer SGC-7901 cells through mammalian target of rapamycin (mTOR) signal pathway, in order to explore its antitumor mechanism and lay a foundation for clinical treatment of gastric cancer. The sole cytotoxic effect of evodiamine on SGC-7901 cells and human peripheral blood mononuclear cells (PBMCs) was observed by MTT assay. After the cells were respectively intervened with single evodiamine or evodiamine combined with z-VAD-fmk, the gene expressions of mTOR, p70S6K and 4EBP1 were analyzed by real-time PCR, and the protein expressions of mTOR and p-mTOR were detected by western blot. The result showed that evodiamine inhibited the apoptosis of SGC-7901 cells in a time-dependent manner, with no cytotoxic effect on human PBMCs. After the respective intervention with single evodiamine or evodiamine combined with z-VAD-fmk, the cells became round and floated in medium. Compared with the control group, both treatment methods can inhibit mTOR, 4E-BP1 and p70S6K gene expressions, with significant differences. Compared with single evodiamine, evodiamine combined with z-VAD-fmk showed a higher inhibitory rate in gene expression. According to the Western Blot result, evodiamine can inhibit the protein expressions of mTOR and p-mTOR regardless of the combination with z-VAD-fmk, with a higher inhibitory rate after z-VAD-fmk blocked caspase. In conclusion, evodiamine may promote the apoptosis of SGC-7901 cells through mTOR signal pathway.
Animals ; Antineoplastic Agents, Phytogenic ; pharmacology ; Apoptosis ; drug effects ; Cell Line, Tumor ; Drugs, Chinese Herbal ; pharmacology ; Humans ; Quinazolines ; pharmacology ; Signal Transduction ; drug effects ; Stomach Neoplasms ; drug therapy ; genetics ; metabolism ; physiopathology ; TOR Serine-Threonine Kinases ; genetics ; metabolism

BACKGROUND AND OBJECTIVEThere is a mounting evidence of the role of HER2 overexpression inpatients with gastric cancer, and it has been solidly correlated with poor outcomes and more aggressive diseases. This study was to investigate the relationship between the expression of HER2/neu and the clinical characteristics of advanced gastric carcinomas, including survival.

METHODSThe clinical data of 83 patients admitted in Cancer Hospital, Chinese Academy of Science, from 2006 to 2008 were reviewed. The HER2/neu status in 83 advanced gastric carcinomas was evaluated using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The survival rate was calculated by Kaplan-Meier method and the log-rank test using SPSS13.0 software.

RESULTSThe median age of the patients was 60 years and the male-to-female ratio was 2.95:1. HER2/neu overexpression (2+ and 3+) and amplification were found in 25 (30.1%) and 29 (34.9%) advanced gastric carcinomas, respectively. HER2/neu amplification/overexpression was associated with worse survival in patients with advanced gastric carcinoma. The median survival of the patients without HER2/neu amplification was 12.6 months and that of those with HER2 amplification was 5.5 months.

CONCLUSIONSHER2/neu status may be a clinical predictor of prognosis in advanced gastric cancer patients.

Adenocarcinoma ; drug therapy ; genetics ; metabolism ; pathology ; secondary ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Carcinoma, Signet Ring Cell ; drug therapy ; genetics ; metabolism ; pathology ; secondary ; Female ; Gene Amplification ; Gene Expression Regulation, Neoplastic ; Genes, erbB-2 ; Humans ; Liver Neoplasms ; secondary ; Lung Neoplasms ; secondary ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Receptor, ErbB-2 ; metabolism ; Stomach Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; Survival Rate

OBJECTIVETo study the expression and function of zinc ribbon gene ZNRD1 in drug-resistant cells of gastric cancer.

METHODSTwo tumor cell lines were used in this study: gastric cancer SGC7901 and its drug-resistant counterpart SGC7901/VCR stepwise-selected by vincristine. The expression of ZNRD1 in SGC7901 and SGC7901/VCR was detected by northern blot and semiquantitative RT-PCR. ZNRD1 antisense nucleic acid was transfected into SGC7901/VCR cells by lipofectamine. The expression of protein in SGC7901/VCR cells and the transfectants was detected by immunochemical method. Fluorescence activated cell scan (FACS) was applied to observe the cell cycle alteration. Growth curve and drug sensitization of cells for vincristine (VCR) and adriamycin (ADM) were analyzed by MTT assay.

RESULTSThe expression of ZNRD1 was higher in SGC7901/VCR than in SGC7901 cells. Immunochemical results showed that the expression level of ZNRD1 protein was lower in anti ZNRD1-SGC7901/VCR cells than in non-transfectants. The anti ZNRD1-SGC7901/VCR cells were gradually accumulated in G(1) phase, with a concomitant decrease of cell population in S phase. MTT assay showed that transfectant cell proliferation was lagged and more sensitive to VCR and ADM than non-transfectants.

CONCLUSIONZNRD1 gene displays high expression in VCR resistant gastric cancer cells. Expression of ZNRD1 protein is effectively blocked in anti ZNRD1-SGC7901/VCR cells by gene transfection. ZNRD1 antisense nucleic acid could reverse, to some degree, the MDR of human drug-resistant gastric cancer cell SGC7901/VCR.

Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; DNA-Binding Proteins ; analysis ; genetics ; physiology ; Doxorubicin ; pharmacology ; Drug Resistance, Neoplasm ; Humans ; Stomach Neoplasms ; chemistry ; drug therapy ; pathology ; Vincristine ; pharmacology