Biomedical subjects

T Toge

Publications and source records attributed to T Toge.

At least 235 records · Page 13Linked to original sources

PubMed1976

Lymphocyte responsiveness to phytohemagglutinin (PHA) and serum inhibitory effect in patients with gastric cancer.

The in vitro lymphocyte response to PHA was determined in patients with gastric cancer in various stages prior to the surgical treatment. The lymphocyte responsiveness in the presence of homologous pooled AB serum in patients of stages II, III and IV were markedly reduced as compared with that in healthy controls (stages II, III; p less than 0.05, stage IV; p less than 0.01). Inhibition of normal lymphocyte responsiveness to PHA by serum from patients in stages III and IV were statistically significant only in the advanced stage. It was concluded that the suppression of the immune response in the early stage of gastric cancer was mainly due to the impairment of lymphocyte itself, which advanced with the progress of the stage and was modified by the serum inhibitory effect in advanced stages. In patients with advanced cancer, the higher was the lymphocyte responsiveness to PHA and PWM prior to the initial treatment, the more effective was the immunotherapy. This shows that the indication of the immunotherapy in patients with advanced cancer could be initiated. Furthermore, the correlation between the lymphocyte responsiveness to PHA and the clinical results of immunotherapy was discussed.

Adult↗

PubMedDate not supplied

Carcinoembryonic antigen levels in the peritoneal cavity: useful guide to peritoneal recurrence and prognosis for gastric cancer.

At the time of laparotomy, peritoneal washings were collected from 155 gastric cancer patients and the levels of carcinoembryonic antigen (CEA) determined. The CEA levels in peritoneal washings were statistically independent of those in sera and could more reliably predict the presence of peritoneal metastasis than a cytologic study. Peritoneal recurrence was seen in 14 of 118 patients after curative operation. Of the 14 patients, 10 (71%) had elevated levels of CEA (100 ng/g protein) at surgery. Of these 10 cases, 2 of the tumors were classified as stage IB and 4 had no serosal invasion. Only one patient with peritoneal metastasis and a low CEA level was free from relapse more than 1 year after operation. Kaplan-Meier's analysis showed that a high CEA level in peritoneal washings was a predictor of poor prognosis in patients who underwent either curative or noncurative resection. A proportional hazards regression analysis showed that a high CEA level in peritoneal washings was statistically significant in terms of predicting a shorter interval until peritoneal recurrence (p = 0.0002) and for survival (p = 0.0001). The CEA level in peritoneal washings is therefore of value as an indicator of peritoneal recurrence and prognosis.

Adult↗

PubMedDate not supplied

Modulation of CD4 antigen expression on the lymphocyte surface by immunosuppressive acidic protein in cancer patients.

The immunomodulatory effect of human immunosuppressive acidic protein (IAP) on lymphocyte surface antigens was investigated. IAP inhibited lymphocyte responses to phytohemagglutinin in a dose-dependent manner. By flow cytometry, using fluorescein-isothiocyanate-labelled antibodies, the mean fluorescence intensity on peripheral blood lymphocytes (PBLs) decreased for CD4, slightly decreased for CD3 but showed no change for the CD8 and T cell receptor alpha-beta antigens in the presence of IAP. This CD4 antigen modulation by IAP was observed in PBLs freshly isolated from patients with unresectable cancer but not in those isolated from patients with resectable tumor or from healthy volunteers. The modulation of the CD4 antigen by IAP on the lymphocyte surface was correlated with an increment of serum IAP levels in cancer patients. The CD4 modulation could be induced in PBLs from healthy volunteers by culturing them with IAP in vitro. It is suggested that IAP may play a role in cancer-related immunosuppression through the down-modulation of the CD4 antigen on the lymphocyte surface.

CD3 Complex↗

PubMedDate not supplied

Chemotherapy combined with or without hyperthermia for patients with oesophageal carcinoma: a prospective randomized trial.

From 1990 to 1991, 40 patients with squamous cell carcinoma of the thoracic oesophagus were admitted to our institutions and chemotherapy (oil Bleomycin p.o. and CDDP d.i.v.) either combined with or without hyperthermia was performed, in a prospective randomized trial carried out to investigate the effects of hyperthermia. The two groups (group A, consisting of 20 patients given chemotherapy alone; and group B, made up of 20 given chemotherapy with hyperthermia) were comparable with regard to various prognostic factors. Following the above treatment regimens, an oesophagectomy was done in 16 and 17 patients from groups A and B, respectively. A subjective improvement of dysphagia was seen in 8 (40.0%), and in 14 patients (70.0%), while a radiographic improvement was recognized in 5 (25.0%) and 10 cases (50.0%) in groups A and B, respectively. In the resected specimen of 16 (group A) and 17 patients (group B), histopathological evidence of the effectiveness of the treatments were recognized in 3 (18.8%) and 7 (41.2%) from groups A and B, respectively. Excluding the cases of superficial carcinoma (T1 tumour), histologic effectiveness of the treatments were recognized in 2 (14.3%) and 7 (58.3%) in groups A and B, respectively (p < 0.05). There was no difference in the occurrence of side effects between the groups. Therefore, the clinical and pathological effects were favourable in the hyperthermia combined with chemotherapy group, especially in the cases with advanced oesophageal cancer.

Aged↗

PubMedDate not supplied

Protein-bound polysaccharide increases survival in resected gastric cancer cases stratified with a preoperative granulocyte and lymphocyte count.

A multicenter comparative trial of mitomycin C and futraful (MMC+FT), with or without protein-bound polysaccharide (PSK), was carried out by the Study Group for Surgical Adjuvant Chemotherapy for Gastric Cancer from 1978 to 1981. In 751 patients who underwent macroscopically curative resection preoperative granulocyte and lymphocyte count ratios (G/L) were measured. These patients were stratified with a preoperative cut-off of G/L:2.0, and those with or without PSK were compared in terms of survival rates. In the overall (non-stratified) series, the 5-year survival rate of the PSK group was 67.9%, while that of the non-PSK group was 61.8% (p=0.053). In the group with a preoperative G/L ratio of >/=2.0, the 5-year survival rate of the PSK group (n=182) was 68.7%, while that of the non-PSK group (n=182) was 55.4% (p=0.007). In the cases with a preoperative G/L ratio of <2.0, there was no significant difference in the survival rates: 67.1% in the PSK group (n=195) and 67.8% in the non-PSK group (n=192). It was found that PSK extended survival in the group of patients with a preoperative G/L ratio of >/=2.0, perhaps through restoration of immunocompetence.

Adjuvants, Immunologic↗

PubMedDate not supplied

A phase II trial of mitomycin C, 5'-deoxy-5-fluorouridine, etoposide and medroxyprogesterone acetate (McVD-MPA) as a salvage chemotherapy to anthracycline-resistant tumor in relapsed breast cancer and its mechanism(s) of antitumor action.

To assess the therapeutic efficacy in the combination of mitomycin C (MMC), 5'-deoxy-5-fluorouridine (5'-DFUR), etoposide (VP-16) and medroxyprogesterone acetate (MPA) (McVD-MPA) to anthracycline-resistant tumor as a salvage chemotherapy, a phase II trial was conducted in patients with relapsed breast cancer. Fifty-five patients were enrolled in this trial and 54 were assessable, who had all previously been treated with an anthracycline regimen. The treatment schedule was designed with the intravenous administration of MMC (6 mg/m2) on day 1 followed by peroral administration of VP-16 (75 mg/m2) on day 2, 4, 6 and the peroral administration of 5'-DFUR (600 mg/m2) and MPA (400 mg/m2) on day 1 through 21 in one cycle. The overall tumor response rate was 40.7% (22/54) including 16.6% (9 cases) in complete response and 24.0% (13 cases) in partial response, and the long no change (NC) was observed in 18.5% (10/54) out of 44.4% (24/54) in NC. Of the patients with primary resistance to anthracycline 30.0% responded to McVD-MPA therapy. Bone and liver metastases responded in 50.0% and 50.0%, whereas soft tissue and lung metastases responded in 36.8% and 35.2%, respectively. The mean time to response and response duration were 2.7 and 15.6 months, respectively. The overall survival of the patient treated with the McVD-MPA was superior to the non-treatment of second line therapy, and the median survival between McVD-MPA and non-treatment was 86 days and 50 days, respectively. The major adverse effect was observed in hematological toxicity (31.7%) such as leukopenia and thrombocytopenia and non-hematological toxicity of gastrointestinal events (31.7%), the toxicity was less than grade 2, and was tolerable during the treatment. In the experiment of MDA-MB-231 breast cancer cell line that was overexpressed with P-glycoprotein (P-gp) and multidrug resistance associated protein (MRP), the mechanism(s) by which McVD-MPA induces the antitumor effect to anthracycline-resistant tumor may be explained at least in part as follows: i) The treatment of MMC suppressed the expression of P-gp and MRP in a dose-and time-dependent manner, connecting the increase of the intracellular concentration of VP-16; ii) The treatment of MMC enhanced the expression of thymidine phosphorylase to increase the production of 5-FU from 5'-DFUR in the antiangiogenic effect of MPA. These results indicate that the combination chemotherapy of the McVD-MPA may be an effective regimen to anthracycline-resistant tumor as a salvage chemotherapy to prolong the survival in the patient with relapsed breast cancer.

ATP Binding Cassette Transporter, Subfamily B↗

PubMedDate not supplied

Dysregulation of telomerase activity and expression in lymphokine-activated killer cells from advanced cancer patients: possible involvement in cancer-associated immunosuppression mechanism.

There exists cancer-associated immunosuppression, and the generation of lymphokine-activated killer (LAK) cells is impaired in patients with advanced cancer. Telomerase has been reported to be upregulated in the activation of lymphocytes to proliferate against immune stimulation as well as in the malignant transformation of immortal cancer cells. We attempted to clarify the involvement of telomerase in the impairment of LAK cell generation in patients with advanced cancer. LAK cells were generated by stimulation with interleukin (IL)-2 and immobilized anti-CD3 antibody (IL-2/CD3 system) from peripheral blood mononuclear cells of healthy volunteers (he-LAK) or patients with advanced cancer (ca-LAK), and proliferative potential of LAK cells was evaluated on the basis of population doubling level (PDL). Telomere length and telomerase activity of LAK cells were measured by the hybridization with oligonucleotide (TTAGGG)4 and by the telomeric repeat amplification protocol (TRAP) assay, respectively. Effects on telomerase activity in LAK cells of serum from cancer patients, transforming growth factor (TGF)-beta, and IL-10 were also examined. The lifespan of ca-LAK (15.2 +/- 5.1 PDLs) was significantly shorter than that of he-LAK (22.6 +/- 8.3 PDLs) (p = 0.0358). There were no significant differences between he- and ca-LAK in telomere length before IL-2/CD3 stimulation and maximal telomerase activity induced. The telomerase activity induced in ca-LAK failed to elongate sufficiently the telomeric ends (-35.2 +/- 46.2 bp) compared with that in he-LAK (16.8 +/- 41.5 bp) (p = 0.0448). The telomerase activity was initially detectable on day 2 in all he-LAK, whereas 8 (61.5%) of 13 ca-LAK expressed telomerase activity on day 3 or later following the stimulation, showing a significant retardation of telomerase expression (p = 0.0116). The addition to the LAK cell generation system of serum from cancer patients, as well as IL-10, but not transforming growth factor (TGF)-beta, suppressed the telomerase activity. This serum-induced suppression of telomerase activity in LAK cells was abrogated with the addition of anti-IL-10 antibody but not with anti-TGF-beta antibody. It is suggested that the dysregulation of telomerase activity and expression exists in LAK cells of cancer patients, resulting in the impairment of LAK cell generation in patients with advanced cancer. Serum IL-10 may be involved in the impairment of LAK cell generation by the suppression of telomerase activity of lymphocytes in vivo. Thus, the dysregulation mechanism of telomerase activity and expression in lymphocytes of cancer patients may be attributable, in part, to cancer-associated immunosuppression.

Aged↗

PubMedDate not supplied

Pharmacokinetic and biochemical analysis in the treatment of weekly paclitaxel in relapsed breast cancer.

The mechanism(s) by which weekly paclitaxel exerted more therapeutic efficacy than the triweekly schedule in relapsed breast cancer is still unclear. To assess the rationale in therapeutic efficacy of weekly paclitaxel in relapsed breast cancer, pharmacokinetic and biochemical analyses were examined in terms of the mean peak plasma concentration at 0 min (Cmax), 30 min, and 24 h after finishing the infusion, and the extracellular domain of HER-2 in response to the treatment with paclitaxel. Twenty-five patients treated with weekly 1 h infusion of paclitaxel in the dose range from 40 mg/m(2) to 80 mg/m(2) were studied. Eleven patients responded to the treatment including 4 cases of complete response (CR) and 7 cases of partial response (PR), while 14 patients did not respond including 12 cases of no change (NC) and 2 cases of progressive disease (PD). The plasma concentration of paclitaxel and extracellular domain of HER-2 in the patients were measured by high-pressure liquid chromatography and enzyme immunoassay, respectively. The peak concentration (Cmax) and the other peaks at 30 min and 24 h in 10 patients including 3 cases of 40 mg/m(2), 3 cases of 60 mg/m(2) and 4 cases of 80 mg/m(2) in the weekly paclitaxel were compared in proportion to the increase of dose escalation, and compared to their tumor response. Further, the plasma levels of extracellular domain of HER-2 in 17 patients treated with the weekly paclitaxel were measured, and also compared to their tumor response. The mean Cmax treated with 40 mg/m(2), 60 mg/m(2) and 80 mg/m(2) in the weekly paclitaxel was 1.94, 2.18 and 1.54 microM, respectively. The dose escalation of paclitaxel and the dose intensity were not correlated with the increase of plasma concentration of paclitaxel nor with the tumor response. In contrast, the plasma level of extracellular domain of HER-2 in responders was higher than that of non-responders in the weekly paclitaxel regimen(p=0.0512, Mann-Whitney's U-test). These results suggest that tumor response to the weekly 1 h infusion of paclitaxel was not associated with the plasma concentration and the dose intensity, rather the plasma level of extracellular domain of HER-2 protein may be a predictor of tumor response in the treatment of weekly paclitaxel in relapsed breast cancer.

Adult↗

PubMedDate not supplied

Down-regulation of IL-10 enhances the efficacy of locoregional immunotherapy using OK-432 against malignant effusion.

To determine the significance of interleukin (IL)-10 in antitumor immune response, the effect of the down-regulation of tumor-derived IL-10 on locoregional immunotherapy was investigated. C3H/HeN mice were intraperitoneally (i.p.) inoculated with IL-10-producing murine breast cancer cell line, FM3A, and treated with locoregional administration of OK-432 with or without anti-IL-10 monoclonal antibody (mAb). Anti-IL-10 mAb did not affect the in vitro growth of FM3A cells. Administration of OK-432 plus anti-IL-10 mAb remarkably delayed the retention of malignant ascites and prolonged the survival of mice compared with the administration of OK-432 alone. Spleen cells which were collected from mice treated with OK-432 plus anti-IL-10 mAb and further stimulated in vitro with inactivated FM3A cells exhibited significantly higher cytotoxicity against FM3A cells than those from mice treated with OK-432 alone or from the control mice. The expression of major histocompatibility complex (MHC) class II molecules on spleen cells was up-regulated in vitro by the addition of OK-432 and anti-IL-10 mAb. Using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), cytokine mRNA levels of peritoneal exudate cells (PEC) and spleen cells were assessed on day 7 (before treatment) and day 14 (after treatment). In PEC, increased expression of IL-2 was observed with the administration of OK-432 plus anti-IL-10 mAb. In spleen cells, the expression of IL-2, IL-12 and IFN-gamma were strongly induced, and IL-4 expression was reduced by the administration of OK-432 plus anti-IL-10 mAb. It is suggested that down-regulation of tumor-derived IL-10 induces the up-regulation of the T helper type (Th) 1 population, resulting in an enhancement of the efficacy of locoregional immunotherapy with OK-432.

Animals↗

PubMedDate not supplied

Introduction of gadd153 gene into gastric cancer cells can modulate sensitivity to anticancer agents in association with apoptosis.

Gadd 153 gene is known as one of the growth arrest and DNA damage inducible genes that may play an important role in signal transduction pathway(s) in response to DNA damage. We have investigated whether the introduction of gadd153 gene into gastric cancer cells could modulate the sensitivity to anticancer agents in association with apoptosis. The transfection of gadd153 gene into MKN45 gastric cancer cells (MKN45gadd153) increased the sensitivity to a variety of anticancer agents, compared to that of neo gene-transfected cells (MKN45neo). The sensitivity to CDDP and VP-16 was increased to a greater extent, whereas the sensitivity to 5-FU and taxotere was increased to a lesser extent. The increase of sensitivity to these drugs was associated with the increase of the formation of internucleosomal DNA ladders in apoptosis. The basal level of gadd153 mRNA was overexpressed in MKN45gadd153 cells, and its induction following the treatment of VP-16 and taxotere was found to a greater extent than that of MKN45neo cells. The analysis of mRNA expression in drug resistance-related genes including mdr1, mrp, topoisomerase II alpha showed that the increase of drug-sensitivity in MKN45gadd153 cells was not due to the changes in expression of drug resistance genes. These results suggest that the introduction of gadd153 gene into gastric cancer cells may modulate the sensitivity to certain anticancer agents by activating AP-1-associated signal transduction pathway(s) leading to apoptosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

T-cell receptor V beta gene usage of human cytotoxic T-cell clones obtained from gastric cancer patients.

Nine T-cell clones have been established from tumor-infiltrating lymphocytes (TIL) isolated from ascitic fluid of a gastric cancer patient. Five of them retained cytotoxicity against autologous tumor cells (AuTu), and were all CD4+. Each clone had different usage of T-cell receptor (TCR) V beta gene as assessed by Southern blot analysis. Using AuTu and two allogeneic gastric cancer cell lines as targets, we selected three clones with unique cytotoxic properties. Two of these clones (Clone 1 and 2) preferentially lysed AuTu, but showed no or marginal cytotoxicity against allogeneic gastric cancer cells, and one clone (Clone 7) showed appreciable cytotoxicity against AuTu and allogeneic gastric cancer cells. In the detailed analysis of TCRV beta gene usage, Clone 1, 2, and 7 expressed V beta 13.1/D beta 1/J beta 1.5/C beta 1, V beta 3/D beta 2/J beta 2.4/C beta 2, and V beta 9/D beta 1/J beta 1.4/C beta 1, respectively, and the primary structures of the three TCRVb genes did not share any common features, neither in the sizes of their complementarity determining region 3 (CDR3) nor in their amino acid compositions. Interestingly, PBL of the same patient expressed CDR3 identical to that of Clone 2 and 7, but not that of Clone 1. CDR3 identical to that of Clone 2 and 7 were also detected in TIL of other gastric cancer patients. These results show that some AuTu-specific CTL included in TIL are circulating in peripheral blood, and that the CDR3 identical to that of the CTL is expressed extensively in TIL among different gastric cancer patients. Screening of the expression of the CDR3 in other gastric cancer patients is recommended to develop an immuno-therapy of gastric cancer based on antigenic peptide.

Adenocarcinoma↗

PubMedDate not supplied

The prognostic significance of p53, p21 (Waf1/Cip1), and cyclin D1 protein expression in esophageal cancer patients.

Recently, various cell cycle regulators have been studied as biological markers of malignant potential. These regulators might influence survival rates and the effects of adjuvant therapies. In this study, we analyzed the expression of p53, p21(Waf1/Cip1), and cyclin D1 in 64 esophageal cancer patients and their relation to clinicopathologic parameters and patient survival. For p53, p21, and cyclin D1 oncoprotein expression, we defined positive cases as those with over 10% of examined cells stained. Positive rates were 48.4%, 42.2%, and 43.8% for p53, p21, and cyclin D1, respectively. In a multivariate analysis, tumor depth, chemotherapy, and p21 expression were determined to be significant prognostic factors. Five-year survival rates of p53-negative/p21-positive and p53-positive/p21-negative patients were 53.0% and 28.5%, respectively, and were not significantly different. These results suggest that, of various cell cycle regulators, p21 might be a good predictor of prognosis for esophageal cancer patients.

Aged↗

PubMedDate not supplied

Immunological properties of tumor cells genetically modified to secrete interleukin-2.

The immunological properties of interleukin-2 (IL-2) gene-transduced tumor cells were investigated in mice. A murine ovarian cancer cell line, OVHM, was retrovirally transduced with the human IL-2 gene (OVHM/IL-2) and the neomycin resistance gene (OVHM/Neo). OVHM/IL-2 cells continuously secreted IL-2 detected by ELISA using an antibody specific for human IL-2, and by a bioassay using an IL-2-reactive cell line (CTLL-2). When OVHM cells were inoculated subcutaneously into syngeneic B6C3F1 mice, OVHM/IL-2 cells but not parental (OVHM/P) or OVHM/Neo cells were regressed even though their rate of in vitro growth was comparable. This was not observed in nude mice, indicating the involvement of T lymphocytes in the regression of OVHM/IL-2 cells. The survival of mice inoculated intraperitoneally with OVHM/IL-2 cells was prolonged compared with those inoculated with OVHM/P cells. In irradiation experiments, IL-2 secretion by irradiated OVHM/IL-2 cells was retained for at least 5 days, although in vitro growth and in vivo tumorigenicity of irradiated OVHM/IL-2 cells were completely diminished. When mice were challenged with viable OVHM/P cells, survival of mice previously immunized with irradiated OVHM/IL-2 cells was prolonged compared to those immunized with irradiated OVHM/P cells, indicating a vaccine property of irradiated OVHM/IL-2 cells. Moreover, survival of mice with established ascites was improved upon injection of irradiated OVHM/IL-2 cells, indicating a therapeutic potential of OVHM/IL-2 cells. Tumor cells genetically engineered to secrete IL-2 may therefore be promising candidates for tumor vaccines and may provide a new mode of cancer immunotherapy.

Animals↗

PubMedDate not supplied

Expression and relationship between topoisomerase I and II alpha genes in tumor and normal tissues in esophageal, gastric and colon cancers.

DNA topoisomerases are known to be nuclear enzymes that are important targets of topoisomerase I (topo I) and topoisomerase II (topo II) inhibitors in cancer chemotherapy. We investigated the mRNA expression of topo I and topo II alpha genes as assessed by northern blot analysis in tumor and the adjacent normal tissues of esophageal, gastric and colon cancers. The surgical specimens consisted of 18 tumor tissues and the adjacent normal tissues including 6 esophageal cancers, 6 gastric cancers and 6 colon cancers. We found that the mRNA expression of topo I gene was not significantly different between tumor and normal tissues in 18 surgical specimens, whereas the mRNA expression of topo II alpha gene in the all types of tumors was significantly higher than that of the adjacent normal tissues. Furthermore, the mRNA expression of topo II alpha gene in tumor and adjacent normal tissues was correlated with the S-phase population in cell cycle. Of great importance was the significant relationship between mRNA expression of topo I and topo II alpha genes in tumor and normal tissues was found in esophageal and colon cancers (p < 0.05), except in gastric cancers. These results indicate that the rationale in tumor specific chemotherapy with topo II inhibitors was based on the finding of its higher expression of topo II alpha gene in tumors than that of normal tissues, an important target of topo II inhibitors, and suggest that the sequential chemotherapy targeting topo I and topo II enzymes by modulating topo II alpha expression by topo I inhibitors might be more effective in esophageal and colon cancers, in terms of their relationship between topo I and topo II alpha expression in tumor cells.

Antigens, Neoplasm↗

PubMedDate not supplied

Taxotere activates transcription factor AP-1 in association with apoptotic cell death in gastric cancer cell lines.

We investigated whether a novel mitotic inhibitor, taxotere can activate the transcription factor AP-1 in association with apoptotic cell death in 8 gastric cancer cell lines. Apoptotic cell death was analyzed by DNA ladder formation assay, and AP-1 binding activity was assessed by gel mobility-shift assay. The activation of AP-1 binding was induced in accordance with the sensitivity to taxotere in gastric cancer cell lines. The relationship between the increase of AP-1 binding and the formation of internucleosomal DNA ladders induced by taxotere was significant (p < 0.05). Furthermore, the activation of AP-1 binding was induced following the treatment of taxotere in a dose and -time dependent manner. Although the sensitivity to taxotere was correlated with the formation of internucleosomal DNA ladders in apoptotic cell death, its sensitivity was not influenced by their p53 genomic states in gastric cancer cell lines. Rather, the activation of AP-1 binding was correlated with the induction of a growth arrest and DNA damage inducible gene, gadd153 (p < 0.05). These results indicate that the activation of AP-1 binding by taxotere seems to be an important factor in determining its sensitivity in association with internucleosomal DNA ladders, and suggest that the induction of gadd153 gene could be a downstream target of AP-1-regulated genes involved in signal transduction pathways leading to apoptosis in gastric cancer cells.

Antineoplastic Agents, Phytogenic↗

PubMedDate not supplied

Microsatellite instability in squamous cell carcinomas and dysplasias of the esophagus.

Microsatellite instability (MSI) caused by the defective functions of mismatch repair genes plays an important role in the carcinogenesis of gastrointestinal tumors. However, little is known about the role of MSI in esophageal carcinogenesis. In the present study, we conducted microsatellite assays on 41 esophageal carcinomas and also on 44 dysplasias of the esophagus with 7 separate microsatellite loci. MSI was detected in 17 cases (42%) among 41 esophageal carcinomas. MSI negative cases revealed greater lymph node metastasis, metastasis at a more advanced stage, a higher recurrence level and a poorer prognosis (statistically not significant). In the analysis of dysplasias, MSI was detected in 26 lesions (59%) among 44 lesions. Interestingly, MSI was detected in 21 lesions (78%) from the mutator phenotype dysplasias, but detected in only 5 lesions (29%) from the non-mutator phenotype cases. Although the significance of MSI in esophageal carcinoma was not clear, these results indicate that MSI occurs in the early stage of esophageal carcinogenesis.

Adult↗

PubMedDate not supplied

Enhancement of chemotherapeutic agents induced-apoptosis associated with activation of c-Jun N-terminal kinase 1 and caspase 3 (CPP32) in bax-transfected gastric cancer cells.

Apoptois is an important determinant in the sensitivity to chemotherapeutic agents in gastric cancer cells. In this study, we examined whether the introduction of the bax gene into MKN45 gastric cancer cells could enhance the sensitivity to chemotherapeutic agents in association with apoptosis. Apoptosis in the bax-transfected gastric cancer cells was enhanced following the treatment of various chemotherapeutic agents including adriamycin (ADM), cisplatin (CDDP), etoposide (VP-16) and taxotere (TXT) as compared to those of neo gene-transfected cells. The enhancement of apoptosis was coincident with the increase of sensitivity in the ratio of IC50 value, that was 1.3-fold in ADM, 4.4-fold in CDDP, 4.6-fold in VP-16 and 2.5-fold in TXT, respectively. Further, the enhancement of apoptosis in the bax-transfected gastric cancer cells was associated with the activation of c-Jun N-terminal kinase 1 (JNK 1) and caspase 3 (CPP32). The increases of sensitivities to these agents in the bax-transfected cells were also demonstrated in in vivo experiments using the tumor cells transplanted into nude mice. The tumor growth in the bax-transfected cells was significantly suppressed following the treatment of CDDP or VP-16 compared to that of neo-transfected cells (p < 0.05). These results indicated that, the bax gene might play a critical role in determination of sensitivity to chemotherapeutic agent in gastric cancer cells in vivo, and that the activation of JNK 1 and CPP32 might be involved in the signal transduction pathways leading to apoptosis.

Adenocarcinoma↗

PubMedDate not supplied

Generation of cytotoxic effector lymphocytes by MLTC using tumor cells genetically modified to secrete interleukin-2.

The in vitro generation of effector lymphocytes cytotoxic to cancer cells, was investigated with a mixed lymphocyte-tumor culture (MLTC) system using genetically modified human cancer cells, followed by stimulation with the interleukin (IL)-2 plus immobilized anti-CD3 antibody (IL-2/CD3) system. A gastric cancer cell line, GC022588 (HLA-A2, 24, B35, 55, C1,3), was retrovirally transduced with the human interleukin (IL)-2 gene (GC/IL-2) or the neomycin-resistance gene (GC/Neo). The secretion of biologically active IL-2 was detectable in GC/IL-2 cells but not in GC/Neo or parental GC022588 cells. The cytotoxic activity against the parental GC022588 cells of peripheral blood mononuclear cells (PBMC) was greater among PBMC activated with MLTC using GC/IL-2 than among those activated with MLTC using GC/Neo or without MLTC. The IL-2/CD3 stimulation could efficiently expand the effector lymphocytes without any reduction of the cytotoxic activity generated. The cytotoxic activity generated by this system was reproducible in several HLA-A2- or A24-positive donors. The effector lymphocytes could kill the other adenocarcinoma cells expressing HLA-A2 or A24. The phenotypes of the effector lymphocytes generated with the system were 40% CD4+ and 70% CD8+. Both phenotypes may have been responsible for the cytotoxicity. The removal of adherent cells from PBMC before the MLTC did not affect the generation of cytotoxicity, whereas neutralization of tumor-derived IL-2 with a specific antibody during the MLTC significantly inhibited the generation of cytotoxicity. These results suggest that IL-2 gene-transduction augments the immunogenicity of the tumor cells that efficiently stimulate lymphocytes to be cytotoxic, and that the IL-2/CD3 system may be practical for the expansion of effector lymphocytes for use in adoptive immunotherapy for cancer. The mechanism by which IL-2 gene-modified tumor cells stimulate immune reactivity was discussed.

Adenocarcinoma↗