Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Generation of cytotoxic effector lymphocytes by MLTC using tumor cells genetically modified to secrete interleukin-2. 1129 24

We have established a practical system for generating antitumor effector lymphocytes using the tumor antigen peptide CEA and cultured dendritic cells (DCs), and have also characterized effector cells. DCs were induced from the adherent cell population of autologous peripheral blood mononuclear cells (PBMCs) obtained from HLA-A0201 normal or tumor-bearing donors using IL-4 and GM-CSF. The cultured DCs were shown to express class I, class II, CD80 and CD86 molecules. The PBMCs were stimulated for 7 days with the DCs pulsed with the HLA-A0201-restricted CEA peptide CEA9 671 and then expanded in an anti-CD3 antibody (1 microgram/ml)-coated flask in the presence of a 80 U/ml IL-2 (IL-2/CD3 system). The effector cells, which were designated as CEA peptide-pulsed dendritic cell-activated killer (CEA-PDAK) cells, were preferentially CD3+CD8+, and capable of killing T2 cells pulsed with CEA peptide but not T2 cells alone. The CA-PDAK cells also lysed the gastric cancer cell line KATO III (HLA-A0201, CEA (+)), but not the WiDr (HLA-A2402, CEA(+)) cells. The cytotoxicity was abrogated when the CEA-PDAK cells were treated with anti-TCR alpha beta antibody or when the target cells were treated with the anti-class I antibody prior to the cytotoxicity assay. The CEA-PDAK cells exerted their cytotoxic activity even in the presence of a high amount of CEA protein at the effector phase, which mimicked the clinical setting. The CEA-PDAK cells showed approximately a hundred-fold expansion in total cell numbers yielded without any loss of the specific lysis, when stimulated with the IL-2/CD3 system compared to those stimulated with IL-2 alone. The TCR V beta gene analysis for the CEA-PDAK cells, conducted by means of RT-PCR-Southern blotting, demonstrated oligoclonal expression of TCR beta 7 and 12, and the latter was shown to be responsible for the killing activity. SSCP analysis indicated the clonotype of the TCR V beta 12 gene, indicating a selective expansion of lymphocytes bearing a limited TCR variable region by the stimulation with CEA peptide-pulsed DCs. Taken together, the effector lymphocytes reactive with the CEA antigen can be generated from PBMCs with the antigenic CEA peptide and cultured DCs. The IL-2/CD3 system is effective and practical in activating the effector cells for the clinical use of CEA-PDAK cells. Adoptive immunotherapy using this system may be promising for treating CEA-expressing tumors.
 ...
PMID:Novel system for generating cytotoxic effector lymphocytes using carcinoembryonic antigen (CEA) peptide and cultured dendritic cells. 1252 70

Cell-mediated immunodeficiency is known to occur in advanced cancer patients, but it is less characterized in earlier stages. Pre-existing immunodeficiency may impair the recovery of postoperative lymphocytopenia, occurring generally within 8-14 days after surgical stress. This study was aimed to verify whether immunodeficiency exists in patients with operable gastric adenocarcinoma and whether radical surgery may restore a count of peripheral blood T helper cells (CD4) and CD4/CD8 ratio within physiological normal values in the late postoperative period. Thirty-five consecutive patients (M/F 18/17; mean age 67 years, range 42-82) with histologically proven gastric adenocarcinoma, undergoing surgery with radical intent, were studied. Assessment of total lymphocyte count and lymphocyte subsets was performed by FAC scan at baseline, then postoperatively 14 and 50 days after surgery. Normal reference values were according to CDC criteria for HIV immunodeficiency (total lymphocyte > 1500/mmc; CD4 cells > 500/mmc; CD4/CD8 > 1.2). Surgical interventions, including D2 locoregional lymphadenectomy, were as follows: 19 Roux Y total gastrectomies; 3 Roux Y subtotal gastrectomies and 13 Billroth II subtotal gastrectomies. Pathological nodal staging was pN0 in 18 and pN+ in 17 cases. Hystotype was intestinal in 14 patients, diffuse in 14 and unclassifiable in 7. Grading was G1 n = 7; G2 n = 7; G3 n = 21. Lymphocyte immunodeficiency was found at baseline in 41% of patients and at 14 days after surgery in 67% of patients. Recovery of postoperative surgery-induced lymphocytopenia occurred on the 50th day only in those patients with normal values at baseline (59%). CD4 deficiency was significantly more frequent in pN+ vs. pN0 patients, either at baseline (p < 0.001 ), on the 14th day (p < 0.02) and on the 50th day (p < 0.007) postoperatively. Cancer-related CD4 deficiency was a frequent finding in our consecutive series of gastric cancer patients; this systemic immune impairment was not restored after complete tumor removal, even in late postoperative period (50th day ). Further studies on a larger number of cases may confirm the prognostic value of lymphocyte count in early gastric cancer stages, and to verify whether early and late postoperative immunodeficiency may be prevented by IL-2 administration.
 ...
PMID:Radical surgery does not recover immunodeficiency associated with gastric cancer. 1286 67

Locoregional administration of the streptococcal preparation OK-432 is effective in treating malignant ascites from gastric cancer. In order to enhance the efficacy, we conducted a pilot study of locoregional immunotherapy for malignant ascites using host-oriented doses of OK-432. Moreover, action mechanisms of OK-432 were further explored in view of the T-helper type 1 (Th1)-Th2 concept. Gastric cancer patients with cytologically determined malignant ascites were locoregionally administered with OK-432. The dose of OK-432 was selected according to the delayed-type hypersensitivity (DTH) reaction levels to OK-432. Cytokine production profiles of ascites cells were determined using whole ascites assay by stimulation with OK-432. IL-10 mRNA expression was analyzed using RT-PCR. It was found that a positive clinical response was observed in 37 of the 51 (73%) patients with the DTH-oriented approach, showing a significantly higher efficacy than traditional dosage methods using empirical doses (31/58, 53%) (p=0.0487). The DTH-oriented administration of OK-432 produced adverse effects such as fever elevation (p<0.0001) and abdominal pain (p=0.0013) to a significantly lesser extent compared with the traditional treatment. Analysis of the action mechanism of OK-432 revealed that the DTH reaction in responders (19+/-6 mm) was stronger than that in non-responders (6+/-4 mm) (p<0.0001). Tumor necrosis factor (TNF)-alpha production of ascites cells was also higher in responders (3943+/-1247 pg/ml) than in non-responders (1217+/-939 pg/ml) (p=0.0002). There was a significant positive correlation (p=0.0085) between the levels of DTH reaction and TNF-alpha production of ascites cells, but not of blood cells. Responders appeared to polarize on the Th1 axis when clinical responses were plotted on Th1-Th2 dimensions according to the cytokine production profiles of TNF-alpha, IFN-gamma, IL-4 and IL-6 of ascites cells. In vitro culture with IL-2 of ascites cells after OK-432 administration demonstrated an almost clonal expansion of CD4+ lymphocytes, which produced TNF-alpha and IFN-gamma, but did not produce IL-4 or IL-6. IL-10 mRNA expression was detectable in ascites cells from non-responders before treatment. These results suggest that the DTH-oriented locoregional administration of OK-432 may be both effective and less toxic in treating malignant ascites from gastric cancer, showing a possibility of the tailored immunotherapy for malignant ascites. Th1 dysfunction exists in the microenvironment of malignant ascites from gastric cancer, in which IL-10 may, in part, play a role. The up-regulation of Th1 responses by OK-432 may result in positive clinical responses. The DTH reaction to OK-432 may be a useful tool not only for predicting clinical response but also for selecting the optimal dose of OK-432.
 ...
PMID:Locoregional immunotherapy of malignant ascites from gastric cancer using DTH-oriented doses of the streptococcal preparation OK-432: Treatment of Th1 dysfunction in the ascites microenvironment. 1501 Aug 36

Biological response modifiers (BRMs) augment the cytotoxic activity of various effector cells by the induction of multiple cytokines and suppression of immunosuppressive factors. BRMs are used extensively in adjuvant therapy for gastric cancer in Japan. In dendritic cell (DC)-based vaccine therapy, the quality of DCs is important in inducing strong antitumor immunity. A good manufacturing practice (GMP) grade agent for DCs maturation is desirable for safety. Here we report the effects of two BRMs, OK432 and PSK, which are GMP grade agents for the functional maturation of DCs. OK432 and PSK were examined in vitro, and compared with lipopolysaccharide (LPS) and a cytokine cocktail (IL-1beta, TNF-alpha, IL-6 and PGE2). In the immunophenotypical analysis, the expression of CD80 and CD83 of DCs stimulated with OK-432 increased significantly compared with PSK and medium, and this up-regulation was the same as levels of DCs stimulated with cytokine cocktail. DCs stimulated with OK-432 showed significantly higher production of IL-12 and Th1-type cytokines (IL-2 and IFN-gamma) compared with DCs stimulated with LPS or cytokine cocktail. OK-432 stimulated DCs could induce the significantly high level of cytotoxic T cell activity compared with PSK-stimulated or unstimulated DCs. These results suggest that OK432 is a GMP-grade reagent that promotes functional maturation of DCs and could be applied in DC-based vaccinations.
 ...
PMID:Usefulness of immunomodulators for maturation of dendritic cells. 1525 44

Cell-mediated immunodeficiency, with Total and T lymphocytes count decrease, is well established in cancer patients and it predicts a poor prognosis and poor survival rates. Furthermore, major surgery induces a transient immunodeficiency, too. Nevertheless, cell-mediated immunity in pancreatic cancer, which has a very poor prognosis, has not been completely outlined. Aim of this study is to evaluate the cell-mediated IL-2 dependent immune status in operable pancreatic cancer patients and to compare it with other gastrointestinal tumors. One hundred and twenty-one cancer patients (22 pancreatic, 48 gastric and 51 colorectal), with a median age of 66 years (range 42-83), 55 males and 66 females, were enrolled. Total lymphocyte count and lymphocytes subset (T helper count - CD4+) were assessed preoperatively and on the 14th and 50th postoperative day. Results obtained were compared between the groups and related to nodal involvement (N0 versus N+). Colorectal and gastric cancer patients showed quantitative lymphocyte deficiency at baseline in 29% and 41% of cases, respectively. Fourteen days after surgery values below normal range were found in 44% and 54% (Total) and 53% and 67% (T helper), respectively. Recovery of postoperative surgery-related lymphocytopenia occurred late only in patients with normal count at baseline. According to regional nodal involvement (pN0/N+) T helper deficiency was significantly more frequent in patients with nodal involvement than in patients without. In pancreatic cancer, percentage of immunodepressed patients at baseline was higher compared to the other two groups (71%). Lymphocyte count was significantly different between pancreatic and gastric/colorectal cancer, reaching a statistical significance at baseline and on the 14th and 50th postoperative day. No differences of T helper deficiency were noted according to nodal involvement (N0 versus N+) neither at baseline nor in the postoperative period. In conclusion, the degree of immunosuppression varies among different tumor types: since initial stages of disease, immunodepression was significantly greater in pancreatic cancer which should be considered always a systemic disease even in early stages and indipendently from the nodal involvement and from tumor load.
 ...
PMID:Immunodeficiency in different histotypes of radically operable gastrointestinal cancers. 1535 2

Peritoneal seeding is frequently detected in patients with gastric cancer. The peritoneal cavity is a compartment in which the immunologic host-tumor interaction can occur. Here, we investigated the gene expression levels of cytokines, and compared these gene expressions with the progression of gastric cancer. Total RNA was extracted from 50 ml of peritoneal washings from 78 patients with gastric cancer and 11 noncancerous patients. The gene expression levels of transforming growth factor-beta (TGF-beta), interleukin (IL)-2, IL-6 and IL-12 were analyzed by real-time reverse transcription-polymerase chain reaction. The gene expression levels of TGF-beta and IL-12 in 16 patients with peritoneal seeding (peritoneal metastasis or free cancer cells) did not differ from those in controls (n = 11) and stage I and II (n = 43) patients. However, the relative gene expression level of IL-2 in patients with peritoneal seeding (0.9) was lower than that in controls (1.4, p = 0.066) and stage I and II patients (1.4, p = 0.036). In contrast, the relative gene expression level of IL-6 in patients with peritoneal seeding (3.3) was higher than that in control (2.4, p = 0.064) and stage I and II patients (2.6, p = 0.065). Low IL-2 gene and high IL-6 gene expressions in the peritoneal cavity may correlate with cancer development in the peritoneal cavity in patients with gastric cancer.
 ...
PMID:Gene expression levels of cytokines in peritoneal washings from patients with gastric cancer. 1536 8

In tumor immunotherapy, there were several reports of attempts to induce anti-tumor immunity by fusion hybrid cells generated with dendritic and tumor cells. One of them reported that vaccination of hybrid cells resulted in a remarkable reduction of tumor cells in a lab mouse experiment. In our study, fusion cells were generated successfully with human matured dendritic and human gastric cancer cells by electrofusion technique and employed to induce CTLs. The evaluated fusion rate was 47.8% by FACS analysis. We tried to induce CTLs by co culture of effector and stimulator cells in the presence of IL-2, IL-7 and IL-12 for 4 weeks. Although it was not statistically significant in tumor cytotoxic assay, effector cells induced by the fusion cells as stimulator cells showed a few cytotoxic responses in an immunological tumor specific manner. Our data suggest that fusion hybrid cells may facilitate stimulation and expansion of tumor-specific T cells, but further investigation is required for clinical application of fusion cells in adoptive immunotherapy.
 ...
PMID:[Immunogenic reactivity of CTLs induced by electrofusion cells of human dendritic cells and gastric cancer cells]. 1555 19

There are only two isoforms of PDCD2 and MGC13096 containing PDCD2(C) domain in human genome. To study the role of PDCD2_C domain in apoptosis, the cDNAs of two isoforms of PDCD2 and MGC13096 were cloned. The RT-PCR products (AY948416, AY948417) of PDCD2 from RNA of human embryonic kidney 293T (HEK293T) and gastric cancer AGS cell line lost common 99 bp when compared with the sequences of NCBI database (NM_002598, NM_144781). The data of expression of PDCD2 and MGC13096 genes in HEK293T cells which induced to undergo apoptosis by various treatments suggested that there was no significant over-regulation of MGC13096 gene and the over-expression of PDCD2 gene did not occur universally. We searched GEO (Gene Expression Omnibus) about PDCD2 and MGC13096. PDCD2 (NM_002598) was over expressed when endothelial cells treated with leukotriene D4 or natural killer cells were activated by IL-2. Perhaps PDCD2_C domain is not universally associated with apoptosis, the function of PDCD2_C domain needs to be studied further.
 ...
PMID:Cloning of cDNAs with PDCD2(C) domain and their expressions during apoptosis of HEK293T cells. 1631 22

Helicobacter pylori infection is associated with gastritis, ulcers, and gastric cancer. The infection becomes chronic as the host response is unable to clear it. Gastric epithelial cells (GEC) play an important role during the host response, and their expression of class II MHC and costimulatory molecules such as CD80 and CD86 suggests their role in local Ag presentation. Although T cells are recruited to the infected gastric mucosa, they have been reported to be hyporesponsive. In this study, we detected the expression of B7-H1 (programmed death-1 ligand 1), a member of B7 family of proteins associated with T cell inhibition on GEC. Quantitative real-time RT-PCR revealed that B7-H1 expression increased significantly on GEC after H. pylori infection. Western blot analysis showed that B7-H1 expression was induced by various H. pylori strains and was independent of H. pylori virulence factors such as Cag, VacA, and Urease. The functional role of B7-H1 in the cross talk between GEC and T cells was assessed by coculturing GEC or H. pylori-infected GEC with CD4+ T cells isolated from peripheral blood. Using blocking Abs to B7-H1 revealed that B7-H1 was involved in the suppression of T cell proliferation and IL-2 synthesis, and thus suggested a role for B7-H1 on the epithelium as a contributor in the chronicity of H. pylori infection.
 ...
PMID:Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection. 1649 58


<< Previous 1 2 3 4 5 6 7 8 Next >>