Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor-infiltrating lymphocytes from 120 samples of human cancers, including melanoma, renal cell carcinoma, breast cancer, sarcoma, and colon cancer, were examined. The percentage of lymphocytes recovered from the cancer varied widely; that of renal cell carcinoma was higher than that of breast or colon cancer (65% vs 45%), which was higher than that of melanomas or sarcomas (30% to 35%). The types of lymphocytes before and after interleukin 2 activation showed specific patterns. CD4+ helper T cells predominated in all tumors except melanomas, which had more CD8+ cytotoxic T cells. CD16+ natural killer cells were recovered in renal cell carcinoma and sarcomas. Three different cytotoxic lymphocytes were identified among interleukin 2-activated tumor-infiltrating lymphocytes: (1) CD3+ CD16- cytotoxic T lymphocytes with cytotoxicity restricted to autologous tumor cells in melanomas, (2) CD3-CD16+ natural killer cells with vigorous major histocompatibility complex-nonrestricted cytotoxicity in renal cell carcinoma, and (3) CD3+ CD16- T cells with modest levels of major histocompatibility complex-nonstricted cytotoxicity in all cancers except melanomas. Thus, there was considerable diversity of tumor-infiltrating lymphocytes among these histologically distinct tumors with respect to magnitude of lymphocyte infiltration, phenotypic expression, and functional capacity.
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PMID:Patterns of human tumor-infiltrating lymphocytes in 120 human cancers. 168 43

In order to improve therapeutic efficacy for metastatic liver cancer, intermittent transarterial administration of BRM in combination with anticancer drugs was performed by use of reservoir apparatus. A total of 22 patients (12 cases of gastric cancer, 6 of colon cancer, 2 of pancreas cancer, 1 of gall bladder cancer and 1 of biliary tract carcinoid) were treated according to the following schedule: both 10 mg of ADM (or MMC) and 0.5 KE (or 1.0 KE) of OK-432 were administered on day 1 and 40 x 10(4) JRU of recombinant interleukin 2 (r-IL 2) on day 4, 7 and 11. The treatment was repeated as many times as possible. In terms of direct antitumor effect and decrease of tumor marker, the response rate was 43% (6 cases out of 14) and 75% (9 cases out of 12), respectively. As for performance status, improvement, no change and deterioration were seen in 4 cases, 8 cases and 3 cases, respectively. Even though 13 patients died, 8 of them survived more than 300 days. In the case of gastric cancer patients with liver metastasis, 50% survival time of 12 cases was 334 days, while that of 30 cases, who were administered anticancer drugs only systemically, was 144 days. In 3 cases the decrease in the size of tumors located in both liver and the other metastases also was seen. Every case developed high grade fever, but an antifebrile was effective. Otherwise severe side effects were not seen. These results indicated that intermittent arterial infusion immunochemotherapy was feasible for the treatment of metastatic liver cancer.
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PMID:[Therapeutic effect of transarterial infusion immunochemotherapy for metastatic liver cancer]. 190 65

Murine monoclonal antibodies (MAB) of the IgG3 subclass generated to colorectal tumor-associated glycolipids were assessed for enhancement of antibody-dependent cell-mediated cytotoxicity (ADCC) by interleukin 2 (IL-2). Mononuclear cell preparations containing large granular lymphocyte effectors required only low doses of IL-2 (0.1-10 units/ml) and short exposure (3 h) for maximal enhancement of ADCC. Exposure of mononuclear cells for longer periods (1-6 days) to higher levels of IL-2 (100-1000 units/ml) resulted in the generation of lymphokine-activated killer N cells which were lytically active without antibody. A non-ADCC MAB of the IgG1 subclass showed no ADCC even after stimulation of effector cells with IL-2. Effector cells pretreated with IL-2 showed an enhanced rate of cytolysis of target cells in the presence of antibody. Pretreatment of effector cells with IgG3 MAB resulted in lower ADCC, but pretreatment of target cells or simultaneous addition of MAB and effectors to target cells gave higher levels. These results indicated that ADCC with murine IgG3 is enhanced by levels of IL-2 achievable in current patient trials. The combination of antibody and IL-2-boosted effector cells gives comparable levels of killing to lymphokine-activated killer cells but should not suffer from similar toxicity. The NR-Co-04 antibody in combination with lymphokine may prove effective in treating colon cancer, a disease for which both chemotherapeutic and current biological therapies suggest a need for improved forms of therapies.
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PMID:Murine monoclonal IgG3 to human colorectal tumor-associated antigens: enhancement of antibody-dependent cell-mediated cytotoxicity by interleukin 2. 278 37

Activated killer cells are generated by the incubation of peripheral blood mononuclear leukocytes (PBL) in the lymphokine interleukin 2 (IL-2). Unseparated populations of these lymphokine-activated killer (LAK) cells lyse a variety of fresh noncultured human tumor targets, but they do not kill normal PBL. This study analyzed the generation and lytic specificity of LAK cell clones. Of 49 (84%) clones isolated by limiting-dilution techniques from a whole population of LAK cells, 41 manifested significant LAK cell activity. LAK cell clones had varied cell surface phenotypes. Clones with high and intermediate LAK cell activity were Leu 2+3-4+7-DR+Tac+ and Leu 2-3+4+7-DR+Tac+, respectively. Single LAK cell clones lysed multiple fresh human tumor targets including autologous sarcoma, 5 allogeneic sarcomas, and a colon cancer in addition to the cultured cell line K562. Autologous PBL were not lysed. Tumor targets were each lysed by multiple LAK cell clones. Sixteen subclones were derived from 5 of these LAK cell clones. These subclones had 99% or greater probability of being derived from a single cell. These subclones also exhibited lysis of multiple tumor targets. These findings suggest the existence of a shared determinant, expressed by multiple human tumors, which is recognized in common by multiple LAK cell clones.
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PMID:Lymphokine-activated killer (LAK) cell phenomenon. IV. Lysis by LAK cell clones of fresh human tumor cells from autologous and multiple allogeneic tumors. 298 4

The colon cancer cell line, HT29, produces a soluble substance (HT29 factor) that blocks mitogen-induced T cell proliferation and the production of interleukin 2 (IL 2). Inhibition of T cell proliferation by the HT29 factor is reversible and is not due to a decline in cell viability or an alteration in the kinetics of T cell proliferation. It occurs even when the HT29 factor is added only 24 hr before terminating the T cell cultures, indicating that the factor affects cell division after activation of T cells has already occurred. No inhibitory activity was found in medium conditioned by human colonic epithelial cells or fibroblasts. The factor has an apparent m.w. of 56,000 and an isoelectric point of 7.9. It is sensitive to endopeptidases, heating to 56 degrees C, and extremes of pH. The HT29 factor also suppresses IL 2 production by T cells. However, low IL 2 availability alone cannot account for the suppressive effect of the factor on T cell proliferation, because the addition of exogenous IL 2 does not reverse the inhibition. This block in IL 2 responsiveness is not primarily due to a decrease in IL 2 receptors because Tac expression on activated T cells is minimally decreased during a 24-hr exposure to the HT29 factor. In addition, IL 2-induced proliferation of mitogen-activated T cells is inhibited only slightly by the HT29 factor, indicating that a block in the interaction of IL 2 with its receptor is not its main mechanism of action. Thus the inhibition of T cell proliferation is likely to be due primarily to a mechanism independent of IL 2.
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PMID:Characterization of an immunosuppressive factor derived from colon cancer cells. 310 53

Adoptive immunotherapy with interleukin 2 (IL-2) and lymphokine-activated killer (LAK) cells (IL-2/LAK) is a technically demanding cancer therapy dependent upon large scale isolation and culture of lymphocytes. An important question is whether this technology can be accomplished routinely outside of highly specialized centers. In addition, no systematic examination of laboratory correlates of IL-2/LAK therapy in humans has been reported to date. The objectives of this report are to address two issues relevant to IL-2/LAK therapy. (a) Can IL-2/LAK therapy be accomplished outside of previously identified centers of expertise? (b) What are the relevant laboratory/clinical parameter correlations? The six institutions in the National Cancer Institute extramural trial treated 83 evaluable patients with renal cancer, malignant melanoma, or colon cancer with IL-2/LAK by a uniform protocol. Patients received 5 days of IL-2 priming, then daily leukaphereses for 5 days starting 48 h after IL-2 to harvest cells. Mononuclear cells were isolated, then cultured in roller bottles in 1-liter aliquots for 3 to 4 days at a cell density of 1.5 x 10(6) per ml with recombinant IL-2, 1500 units per ml. Cells were harvested and administered to patients with additional IL-2. Administration of IL-2 regularly induced lymphopenia and rebound lymphocytosis. Leukapheresis yields and numbers of LAK cells generated in culture and reinfused into patients correlated directly with peak lymphocyte counts achieved by IL-2 administration. Mean mononuclear cell recovery per 5 days of leukapheresis (+/- SEM) was 14.3 +/- 0.8 x 10(10). Average volume of cells cultured per patient was 95 liters (range, 41 to 235). Mean yield of cells harvested from cultures was 53%. Mean total number of LAK cells infused per patient was 7.6 +/- 0.4 x 10(10) (range, 2 to 15.2 x 10(10]. LAK activity was measured in vitro by lysis of 51Cr-labeled natural killer-resistant Daudi and fresh tumor targets. LAK effector cells regularly lysed these targets in vitro. Neither tumor reduction nor clinical toxicity correlated with dose or with cytolytic activity of LAK cells, or with other laboratory parameters including base-line lymphocyte count and IL-2-induced lymphocytosis. We conclude: (a) large quantities of LAK effector cells with tumoricidal activity can be generated routinely at different centers; (b) neither in vitro LAK activity nor numbers of LAK cells infused were predictive of clinical efficacy or toxicity. There is a need to identify other laboratory or clinical parameters more predictive of IL-2/LAK therapeutic efficacy or toxicity.
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PMID:Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans. 326 May 37

Patients with colorectal cancer respond poorly to in vivo immunotherapy with lymphokine-activated killer (LAK) cells generated from peripheral blood mononuclear cells (PBMC). We postulated that gut-derived immune cells could be a more relevant source of LAK cells directed against colorectal cancer. Intestinal lamina propria mononuclear cells (LPMC) and colonic adenocarcinoma cells were isolated from operative specimens by combination of mechanical and enzymatic dissociation methods. LAK cells were generated by culturing PBMC and LPMC with recombinant interleukin 2 (IL2), with and without OKT3 monoclonal antibody, in short- (4 days) and long-term (21 days) cultures. Other cultured tumor cells, normal intestinal fibroblasts, and hapten-modified autologous LPMC were used as control targets. Cytotoxicity was measured by a 4-hr 51Cr release assay. Short-term cultured LAK cells exhibited a strong to moderate degree of killing against normal intestinal fibroblasts, hapten-modified self cells, and four different tumor cell lines. Instead, fresh colon cancer cells were resistant to cytotoxicity, regardless of their degree of histologic differentiation and the autologous or allogeneic nature of the LAK cells. Long-term culture with IL2 remarkably increased LAK cell activity against all tumor targets, but not against colonic adenocarcinoma cells. The results of this study, showing that freshly isolated colon cancer cells are intrinsically resistant in vitro to highly activated cytotoxic effector cells, may explain the poor clinical results observed in human trials with in vivo administration of IL2 or LAK cells.
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PMID:Lymphokine-activated killer (LAK) cells from human intestinal mucosa: cytotoxic activity against tumor cell lines and modified self but not autologous and allogeneic colon cancer cells. 336 87

The mouse monoclonal antibody, m30.6 (IgG2b), detects an antigenic determinant expressed predominantly on the surface of colorectal adenocarcinoma cells and has been shown previously to be a potentially useful therapeutic and diagnostic reagent for human colon cancer. We report the production and characterization of a mouse/human chimeric antibody, c30.6, with potent in vitro and in vivo antitumor activity. The genes encoding the variable domains for heavy and light chains were amplified by thermal cycling using degenerate oligonucleotide primers complementary to conserved immunoglobulin framework sequences. The gene segments were sequenced, subcloned into eukaryotic expression vectors containing human constant region genes (IgG1 and kappa), and cotransfected into nonsecreting Sp2/0 mouse myeloma cells. There were significant differences in the biological activities of the murine and chimeric antibodies. The i.p. administration of c30.6 but not of m30.6 produced a marked growth inhibition of s.c. 30.6+ COLO 205 tumors in scid/scid mice (approximately 40% reduction in tumor size, measured 21 days after tumor inoculation). Reduced tumor growth was not due to altered binding characteristics of c30.6 because: (a) the chimeric antibody was shown by flow cytometry to bind exclusively to cell lines that expressed the 30.6 determinant; (b) c30.6 was able to completely inhibit the binding of m30.6 on 30.6+ cells; and (c) the affinity of binding of the two antibodies was the same (Ka, approximately 1.50 x 10(8)). Up to 15% of the total injected antibody dose/g tissue was localized in 30.6+ tumors at 24 h, approximately 13% was present in the tumors at 48 h, and approximately 10% was present at 72 h. Furthermore, c30.6 demonstrated a shorter circulating half-life (53 h; m30.6, 72 h) when given i.p. to C57BL6 x BALB/cF1 mice. Unlike m30.6, c30.6 was also strongly active in antibody-dependent cell-mediated cytotoxicity against a range of 30.6+ tumor target cells in vitro. Up to 80% specific 51Cr release was achieved using either freshly isolated human peripheral blood mononuclear cells or 2-day-old interleukin 2-stimulated human peripheral blood mononuclear cells as effectors. The enhanced antitumor activity of c30.6 suggests that it might be a useful immunotherapeutic reagent for colorectal carcinoma.
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PMID:Chimeric (mouse/human) anti-colon cancer antibody c30.6 inhibits the growth of human colorectal cancer xenografts in scid/scid mice. 795 62

To ascertain whether the tumor cells can regulate the host immune systems through the production of the cytokines or their receptors, we examined the expressions of tumor necrosis factor alpha (TNF alpha), tumor necrosis factor beta (TNF beta), interleukin 2 (IL-2) and interleukin 2 receptor alpha chain (IL-2R alpha) on the human cancer cell lines by Northern blot analysis. We used K562 (leukemia cell line), MCF-7 (breast cancer cell line), LS180, HT29 (colon cancer cell lines), SH101 (gastric cancer cell line) and PH101 (pancreas cancer cell line). Expressions of TNF alpha, TNF beta and IL-2 mRNA were not detected in any of the tumor cell lines. However, 1.4 and 3.5 kilobases of the IL-2R alpha mRNA were expressed in the PH101 cells, but not in the other five cell lines. Furthermore, IL-2R alpha was detected on the cell surface of the PH101 cells by the flow-cytometric analysis with an anti-IL-2R alpha monoclonal antibody. Interestingly, the soluble IL-2R alpha (sIL-2R alpha) was found in the conditioned media obtained from the PH101 cell culture with a sandwich enzyme immunoassay. Moreover, the sIL-2R alpha secreted from the PH101 cells blocked the IL-2 dependent lymphocyte proliferation. These results indicate that the expression of IL-2R alpha on PH101 might suppress the IL-2 induced lymphocyte proliferation.
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PMID:The expression and biological activity of IL-2 receptor on a human pancreas cancer cell line. 850 43

A recombinant humanized antibody-interleukin 2 fusion protein (huKS1/4-IL-2) was used to direct IL-2 to the tumor microenvironment and elicit a T cell-mediated eradication of established pulmonary and hepatic CT26-KSA colon carcinoma metastases in syngeneic BALB/c mice. This antitumor effect was specific because a fusion protein, which was nonreactive with these tumor cells, failed to exert any such effect. The efficacy of the huKS1/4-IL-2 fusion protein in eliminating metastases was documented because mixtures of monoclonal antibody huKS1/4 with recombinant human IL-2 were ineffective and, at best, only partially reduced tumor load. Two lines of evidence indicated the eradication of metastases and the absence of minimal residual disease in animals treated with the fusion protein: first, the lack of detection of CT26-KSA cells by reverse transcription-PCR, which can detect one tumor cell in 10(6) liver cells; and second, the tripling of life span. The effector mechanism involved in this tumor eradication is dependent on T cells because the IL-2-directed therapy is ineffective in T cell-deficient SCID mice. The essential effector cells were further characterized as CD8+ T cells by in vivo depletion studies. Such T cells, isolated from tumor-bearing mice after fusion protein therapy, elicited MHC class I-restricted cytotoxicity in vitro against colon carcinoma target cells. Taken together, these data indicate that fusion protein-directed IL-2 therapy induces a T cell-dependent host immune response capable of eradicating established colon cancer metastases in an animal tumor model.
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PMID:Elimination of established murine colon carcinoma metastases by antibody-interleukin 2 fusion protein therapy. 935 62


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