Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have demonstrated that pretreatment of mouse brain microvascular endothelial cells (MBE) with tumor necrosis factor-alpha (TNF), IL-1, or LPS augmented the binding of P815 mastocytoma cells in vitro. The effect of these agents was dose and time dependent. PMA was able to mimic the influence of these factors to a limited degree. The effect of TNF on endothelium was accompanied by the appearance of changes in the expression of proteins isolated from endothelial cell membranes. The adherence of tumor cells to endothelium was not inhibited by RGD-containing peptides but could be decreased by preincubation of endothelium with high concentrations of FCS. Our data suggest that cytokines regulate the synthesis of endothelial adhesion proteins which may be involved in tumor cell adherence leading to metastasis. These results raise the possibility that cytokines may exert paradoxical effects in vivo, i.e., a cytotoxic effect that reduces tumor mass accompanied by a metastasis-enhancing effect that actually promotes dissemination of the remaining tumor cells. Definition of the molecular events involved in tumor cell-endothelial cell interactions may lead to strategies for minimizing the latter effect in therapeutic settings.
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PMID:Effect of inflammatory cytokines on the adherence of tumor cells to endothelium in a murine model. 190 52

Monoclonal antibodies (MAbs) which recognize a human tumor antigen, termed tumor-associated glycoprotein-72 (TAG-72), have successfully been used to localize primary as well as metastatic colorectal tumor lesions in patients. The localization of the anti-TAG-72 MAbs has also been exploited intraoperatively using a hand-held gamma probe. That procedure, termed radioimmunoguided surgery (RIGS), has identified occult tumors which were not detected using standard external imaging techniques. In another clinical trial, interferon-gamma (IFN-gamma) was administered intraperitoneally to patients diagnosed with either gastrointestinal or ovarian carcinoma with secondary ascites. Analysis of the tumor cells isolated from the malignant ascites revealed a substantial increase in TAG-72 expression on the surface of tumor cells isolated from seven of eight patients. The results provide evidence that the combination of an anti-carcinoma MAb with the administration of a cytokine, such as IFN-gamma, may be an effective approach for the detection and subsequent treatment, of colorectal carcinoma.
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PMID:Applications of monoclonal antibodies and recombinant cytokines for the treatment of human colorectal and other carcinomas. 190 69

Two differently timed extracellular and intracellular enzymatic and mRNA peaks of tissue-type plasminogen activator (t-PA) were induced following ionizing radiation. The first peak appeared within 10 min following X-irradiation but rapidly declined. The appearance of early t-PA mRNA transcripts and enzymatic activity were not prevented by actinomycin D treatment. In contrast, cycloheximide prevented the early, minor enzymatic induction peak of t-PA. Stabilization of t-PA mRNA transcripts appears to be an early initial response of human cells to ionizing radiation, since the synthesis of new mRNA transcripts within the first 30 min was not observed via nuclear run-on analyses. Nearly 12 h following X-irradiation, a second major enzymatic peak of t-PA was observed. Cycloheximide or actinomycin D treatments blocked the later t-PA response. t-PA mRNA levels were induced greater than 100-fold in 4 h by ionizing radiation as assayed via Northern or nuclear run-on analyses. During the major induction period, t-PA mRNA transcripts reached their maximum levels at 4-8 h, and intracellular enzyme levels accumulated 6-8 h after X-irradiation. Unirradiated U1-Mel cells demonstrated only low basal levels of t-PA mRNA and enzymatic activity. Similar induction responses were found following UV-irradiation or 12-O-tetradecanoyl-phorbol-13-acetate (PMA) treatments. Normal human fibroblast (i.e., GM 2936B, GM2907A, and IMR-90) cells also demonstrated the induction of t-PA, although only one later enzymatic peak was detected. The induction of t-PA mRNA levels and intracellular and extracellular enzymatic activities for these cells were 50-fold lower than with U1-Mel cells given equitoxic doses of X-rays. Differential expression of t-PA in some tumor as compared to normal tissues may be utilized in future chemotherapeutic regimens.
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PMID:Induction of tissue-type plasminogen activator by ionizing radiation in human malignant melanoma cells. 191 77

Gelatinases (type IV collagenases) produced by normal peripheral blood leukocytes were studied by the use of a substrate conversion assay. When monocytes were stimulated with IL-1 beta discrete amounts of a 85-kDa gelatinase were detected. This type of gelatinase comigrated with a phorbol ester-inducible metalloproteinase from human tumor cells. The levels of induction of the monocytic enzyme after stimulation with IL-1, double-stranded RNA, LPS, and mitogens paralleled those of the secondary cytokine IL-6. When peripheral blood neutrophils were stimulated with IL-8 or PMA significant amounts of a 91-kDa neutrophil gelatinase were released, whereas with IL-1 beta no effect was observed. Both neutrophil and monocyte gelatinases cross-reacted in immunoprecipitation experiments with tumor cell-derived gelatinases. Further evidence for structural similarity between the IL-1-inducible monocytic (85 kDa) and the IL-8-regulated neutrophilic (91 kDa) gelatinases was obtained after purification of the proteins to homogeneity: both gelatinases possessed an identical amino terminal amino acid sequence and appeared as truncated forms of gelatinase from tumor cells. Synovial fluids of arthritic joints contained extremely high concentrations of the 91-kDa gelatinase. The concentrations of this type of gelatinase were correlated with the titers of the marker cytokine IL-6. The controlled production and activity of leukocyte-derived gelatinase may play an essential role in local proteolysis of the extracellular matrix and in leukocyte migration. In the arthritis patient this enzyme might contribute to the pathogenesis of joint destruction and might constitute a useful marker of disease status.
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PMID:Cytokine-mediated regulation of human leukocyte gelatinases and role in arthritis. 193 76

Fluorescence recovery after photobleaching (FRAP) has been used previously to investigate the kinetics of binding to biological surfaces. The present study adapts and further develops this technique for the quantification of mass transport and reaction parameters in bulk media. The technique's ability to obtain the bulk diffusion coefficient, concentration of binding sites, and equilibrium binding constant for ligand/receptor interactions in the reaction limited binding regime is assessed using the B72.3/TAG-72 monoclonal antibody/tumor associated antigen interaction as a model in vitro system. Measurements were independently verified using fluorometry. The bulk diffusion coefficient, concentration of binding sites and equilibrium binding constant for the system investigated were 6.1 +/- 1.1 x 10(-7) cm2/s, 4.4 +/- 0.6 x 10(-7) M, and 2.5 +/- 1.6 x 10(7) M-1, respectively. Model robustness and the applicability of the technique for in vivo quantification of mass transport and reaction parameters are addressed. With a suitable animal model, it is believed that this technique is capable of quantifying mass transport and reaction parameters in vivo.
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PMID:Measurement of mass transport and reaction parameters in bulk solution using photobleaching. Reaction limited binding regime. 193 50

Eighty-two patients diagnosed with gastrointestinal (GI) adenocarcinoma were evaluated before and for 26 months after primary tumor resection for the presence of two serum tumor markers: tumor-associated glycoprotein-72 (TAG-72) and carcinoembryonic antigen (CEA). Elevated TAG-72 and CEA serum levels were found preoperatively in 32 (39%) and 34 (41.5%) of the 82 patients, respectively. The percentage of patients with elevated serum levels of either TAG-72 or CEA was 56.1% (46 of 82). Twelve (15%) patients who had normal CEA serum levels had elevated TAG-72 serum levels, and conversely, serum from 14 (17%) patients who were TAG-72 negative were CEA positive. Forty-five of the 82 patients were diagnosed with advanced disease (i.e., Stages C and D for colorectal, Stages III and IV for stomach), and 29 (64.4%) and 26 (57.8%) of those patients had elevated serum levels of TAG-72 or CEA, respectively. Elevated levels of either TAG-72 or CEA, however, were found in sera of 82.2% of patients with advanced GI cancer, which is an increase of 24.4% over the use of CEA antigen alone as a marker of disease. The measurement of both TAG-72 and CEA may improve the diagnosis of patients with GI malignant disease due to the apparent complementary association which exists between these tumor markers. Serum TAG-72 and CEA levels were monitored in 31 patients for varying lengths of time after resection of the carcinoma; 11 patients developed recurrent disease. Sera from nine of 11 (81.8%) of these patients had elevated TAG-72 levels and six of 11 (54.5%) had elevated CEA levels. Tumor marker elevations were observed either before (35 to 166 days) or at the time of diagnosis of recurrence. The elevation of one or both markers correlated with the clinical status in ten of 11 (90.9%) patients with recurrence. In addition, 20 patients who were clinically free of disease after more than 700 days' follow-up had normal serum levels of both TAG-72 and CEA. These findings suggest that the combined use of serum TAG-72 and CEA measurements may improve detection of recurrence in patients with GI cancer and may be useful in the postsurgical management of GI adenocarcinoma patients.
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PMID:Tumor-associated glycoprotein-72 serum levels complement carcinoembryonic antigen levels in monitoring patients with gastrointestinal carcinoma. A longitudinal study. 193 81

CC49 is a "second generation" monoclonal antibody to B72.3, which reacts with the pancarcinoma antigen TAG-72. CC49 has been shown to efficiently target human colon carcinoma xenografts and is currently being evaluated in both diagnostic and therapeutic clinical trials. We describe here the construction and characterization of a recombinant single-chain Fv (sFv) of CC49. The sFv was shown to be a Mr 27,000 homogeneous entity which could be efficiently radiolabeled with 125I or 131I. Comparative direct binding studies and competition radioimmunoassays using CC49 intact IgG, F(ab')2, Fab', and sFv revealed that the monomeric CC49 Fab' and sFv had relative binding affinities 8-fold lower than the dimeric F(ab')2 and intact IgG. Nonetheless, the 131I-labeled sFv was shown to bind biopsies of TAG-72-expressing tumors. Metabolism studies in mice, using radiolabeled CC49 IgG, F(ab')2, Fab', and sFv, demonstrated an extremely rapid plasma and whole body clearance for the sFv. CC49 sFv plasma pharmacokinetic studies in rhesus monkeys also showed a very rapid plasma clearance (T1/2 alpha of 3.9 min and T1/2 beta of 4.2 h). Tumor targeting studies with all four radiolabeled Ig CC49 forms, using the LS-174T human colon carcinoma xenograft model, revealed a much lower percentage injected dose/g tumor binding for the CC49 monomeric sFv and Fab' as compared to the dimeric F(ab')2 and intact IgG. However, tumor:normal tissue ratios (radiolocalization indices) for the sFv were comparable to or greater than those of the other Ig forms. High kidney uptake with 125I-labeled Fab' and F(ab')2 was not seen with 125I-sFv. Gamma scanning studies also showed that 131I-CC49 sFv could efficiently localize tumors. The CC49 sFv may thus have utility in diagnostic and perhaps therapeutic applications for a range of human carcinomas.
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PMID:Construction, binding properties, metabolism, and tumor targeting of a single-chain Fv derived from the pancarcinoma monoclonal antibody CC49. 193 99

The ongoing development of monoclonal antibody technology may eventually lead to the selective targeting of human carcinoma lesions of MoAbs conjugated with a variety of cytotoxic agents (i.e. radionuclides, drugs, etc.). The antigen phenotype of the carcinoma cell will play an important role in the efficacy of the MoAbs. Clearly, the human tumor antigens that are expressed on all carcinoma cells and with a high antigen density should provide the optimal target for the MoAbs. More often, however, the human tumor antigens whose expression is highly selective for human tumor cells will also exhibit a certain degree of heterogeneity. Therefore, the ability of a cytokine, such as interferon or 8-Cl-cAMP, to augment the level of expression of human tumor antigens such as TAG-72 and CEA, may play an important role in an adjuvant setting for immunoscintigraphy and/or immunotherapy. Further research will focus on experimental model system as well as clinical trials to determine whether human recombinant interferon administered with an anti-carcinoma MoAb will be an effective combination to enhance tumor detection and/or therapy. It is conceivable that in subsequent years effective approaches of treating malignancies may include a new combination of biological/immunological therapy based on the biology of the tumor cell population.
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PMID:Regulation of human tumor antigen expression by biological response modifiers (BRMs). 195 31

Mycobacterial antigens not only stimulate Th cells that produce macrophage-activating factors, but also CD4+ and CD8+ CTL that lyse human macrophages. The mycobacterial recombinant 65-kD hsp was previously found to be an important target antigen for polyclonal CD4+ CTL. Because of the major role of 65-kD hsp in the immune response to mycobacterial as well as autoantigens, we have studied CTL activity to this protein at the clonal level. HLA-DR or HLA-DQ restricted, CD4+CD8- T cell clones that recognize different peptides of the M. leprae 65-kD hsp strongly lysed EBV-BLCL pulsed with specific but not irrelevant peptide. No bystander lysis of B cells, T cells, or tumor cells was seen. Target cell lysis could not be triggered by PMA + Ca2+ ionophore alone and depended on active metabolism. Interestingly, these CD4+ CTL also strongly lysed themselves and other HLA-class II compatible CD4+ (TCR-alpha/beta or -gamma/delta) or CD8+ CTL clones in the presence of peptide, suggesting that CTL are not actively protected from CTL-mediated lysis. Cold target competition experiments suggested that EBV-BLCL targets were more efficiently recognized than CD4+ CTL targets. These results demonstrate that hsp65 peptide-specific HLA class II-restricted CD4+ T cell clones display strong peptide-dependent cytolytic activity towards both APCs, and, unexpectedly, CD4+ and CD8+ CTL clones, including themselves. Since, in contrast to murine T cells human T cells express class II, CTL-mediated T cell killing may represent a novel immunoregulatory pathway in man.
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PMID:Specific killing of cytotoxic T cells and antigen-presenting cells by CD4+ cytotoxic T cell clones. A novel potentially immunoregulatory T-T cell interaction in man. 197 78

Differentiation between primary colonic adenocarcinoma arising in flat mucosa and carcinoma metastatic to the colon is often difficult. Examination of the mucosa adjacent to the tumor, the so-called transitional mucosa (TM), may be helpful. The morphologic, ultrastructural, and histochemical characteristics of the TM have been reported previously in detail. In this study the morphologic and immunohistochemical characteristics of the TM have been compared in 18 cases of primary colonic adenocarcinoma and 13 cases of metastasis to the colon. Five immunophenotypic markers were used: carcinoembryonic antigen (CEA), Lewis (x) and (y) blood group antigens, ras oncogene p21, and tumor-associated glycoprotein (TAG-72). Neoplastic transformation of colonic epithelium is associated with altered expression of these antigens. The morphologic and immunohistochemical profile of the TM was similar in both primary colonic adenocarcinomas and metastases to the colon. In some cases the TM adjacent to colonic metastases stained with one or more antibodies while the metastatic tumor was negative. Therefore, in cases where differentiation between primary colonic adenocarcinoma arising in flat mucosa and metastasis is difficult, the use of these reagents, particularly CEA, TAG-72, or ras oncogene p21, may be helpful. The similar immunohistochemical staining pattern of the TM in both primary and metastatic colon lesions supports a reactive, non-neoplastic origin of the TM. Furthermore, expression of these antigens is not limited to neoplastic epithelial cells.
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PMID:Role of the transitional mucosa of the colon in differentiating primary adenocarcinoma from carcinomas metastatic to the colon. An immunohistochemical study. 198 61


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