Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The humoral interactions between three malignant glioma early-passage cell cultures and in vitro interleukin (IL)-1 alpha- and IL-2-activated autologous peripheral blood mononuclear cells (PBMC's) were investigated, employing standard and modified (separated by permeable membranes) mixed lymphocyte tumor cell (MLTC) cultures. In modified MLTC's, glioma cells clearly inhibit proliferation of PBMC's (up to 60%), whereas lymphokine-activated PBMC's enhance glioma cell growth up to 12-fold, as determined by 3H-thymidine incorporation assays. Glioma cells produce both stimulatory (IL-6) and inhibitory proteins (transforming growth factor-beta) for PBMC's. Lymphokine-activated PBMC's secrete IL-1 alpha, IL-2, IL-4, IL-6, interferon-gamma, and tumor necrosis factor-alpha, which may modulate glioma cell proliferation. None of these cytokines stimulated glioma cells as intensely as modified MLTC systems. These observations indicate that in vitro lymphokine-activated PBMC's, although suppressed by humoral glioma-derived factors, may enhance glioma cell proliferation with soluble factors secreted into the culture medium. The authors conclude that glioma-lymphocyte growth regulatory networks include stimulatory and inhibitory factors from both cell populations, which may modulate tumor progression. These observations may have relevance for adoptive immunotherapy in patients with gliomas.
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PMID:In vitro studies of cytokine-mediated interactions between malignant glioma and autologous peripheral blood mononuclear cells. 793 92

To determine the gene expression for tumor necrosis factor (TNF) alpha and its main site of production in gastric cancer patients, serum levels in the peripheral venous blood of 50 patients and the portal blood from 15 of these 50 patients were measured by enzyme-linked immunosorbent assay (ELISA). TNF gene expression in the peripheral blood mononuclear cells (PBMC) and in the surgically resected tissues was then studied in 16 patients by reverse transcription-polymerase chain reaction (RT-PCR) assay. Whereas TNF mRNA expression was detected in the PBMC from 13 of 16 gastric cancer patients (81.3%), it was detected in only one tumor tissue (6.3%). Preoperatively, TNF was detected in the serum from 13 of 50 patients (26.0%). In the portal blood sampled immediately after laparotomy, TNF was positive in 4 of 15 patients (26.7%). TNF gene expression was much more frequently detected in PBMC than in other resected tissues, and its expression was higher than in the serum. Various clinicopathological factors for gastric cancer were not related to the preoperative detection of TNF in the serum. It appears that TNF is produced mainly in PBMC but not in the cancer regions or the regional lymph nodes of gastric cancer patients. It is suggested that TNF is not always secreted even when TNF mRNA is expressed, and its preoperative production is not related to tumor progression.
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PMID:Gene expression for tumor necrosis factor alpha and its production in gastric cancer patients. 796 Nov 4

Highly malignant and metastatic tumor cells are thought to arise within primary tumors and become predominant during cancer progression. We demonstrated, by the analysis of > 500 surgical specimens, that colorectal carcinomas with increased metastatic potential were characterized by an increased expression of sialyl-Le(x) antigens expressed on mucins. The biological role of sialyl-Le(x) antigens expressed on mucins produced by colon carcinoma cells has been investigated using variant cell lines selected for their expression of this antigen. KM12-HX and KM12-LX, high and low expresser variant cells, differed in their metastatic potential in nude mice after intrasplenic injection. KM12-HX cells contain higher levels of polyA+mRNA for alpha(1-3/4) fucosyltransferase than KM12-LX cells. Sialyl-Le(x) antigenic carbohydrate chains were attached to mucins as well as glycoproteins with various M(r). KM12-HX cells adhered more strongly than KM12-LX cells to human umbilical vein endothelial cells treated with tumor necrosis factor-alpha and to mouse hepatic sinusoidal endothelial cells. We have retrospectively evaluated post-operative survival of colon carcinoma patients for their sialyl-Le(x) antigen levels in the primary tumors according to the percentage of stained cells by specific antibodies. The adjusted survival rate of the patients with high levels of sialyl-Le(x) antigen in their primary tumors was much lower due to recurrence and metastasis than that of the patients with tumors containing low levels of sialyl-Le(x) antigen. The results suggested that sialyl-Le(x) antigen has a potential to be used as a predictive marker for colorectal cancer metastasis.
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PMID:[Ectopic expression of carbohydrate antigens that determine the metastatic potential of human colorectal carcinoma]. 809 51

This review concentrates on growth autonomy of tumor cells in relation to tumor progression. Human malignant melanoma serves as an example for progressive growth factor independence at subsequent stages of tumor progression. Mechanisms by which malignant cells acquire growth factor independence are discussed. In melanoma, deregulation of growth regulatory pathways has been described on four levels: 1) aberrant production of autocrine growth factors that substitute for exogenous growth factors (basic fibroblast growth factor [bFGF]); 2) alterations in the response to negative autocrine growth factors (interleukin [IL]-6 and transforming growth factor [TGF]-beta); 3) overexpression of epidermal growth factor receptors (EGF-R); and 4) alterations of cellular protooncogenes involved in signal transduction (RAS, MYB) and growth suppression (p53). In addition to bFGF and IL-6, multiple other growth factor genes are activated in malignant melanoma cells but not normal melanocytes. These include both chains of platelet-derived growth factor (PDGF), TGF-alpha, IL-1, IL-8, and tumor necrosis factor (TNF)-alpha. Of these, PDGF-B has been investigated in more detail. Melanoma-derived PDGF clearly does not act in a direct autocrine mode, but has important paracrine effects on normal tissue constituents, notably fibroblasts and endothelial cells, that are essential for tumor development in vivo. It is speculated that other melanoma-derived growth factors with as yet undefined functions similarly exert such paracrine or 'indirect' autocrine effects that cannot be sufficiently addressed in studies on cultured cells.
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PMID:Growth factor independence and growth regulatory pathways in human melanoma development. 828 9

The efficacy of combination treatment with actinomycin D (Act D), recombinant human tumor necrosis factor-alpha (TNF-alpha), and recombinant murine interferon-gamma (IFN-gamma) was examined on established MmB16 melanoma in mice. TNF-alpha alone had marginal effect in vitro on melanoma cells. However, when this cytokine was combined with either Act D or IFN-gamma, synergistic cytostatic/cytotoxic effects were observed. The highest cytotoxicity was demonstrated in cultures of melanoma cells in which all three agents together were added. In mice inoculated with 10(6) melanoma cells (into the footpad of the hind limb) and treated locally with Act D, TNF-alpha and IFN-gamma, beneficial therapeutic effects were found. When initiated 1 week after tumor cell inoculation, the 7-day treatment with all these agents administered together at daily doses: 0.2 microgram (Act D), 1 microgram (TNF-alpha), and 200 U (IFN-gamma) resulted in a significant delay of tumor progression in comparison to the therapy that included either Act D alone or TNF-alpha in combination with IFN-gamma. Side effects of such a treatment, both local and systemic, were negligible. The results of this study demonstrate that combination of regional chemotherapy (actinomycin D) and immunotherapy (TNF-alpha/IFN-gamma) may display higher efficacy than either treatment alone and may increase therapeutic index without augmenting toxic effects.
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PMID:Augmentation of antitumor efficacy by the combination of actinomycin D with tumor necrosis factor-alpha and interferon-gamma on a melanoma model in mice. 857 Jan 28

The host-tumor interaction may play an important role in determining tumor progress. Recent studies have shown that this interaction can be influenced by the release of soluble factors by tumor cells and tumor-infiltrating lymphocytes (TIL). The aim of our study is to characterize the nature of cytokines and growth factors and their relationship to the cellular infiltrates in 16 patients with ovarian cancer using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Total RNA from 20 malignant and 10 benign specimens were used to assay for expression of 12 cytokines. Additionally, monoclonal antibodies (MAbs) were used to detect T cells, CD4+ helper and CD8+ cytotoxic/suppressor T-cell subtypes, B cells, and macrophages. Our results showed the expression of transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in 19, 17, and 10 malignant specimens, P < .001, .001, and .05, respectively. Other cytokines such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), TNF-beta/LT, IL-2, and IL-6 were expressed in a few cases, and IL-1alpha and IL-4 expression were not detected. The benign samples did not express IL-10, but GM-CSF, TGF-beta1, and IL-8 were expressed in one, one, and four specimens, respectively. Interestingly, in four cases in which samples from the primary and relapse tumors were available for analysis, the tumors in relapse showed a significant increase for TGF-beta1 (P < .05) and a decreased trend in IL-10 mRNA levels. The source of these factors was tumor cells as detected immunohistochemically. This combined alteration of TGF-beta1 and IL-10 was associated with a significant reduction in number of TIL in general, and CD8+ and macrophages in particular (P = .036 and .049, respectively). Our findings suggest the important role of certain soluble factors in the complex process of tumor progression. Furthermore, understanding the tumor-host relationship and the factors influencing the interaction may be helpful in developing effective and innovative treatment methods.
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PMID:Tumor-host interaction: analysis of cytokines, growth factors, and tumor-infiltrating lymphocytes in ovarian carcinomas. 904 97

This study sought to determine if pretreatment with low-dose tumor necrosis factor-alpha (TNF-alpha) can enhance the effects of radiation in an NCI-H441 human lung tumor xenograft model. In vitro assays were performed on spleen cells, blood leukocytes, and plasma from the animals, as well as on cultured tumor cells. Tumors in animals given only TNF-alpha grew as well as, or better than, tumors in their untreated counterparts at all time-dose regimens employed. In contrast, early treatment with a total radiation dose of 16 Gy resulted in complete tumor inhibition, whereas 8 Gy modestly (but significantly, P < 0.05) slowed tumor progression. However, the administration of TNF-alpha (4 x 10(4) total units/mouse) 16-18 h prior to irradiation (8 Gy total dose) enhanced the antitumor effects of radiation when treatment was initiated early (P < 0.05). Oxygen radical production and response to mitogenic stimulation by splenocytes were greatest in untreated tumor-bearing animals. Total leukocyte counts in mice given radiation or TNF-alpha + radiation were low, and treatment-related changes were found in percentages of neutrophils and lymphocytes. In vitro assays of tumor cells showed that TNF-alpha + radiation resulted in greater suppression of clonogenic survival and incorporation of [3H]TdR and [3H]UdR incorporation than either agent alone. These results suggest that the use of low-dose TNF-alpha together with radiation may be beneficial in the clinical setting and so warrant further investigation.
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PMID:Evaluation of TNF-alpha effects on radiation efficacy in a human lung adenocarcinoma model. 916 Mar 52

The microbial immunostimulant OK-432 has been studied intensively in preclinical systems and has shown promise as an anticancer agent in trials that have been conducted over the past 20 years in Japan. To date, no systematic dose response evaluation of this agent has defined its dose-limiting toxicity or immunobiological activity. A phase IA study has been conducted in 25 patients with metastatic cancer at the University of Pittsburgh Cancer Institute Melanoma Center, establishing 30 KE as the maximal tolerable dosage, on the basis of cutaneous reactions. Subsequently, 48 patients with resected high-risk melanoma participated in a phase IB study of OK-432. This study has evaluated the immunomodulatory activity of OK-432 at five dosages ranging from 1 KE to 20 KE, administered ID twice weekly for 3 months. A formal analysis of the treated population in comparison to the randomized control group has been conducted, and profound immunological effects have been defined in the group of patients treated with OK-432. Patients who participated in this trial had a significant depression of OK-432-inducible cytokine production (interleukin-1 beta, interferon gamma, and tumor necrosis factor alpha) at baseline. Treatment with OK-432 reversed this deficit for interferon gamma (IFN gamma) production in a dose-dependent manner, and mitigated the inhibition for interleukin-1 (IL-1) across all dosage groups. The impact of OK-432 upon other immunological functions of the treated cohorts is more variable, with durable suppression of mononuclear cell superoxide production, and in vitro cytotoxicity to tumor. Immunological characteristics of the entire cohort demonstrate a strong and significant correlation of elevated blood CD16+ cell counts and natural killer activity with early tumor progression and death due to melanoma. Favorable prognosis is associated with monocyte capacity to produce tumor necrosis factor (TNF), and polymorphonuclear leukocyte formylmethionyl-leucylphenylalanine-inducible superoxide release. This study reveals several new immunological correlates of tumor progression and lethal outcome in resected high-risk melanoma. It demonstrates that the depressed IL-1, TNF, and IFN gamma release associated with melanoma may be mitigated by treatment with OK-432. This study has defined treatment and dose response patterns of immunomodulation associated with one of the most complex immunological agents yet evaluated in phase IB trials, in a well-defined population of high-risk patients with resected melanoma.
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PMID:Phase IB trial of picibanil (OK-432) as an immunomodulator in patients with resected high-risk melanoma. 919 73

Long-term control of high-grade brain tumors is rarely achieved with current therapeutic regimens. The aim of this study was to determine if low doses of tumor necrosis factor-alpha (TNF-alpha) could augment the effects of radiation in a glioma xenograft model and to evaluate hematological and other parameters that might indicate treatment-related toxicity. Nude mice were injected subcutaneously with C6 rat glioma cells and randomized into groups. Two different time-dose protocols were employed using intravenous human recombinant TNF-alpha and radiation beginning within 24 h after tumor cell implantation. The administration of radiation as a single agent slowed tumor progression, whereas TNF-alpha alone had no effect. However, TNF-alpha, especially when given twice per week before radiation for a total of four doses each, significantly increased the efficacy of the radiation. Low leukocyte counts were associated with combination treatment, whereas transforming growth factor-beta 1 levels were depressed in all treated groups. TNF-alpha did not modulate radiation-induced inhibition of C6 cell proliferation in vitro. The data show that TNF-alpha at relatively nontoxic doses can significantly enhance the antitumor effects of radiation against a rapidly growing glioma. This effect was more than additive, because TNF-alpha alone did not slow tumor progression.
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PMID:Tumor necrosis factor-alpha enhances antitumor effects of radiation against glioma xenografts. 930 29

Mouse myeloma cell line VKCK/RM4-TNF secreting the recombinant fusion protein RM4/TNF was used to study the relationship between tumor necrosis factor (TNF) secretion of tumor cells and its tumorigenicity, and to study the potential mechanisms responsible for the antitumor immune response. To evaluate tumorigenicity, 5 x 10(5) viable TNF-secreting VKCK/RM4-TNF and non-TNF-secreting VKCK tumor cells were subcutaneously injected into BALB/c mice. Tumor progression or regression was evaluated 2 weeks after tumor inoculation. Our animal studies showed that RM4/TNF secretion by VKCK/RM4-TNF tumor cells curtailed its tumorigenicity in BALB/c mice and induced a long-term, protective immune response against a subsequent challenge of the parental VKCK tumor cells. Our animal studies in T-cell subset-depleted BALB/c mice and in T-cell-deficient nude mice demonstrated that both CD4+ and CD8+ T cells play a major role in the reduction of tumorigenicity. In addition, our results further showed that local inoculation of irradiated VKCK/RM4-TNF cells secreting TNF was able to significantly inhibit the established VKCK tumors in syngeneic mice. This study thus highlights the potential utility of engineered tumor cells secreting RM4/TNF in cancer gene therapy.
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PMID:Inhibition of established tumor growth in syngeneic mice by local inoculation of engineered mouse myeloma cells secreting a recombinant fusion protein RM4/TNF. 940 5


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