Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary biopsies from 149 patients with malignant lymphomas were examined by histological and immunohistochemical techniques. Twenty eight cases were classified as Hodgkin's disease and 121 as non-Hodgkin's lymphomas. The immunohistochemical distribution of cytokine expression (Il-1 alpha, Il-1 beta, Il-6 and TNF-alpha) was demonstrated in neoplastic cells and in tumor-associated macrophages (TAM). Neoplastic cells showed mostly weak positivity for TNF-alpha in 40% of Hodgkin's disease and in 20% of T cell lymphoma cases. Two groups of malignant lymphomas were established which differed in the numbers of cytokine expressing TAM. The first group consisted of malignant lymphomas which contained large quantities of cytokine-possessing TAM. In the second group significantly lower frequencies of cytokine expressing TAM were found. In both groups high and low grade malignant lymphomas were encountered. There was a significantly positive correlation between the number of Il-6 possessing TAM and the proliferation of lymphoma cells in only the non-Hodgkin's lymphomas. Our results suggest a paracrine tumor growth stimulating mechanism which is created by a self perpetuating cytokine production loop. A supposed cytokine produced by neoplastic cells dependent from their proliferative activity may induce Il-6 secretion by TAM. Il-6 in turn may stimulate the proliferation of the lymphoma cells without maturation thus leading to a self-sustaining growth.
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PMID:[Immunohistochemical in situ demonstration of cytokines in Hodgkin and non-Hodgkin lymphoma]. 128 51

Peritumoral injection of human IL-2-activated natural killer cells into nude mice consistently induced regression of xenografts of human squamous cell carcinoma of the head and neck (SCCHN). To determine the mechanisms responsible for the tumor regression, the lymphoid cells infiltrating the tumor stroma at 24 to 48 h after adoptive immunotherapy were examined by in situ hybridization for the presence of mRNA for cytokines or IL-2R. Numerous lymphoid cells expressing cytokine or IL-2R genes were observed in these tumors, whereas the cultured IL-2-activated NK cells used for therapy were negative. Thus, it appeared that the transferred NK cells became activated in situ after coming into proximity with the tumor cells. To analyze this phenomenon, fresh or cultured human NK cells were coincubated in vitro with irradiated human SCCHN cell line, PCI-1, with or without the presence of IL-2. Expression of mRNA for IL-2R, perforin, and various cytokines was observed within 5 h. Contact with the tumor cells stimulated NK cells to proliferate, secrete IFN-gamma, TNF-alpha, and soluble IL-2R, up-regulate cell surface expression of IL2R p55 and p75 as well as CD16 Ag, and mediate higher levels of antitumor activity in 51Cr-release assays. In addition, supernatants of in vitro-activated NK cells significantly inhibited proliferation of SCCHN cell lines. By examining the effects of neutralizing mAb to various cytokines, this inhibitory activity was shown to be partially attributable to IFN-gamma. To determine the possible in vivo role of soluble factors produced by activated human NK cells, the supernatants (0.2 ml) or rIFN-gamma (10(5) U) were injected perilesionally each day for 2 wk into 3-day SCCHN established in immunosuppressed nude mice. These treatments caused significant (p less than 0.02) inhibition of tumor growth. The results of our studies indicate that human NK cells are strongly activated by SCCHN cells and that the consequent release of cytokines contribute to the regression of SCCHN growing in nude mice.
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PMID:Role of cytokines in the adoptive immunotherapy of an experimental model of human head and neck cancer by human IL-2-activated natural killer cells. 153 88

A double grafted tumor model (colon 26 and Meth-A) was established in BALB/c mice. The primary colon 26 tumor growth was inhibited by the secondary transplantation of Meth-A tumor cells into the same host, and the prolongation of mean survival time was also observed. To investigate the mechanism of the prolongation of survival, the role of tumor necrosis factor (TNF) was examined. The intraperitoneal inoculation of human TNF-alpha (1 x 10(4) units) for 5 days, as well as the secondary Meth-A tumor cell transplantation, resulted in the prolongation of survival. Moreover, the prolongation of survival disappeared by the inoculation of rabbit anti-TNF-alpha antibodies. These results suggest that TNF-alpha play an important role in the mechanism of a prolongation of survival by the secondary transplantation of the tumor cells.
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PMID:[Establishment of double grafted tumor model in mice and role of "tumor necrosis factor" (TNF)]. 180 96

We have compared the mechanisms by which human PBL targeted with bispecific antibodies either lyse tumor cells or block their growth in culture or in mice. We found that resting PBL were unable to mediate lysis, but were able to block tumor growth. Moreover, targeted PBL were unable to lyse bystander cells, whereas targeted PBL did block the growth of bystander tumor cells in culture and in nude mice. Supernatants from cultures of targeted PBL, or from PBL grown on anti-CD3-coated flasks, blocked the growth of tumor cells in the absence of added effector cells, and antibodies against TNF-alpha and IFN-gamma reversed the inhibition of tumor growth, but had no effect upon cytolysis mediated by targeted by PBL. Our results show that targeted human PBL mediate two different antitumor activities: lysis, which occurs rapidly and requires the direct attachment of the target cell to the cytotoxic cell, and tumor growth inhibition, which is mediated by cytokines released into the medium as a result of receptor cross-linking. The inhibition of bystander tumor growth in mice by targeted PBL suggests that factor release is sufficient to block tumor growth in vivo. Targeted factor release therefore provides a mechanism by which targeted PBL could block the growth of tumor cells in vivo that were not bound by the effector cells, but which were located in the vicinity of tumor cells that were bound.
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PMID:Human peripheral blood lymphocytes targeted with bispecific antibodies release cytokines that are essential for inhibiting tumor growth. 182 9

We have studied the effects of high-energy shock waves (HESW) alone or in combination with biological response modifiers on the growth of five human kidney cancer xenografts in mice. Exposure of the tumors to three sessions of 800 shock waves every 48 hours with 18.4 kV, 37.5 MPa, on the commercially available Lithostar resulted in a temporary growth delay. The sensitivity for HESW was related to the doubling time of the tumor. Several days after stopping the HESW administration, the tumors regained their original growth potential with the same doubling time. The systemic application of Tumor Necrosis Factor-alpha (TNF-alpha, 500 ng/g body weight, 5 times/week) and/or Interferon-alpha (IFN-alpha, 5.0 ng/g body weight, 3 times/week) subcutaneously around the tumor also had a limited effect on the growth of these established tumors (60-80 mm3). The combination of HESW with TNF-alpha and IFN-alpha resulted in an almost complete cessation of tumor growth in the NU-1 human kidney xenograft and had an additive antitumor effect in the NU-3. Synergism was also seen in the NU-1 and NU-3 with the combination of HESW and TNF-alpha, while the combination with IFN-alpha had only a limited effect on tumor growth. So TNF-alpha was the active agent, that enhanced the antiproliferative effects of shock waves. In the NC-65 tumor (same doubling time as the NU-1 and NU-3, but less well vascularized), the antiproliferative effect of HESW was not potentiated by TNF-alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of high-energy shock waves combined with biological response modifiers in different human kidney cancer xenografts. 194 50

Studies of the anti-tumor activity of TNF-alpha in vivo have been hampered by the need to administer systemically toxic doses of the cytokine to obtain a curative response. To facilitate studies of the effect of high local concentrations of TNF-alpha on tumor growth and host immunity, a newly induced murine sarcoma was transduced with the gene for human TNF-alpha and the biologic characteristics of these cells were examined. We identified high and low TNF-producing tumor clones which exhibited stable TNF secretion over time. Significant amounts of membrane associated TNF were found in a high-TNF producing clone as well. No difference in the in vitro growth rates between TNF-producing and nonproducing cell lines was observed. In contrast, in vivo studies demonstrate that although unmodified parental tumor cells grew progressively when implanted s.c. in animals, tumor cells transduced with the TNF gene were found to regress in a significant number of animals after an initial phase of growth. This effect correlated with the amount of TNF produced and could be blocked with a specific anti-TNF antibody. Regressions of TNF-producing cells occurred in the absence of any demonstrable toxicity in the animals bearing these tumors. TNF-producing tumor cells could function in a paracrine fashion by inhibiting the growth of unmodified, parental tumor cells implanted at the same site. The ability of tumor cells to regress was abrogated by in vivo depletion of CD4+ or CD8+ T cell subsets and animals that had experienced regression of TNF-producing tumors rejected subsequent challenges of parental tumor. Our studies thus show that tumor cells elaborating high local concentrations of TNF regress in the absence of toxicity in the host and that this process requires the existence of intact host immunity. Studies of the lymphocytes infiltrating the gene modified tumors and attempts to use TNF gene modified tumor infiltrating lymphocytes to deliver high local concentrations of TNF to the tumor site without inducing systemic toxicity are underway.
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PMID:Murine tumor cells transduced with the gene for tumor necrosis factor-alpha. Evidence for paracrine immune effects of tumor necrosis factor against tumors. 201 45

The protein-bound polysaccharide extracted from a fungus, PSK, has been used as a biological response modifier in the treatment of cancer patients in Japan for over ten years. Although the antitumor mechanism of PSK is not fully understood, host-mediated antitumor activity has been claimed to play a significant role. The administration of PSK to tumor-bearing rodents inhibited tumor growth and modulated immune responses. To clarify the potential immunomodulating activities of PSK, we examined the direct effect of PSK on cytokine gene expression and production in human peripheral blood mononuclear cells (PBMC) in vitro. As determined by Northern blotting, PSK was a potent inducer of gene expression for IL-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor (TNF-alpha) and monocyte chemotactic and activating factor (MCAF), but not for IL-2 and lymphotoxin (LT). Expression of mRNA occurred at 1-3 hr in a dose dependent manner using from 5-400 micrograms/ml of PSK. Furthermore, these cytokines were also produced in response to PSK as detected by ELISA, RIA or bioassays. We speculate that these cytokines may mediate immunoenhancing actions of PSK in vivo.
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PMID:Induction of gene expression and production of immunomodulating cytokines by PSK in human peripheral blood mononuclear cells. 209 Aug 74

Weight-stable mice bearing a syngeneic, methylcholanthrene-induced, rapidly growing tumor lost approximately 22% of their lean tissue, became significantly hypoalbuminemic and had a marked increase in serum amyloid P concentrations during progressive tumor growth. Tumors from cachectic mice were producing both TNF-alpha and IL-1 alpha in vivo as documented by the presence of TNF-alpha and IL-1 alpha mRNA and immune-reactive protein for IL-1 alpha. Only spleens from tumor-bearing mice had statistically significantly elevated quantities of IL-1 mRNA. In general, alterations in tissue concentrations of IL-1 mRNA in tumor-bearing animals agreed qualitatively with those found in endotoxin-stimulated, non-tumor-bearing control mice. However, endotoxin-stimulated mice had significantly elevated tissue concentrations of TNF mRNA in spleen and livers, while TNF mRNA levels were not significantly increased in any host tissues. Cytokine mRNA levels in tumor tissue were not higher than those found constitutively in various tissues from non-tumor-bearing control animals. Plasma from tumor-bearing mice and endotoxin-stimulated controls contained high levels of IL-6 but low (endotoxin-stim.) or no measurable levels (tumor-bearing) of either IL-1 or TNF. When tumor cells from cachectic mice were placed into long-term cell culture, immune reactive TNF-alpha and IL-1 alpha were produced, but IL-6 bioactivity ws not produced in measurable amounts.
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PMID:Tumor necrosis factor-alpha and interleukin-1 alpha production in cachectic, tumor-bearing mice. 222 17

Peri-tumoral injection of recombinant human interleukin-1 beta in mice transplanted s.c. with Friend erythroleukemia cells (FLC) resulted in marked inhibition of tumor growth and increased survival. However, in vitro treatment of FLC (745 or 3Cl-8) with IL-1 beta barely inhibited cell multiplication. IL-1 beta, injected into established solid tumors, induced marked morphologic changes. Vascular congestion and focal extravasation of erythrocytes were observed as early as 6 hr after injection with IL-1 beta of FLC and L1210 tumors and HeJ16 fibrosarcomas. Focal areas of disaggregation of tumor cells and tumor necrosis were observed 6 and 24 hr after IL-1 injection. These morphologic changes were similar to those observed in FLC tumors or HeJ16 fibrosarcomas treated with TNF-alpha or beta. These cytokines determined morphological changes in tumor blood vessels of FLC tumors within 1 hr of injection. Freshly dissected FLC tumors and their tissue extracts were studied by Nuclear Magnetic Resonance (NMR) spectroscopy, shortly after peri-tumoral injection of IL-1 beta or TNF-beta. After 6 hr, both cytokines induced a 3-fold reduction in the levels of two catabolites, glycerophosphorylcholine and glycerophosphorylethanolamine, an accumulation of sn-glycerol 3-phosphate and a more than 10-fold increase in the choline/phosphorylcholine ratio. These results are similar to those reported for TNF-alpha, and can be interpreted on the basis of an activation of glycerophosphorylcholine phosphodiesterase (EC 3.1.4.2) and partial inhibition of choline kinase (EC 2.7.1.32). IL-1 beta and TNF-beta (like TNF-alpha) also induced alkaline shifts (0.10-0.25 units) in the average intratumoral pH value. We suggest that alterations of tumor blood vessels may be the primary events in solid tumors treated with IL-1 beta or TNF. Such alterations lead to early changes in tumor metabolism and subsequent tumor cell degeneration.
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PMID:Interleukin-1 beta induces tumor necrosis and early morphologic and metabolic changes in transplantable mouse tumors. Similarities with the anti-tumor effects of tumor necrosis factor alpha or beta. 278 94

A synergistic antitumor effect of natural human tumor necrosis factor-beta (TNF-beta) in combination with hyperthermia was found, in comparison with that of TNF-alpha, using an in vitro antiproliferative assay on a human colon cancer cell line (RPMI4788) and an in vivo tumor growth inhibition assay on Meth A sarcoma cells. In vitro combined treatment with TNF-beta (10,000 U/ml) and hyperthermia (at 43 degrees for 60 min) synergistically inhibited the proliferation of the cells. Combined effects of TNF-alpha or natural human interferon-alpha or -gamma (IFN-alpha, -gamma) and hyperthermia were also examined, and furthermore, the combinations of TNFs and IFNs were examined in combination with hyperthermia at 42 degrees; their antiproliferative effects were further augmented by hyperthermia. In vivo growth of Meth A sarcoma cells (5 x 10(5)), transplanted subcutaneously into BALB/c mice, was inhibited significantly (P less than 0.05) with the combination of TNF-alpha or -beta (2 x 10(5) U/mouse) and hyperthermia (at 43 degrees for 60 min) as compared to either a single intravenous injection of TNF-alpha or -beta alone or the hyperthermia alone. The influence of TNF-beta and hyperthermia on the cell cycle was examined. Flow cytometric analysis showed that RPMI4788 cells treated with TNF-alpha or -beta accumulated in the S phase of the cell cycle, and that hyperthermia (at 42 degrees for 60 min) alone had no influence on the cell cycle and did not augment the S phase accumulation of the cells treated with TNF-alpha or -beta.
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PMID:Hyperthermic enhancement of the antitumor effect of natural human tumor necrosis factor-alpha and -beta: an in vitro and in vivo study. 314 36


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