Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to determine the pathogenesis of fever in solid tumors, we studied the association of fever at diagnosis in children with solid tumors (malignant lymphoma, rhabdomyosarcoma, and neuroblastoma), serum levels of interleukin 1 (IL-1), and tumor necrosis factor. Thirteen of 20 patients (65%) with solid tumors were complicated with fever at diagnosis. There was no difference in C-reactive protein or IL-1 levels between the patients with and without fever, while the erythrocyte sedimentation rate and TNF levels were higher in the former than in the latter by Wilcoxon's rank sum test (p less than 0.01). These findings suggest that most febrile episodes at diagnosis in children with solid tumors are associated with the release of tumor necrosis factor.
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PMID:Tumor necrosis factor and fever at diagnosis in children with solid tumors. 169 36

A phase I study with recombinant human tumor necrosis factor alpha (rhuTNF-alpha; Knoll AG, Ludwigshafen, FRG) in patients with advanced malignant disease was undertaken to evaluate drug toxicity (organ specificity, time course, predictability, reversibility, maximal tolerated dose), effectiveness, antigenicity and pharmacokinetics. TNF was administered as a test dose followed by daily i.v. infusions for 5 days, every 3 weeks (single i.v. infusion lasting 10 min, TNF dissolved in 50 ml 5% human albumin). Dosage was increased in groups of 3 or 4 patients from 0.04 mg/m2 to 0.28 mg/m2. A total of 19 patients with different cancers, including seven large-bowel carcinomas, three chronic myelogenous leukemias, three hypernephromas, two small-cell lung cancers, one malignant melanoma, one malignant lymphoma, one rhabdomyosarcoma and one fibrosarcoma were treated. Major side-effects were chills and fever (maximum 40.4 degrees C, median 38.7 degrees C, 19/19), headache (12/19), nausea and vomiting (12/19) and pronounced (greater than 20%) hypotension (4/19). Acute side-effects could be diminished by paracetamol or indomethacin pretreatment, and with one possible exception no tachyphylaxis to TNF was noted. Mild renal toxicity was seen during TNF treatment. Pharmacokinetic studies showed a serum half-life (t1/2) ranging from 11 min to 17 min for doses from 0.04 mg/m2 to 0.16 mg/m2 and prolonged clearance with t1/2 ranging from 54 min to 70 min in the 0.20-0.28 mg/m2 dose range. No objective antitumor effects were observed in this phase I study.
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PMID:Phase I study of recombinant human tumor necrosis factor alpha in advanced malignant disease. 272 Jul 7

Adoptive immunotherapy (AIT) involving transfer of tumor-sensitized T lymphocytes in combination with cyclophosphamide (CY)-injection results in the eradication of the C57BL/6J (B6) rhabdomyosarcoma, 76-9 and is associated with the accumulation of a large number of tumor-infiltrating lymphocytes (TIL). Using immune spleen cells (ISC) from B6 and congenic B6. PL. Thy-1a mice, it was shown that most (> or = 97%) of the TIL were donor-derived. This in situ increase in donor-derived T cells was confirmed by using positively-selected Thy- 1.1+ and Thy- 1.2+ TIL for AIT after isolating them from regressing tumors and expanding them in rIL-2. The extent of CD8+ TIL expansion in vivo correlated with the numbers of TIL adoptively transferred and this in turn determined the degree of anti-tumor effects. It was evident, however, that these in vitro-expanded TIL expressing mRNA for TNF alpha and IFN gamma were qualitatively different and therapeutically less efficacious than the T cells associated with ISC or with freshly-isolated TIL. Unlike freshly isolated TIL that expressed specific cytotoxicity towards the 76-9 targets in vitro, IL-2 expanded TIL killed 76-9 cells and unrelated tumor targets to the same extent. A cytotoxic CD8+ T cell line derived from ISC and selected for activity against the 76-9 tumor cells showed no therapeutic efficacy. The data suggest that, in this tumor model, expansion of CD8+ T cells in vitro selects against anti-tumor efficacy.
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PMID:The therapeutic efficacy of murine anti-tumor T cells: freshly isolated T cells are more therapeutic than T cells expanded in vitro. 776 19

KYM-1D4 cells are a subline derived from a human rhabdomyosarcoma which are highly sensitive to TNF-mediated cytotoxicity. They were selected for this study because they express human TNF-R and are therefore a more relevant target for comparing the potential therapeutic value of human TNF-inhibitory agents than the usual murine cell lines. Two recombinant soluble TNF-R-IgG fusion proteins, one containing p55 TNR-R, the other containing p75 TNF-R, and a recombinant monomeric soluble p55 TNF-R were all found to block the cytotoxicity generated by human TNF-alpha and LT as well as also murine TNF. The p55 TNF-R-IgG fusion protein (p55-sf2) was the most effective of the antagonists tested, requiring an equimolar, (based on a monomeric configuration of TNF-alpha) or a 3-fold higher (based on a trimeric configuration of TNF-alpha) molar concentration to inhibit the cytotoxicity mediated TNF-alpha by 50%. p55-sf2 was also as effective at inhibiting the cytotoxicity mediated by LT or murine TNF in the KYM-1D4 assay. In contrast, the monomeric soluble p55 TNF-R was the least effective inhibitor, requiring a > 4000-fold higher molar concentration than p55-sf2 to achieve a similar degree of protection. The fusion proteins, particularly p55-sf2, may be useful as human therapeutic agents, as at low concentrations they can prevent both TNF-alpha-mediated and LT-mediated effects on human cells. As TNF-R-IgG fusion proteins also block the action of murine TNF in vitro, they may also be useful in the investigation of murine models of human inflammatory disease.
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PMID:TNF receptor fusion proteins are effective inhibitors of TNF-mediated cytotoxicity on human KYM-1D4 rhabdomyosarcoma cells. 789 70

Using agonistic antibodies (Ab) we have examined whether the 75-kDa chain of the tumor necrosis factor receptor (p75 TNFR) is capable of mediating cytotoxic response and gene regulation alone or in cooperation with p55 TNFR. Addition of an anti-p75 TNFR polyclonal antiserum or anti-p75 monoclonal antibody (mAb) plus anti-immunoglobulin (Ig) led to cytotoxic response of human KYM-1 rhabdomyosarcoma cells. Anti-p75 mAb alone had no effect pointing out the importance of strong receptor stimulation for signal transduction into the cell. Simultaneous triggering of both the p55 and p75 TNFR by agonistic Ab resulted in additive cytotoxic action on KYM-1 cells. The anti-p75 mAb 3H5, directed to a non-TNF binding site on the human p75 TNFR, was used to confirm further the ability of the p75 TNFR to potentiate p55 TNFR-mediated cell death. While exhibiting no cytotoxicity by its own, 3H5 significantly augmented the cytotoxic effect of the anti-p55 mAb htr9 towards KYM-1 cells. Neither the anti-p75 TNFR antiserum nor anti-p75 mAb were cytotoxic for human U937 cells suggesting that the cytolysis resulting from p75 TNFR cross-linking is cell specific. Noteworthy, stimulation of the p75 TNFR with mAb plus anti-Ig or polyclonal antiserum led to a marked enhancement of the p55 TNFR-induced U937 cell death, indicating collaboration between the two TNFR in induction of cytotoxicity also in this cell line. However, 3H5 mAb did not affect the ability of anti-p55 mAb to lyse U937 cells. Altogether, these data demonstrate the difference between KYM-1 and U937 cell lines with respect to the role for the p75 TNFR in mediating cytotoxicity. Both TNFR were found to mediate cytomegalovirus (CMV) promoter activation in human SW480T-beta Gal cells and nuclear transcription factor kappa B (NF-kappa B) induction in this cell line as well as in KYM-1 cells. It was demonstrated for the first time that independent stimulation of both TNFR resulted in an additive effect on the CMV promoter activation and induction of the NF-kappa B. Taken together, these results indicate that the p75 TNFR induces cytotoxicity in a cell-specific manner and potentiates p55 TNFR-mediated cytotoxic response and gene regulation.
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PMID:Involvement of the tumor necrosis factor receptor p75 in mediating cytotoxicity and gene regulating activities. 795 75

TNF membrane receptors are usually co-expressed in many tissues but their relative contribution to cellular TNF responses is for most situations unknown. In a TNF cytotoxicity model of KYM-1, a human rhabdomyosarcoma cell line, we recently demonstrated that each of the two TNFRs is on its own capable of inducing cell death. Here we show that both receptors are able to induce apoptosis, as revealed from a similar onset of DNA fragmentation and typical morphologic criteria. To obtain additional information about the signaling pathways involved in TR60- and TR80-induced programmed cell death, we have used a series of selective inhibitors of intracellular signaling molecules. The overall pattern emerging from these experiments provides strong evidence for distinct signal pathway usage of TR60 and TR80, indicating protein kinase(s)-mediated control of TR60 signaling and a tight linkage of TR80 to arachidonate metabolism. The subsequent establishment of KYM-1-derived cell lines that display TNFR selective resistance further supports a segregation of TR60 and TR80 signaling pathways for induction of apoptotic cell death. Moreover, these results demonstrate an independent control of the distinct signaling cascades used by TR60 and TR80. This allows a highly flexible regulation of a cellular TNF response in those cases in which both receptors contribute to overall TNF responsiveness.
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PMID:TNF receptors TR60 and TR80 can mediate apoptosis via induction of distinct signal pathways. 805 1

Adoptive immunotherapy (AIT) of mice bearing the MCA/76-9 rhabdomyosarcoma in combination with cyclophosphamide (CY) injection results in the permanent regression of tumors. This report is concerned with changes in the tumor-associated macrophage (TAM) population and the influence of both CY injection and CY/AIT on their potential functions. Sequential analyses of FcR, MAC-I and Class-II MHC antigen expressed by tumor-associated cells (TAC) showed that CY injection or CY/AIT induced marked increases in the proportions of all 3 parameters as compared with the relatively stable levels in progressing tumors. These changes were time- and treatment-related. The mean MAC-I fluorescence (antigen density per cell) increased nearly 2-fold by 48 hr after CY injection, regardless of subsequent AIT. In contrast, the density of Class-II antigen per cell declined by as much as 75% within 48 hr after CY injection and did not recover by 7 days. This initial decline was also seen after CY/AIT and was followed by a rapid recovery to near-normal values by day 7. Northern analysis of RNA isolated from whole tumor tissue indicated wide fluctuations in expression of the typical macrophage genes encoding the proteins MAC-I, IL-I alpha, IL-I beta, TNF alpha, IA beta and c-fms. However, with the exception of MAC-I and IL-1 alpha/IL-1 beta mRNA, the modifications appeared to be qualitative rather than representing changes in the proportions of TAM. The data suggest that the changes in membrane antigen and gene expression by TAM reflect a complex interaction between TAM and their environment, in particular tumor cells and tumor-infiltrating lymphocytes. In addition, it is evident that CY injection per se is responsible for defined fundamental changes that presumably influence the outcome of AIT.
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PMID:Qualitative and quantitative intratumoral changes in gene expression following cyclophosphamide injection and the adoptive transfer of T cells: the potential contribution of tumor-associated macrophages. 811 93

In this study, we investigated the type of TNF receptor expressed by the human rhabdomyosarcoma cell line KYM-1 and related TNF-sensitive sublines and showed that the majority (> 90%) of TNF receptors were type II (p75) receptors with only a relatively small number (< 10%) of type I (p55) receptors. Selection with TNF alpha led to the isolation of KYM-1 related TNF-resistant cell lines of which three cloned lines showed a near to total loss of type II TNF receptors. To investigate further the role of each type of TNF receptor in the regulation of TNF-mediated cytotoxicity and the development of TNF resistance, we used receptor-specific antibodies and antisera, able to compete with ligand binding to the respective receptor molecules, but representing efficient agonists via crosslinking of receptors. We found that in KYM-1 and related TNF-sensitive sublines both type I and type II TNF receptors can be functional on their own, as selective cross-linking of each receptor subset lead to cytolysis. However, investigation of three TNF-resistant KYM-1 related cell lines by selective receptor stimulation via cross-linking indicated different mechanisms underlied the development of TNF-resistant for each receptor type. Our data indicate that resistance to TNF-mediated cytotoxicity in KYM-1 related cell lines can be developed both by a selective loss of type II receptor expression and the selective loss of type I receptor function without reduction in type I receptor numbers.
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PMID:Development of resistance to tumour necrosis factor (TNF alpha) in KYM-1 cells involves both TNF receptors. 818 67

The production of cytokines by HIV-infected cells from adherent tissues as well as their effects on HIV replication in the same cells were investigated. CD4-transfected HeLa-T4-6c epithelial cells, CD4-positive normal lung fibroblasts and CD4-negative RD rhabdomyosarcoma cells were infected with HIV-1. All cultures were permissive for virus replication, which was completed within 48-72 h by Hela-T4-6c and RD cells and 2-3 weeks in normal fibroblasts. During the course of HIV replication, a series of cytokines (particularly IL-6 and TNF alpha) was produced and released in parallel to the peak of virus growth, in amounts varying with the cell system studied. Treatment of cultures with recombinant cytokines given at concentrations in the range of those induced by HIV-1 indicated that IL-6 and TNF alpha caused an increase of: i) CD4 expression, ii) HIV absorption to uninfected cells, and iii) release of infectious virions by infected cells. The fact that HIV-1 absorption and spread can be mediated by HIV-induced cytokines may be relevant in the pathogenesis of the in vivo disease, as it may constitute a possible self-enhancing model of HIV infection also in the solid tissues.
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PMID:Mutual interactions between HIV-1 and cytokines in adherent cells during acute infection. 827 51

We have previously hypothesized that the pro-inflammatory cytokine TNF alpha has a pivotal role in the pathogenesis of rheumatoid arthritis (RA). It mediates its effects by cross-linking surface p55 TNF receptors (TNF-R), which can be proteolytically cleaved to yield soluble fragments. Upon binding TNF alpha soluble TNF-R (sTNF-R) can inhibit its function. We investigated the enzymatic nature of the proteases involved in TNF-R cleavage, and found that this process is blocked by a synthetic inhibitor of matrix metallo-proteinase activity (MMP), BB-2275. Inhibition of TNF-R cleavage was observed in a number of different cell types, as detected by retention of surface bound TNF receptor and by less sTNF-R released into the cell supernatant. The augmentation of surface TNF-R expression was of biological relevance as TNF alpha-mediated necrosis of human KYM.1D4 rhabdosarcoma cells was enhanced approximately 15-fold in the presence of BB-2275. The addition of BB-2275 to rheumatoid synovial membrane cell cultures totally inhibited MMP activity and also significantly reduced the levels of soluble TNF alpha (P < 0.006), p55 sTNF-R (P < 0.006), and p75 sTNF-R (P < 0.004). Paradoxically, despite the reduction in soluble TNF alpha levels, the production of IL-1 beta, IL-6, and IL-8, cytokines whose production was previously demonstrated to be inhibited by the addition of neutralizing anti-TNF alpha antibody were not down-regulated by BB-2275. These results raise the interesting possibility that a close relationship exits between the enzyme(s) which process membrane-bound TNF alpha, and those involved in surface TNF-R cleavage. Furthermore our observations suggest that hydroxamate inhibitors of MMP activity which block TNF alpha secretion and TNF-R cleavage may not modulate down-stream effects of TNA alpha, and as such suggest that the precise specificity of these compounds will be highly relevant to their clinical efficacy in inflammatory diseases.
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PMID:Paradoxical effects of a synthetic metalloproteinase inhibitor that blocks both p55 and p75 TNF receptor shedding and TNF alpha processing in RA synovial membrane cell cultures. 867 95


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