Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The management of locally advanced soft-tissue sarcomas (STS) of the extremities in patients who present with regional and/or distant metastases at the time of diagnosis remains an unsolved problem. The recently introduced hyperthermic isolated limb perfusion (HILP) with tumour necrosis factor (TNF)-alpha and melphalan has been shown to be an effective limb-saving treatment modality, but is it feasible to use this approach with palliative intent? Nine patients, five men and four women, mean age 41 (range 21-75) years with locally advanced extremity STS and regional (n = 3) or distant (n = 6) metastases at the time of diagnosis, underwent a palliative HILP with TNF-alpha and melphalan. Resection of the residual tumour mass was performed, if possible, 6-8 weeks after HILP. Treatment-related morbidity, local recurrences and the limb salvage rate were scored during follow-up. The median follow-up period was 9 (range 3-39) months (seven deaths, but six were due to metastatic disease). Treatment-related morbidity was seen after 3 of the 10 perfusions performed (30%) and consisted of superficial wound infections (n = 2), blow out of the external iliac artery followed by an iliac thrombosis (n = 1). Two patients showed local recurrences after HILP followed by resection of the residual tumour mass, and one patient showed local progression after two perfusions without resection. Limb salvage was achieved in 8 patients (89%). Therefore, HILP with TNF-alpha and melphalan for locally advanced extremity STS in patients with disseminated disease is feasible. The local management of locally advanced extremity STS should be the same whether the intent is curative or palliative, as the local control improves the quality of life.
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PMID:Hyperthermic isolated limb perfusion with tumour necrosis factor-alpha and melphalan as palliative limb-saving treatment in patients with locally advanced soft-tissue sarcomas of the extremities with regional or distant metastases. Is it worthwhile? 983 10

The cytokine-inducible endothelial cell adhesion receptor E-selectin has been implicated in cancer metastasis. Previously, we reported that experimental liver metastasis of Lewis lung carcinoma subline H-59 cells could be abrogated in animals treated with an anti-E-selectin antibody. To gain further insight into the functional relevance of E-selectin expression to liver colonization, we investigated here the time course of cytokine and hepatic E-selectin expression after the intrasplenic/portal inoculation of H-59 cells by using a combination of reverse transcription-PCR, Northern blot analysis, immunohistochemistry, and in situ hybridization. In parallel, we analyzed cytokine induction in response to the injection of Lewis lung carcinoma subline M-27 and murine melanoma B16-F1 cells, which do not spontaneously metastasize to the liver. In livers derived from normal or saline-injected mice, only minimal basal levels of TNF-alpha and IL-1 mRNA were detectable by RT-PCR. Rapid cytokine mRNA induction was noted within 30-60 min of H-59 injection, reaching maximal levels at 4-6 h. This was followed by the appearance of E-selectin mRNA, which was detectable at 2 h after injection and reached maximal levels at 6-8 h, declining to basal levels by 24 h. In situ hybridization analysis and immunohistochemistry localized E-selectin mRNA and protein, respectively, to the sinusoidal endothelium. M-27 cells failed to induce cytokine or E-selectin expression, whereas B-16 cells elicited a delayed and more short-lived response. The results demonstrate that upon entry into the hepatic circulation, tumor cells can rapidly trigger a molecular cascade leading to the induction of E-selectin expression on the sinusoidal endothelium and suggest that E-selectin induction may contribute to the liver-colonizing potential of tumor cells.
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PMID:Rapid induction of cytokine and E-selectin expression in the liver in response to metastatic tumor cells. 1009 70

Based on our initial work with green tea, in which repeated topical applications of (-)-epigallocatechin gallate (EGCG), the main green tea polyphenol, inhibited tumor promotion in a two-stage carcinogenesis experiment on mouse skin (Phytother Res 1, 44-47, 1987), numerous scientists have since provided so much additional evidence of the benefits of drinking green tea that it is now an acknowledged cancer preventive in Japan, and will possibly soon be recognized as such in other countries. Our work has so far produced several important results with EGCG and green tea: a wide range of target organs in animal experiments for cancer prevention, wide bioavailability of 3H-EGCG in various organs of mice, delayed cancer onset of patients with a history of consuming over 10 cups of green tea per day, and absence of any severe adverse effects among volunteers who took 15 green tea tablets per day (2.25 g green tea extracts, 337.5 mg EGCG, and 135 mg caffeine) for 6 months. This paper introduces three new findings: 1) EGCG interacted with the phospholipid bilayer membrane resulting in confirmation of the sealing effect of EGCG; 2) EGCG inhibited TNF-alpha gene expression in the cells and TNF-alpha release from the cells; 3) high consumption of green tea was closely associated with decreased numbers of axillary lymph node metastases among premenopausal Stage I and II breast cancer patients, and with increased expression of progesterone and estrogen receptors among postmenopausal ones. These results provide new insights into our understanding of the mechanisms of action of tea polyphenols and green tea extract as a cancer preventive.
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PMID:Mechanistic findings of green tea as cancer preventive for humans. 1020 93

We hypothesize that a major factor regulating hepatic metastasis is the ability of CEA (carcinoembryonic antigen) producing colorectal carcinomas to activate Kupffer cells. CEA and NCA (nonspecific cross-reacting antigen) bind to an 80 kDa Kupffer cell receptor by the peptide sequence PELPK and stimulate cytokine production. Cytokines induce sinusoidal endothelial cells to express intercellular adhesion molecules and increase adhesion of the tumor cells and retention in the liver. In this study human Kupffer cells were activated in vitro with CEA, NCA, and the peptide PELPK. This resulted in release of IL-1beta, TNF-alpha and IL-6. CEA non-producing MIP-101 colon carcinoma cells labeled with 51Cr were incubated on monolayers of ECV-304 human umbilical vein endothelial cells treated with these Kupffer cell derived cytokines or with comparable recombinant human (rH) cytokines. Specific antibodies to the adhesion molecules ICAM-1, VCAM-1, E-selectin and beta2integrin were used to block their functions. A significant enhancement in the adhesion of colorectal carcinoma cells occurred when endothelial cells were stimulated with a very low concentration of Kupffer-cell derived cytokines. Activated endothelium demonstrated significant up-regulation primarily of ICAM-1. The adhesion was blocked by an antibody to ICAM-1. A combination of Kupffer-cell derived cytokines was more effective than IL-1beta or TNF-alpha alone. IL-6 alone did not influence adhesion under our conditions. Our results suggest a mechanism for CEA in the modulation of colorectal carcinoma adhesion to the hepatic endothelium and its enhancement of metastatic potential.
Clin Exp Metastasis 1998 Nov
PMID:Adhesion of colorectal carcinoma cells to the endothelium is mediated by cytokines from CEA stimulated Kupffer cells. 1021 83

Based on the likelihood of antitumor interactions between cytokines and cytotoxic drugs, we designed a pilot study to evaluate feasibility, clinical, pharmacologic, and immunologic effects of concomitantly administered subcutaneous (SQ) recombinant interleukin-2 (r-IL-2) and doxorubicin (ADR) in patients with advanced solid tumors (AST). Patients received one injection of ADR alone (70 mg/m2) and 3 weeks later a combination of r-IL-2 (18 MIU/m2 days 1-5 s.q.) and ADR at the same dose either 3-4 h after the first r-IL-2 injection (arm 1) or 2 days after the last r-IL-2 injection (arm 2). The same combination was repeated every 4 weeks according to the evolution of the disease. Pharmacokinetics were assessed over 48 h after injection of ADR alone and after the first ADR-IL-2 cycle and immunologic monitoring at days 1 and 8 of the first ADR-IL-2 cycle. Tumors were measured at baseline, after ADR alone, and after each ADR-IL-2 cycle until progression. Twenty-one adult patients with various AST including 14 soft-tissue sarcomas (STS) entered the study, 11 in arm 1 and 10 in arm 2. All patients were heavily pretreated; 16 had received an anthracycline-containing chemotherapy regimen. Eleven patients were ADR refractory and 1 ADR resistant. Grade 4 neutropenia occurred in 28, 82, and 40% of patients after ADR alone, ADR-IL-2 in arm 1 and ADR-IL-2 in arm 2, respectively. Mucitis was higher in arm 1 (7 of 11 patients) compared with arm 2 (0 of 10) and ADR alone (0 of 21). SQ injections of r-IL-2 did not affect ADR pharmacokinetics. ADR injection in arm 1 prevented IL-2-induced lymphocyte rebounds in all patients but did not alter qualitatively non-major histocompatibility complex-restricted cytotoxicity. There was no response after ADR alone. Two patients, one in each arm, experienced a prolonged (8 and 5 months) objective response after ADR-IL-2. Both had ADR-refractory STS with a local relapse and metastatic metastases. Interestingly, both patients had unusually elevated TNF-alpha levels before and after the first ADR cycle. Combination ADR-IL-2, although toxic, is feasible and manageable with routine clinical support. r-IL-2 enhanced ADR hematologic and extrahematologic toxicities. The two objective responses observed in these heavily pretreated patients refractory to ADR supports the hypothesis of a modulation of ADR resistance, possibly mediated by means of a mechanism involving TNF-alpha. Elevated baseline TNF-alpha levels could be predictive of response to ADR-IL-2 and deserves further investigation.
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PMID:Combination interleukin-2 and doxorubicin in advanced adult solid tumors: circumvention of doxorubicin resistance in soft-tissue sarcoma? 1033 87

We reported previously that tumor cells isolated from metastases of the in vitro transformed squamous cell carcinoma line Pam 212 exhibit an elevation in constitutive production of proinflmmatory cytokines interleukin (IL)-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor, and KC (the murine homologue of chemokine Gro-alpha). The basis for constitutive expression of these cytokines after tumor progression in vivo is unknown. Regulation of the expression of these proinflammatory cytokines involves transcription factor nuclear factor kappaB (NF-kappaB), which can be activated by cytokines such as tumor necrosis factor (TNF)-alpha. In this study, we compared the constitutive and TNF-alpha-induced expression of proinflammatory cytokines in parental Pam 212 and metastatic LY-2 and LY-8 cell lines and determined the relationship of cytokine expression to activation of NF-kappaB. We found that the metastatic cell lines exhibited an increase in constitutive and TNF-alpha-inducible expression of proinflammatory cytokines when compared with parental Pam 212 cells. The increased cytokine expression was associated with an increase in constitutive and TNF-alpha-inducible activation of NF-kappaB as demonstrated by electrophoretic mobility shift assay and luciferase-reporter gene assay. Constitutive nuclear localization of NF-kappaB p65 was observed in LY-2 and LY-8 cells in culture and in tumor specimens but rarely in Pam 212 cells, consistent with the constitutive activation of NF-kappaB in tumor cels after selection in vivo. Induction of NF-kappaB by TNF-alpha was inhibited by the addition of protease inhibitors calpain inhibitor I and N-tosyl-phechloromethyl ketone and antioxidant 1-pyrrolidinecarbodithioic acid, whereas constitutive activation of NF-kappaB and cytokine KC mRNA expression was inhibited by N-tosyl-phechloromethyl ketone alone. Overexpression of a human Ikappa(B)alpha dominant suppresser in Pam 212 cells inhibited TNF-alpha-induced NF-kappaB binding activity and KC expression. These data indicate that activation of NF-kappaB contributes to increased expression of proinflammatory cytokines during metastatic tumor progression of squamous cell carcinoma, and that distinct mechanisms may be involved in the regulation of constitutive and TNF-alpha-induced activation of NF-kappaB in squamous cell carcinoma.
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PMID:The host environment promotes the constitutive activation of nuclear factor-kappaB and proinflammatory cytokine expression during metastatic tumor progression of murine squamous cell carcinoma. 1041 16

Our laboratory has recently developed a lipopolyplex consisting of DOTAP:cholesterol liposomes, protamine sulfate, and plasmid DNA (LPD) that provides improved systemic gene delivery compared with lipoplex following tail vein injection in mice. Because endothelial cells are the primary cells transfected in the lung, it was hypothesized that LPD might be an effective vector for gene therapy of pulmonary metastases. This hypothesis was examined by testing the efficacy of cytokine (IL-12) and tumor suppressor (p53) strategies for treatment of an experimental model of pulmonary metastasis in C57Bl/6 mice. Surprisingly, all LPD complexes including those containing an 'empty' plasmid provided a potent (>50% inhibition) and dose-dependent antitumor effect, compared with dextrose-treated controls. In addition, i.v. injections of LPD containing 'empty' plasmid also inhibited tumor growth in a subcutaneous model of C3 fibrosarcomma. The antitumor effect correlated well with a strong and rapid proinflammatory cytokine (TNF-alpha, IL-12 and IFN-gamma) response. Naked plasmid DNA did not elicit a cytokine response and the response required assembly of DNA into a lipoplex or the LPD lipopolyplex. Except for the heart, elevated levels of cytokine were observed in all organs (lung, liver, kidney and spleen) where LPD is known to have gene transfer activity. Methylation of immune-stimulatory CpG motifs in the plasmid component of LPD inhibited the proinflammatory cytokine response as well as the antitumor effect of LPD in both tumor systems. This suggests that i. v. administration of LPD elicits a systemic proinflammatory cytokine response that mediates the antitumor activity of the lipopolyplex. In addition, the antitumor activity was not observed in SCID mice suggesting a possible role for B or T lymphocytes in the antitumor response initiated by LPD. This represents the first demonstration that an intravenously administered cationic liposome-based nonviral vector can promote a systemic, Th1-like innate immune response. The immune adjuvant properties of LPD might prove to be suitable for delivering tumor-specific antigens in the context of DNA vaccination.
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PMID:LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth. 1060 82

Newcastle Disease Virus (NDV), an agent with interesting immune stimulatory and anti-tumor activity, was investigated for its capacity to activate anti-tumor activity in murine macrophages in vitro and in vivo. Direct macrophage activation was seen under a variety of experimental conditions using two different strains of NDV, different sources of macrophages (spleen and peritoneum) and different strains of mice (DBA/2, C57BL/6, 615). Various macrophage enzymes (ADA, iNOS, lysozyme, acid phosphatase) became upregulated and anti-tumor effector molecules such as nitric oxide (NO) and TNF-alpha were found in the supernatant. NDV activated macrophages performed anti-tumor activity in vitro such as anti-tumor cytostasis and anti-tumor cytotoxicity. The cytotoxic anti-tumor activity was broad and active against all tumor lines tested including mammary carcinoma, lung carcinoma, mastocytoma and immune escape variants (lymphoma). Macrophage activation via BCG/LPS also caused a broad range anti-tumor cytotoxic activity while activation via mixed lymphocyte culture conditioned medium had restricted anti-tumor activity. Anti-tumor activity of NDV activated macrophages could be transfered in vivo. Transfer of macrophages which had not been appropriately activated exerted either no effect or a tumor growth augmenting effect. Repeated intravenous transfer of NDV activated macrophages exerted a significant suppressive effect on pulmonary metastases in a mammary carcinoma tumor model as well as in a lung carcinoma model. Taken together these results demonstrate that NDV can strongly activate macrophages to perform anti-tumor activities in vitro and in vivo.
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PMID:Newcastle disease virus activates macrophages for anti-tumor activity. 1063 82

This study focuses on the specific CD4+ T cell requirement for optimal induction of cytotoxicity against MHC class II negative autologous tumors (AuTu) collected from patients with various types of cancer at advanced stages. CD4+ T cells were induced in cultures of cancer patients' malignant effusion-associated mononuclear cells with irradiated AuTu (mixed lymphocyte tumor cultures (MLTC)) in the presence of recombinant IL-2 and recombinant IL-7. Tumor-specific CD4+ T cells did not directly recognize the AuTu cells, but there was an MHC class II-restricted cross-priming by autologous dendritic cells (DCs), used as APC. CD8+ CTL, also induced during the MLTC, lysed specifically AuTu cells or DCs pulsed with AuTu peptide extracts (acid wash extracts (AWE)) in an MHC class I-restricted manner. Removal of CD4+ T cells or DCs from the MLTC drastically reduced the CD8+ CTL-mediated cytotoxic response against the AuTu. AWE-pulsed DCs preincubated with autologous CD4+ T cells were able, in the absence of CD4+ T cells, to stimulate CD8+ T cells to lyse autologous tumor targets. Such activated CD8+ T cells produced IL-2, IFN-gamma, TNF-alpha, and GM-CSF. The process of the activation of AWE-pulsed DCs by CD4+ T cells could be inhibited with anti-CD40 ligand mAb. Moreover, the role of CD4+ T cells in activating AWE-pulsed DCs was undertaken by anti-CD40 mAb. Our data demonstrate for the first time in patients with metastatic cancer the essential role of CD4+ Th cell-activated DCs for optimal CD8+ T cell-mediated killing of autologous tumors and provide the basis for the design of novel protocols in cellular adoptive immunotherapy of cancer, utilizing synthetic peptides capable of inducing T cell help in vivo.
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PMID:Tumor-specific CD4+ T lymphocytes from cancer patients are required for optimal induction of cytotoxic T cells against the autologous tumor. 1072 53

We describe a 27-year-old woman with systemic chemoresistant and radioresistant metastatic disease secondary to a recurrence of human papillomavirus (HPV) 18 infected cervical adenocarcinoma of the uterine cervix who received adoptive transfer of peripheral blood T cells stimulated with HPV 18 E7-pulsed autologous dendritic cells (DC). Extensive in vitro characterization of the DC-activated T cells derived from peripheral blood mononuclear cells (PBMC) included phenotypic analysis, cytotoxicity and intracellular cytokine production. High cytotoxicity activity was observed by CD8+T cells against autologous tumor cells, but not against NK-sensitive K562 cells, autologous Con-A lymphoblasts, or autologous Epstein-Barr virus-transformed lymphoblastoid cells. Blocking studies demonstrated that lytic activity was significantly inhibited by pretreatment of tumor targets with MAb specific for HLA class I as well as that of effector cells with anti-CD8, anti-LFA-1, but not anti CD3 MAb. Two-color flow cytometric analysis of the cytotoxic T cells revealed that a significant proportion of CD8+ cells was also CD56+. These double positive CTLs were thymically derived, as shown by expression of heterodimeric CD8 molecules (alpha/beta CD8) and were endowed with high cytotoxic activity against tumor cells. Analysis of intracellular cytokine expression showed that the striking majority of E7-pulsed DC activated CD8+ T cells strongly expressed IFN-gamma, TNF-alpha and IL-2 but not IL-4. The patient received two infusions of cytotoxic tumor-specific T cells at 2 week intervals, and in vivo distribution of the T cells was followed by 111 oxine labeling and serial gamma camera imaging. Persistent accumulation of radioactivity in the lungs, which harbored extensive metastatic disease, was detected up to 120 hrs after the infusion. Taken together, these results illustrate the potential of E7-specific and tumor-specific CTL-based immunotherapy for the treatment of patients with invasive cervical cancer.
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PMID:Development, characterization and distribution of adoptively transferred peripheral blood lymphocytes primed by human papillomavirus 18 E7--pulsed autologous dendritic cells in a patient with metastatic adenocarcinoma of the uterine cervix. 1072 12


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