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)

A body of evidence that vascular-mediated damage occurs in murine tumours after many existing forms of anti-tumour therapy is rapidly accumulating (see Gray Conference Proceedings edited by Moore & West, 1991). Rapid conventional screens of cells in vitro or using leukaemias of lymphomas will not detect this mode of action and such screens will therefore miss effective agents. A change in the approach to experimental cancer therapy is needed to ensure that this important new avenue is fully investigated. Solid tumours will need to be studied and the importance of specific tumour cell biochemistry (e.g. on tissue factor procoagulant activity), of endothelial status and the immunocompetence of the host are all likely to be important. It is a subject of considerable debate at present whether transplanted subcutaneous mouse tumours are adequate models and whether they will reflect the response of spontaneous tumours, or even of transplants into other sites. Xenografts are not likely to be appropriate if the immuno-suppressed hosts lack the cells needed for the cytokine component of the pathway. The strategy of design and screening of new agents, for scheduling of existing agents and particularly the sequencing of adjunctive therapies are likely to be completely different for the "direct" tumor cell or "indirect" vascular-mediated approaches. It may eventually be appropriate to combine vascular manipulation with direct cytotoxicity aimed at malignant cells but the two mechanisms must be recognized as distinct entities and considered separately before attempting to coordinate them. It is important therefore to identify the "hallmarks" of vascular mediated injury and the means by which this can be distinguished from direct cell kill. These may be detectable in the tumour response but clues can also be gained from the side effects that are seen in normal tissues both with existing and with novel therapies (Figure 7). The appeal of vascular-mediated ischaemic therapy is that it is systemic and will have the potential of being effective on any tumour with a newly evoked vascular network, i.e. of about 1 mm in diameter, but it will be even more effective on large tumours than on small. Thus it should affect both large primary tumours and disseminated small metastases. The studies with many different anti-cancer agents have illustrated the potential complexity of responses that can appear to cause tumour cell death by collapse or occlusion of the blood supply. They have also focused attention on features of disparate agents, e.g. TNF, FAA, PDT, which may share similar pathways. No single feature of neovasculature can be highlighted as the sole route by which such antivascular therapy should be targeted. Rapid proliferation of the endothelial cells may prove to be a target, but it also influences differentiation characteristics, so that the immature cells will function abnormally. The permeability of these poorly formed vessels may lead to extravasation of proteins leading to increase interstitial pressures and by this means to an imbalance between intravascular and extravascular pressures and hence to collapse of the thin-walled vessels. Changes in systemic blood pressure, cardiac output, viscosity or coagulation and especially a redistribution of regional perfusion would all have differential effects in tumours and normal vessels. Clearly both vascular patho-physiology and the complexity of endothelial cell function and its imbalance in neovasculature will be important in understanding the mechanism of action of antivascular strategies. This very challenging boundary between oncology and a number of other medical and biological fields promises to lead to altered attitudes to existing therapies and the discovery of completely new classes of anti-cancer agents. The next decade should translate into clinical benefit for patients if the progress in this field continues to be as rapid as it has been in the late eighties. We must now determine what characteristics make one tumour more sensitive than another to agents such as heat, PDT, cytokines and FAA, and learn how to extrapolate from those rodent tumours to the human.
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PMID:Review article: angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy. 768 69

A static adhesion assay employing 6-carboxy-3',6'-diacetylfluorescein (6-CFDA) as a fluorescent marker has been developed to study the interactions of tumour cell lines with endothelial monolayers. This assay allows simple, safe quantification of cell-cell adhesion using living cells. It has been used to demonstrate that the integrin adhesion molecule VLA-4 mediates the attachment of RPMI-7951 melanoma cells to human umbilical vein endothelial cells (HUVEC) which have been activated by TNF alpha. In addition, MDA-MB-231 breast adenocarcinoma cells display greater adhesion to microvessel endothelial cells than to large vessel endothelial cells.
Clin Exp Metastasis 1995 May
PMID:A simple fluorometric assay for quantifying the adhesion of tumour cells to endothelial monolayers. 775 Feb 3

Recombinant tumor necrosis factor-alpha (rTNF alpha) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNF alpha is hampered by severe systemic side-effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 10-fold less than the efficient dose in animals. Isolation perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response, compared with 52% after ILP with melphalan alone. Release of nanograms levels of TNF alpha in the systemic circulation was evident but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and electively lyses the tumor endothelial cells while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in man.
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PMID:Rationale for using TNF alpha and chemotherapy in regional therapy of melanoma. 780 92

Isolated perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response compared with 52% after ILP with melphalan alone. Leakage and release of nanograms levels of TNF alpha in the systemic circulation can be abrogated in most patients by low pump flow, continuous leak monitoring, extensive washout, and limb massage. In case of unavoidable leakage, appropriate intensive care results in minimal toxicity. The ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in humans.
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PMID:Clinical experience with high-dose tumor necrosis factor alpha in regional therapy of advanced melanoma. 789 25

Models for experimental metastasis were established to investigate the influence of rmTNF on tumor-colony formation in the liver. Highly metastatic lymphoma tumor cells were either injected i.v. or inoculated s.c. to form spontaneous metastases. In both systems, administration of rmTNF to the animals led to significant enhancement of the number of liver metastases in comparison with control groups. The number of metastatic tumor-cell colonies at an early stage of metastasis was increased, as well as the number of surface metastases in a late stage. Consequently, TNF-treated animals revealed a higher mortality. The optimal time for TNF to exert this metastasis-enhancing effect was found to be 7 days after tumor inoculation. In vitro adhesion of the lymphoma tumor cells to a mouse endothelioma cell line was strongly inhibited by monoclonal antibodies interfering with the interaction of VCAM-1 with VLA-4. These results support and extend earlier results with a fibrosarcoma lung colonization model. In addition, they show that stimulation of the immune system in tumor-bearing hosts activates tumor-promoting pathways, in addition to having possible beneficial effects.
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PMID:Promotion of experimental liver metastasis by tumor necrosis factor. 789 59

Even though alterations in receptor and nonreceptor kinases are involved in the development of human cancer, many cancer cell lines still retain their responsiveness to growth factors. We have investigated the hypothesis that cellular signaling events regulate the sensitivity of cancer cells to chemotherapeutic agents. In 2008 human ovarian carcinoma cells, activation of a number of different transduction pathways resulted in a 2 to 4-fold increase in the sensitivity to cisplatin. These signaling events include pathways activated by the epidermal growth factor (EGF) receptor, tumor necrosis factor alpha (TNF alpha) receptor, bombesin receptor, protein kinase A (PKA), and protein kinase C (PKC). Enhanced sensitivity to chemotherapeutic agents is presumed to be mediated by phosphorylation of critical target protein(s). beta-tubulin has been identified as one such target for the protein kinase signaling cascade. For other signal transduction pathways the key substrates that regulate drug sensitivity have not yet been identified. Recent work has shown that DNA damaging agents activate signaling cascades one of which involves the Src, Ras, and Raf proteins as intermediates and results in induction of a number of genes, including c-fos, c-jun, and the growth arrest and DNA damage-inducible (gadd) genes. This signaling cascade has been shown to involve activation of protein kinase C and to have a protective function. With the growing understanding of how signaling events relate to damage response and drug sensitivity, new and potentially useful strategies for modulating drug sensitivity are evolving.
Cancer Metastasis Rev 1994 Jun
PMID:Signaling and drug sensitivity. 792 49

The number of NK cell in peripheral blood, plasma levels of TNF and PGE2 were determined in 67 patients with esophageal squamous cell carcinoma of various stages (II, III, IV) before and after operation, in 22 postoperative follow-up patients and in 20 healthy volunteers. The findings showed a significantly decreased number of NK cells and higher levels of TNF and PGE2 in patients with cancer compared with the healthy control subjects (P < 0.01). The three parameters were found to be closely related to the TNM staging of the tumors. The number of circulating NK cells increased and the plasma TNF and PGE2 levels decreased in patients after radical operation after compared with the preoperative ones, but didn't reach the normal levels. Those who developed tumor recurrence or metastases had a fall in NK cell number and a rise in the plasma TNF and PGE2 levels compared with disease-free patients and normal controls. Moreover, the decrease of NK cell number and increase of TNF, PGE2 levels occurred 2-8 months (mean 5 months) before relapse or metastases was clinically diagnosed. Additionally, the NK cell number was found to be negatively correlated with the serum PGE2. We would conclude that determination of number of circulating NK cells and plasma TNF and PGE2 concentration is of great significance in assessing prognosis and monitoring early tumor recurrence or metastasis.
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PMID:[Pre- and postoperative NK cell number and plasma levels of TNF and PGE2 in patients with esophageal carcinoma and their clinical significance]. 792 64

High levels of the macrophage activation marker neopterin have been described in metastatic cancer patients. Since macrophages may either counteract or stimulate tumor development, it is important to establish which macrophage activity is mainly related to neopterin release. The present study was carried out to evaluate neopterin levels in metastatic solid tumor patients in respect with the antitumor macrophage cytokine TNF and with soluble IL-2 receptor (SIL-2R), whose secretion is stimulated by macrophages and it is associated with the immunosuppressive status of cancer patients. The study included 35 patients with metastatic solid neoplasms. Serum levels of neopterin, TNF and SIL-2R were measured in blood samples collected during the morning. Abnormally high concentrations of neopterin were seen in 18/35 (51%) patients. Patients with high levels of neopterin showed significantly higher concentrations of SIL-2R than those with normal neopterin values, whereas no difference was found in TNF levels. This study would suggest that the increased secretion of neopterin may reflect macrophage-mediated immunosuppression in metastatic solid neoplasms, rather than to be associated with the antitumor activity of macrophages.
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PMID:A study of interactions among markers of macrophage functions in metastatic solid tumors: neopterin levels in relation to those of tumor necrosis factor-alpha and of soluble interleukin-2 receptors. 797 92

We report an update of a multi-centre pilot study previously published. Fifty-three patients (42 women, 11 men) were accrued between October 1988 and May 1992: 34 had stage IIIA, 15 had stage IIIAB, and four had stage IV melanoma. Most of them had more than five in-transit metastases; 50% had been previously treated by regional chemotherapy. Protocol included 90-min isolation perfusion at 40 degrees C with 2-4 mg rTNF-alpha, 0.2 mg rIFN-gamma and 10/13 mg/l melphalan. We prevented severe TNF systemic side effects by administration of dopamine and fluid loading. There has been no toxic death and the toxicity remained acceptable, with only one multi-organ failure (MOF) and no prolonged shock. Response rates remained very high, with 90% complete remission, 10% partial response and no failure. With a median follow-up time of 26 months, there were 12 regional recurrences, 15 distant metastases and nine local and distant recurrences. The median overall survival has been 28 months. We conclude that high-dose rTNF-alpha associated with melphalan in isolation perfusion is the therapy of choice for in-transit melanoma metastases.
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PMID:Isolated perfusion of the limb with high-dose tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and melphalan for melanoma stage III. Results of a multi-centre pilot study. 803 91

The growth of a poorly immunogenic methylcholanthrene (MCA)-induced murine (m) sarcoma genetically engineered to secrete human (h) TNF-alpha (MCA-102-hTNF) was studied. MCA-102-hTNF tumor cells were implanted in animals bearing three- or 7-day pulmonary metastases established with the parental line MCA-102-WT (wild type). This model approximates the clinical situation in which patients with metastatic cancer would be vaccinated with autologous tumor genetically modified to stimulate the host immune response. Reduction in the number of pulmonary metastases was occasionally seen but was not consistently reproducible. Other cytokine-producing tumors had either no effect on distant pulmonary metastases (mIL-4, IFN-gamma) or a mild, inconclusive effect similar to hTNF-alpha (mTNF-alpha). Significant growth inhibition of MCA-102-hTNF was noted in animals bearing pulmonary metastases. This inhibition was: 1) tumor specific (regression occurred only in animals bearing pulmonary metastases from the same parental line), 2) TNF specific (it was inhibited by in vivo administration of anti hTNF mAbs), 3) dependent on cellular immunity (immune-depletion with anti-CD4 or CD8 mAbs permitted growth). Tumor-infiltrating lymphocytes (TIL) could not be grown from MCA-102-WT or MCA-102-hTNF tumors nor from MCA-102-WT subcutaneous implants in mice bearing MCA-102-WT pulmonary metastases. However, TIL could be grown from hTNF-secreting tumors implanted in mice bearing MCA-102-WT metastases. These TIL were therapeutic against established lung metastases from the parental tumor in adoptive immunotherapy models. These studies suggest a strategy for using gene modified tumors for the therapy of established cancer.
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PMID:Treatment of established lung metastases with tumor-infiltrating lymphocytes derived from a poorly immunogenic tumor engineered to secrete human TNF-alpha. 814 31


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