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 macrophage activator muramyl tripeptide-phosphatidyl ethanolamine (MTP-PE) was infused in liposomal form in 14 metastatic cancer patients (4 mg i.v. during 30 min twice weekly for 12 weeks). Clinical, pharmacokinetic and immunological parameters were studied before and 0.5, 2, 4, 24 and 72h after start of drug infusion in week 1, 4, 8 and 12. No tumor regressions were seen. Tumors progressed in 11 patients, in 4 of them within 2 months; 3 patients had stable disease. The intensity and frequency of side effects (fever and nausea) diminished from week 1 to 12. The rate of disappearance of total and free MTP-PE from blood was rapid and mean serum concentration-time curves remained unchanged throughout 12 study weeks. MTP-PE caused a marked increase of serum TNFa, IL-1 receptor antagonist (IL-1ra) and IL-6 in week 1, but not thereafter. In contrast, MTP-PE caused a persistent, 2-fold increase in serum neopterin and young forms of granulocytes (bands) during week 1 to 12. Before therapy, monocyte tumor cytotoxicity and in-vitro monocyte derived TNFa, IL-1 beta and IL-6 production were low in 9 patients (group L, < 15%) and high in 5 patients (group H, > 40%). Monocyte cytotoxicity and in-vitro cytokine production was transiently enhanced in week 1 in group L, it declined under therapy in group H. In conclusion, MTP-PE induced marked initial immunomodulation; the extent of the ex vivo monocyte cytokine and tumor cytotoxic response was dependent on pre-therapy cell activity. A decrease of the cytokine and IL-1ra response during prolonged therapy contrasted with a persistent increase of neopterin and juvenile blood granulocytes. The long lasting biologic effects may be relevant to direct future clinical studies with liposomal MTP-PE in an adjuvant setting.
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PMID:Pharmacokinetics and immunomodulatory effects on monocytes during prolonged therapy with liposomal muramyltripeptide. 806 81

Adoptive immunotherapy using in vitro activated T-cells can mediate the destruction of metastatic tumor deposits in animal models. These antitumor effector cells can be generated from mice with subcutaneous tumor by the sequential in vitro activation of tumor-draining lymph node (TDLN) cells with monoclonal antibody to the T-cell receptor complex (anti-CD3) and expansion in low concentrations of interleukin-2 (IL-2). In this animal model, the concomitant presence of visceral tumor can suppress the sensitization of tumor-reactive TDLN cells. We investigated whether IL-1 alpha added during in vitro activation and/or expansion of TDLNs could augment their antitumor activity in adoptive therapy. Mice were inoculated subcutaneously with MCA 205 tumor. TDLN cells were harvested and activated in vitro with 1 microgram/ml anti-CD3 for 2 days (anti-CD3 phase), followed by expansion in 10 U/ml IL-2 for 3 days (IL-2 phase). Experimental cultures had IL-1 (10-10,000 U/ml) added in either or both phases. After the 5-day culture period, cells were counted to determine in vitro cellular proliferation and then adoptively transferred to mice bearing 3-day established lung metastases to assess in vivo antitumor efficacy. IL-1 added during the anti-CD3 or IL-2 phase did not alter in vitro cellular proliferation. The presence of IL-1 during the anti-CD3 phase led to the generation of cells that were significantly more therapeutically efficacious than cells generated in the absence of IL-1. The effect of IL-1 during anti-CD3 activation appeared to be dose dependent in the concentration range 10-1,000 U/ml. The addition of IL-1 during the IL-2 phase only did not enhance the antitumor reactivity of the activated cells. The beneficial effect of IL-1 during the anti-CD3 activation phase was specific for the tumor against which the TDLN had been initially sensitized; also, there was no evidence that non-tumor bearer lymphocytes developed significant antitumor reactivity when "activated" with IL-1 and anti-CD3. Furthermore, addition of IL-1 during the anti-CD3 activation phase abrogated suppression induced by the concomitant presence of lung metastases during subcutaneous tumor growth. IL-1 appears to up-regulate the in vitro activation of tumor-reactive lymphocytes derived from TDLN, in both the presence and the absence of visceral metastases.
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PMID:Effect of interleukin-1 alpha on the in vitro activation of tumor-draining lymph node cells for adoptive immunotherapy. 808 55

In this study, we describe the origin and characterization of a new metastatic tumor cell line (p11-R-Eb) obtained after i.p. passages of the nonmetastatic Eb lymphoma cells into DBA/2 mice. The p11-R-Eb cells exhibited the same morphology and in vitro growth properties and chromosome markers as the original Eb cells. FACS analysis of the p11-R-Eb cells also revealed a close similarity to the Eb cells. Moreover, the p11-R-Eb cells were specifically killed by anti-Eb cytotoxic lymphocytes. In spite of all these characteristics of the Eb line, p11-R-Eb cells metastasized to the liver when injected i.v. or s.c. in DBA/2 mice. Peritumoral interleukin (IL)-2 treatment resulted in a potent antitumor response in DBA/2 mice transplanted s.c. with p11-R-Eb cells. In contrast, the same IL-2 regimen did not significantly increase the survival time of mice transplanted with the highly metastatic ESb cell line. Combined IL-1/IL-2 treatments of established p11-R-Eb tumors resulted in a synergistic antitumor effect and in tumor regression in 70% of the injected mice. Similarly, combined peritumoral treatment with IL-1 and interferon-alpha/beta, which were poorly effective or ineffective as single cytokine therapy, resulted in a marked antitumor effect, and 30% of the mice were cured. Spleen cells from IL-1/IL-2-treated p11-R-Eb-cell-injected mice showed a marked antitumor activity when assayed in a Winn assay with homologous tumor cells. This antitumor activity was eliminated by preincubation of spleen cells with antibodies to CD4 and complement and markedly inhibited by anti-asialo GM1 antibodies. P11-R-Eb cells represent, therefore, a new tumor model which may be useful for investigating the relevant mechanisms which need to be activated to achieve a potent antitumor response to cytokine therapy in the DBA/2 mouse host.
Invasion Metastasis 1993
PMID:Isolation and characterization of a metastatic Eb-like tumor variant highly responsive to interleukin (IL)-2 and to combination cytokine therapy with IL-2/IL-1 beta and IL-1 beta/interferon-alpha/beta. 811 75

This study examined the ability of the recombinant human interleukin 1 receptor antagonist (IL-1ra) to block interleukin 1 (IL-1)-mediated experimental metastases from the A375M human melanoma. In vivo, IL-1ra administrated at concentrations > or = 200 times IL-1 significantly inhibited the increase in lung colonies induced by IL-1 in nude mice. The response to IL-1 was significantly inhibited when IL-1ra was administered simultaneously with or 1 to 3 h before IL-1. In vitro, the incubation of IL-1-activated endothelial cells with IL-1ra prevented the increase in adhesion of A375M melanoma cells. At the same experimental conditions, IL-1ra inhibited the augmented expression of the intracellular and vascular cell adhesion molecules 1 and E-selectin induced by IL-1 on endothelial cells. Lipopolysaccharide, an IL-1 inducer, increased the number of lung colonies in nude mice. IL-1ra injected with or 1 h after lipopolysaccharide inhibited this augmentation, suggesting a role for host-produced IL-1 in metastasis formation.
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PMID:Interleukin 1 receptor antagonist inhibits the augmentation of metastasis induced by interleukin 1 or lipopolysaccharide in a human melanoma/nude mouse system. 826 95

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.
Cancer Metastasis Rev 1993 Sep
PMID:Growth factor independence and growth regulatory pathways in human melanoma development. 828 9

Interleukin-2 (IL-2) therapy is dose limited by a severe vascular leak with resulting systemic and pulmonary toxicity. Although recognized as a mediator of septic shock and vascular leak, the relative role of IL-1 in IL-2 toxicity is unclear. We evaluated the effect of IL-1 receptor antagonist (IL-1ra) on IL-2 lethality, pulmonary vascular leak, and treatment of pulmonary metastases in a murine model. In vivo induction of mRNA for IL-1 alpha was evaluated in liver by Northern blots after 0, 5, 8, and 11 doses of IL-2 in C3H/HEN mice. The expression index for the IL-1 alpha gene increased from 0.16 to 0.74 after 5 doses of IL-2, and further increased to 1.04 after 11 doses of IL-2. C3H/HEN mice (n = 56) were randomized to receive phosphate-buffered saline (PBS), IL-1ra high dose (HD), or IL-1ra low dose (LD) by continuous subcutaneous infusion via Alzet mini-pumps. The biologic effectiveness of the dose and administration of IL-1ra was determined by the ability to block IL-1-induced IL-6 production in vivo. Mean serum IL-6 levels 3 hr after intraperitoneal IL-1 alpha (10 micrograms/kg) were: PBS, 3730 +/- 526 (mean +/- SEM pg/ml); IL-1ra (LD), 1156 +/- 398; and IL-1ra (HD), 594 +/- 30 (P < 0.01, IL-1ra HD or LD vs PBS). Pulmonary vascular leak was measured by iv I125 albumin after 8 doses of IL-2 (100,000 U ip q 8 hr).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:IL-1 receptor antagonist (IL-1ra) augments IL-2-induced pulmonary vascular leak. 833 27

The production of cytokines by tumor cells has been suggested as the molecular perturbation responsible for the development of malignant tumors. The behavior of tumor cells in animals is presumed to be affected by these factors, which include such hematopoietic cytokines as GM-CSF, IL-1, and IL-6. Here, we report findings demonstrating that GM-CSF is produced by many murine transplantable tumors with metastatic ability in the lungs, and IL-6 and/or IL-1 are produced by the tumors metastatic in the liver. We discuss the notion that the particular organ or organs in which tumor cells metastasize may be associated with the type of cytokines produced by the tumors. Metastatic spread requires interactions of tumor cells with components of the extracellular matrix of host tissues or with other cells, almost all of which depend on cell surface determinants such as cell adhesion molecules. We also discuss the possibility that the expression and adhesive potentials of adhesive protein (CD44) may be regulated by the cytokine (GM-CSF) excreted from the tumor cells. We then emphasize the possibility that both gene expression of cytokines and adhesive proteins play a critical role in tumor metastasis and in determining organ specificity in metastasis.
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PMID:[The roles of cytokine in organ-specific tumor metastasis]. 834 46

Bone marrow-derived dendritic cells (DC) function as antigen presenting cells (APC). Little is known of their capability to exert regulatory effects on the epithelial cells in various organs. It was reported that injection of the bacterial cell wall preparation OK432 into mouse skin resulted in the activation of IL-1 and TNF-alpha gene expression in Langerhans cells (LC). In addition to studies on LC/DC in normal tissues, numerous investigators reported that DC can infiltrate primary tumors in experimental animals and humans and cause tumor regression. Human tumors in which DC infiltrates were detected did not develop metastases. The presence of DC in tumor biopsies correlated with the survival of patients. Absence of DC from tumors suggested poor prognosis. Activation of DC by immunomodulators seemed to enhance the ability of DC to prevent the development of metastatic tumors. Information on the role of DC as anticancer cells was recently reviewed, but information on the molecular basis of the anticancer activity of DC is needed. Another problem which needs to be answered is the ability of some tumors to prevent DC from entering the tumor. It is possible that DC and tumor cells, interact and counteract by releasing cytokines which abrogate tumor cells or DC, respectively. In the present analysis the DC responses to extrinsic cytokines and immunomodulators will be discussed. The ability of DC to induce the expression of the nitric oxide synthase gene will be discussed in relation to the anticancer activity of DC and in comparison with the reported anticancer activity of macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dendritic cell activity against primary tumors: an overview. 835 60

A single dose of inactivated streptococci (OK-432) was injected into the popliteal lymph nodes of male CDF1 mice and its effects on popliteal, inguinal, and para-aortic lymph node cells and spleen cells were investigated and compared with the effects of subcutaneous injections of the same dosage of OK-432. Regional lymph node cells and spleen cells obtained from intralymphnodally injected mice lysed not only natural killer (NK)-sensitive YAC-1 cells, but also NK-resistant P-815 and meth-A cells. Lysis of target cells was inhibited when effector cells were treated with anti-Thy-1.2 or anti-Lyt-2.2 monoclonal antibody and complement, but no inhibition was apparent after treatment with anti-asialo-GM1 or anti-Lyt-1.2 antibody and complement. These results suggest that the effector cells are lymphocyte-activated killer (LAK) cells. An enhanced capacity of lymph node cells to produce cytokines, tumor necrosis factor and interleukin 1 upon restimulation with lipopolysaccharide was found only in intralymphnodally injected mice. Thus, the induction of LAK-like cells and cytokine production in regional lymph nodes and spleen cells by the intralymphnodal administration of OK-432 should be effective for the inhibition or treatment of lymph node metastases.
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PMID:Enhancement of LAK-like activity and cytokine induction in regional lymph nodes and spleen cells of mice after intralymphnodal injection of OK-432, a killed streptococcal preparation. 835 67

Hypercalcemia is relatively frequent in malignancy with or without osteolytic bone metastases. It is thought that neoplastic cells may secrete substances which not only stimulate osteoclastic activity but are also capable of modifying the absorption, excretion, and resorption of calcium and phosphate ions. Since 1987, we have studied 24 breast cancer patients with hypercalcemia (22 with bone metastases and two without). The group of 22 patients with bone metastases were divided into two subgroups. The first consisted of 10 patients with high serum levels of humoral factors, such as parathyroid hormone-related protein (PTHrP), and/or prostaglandin E2 (PGE2) and/or interleukin 1 (IL-1), and high levels of bone markers, such as alkaline phosphatase, bone Gla protein and urinary hydroxyproline. The second subgroup consisted of 12 patients with high levels of bone markers alone. Bone histologic analysis showed an osteoclastic activation surrounding metastatic tumor tissue in six out of 10 patients of the first subgroup, while an evident osteolysis caused by the tumor cells was noted in seven out of 12 patients of the second subgroup. The two patients without bone metastases showed normal biochemistry and bone histologic examination. The authors, having tried to explain the pathogenesis of hypercalcemia, emphasize the importance of humoral factors secreted by tumor cells as a direct or indirect cause of hypercalcemia. The origin of hypercalcemia remains unclear in two patients without bone metastases.
Clin Exp Metastasis 1993 Sep
PMID:Hypercalcemia in breast cancer. 837 11


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