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)

Interleukin 7 (IL-7) is a 25-kD cytokine that was initially described as a pre-B cell growth factor. This cytokine has also been shown to have T cell proliferative and differentiation effects. In this report, we demonstrate that antitumor cytotoxic T lymphocytes (CTL) generated by secondary in vitro sensitization of draining lymph node cells in IL-7 are effective in treating 3-day syngeneic methylcholanthrene (MCA) sarcoma pulmonary metastases in mice. In vivo titrations comparing IL-7 to IL-2 antitumor CTL show that they have equivalent potency in adoptive immunotherapy. IL-7 antitumor CTL generated against MCA sarcomas of weak immunogeneity are also tumor specific in their in vivo efficacy. This study represents the first successful use of a cytokine other than IL-2 for the generation of cells with in vivo efficacy in cellular adoptive transfer.
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PMID:Interleukin 7 generates antitumor cytotoxic T lymphocytes against murine sarcomas with efficacy in cellular adoptive immunotherapy. 174 82

Increasing evidence suggests that an intimate correlation may exist between the production of a cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF) and the ability to metastasize spontaneously in the lungs in murine transplantable tumors. In the present study, we further examined the cytokine production by tumor cells with the ability to metastasize in the liver. Four out of 8 test tumors, which produced metastasis in the lungs but not in the liver, exhibited the ability to produce GM-CSF activity in culture. Three other tumors produced metastasis in the liver but not in the lungs. These tumor cells exhibited no ability to produce GM-CSF, but two of them expressed an interleukin-6 (IL-6) mRNA and also produced IL-6 activity in the culture fluids. One of the two IL-6-producing tumors and the remaining liver metastatic tumor produced interleukin-1 (IL-1) as revealed by bioassay and neutralization test. In the tumor cells producing pulmonary metastasis, neither IL-6 gene expression nor IL-1 production could be detected. The last test tumor, which produced no metastasis either in the lungs or liver, produced neither GM-CSF, IL-1 nor IL-6. Furthermore, injection of antisera reactive to recombinant murine IL-6 caused a marked decrease of the number of liver metastases of an IL-6-producing tumor, but not lung metastases of a GM-CSF-producing tumor, which could be markedly inhibited by injection of anti-recombinant murine GM-CSF sera. These results suggest the possibility that there may be a correlation between the cytokines produced by tumor cells and their organ specificity in spontaneous metastasis, and also indicate that these tumor models may provide a useful tool for studies on the role of cytokines in tumor metastasis.
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PMID:Murine tumor cells metastasizing selectively in the liver: ability to produce hepatocyte-activating cytokines interleukin-1 and/or -6. 175 86

Peritumoral injection of relatively low doses of either mouse interferon (IFN)-alpha/beta (10,000-20,000 units/injection) or of recombinant human interleukin-1 (IL-1) beta (125-250 ng/injection) in mice transplanted s.c. with Friend erythroleukemia cells (FLC) resulted in some inhibition of primary tumor growth, inhibition of liver and splenic metastases and increased survival time. A synergistic anti-tumor effect was observed in mice injected with both IL-1 and IFN-alpha/beta. Highly purified mouse IFN-beta also exerted a synergistic anti-tumor effect when combined with IL-1-beta in mice injected with FLC. The anti-tumor action of IL-1/IFN was markedly reduced in mice treated with antibodies to CD4 antigens. Antibodies to asialo-GM1 also diminished the anti-tumor effect by the combined cytokine treatment. The combined IL-1/IFN therapy was effective in NK-deficient bg/bg mice, although the extent of the anti-tumor response in these mice was less than that observed in bg/+mice.
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PMID:Synergistic anti-tumor effects of combined IL-1/IFN-alpha/beta therapy in mice injected with metastatic Friend erythroleukemia cells. 187 71

This study was designed to investigate acute effects of various doses of the cytokines IFN-alpha, IFN-gamma, Interleukin 2 and tumor necrosis factor alpha on white blood cell differential counts. Before initiation of phase II trials, a dose-determination phase was performed, where three different dose levels of each cytokine were applied as a single dose. White blood cell differential counts were assessed immediately before and 2, 12, 24, 48 and 168 h after injection. Patients enrolled suffered from metastatic cancer or chronic active hepatitis. In addition, IFN-alpha was administered to five healthy volunteers. Results indicate that cytokines cause rapid and transient changes in the numbers of leukocyte subsets. Hematologic changes were cell-type- and cytokine-specific: transient lymphopenia was observed after administration of all four cytokines, reaching a nadir 12 to 24 h after subcutaneous injection. Administration of TNF-alpha and IFN-gamma also caused transient monocytopenia. Neutrophilia developed after administration of Interleukin 2, IFN-alpha and TNF-alpha. We conclude that cytokines play a key role in the regulation of peripheral blood cell traffic by their capacity to influence homing patterns of peripheral blood leukocytes.
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PMID:Acute hematologic effects of interferon alpha, interferon gamma, tumor necrosis factor alpha and interleukin 2. 190 9

Preincubation of murine colon 26 colon adenocarcinoma cells with gamma-interferon (IFN-gamma), but not alpha-interferon, produced a significant increase in experimental pulmonary metastases in syngeneic BALB/c and T-cell-deficient BALB/c nude mice. The enhancement was seen after as little as 1 h of exposure to 1 unit/ml of IFN-gamma and persisted for at least 72 h following removal of the cytokine. IFN-gamma exerted its effects by increasing the pulmonary retention of cells during the first 6 h following tumor cell injection. During this period all cells visualized in the lung were trapped in pulmonary capillaries. The enhancement was not due to modulations in class I major histocompatibility complex surface antigen expression; nor was it due to alterations in cell size, adhesion to components of the extracellular matrix in vitro, heterotypic or homotypic adhesion, sensitivity to lysis by activated peritoneal macrophages, osmotic fragility, enhancement of surface class II major histocompatibility complex antigen expression, or enhancement of intercellular adhesion molecule-1 (ICAM-1). Colon 26 was completely resistant to natural killer cell-mediated lysis in vitro, and IFN-gamma did not modulate the ability of colon 26 to form conjugates with isolated splenocytes. In vivo elimination of anti-asialo GM1 + cells increased pulmonary metastasis, and in such mice, there was no longer a difference in metastatic potential between control and IFN-gamma-treated cells. We conclude that low doses of IFN-gamma generated at the site of the tumor by host-infiltrating cells or during cytokine therapy could enhance the survival of tumor cells in the circulation and enhance their metastatic potential.
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PMID:Enhancement of metastatic potential by gamma-interferon. 190 80

We have recently reported that a synthetic nucleoside, 7-thia-8-oxoguanosine (7T8OG) is a potent activator of a number of effectors which are involved in anti-tumor immune responses. 7T8OG was found to induce interferon (IFN) production, to activate asialo-GM1 positive (AGM+1) killer cells, and to enhance specific antibody responses. In the present study, we investigated the effect of 7T8OG on growth of the murine pulmonary B16 melanoma and on formation of metastases. C57BL/6 mice were injected i.p. with 50-150 mg/kg 7T8OG before or after i.v. inoculation of B16 melanoma tumor cells, and 17-19 days after tumor inoculation, the number of metastases in the lungs were counted. 7T8OG given systemically in a single or a divided dose 24 h prior to the challenge of tumor cells reduced the number of lung tumor metastases by 89-99% which is highly significant as compared to untreated control (P less than 0.001). Occasional extra pulmonary tumor growth in the thoracic cavity and neck lymph node was also completely inhibited. The reduction in the number of tumor nodules was dose dependent. A single dose of 150 mg/kg of 7T8OG was also effective in inhibiting the growth of 3-5 day old metastatic tumors. The cytotoxic activity of killer cells induced in vivo by 7T8OG was completely abolished by in vitro treatment of cells with anti-AGM1 antibody plus complement. Administration of anti-AGM1 antibody following the 7T8OG treatment completely abrogated the anti-tumor effect of 7T8OG, resulting in a massive increase in the number of tumor foci in the lungs. Administration of carageenan or silica followed by injection of 7T8OG caused a significant increase (P less than 0.01) in the number of pulmonary tumor nodules compared to treatment with 7T8OG only. These findings indicate that activated macrophages or perhaps their cytokine (tumor necrosis factor) also contribute to the host tumor defense by 7T8OG.
Clin Exp Metastasis
PMID:Successful immunotherapy of murine melanoma metastases with 7-thia-8-oxoguanosine. 191 79

A phase I clinical trial was conducted to evaluate the toxicology and biological activity of a new liposome-incorporated lipophilic disaccharide tripeptide, ImmTher. Twelve patients with advanced nonhematological malignant disease received 13 courses of therapy at dose levels of 200-1,200 micrograms/m2. A course of therapy consisted of once-weekly administration of the drug for 2-12 weeks. The major clinical toxicities observed were chills and hypotension. No renal, hepatic, cardiac, or hematological toxicity was observed. A small decrease in pulmonary diffusion capacity was observed. Biological activity was demonstrated by changes in plasma cytokine levels, changes in in vitro monocyte cytotoxicity, and by a decrease in tumor size. Improvement was observed in three of three patients with metastatic disease to the liver. Response in these three patients correlated with an increase in their tumor necrosis factor and neopterin levels compared with nonresponders. These preliminary indications of biological and clinical activity of a liposome-incorporated lipophilic disaccharide tripeptide in patients with advanced metastatic hepatic disease suggest a potential new therapeutic approach to this common problem.
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PMID:Phase I trial of ImmTher, a new liposome-incorporated lipophilic disaccharide tripeptide. 193 63

Adoptive immunotherapy in patients with advanced cancer produces significant regression of metastatic disease in selected patients, but it is complicated by severe side effects. Prevention of these complications is still limited because their precise mechanisms remain unknown. For this reason we have investigated renal function and hemodynamic parameters in 16 patients with renal cell carcinoma before and during treatment with a combination of high doses of both recombinant interleukin-2 (rIL2) and recombinant alpha-interferon. After patients had received three injections of combined immunotherapy, there was a decrease in mean blood pressure (-20%), glomerular filtration rate (-25%), urine output (-50%), and fractional sodium excretion (-0.8%). This was associated with an increase in heart rate (+30%), plasma creatinine level (+30%), fractional potassium excretion (+14%) and microalbuminuria (+130%). However, renal plasma flow remained constant. The increment in microalbuminuria may reflect an alteration of glomerular capillary permeability. The reduction in GFR may be accounted either for a decrease in efferent to afferent arteriolar resistance ratio, leading to a decrease in glomerular capillary pressure, or for a decrease in ultrafiltration coefficient, or both. Nonsteroidal antiinflammatory drugs, such as ketoprofen, used to minimize side effects, could considerably worsen renal function and should be avoided in patients treated by rIL2. Our results bring new insights into the pathogenesis of functional acute renal failure and provide a rational basis for the use of vasopressors in the treatment of cytokine-induced acute renal failure.
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PMID:Acute renal failure with preserved renal plasma flow induced by cancer immunotherapy. 194 80

Renal cell carcinoma (RCC) represents an unusual solid tumor for which no treatment other than surgical therapy has been effective. The remarkable heterogenous behavior of this tumor and the documented rare spontaneous regressions suggest an unusual sensitivity to host immunologic control. In recent years, exciting developments in molecular genetics, growth factors, modulators of invasion of metastases, and cytokine-lymphocyte interactions have produced new hypotheses and a wealth of information regarding the origin, behavior, and control of RCC. Interest in the immunotherapy of metastatic RCC has recently increased with the demonstrated reproducible tumor responses obtained with recombinant human interferon-alpha or interleukin-2. Durable clinical remissions in some patients with advanced RCC can now be achieved by using cytokine therapy alone or in combination with activated killer cells. This article reviews the current understanding of the basic biology of RCC, surgical approaches to localized RCC, and biologic therapy for advanced disease.
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PMID:Renal cell carcinoma: basic biology and current approaches to therapy. 194 36

Using 14 transplantable murine tumors, we investigated a possible correlation between their ability to produce the cytokine GM-CSF and the spontaneous metastatic potential when mice were subcutaneously inoculated. The following results were obtained: (1) seven tumors, which produced severe pulmonary metastases and metastatic swelling of lymph nodes, exhibited the ability to produce GM-CSF activity in culture. The cell population analysis revealed that the cells producing GM-CSF were tumor cells themselves, but that contaminating macrophages/granulocytes and T lymphocytes did not produce GM-CSF. The mRNA for GM-CSF was also found in all of these highly metastatic tumors tested. In mice inoculated with a highly metastatic tumor, the GM-CSF mRNA was also found in lungs; (2) in 3 other tumors, which produced histological but not macroscopical pulmonary metastases, no GM-CSF activity could be detected in the culture fluids. GM-CSF mRNA was, however, detected in the tumor cells in the presence of an mRNA-stabilizing agent, cycloheximide, suggesting the possibility that the tumor cells of this type were transcribing GM-CSF gene, and secreting it in undetectable levels; (3) in culture of the 4 remaining poorly or non-metastatic tumors, neither CSF activity nor GM-CSF mRNA could be detected even in the presence of cycloheximide. GM-CSF mRNA was also not found in lungs of tumor-bearing mice. Our results indicate that there may be a correlation between GM-CSF gene expression in tumor cells and spontaneous metastases.
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PMID:A correlation between GM-CSF gene expression and metastases in murine tumors. 199 49


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