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 (IL)-12 can activate cytotoxic lymphocytes, stimulate natural killer cell activity, induce the production of INF-gamma and inhibit the development of various experimental tumors. We previously demonstrated that immunotherapy of melanoma bearing mice with an irradiated melanoma vaccine (IMV) coupled with IL-2 or GM-CSF had beneficial effects against primary melanoma growth and against subsequent spontaneous metastasis. We also had found that treatment of melanoma bearing mice with IL-12 (300 ng/day) for 4 weeks inhibited the development of primary melanoma tumors in 40% of mice. The purpose of this study was to investigate the efficacy of combined therapy of experimental melanoma with an IMV prepared from B16F10 melanoma cells coupled with IL-12 treatment. C57BL/6 mice were challenged subcutaneously in the tail with B16F10 melanoma cells and by the 45th day, more than 50% of the mice had developed visible primary melanoma tumors at the injection site. Subsequent immunotherapy of mice with IMV, when coupled with IL-12, provided partial inhibition of primary melanoma tumor growth. Optimal results against primary tumor growth were observed when IMV therapy was coupled with IL-12 at a dose of 50 ng/day. Combination of IMV with IL-12 at a dose of 100 ng/day significantly reduced melanoma metastasis to the lungs compared with control mice, and an improvement in mean survival time was observed in mice treated with a combination of IMV with IL-12 (300 ng/day).
Clin Exp Metastasis 1999 Feb
PMID:Immunotherapy of mice with an irradiated melanoma vaccine coupled with interleukin-12. 1039 Jan 49

Interleukin-10 (IL-10) has a wide range of in vivo biological activities and is a key regulatory cytokine of immune-mediated inflammation. The authors found that murine IL-10 given 12 hours after a recombinant vaccinia virus (rVV) containing the LacZ gene significantly enhanced the treatment of mice bearing 3-day-old pulmonary metastases expressing beta-galactosidase. Because IL-10 has been shown to inhibit the functions of key elements of both innate and acquired immune responses, the authors hypothesized that IL-10 might act by inhibiting clearance of the rVV, thus prolonging exposure to the experimental antigen. However, evidence that IL-10 was not acting primarily through such negative regulatory mechanisms included the following: (a) IL-10 also enhanced the therapeutic effectiveness of a recombinant fowlpox virus, which cannot replicate in mammalian cells; (b) Titers of rVV in immunized mice were lower, not higher; and (c) Although IL-10 did not alter levels of anti-vaccinia anti-bodies or natural killer cell activity, rVV-primed mice treated with IL-10 had enhanced vaccinia-specific cytotoxic T-lymphocyte activity. Thus, IL-10 enhanced the function of a recombinant poxvirus-based anti-cancer vaccine and may represent a potential adjuvant in the vaccination against human cancers using recombinant poxvirus-based vaccines.
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PMID:Interleukin-10 enhances the therapeutic effectiveness of a recombinant poxvirus-based vaccine in an experimental murine tumor model. 1057 Jul 47

We hypothesize that adenovirus (Ad) vector-mediated delivery of the human interleukin-2 (IL-2) cDNA (AdIL2) or the murine IL-12 cDNA heterodimer (AdIL12) would produce high concentrations of cytokines in the local hepatic milieu to induce host responses sufficient to inhibit the growth of experimental colon carcinoma-derived hepatic metastases. Ad vectors administered intravenously, which is a route known to deliver >90% of the vector to the hepatic parenchyma, achieved significant levels of each cytokine locally, with minimal levels in the sera. To examine the therapeutic effect, the AdIL2 and AdIL12 vectors were evaluated in a hepatic metastasis model that was established by injecting 3 x 10(4) cells from the poorly immunogenic syngeneic C26 colon carcinoma cell line into the right lobe of the livers of BALB/c mice. Animals received AdIL2, AdIL12, or control virus (10(8) plaque-forming units each) intravenously for 2 days after tumor implantation, and tumor growth was compared with naive controls. The AdNull control tumors measured 116 +/- 25 mm2 at 2 weeks. The control virus showed no significant antitumor effect. In marked contrast, both AdIL2 and AdIL12 vectors that were delivered regionally had significant antitumor effects, with AdIL2-treated animals having an average tumor size of 16 +/- 8 mm2; AdIL12-treated tumors measured 6 +/- 6 mm2 (P < .01, both compared with control). Both the AdIL2 and AdIL12 vectors provided a significant survival advantage by log-rank analysis (P < .01), but only AdIL12 translated into an increase in mean survival from 27 (naive control) to 37 days. To evaluate whether these antitumor effects were T-cell-mediated, splenocytes from AdIL2-treated, AdIL12-treated, and naive control groups were stimulated in vitro with gamma-irradiated C26 tumor cells for 5 days and tested for C26 tumor cell cytolysis by an in vitro cytotoxicity assay. Splenocytes from both AdIL2- and AdIL12-treated animals showed a dose-dependent, T-cell-mediated, specific cytolysis of CT26 cells. AdIL12 and to a lesser extent AdIL2 induced natural killer cell activity, as determined by a dose-dependent increase in lysis of the natural killer-specific target cell YAC-1. Overall, these data suggest that regional Ad-mediated delivery of IL-2 and IL-12 cDNAs may be useful for local tumor control and may warrant further investigation as a potentially useful adjuvant for the treatment of hepatic micrometastasis.
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PMID:Regional treatment of hepatic micrometastasis by adenovirus vector-mediated delivery of interleukin-2 and interleukin-12 cDNAs to the hepatic parenchyma. 1060 45

The colon adenocarcinoma cell line CC531 was adopted as a model for immunotherapeutical treatment of experimental colorectal metastases in a syngeneic rat model. We studied the presence and localization of T and natural killer cells, vessels and matrix proteins in in vivo growing CC531 tumours by immunohistochemistry. CC531 tumours were induced either in the lungs by injecting CC531 tumour cells into a tail vein or in the liver by injection of CC531 tumour cells under the liver capsule or into a mesenteric vein. All 3 tumour types were composed of islets of tightly apposed tumour cells surrounded by abundantly present tumour-stroma which contained tumour vessels and matrix proteins. Some of these matrix proteins, especially laminin and collagen IV formed a basal membrane-like structure around the tumour nodules. This structure was most pronounced in mesenteric vein-induced liver tumours and less prominent in subcapsular-induced liver tumours and tail vein-induced lung tumours. Tumour-infiltrating lymphocytes of both T and natural killer cell origin were found in the tumours, but predominantly in the tumour stroma, separated from the islets of tumour cells by the basal membrane-like structure. We hypothesize that the matrix proteins of these tumours play an ambivalent role: they may provide a substratum for migration of effector cells into the tumour stroma but may also provide a barrier preventing direct contact between tumour target cells and immune effector cells.
Clin Exp Metastasis 2000
PMID:The microscopic anatomy of experimental rat CC531 colon tumour metastases: consequences for immunotherapy? 1123 95

IFN-gamma is a pleiotropic cytokine that plays an important role in regulating the growth of primary tumors. Although numerous studies of the effects of IFN-gamma on primary-solid-tumor growth have been performed and several potential mechanisms for its efficacy have been proposed, it remains unclear how IFN-gamma modulates tumor progression and whether it exerts its effects indirectly via host cells or directly by interacting with tumor cells. Using the well-characterized mouse metastatic mammary carcinoma 4T1 in a postsurgery setting, IFN-gamma-deficient mice were found to have significantly shorter survival time relative to wild-type mice, demonstrating that IFN-gamma is also a critical component in regulating innate immunity to metastatic disease. Experiments quantifying lung and liver metastasis indicate that decreased survival of IFN-gamma-deficient mice is attributable to increased metastatic disease. To determine whether IFN-gamma is acting directly on the tumor cells, IFN-gamma-nonresponsive 4T1 cells were generated by transfection (4t1/IRt). Metastasis experiments with 4T1/IRt demonstrated that IFN-gamma mediates its effects via host-derived cells, rather than by directly affecting tumor growth. To identify the population of cells responsible for IFN-gamma efficacy, perforin-deficient, T-cell subset-depleted, natural killer cell-depleted, or carrageenan-treated phagocytic cell-depleted mice were inoculated with 4T1 and assessed for primary tumor growth and metastatic disease. None of the conditions altered primary tumor growth; however, the carrageenan treatment significantly increased metastatic disease in the liver and lungs. Survival experiments in 4T1-inoculated, carrageenan-treated mice confirmed that the elimination of phagocytic cells significantly reduces survival time and yields a survival phenotype comparable with IFN-gamma deficiency. Therefore, IFN-gamma is a critical component of innate immunity to metastatic mammary carcinoma that probably mediates its effects via host-derived phagocytic cells.
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PMID:Interferon-gamma-dependent phagocytic cells are a critical component of innate immunity against metastatic mammary carcinoma. 1215 47

Our laboratory has previously reported that natural killer (NK) cells bind to angiogenic microvessels in established cancer metastases. Vascular endothelial growth factor (VEGF) plays an important role in solid tumor angiogenesis by enhancing new blood vessel formation to transport nutrients and oxygen into tumors. Here we report that the human natural killer cell lines, NK-92 and YT, express the mRNA message and protein product for VEGF-B and its receptor, VEGFR-1/Flt-1. While stimulation of these cells by the potent angiogenic factor VEGF-A165, which also binds to VEGFR-1, does not alter the proliferation of the cells, it does increase adhesion to a model basement membrane-like extracellular matrix, Matrigel. VEGF-A165 also induces NK cell binding to human microvascular endothelial cells in newly forming but not established microvessels in vitro. These results suggest that human NK cells produce an angiogenic factor which may be involved in autocrine and paracrine regulations of angiogenesis. VEGF-A165 appears to stimulate NK cell adhesion to the microvasculature within established cancer metastases.
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PMID:Modulation of human NK cell lines by vascular endothelial growth factor and receptor VEGFR-1 (FLT-1). 1249 87

In the present study, we examined the effects of a newly developed bisphosphonate, minodronate (YM529), on osteolytic bone metastasis caused by lung cancer. Human small-cell lung cancer (SBC-5) cells, injected intravenously into natural killer cell-depleted SCID mice, produced radiologically detectable bone metastasis by day 18 and macroscopically visible visceral metastases (lung, liver, kidney, systemic lymph node) by day 35. Prophylactic treatment with YM529 on day 1 significantly inhibited the formation of osteolytic bone metastasis evaluated on X-ray photographs in a dose-dependent manner. In addition, treatment with YM529 after establishment of bone metastasis (on day 21) also inhibited bone metastasis, although the treatment was more effective when started earlier. Single administration was as effective as repeated treatment, suggesting a sustained inhibitory effect of YM529 on bone metastasis. YM529 reduced the number of osteoclasts in the bone metastatic lesions in vivo, but had no effect on the proliferation or cytokine production of SBC-5 cells in vitro. These results suggest that YM529 is a potent inhibitor of bone metastasis of human lung cancer, probably by suppressing osteoclastic bone resorption. In contrast, treatment with YM529 had no effect on visceral metastasis, even if started on day 1, and did not prolong the survival of the mice. Therefore, development of a combined modality is necessary for prolonging the survival of small-cell lung cancer patients with multiple-organ metastasis.
Clin Exp Metastasis 2003
PMID:A novel bisphosphonate minodronate (YM529) specifically inhibits osteolytic bone metastasis produced by human small-cell lung cancer cells in NK-cell depleted SCID mice. 1270 36

We show that mouse embryonic endothelial progenitor cells (eEPCs) home preferentially to hypoxic lung metastases when administered intravenously. This specificity is inversely related to the degree of perfusion and vascular density in the metastasis and directly related to local levels of hypoxia and VEGF. Ex vivo expanded eEPCs that were genetically modified with a suicide gene specifically and efficiently eradicated lung metastases with scant patent blood vessels. eEPCs do not express MHC I proteins, are resistant to natural killer cell-mediated cytolysis, and can contribute to tumor vessel formation also in nonsyngeneic mice. These results indicate that eEPCs can be used in an allogeneic setting to treat hypoxic metastases that are known to be resistant to conventional therapeutic regimes.
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PMID:Embryonic endothelial progenitor cells armed with a suicide gene target hypoxic lung metastases after intravenous delivery. 1514 46

To test the hypothesis that platelet activation contributes to tumor dissemination, we studied metastasis in mice lacking Galphaq, a G protein critical for platelet activation. Loss of platelet activation resulted in a profound diminution in both experimental and spontaneous metastases. Analyses of the distribution of radiolabeled tumor cells demonstrated that platelet function, like fibrinogen, significantly improved the survival of circulating tumor cells in the pulmonary vasculature. More detailed studies showed that the increase in metastatic success conferred by either platelets or fibrinogen was linked to natural killer cell function. Specifically, the pronounced reduction in tumor cell survival observed in fibrinogen- and Galphaq-deficient mice relative to control animals was eliminated by the immunologic or genetic depletion of natural killer cells. These studies establish an important link between hemostatic factors and innate immunity and indicate that one mechanism by which the platelet-fibrin(ogen) axis contributes to metastatic potential is by impeding natural killer cell elimination of tumor cells.
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PMID:Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. 1536 35

Systemic gene delivery using cationic liposome-DNA complexes (LDCs) has been shown to elicit potent antitumor activity in mice with tumor metastases to the lungs. However, intravenous gene delivery for treatment of established cancer has not been evaluated previously in a spontaneous, large animal model. We therefore evaluated the safety, toxicity, and efficacy of intravenous gene delivery, using LDCs in dogs with established tumor metastases. Twenty dogs with chemotherapy-resistant osteosarcoma metastases to the lungs received a series of intravenous infusions of cationic liposomes and plasmid DNA encoding the canine interleukin-2 (IL-2) cDNA. Effects of intravenous gene delivery on immune activation, clinical and hematologic parameters, tumor responses, and survival times were assessed. We found that slow intravenous administration of IL-2 LDCs resulted in detectable IL-2 transgene expression in lung tissues of dogs. Repeated intravenous infusions of LDCs were well tolerated by dogs with lung tumor metastases and elicited systemic immune activation, as reflected by fever, leukogram changes, monocyte activation, and increased natural killer cell activity. Three of 20 dogs experienced partial or complete regression of lung metastases after infusion of IL-2 LDCs. Overall survival times were significantly increased in treated dogs compared with historical control animals with the same stage of disease. We conclude that repeated intravenous infusion of LDCs in cancerbearing dogs is safe and well tolerated at low doses and may be capable of eliciting antitumor activity in some animals with advanced tumor metastases.
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PMID:Phase I study of liposome-DNA complexes encoding the interleukin-2 gene in dogs with osteosarcoma lung metastases. 1607 52


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