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 findings summarized here provide a direct comparison of the immunogenicity of various DC loading strategies included pulsing with protein, peptide, tumor cell lysate, irradiated tumor cells and electrofusion of DCs and tumor cells. For the treatment of 3-day established pulmonary metastases, electrofusion of DCs and tumor cells generated a therapeutic vaccine far superior to other methods of DC loading. Consistent with their therapeutic activity, fusion hybrids stimulated the release of the largest amount of interferon-gamma from immune T cells. However, IL-10 secretion did not correlate with in vivo therapeutic reactivity. In conclusion, DC-tumor fusion hybrids were the most effective vaccine to eradicate existing tumors. These data support the use of DC-tumor electrofusion cells for the treatment of human cancer.
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PMID:[Immunotherapeutic reactivity of dendritic cells loaded with a variety of antigen preparations]. 1555 68

Adoptive transfer of effector T cells has been used successfully to eliminate metastases in animal models. Because antitumor activity depends on the number of effector cells transferred, some human trials have used in vitro-repetitive activation and expansion techniques to increase cell number. We hypothesized that the prolonged culture period might contribute to the lack of human trial success by decreasing the potency of the effector T cells. Lymph nodes draining a progressively growing murine melanoma tumor transduced to secrete granulocyte/macrophage colony-stimulating factor were harvested and activated in vitro with anti-CD3 monoclonal antibody followed by expansion in IL-2 for a total of 5 days in culture. Some lymphocytes were reactivated and further expanded for a total of 9 days in culture. In vivo activity of the effector T cells was measured by the reduction in lung metastases and is shown to be dose dependent. The prolonged culture period resulted in nearly 3-fold more T cells but at least 8-fold less antitumor activity. This was accompanied by decreased secretion of the proinflammatory cytokine, IFN-gamma, and increased secretion of the anti-inflammatory cytokine, IL-10. Thus, although increased cell number is important to maximize the effectiveness of adoptive immunotherapy, some culture conditions may actually be counterproductive in that decreases in cell potency can outweigh the benefits of increased cell numbers. The T-cell cytokine secretion pattern predicts decreased effector cell function and may explain the decreased antitumor effect.
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PMID:Prolonged culture of vaccine-primed lymphocytes results in decreased antitumor killing and change in cytokine secretion. 1560 82

We have previously described the antitumor reactivity of tumor-draining lymph node (TDLN) cells after secondary activation with antibodies. In this report, we examined the effects of interleukin (IL)-12 and IL-18 on modulating the immune function of antibody-activated murine TDLN cells. TDLN cells were activated with anti-CD3/anti-CD28 monoclonal antibody followed by stimulation with IL-12 and/or IL-18. IL-18 in combination with IL-12 showed a synergistic effect in augmenting IFNgamma and granulocyte macrophage colony-stimulating factor secretion, whereas IL-18 alone had minimal effect. Concurrently, IL-18 prevented IL-12-stimulated TDLN cells from producing IL-10. The IL-12/IL-18-cultured TDLN cells therefore manifested cytokine responses skewed towards a Th1/Tc1 pattern. IL-12 and IL-18 stimulated CD4(+) TDLN cells and enhanced IFNgamma production by CD4(+) cells to a greater extent than by CD8(+) cells. Use of NF-kappaB p50(-/-) TDLN cells suggested the involvement of NF-kappaB in the IL-12/IL-18 polarization effect. Furthermore, a specific NF-kappaB inhibitor significantly suppressed IL-12/IL-18-induced IFNgamma secretion, thus confirming the requirement for NF-kappaB activation in IL-12/IL-18 signaling. In adoptive immunotherapy, IL-12- and IL-18-cultured TDLN cells infiltrated pulmonary tumor nodules and eradicated established tumor metastases more efficiently than T cells generated with IL-12 or IL-18 alone. Antibody depletion revealed that both CD4(+) and CD8(+) cells were involved in the tumor rejection induced by IL-12/IL-18-cultured TDLN cells. These studies indicate that IL-12 and IL-18 can be used to generate potent CD4(+) and CD8(+) antitumor effector cells by synergistically polarizing antibody-activated TDLN cells towards a Th1 and Tc1 phenotype.
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PMID:Synergistic effects of IL-12 and IL-18 in skewing tumor-reactive T-cell responses towards a type 1 pattern. 1570 8

The therapeutic efficacy in the treatment of metastatic cancer with high doses of interleukin-2 (IL-2) has been limited by the onset of vascular leak syndrome (VLS) and related toxicities. VLS is characterized by an increase in vascular permeability and severe hypotension resulting in interstitial edema and organ failure. This study explores the protective effects of histamine dihydrochloride (HDC) against IL-2-induced toxicities in mice. Treatment with HDC administered before or after IL-2 (1.25 x 10(6) IU, BID) was shown to protect mice from VLS-related toxicities and mortality in a dose-dependent manner. Survival rates when HDC was added were 56, 75 and 81% at doses of 0.47, 4.7 and 47.0 mg/kg, respectively, compared to 42% survival with IL-2 alone. HDC protected against IL-2-induced macroscopic pulmonary lesions, reduced edema (up to 62% reduction in lung wet/dry weight ratio) and reduced capillary leakage into the lungs as measured by a reduction in Evans Blue dye content. In addition, the systemic effect on serum cytokine levels showed that HDC only moderately lowered IL-2 induced IFN-gamma, IL-6, IL-10, IL-18 and TNF-alpha. Serum levels of IL-1beta, IL-4 and IL-12 were not measurably induced by IL-2 treatment. HDC modulates many cellular functions including regulating cytokines and blocking immune-suppression caused by reactive oxygen species (ROS) generated by the NADPH oxidase. However, the protective effect of HDC on alleviating IL-2-induced pulmonary edema was not related to ROS inhibition. Our data indicate that HDC treatment improves survival and protects against IL-2 induced VLS independent of ROS regulation in mice.
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PMID:Histamine improves survival and protects against interleukin-2-induced pulmonary vascular leak syndrome in mice. 1582 Apr 45

In this study, we have concurrently assayed for IL-2, IL-4, IL-6, IL-10, TNF-alpha, and IFN-gamma in 24-h serum-free cultures of peripheral blood mononuclear cells (PBMC) obtained from seventeen patients with prostate cancer (CaP) per cytokine bead array analysis. The purpose of the study is to examine the nature of the cytokine profile operating among patients and to correlate with their physical, biochemical, and clinical parameters. Unstimulated PBMC cultures from patients with hormone-sensitive metastatic disease demonstrated elevated level of baseline TNF-alpha compared to patients with high-risk, locally advanced disease. Younger patients exhibited significantly higher levels of IL-4 and TNF-alpha compared to older patients following PHA stimulation. Similarly, significantly higher ratios of IFN-gamma/IL-4, IFN-gamma/IL-10, and IL-2/IL-4, a favorable type-1 cytokine pattern, were observed in patients with lower serum PSA compared to patients with high serum PSA. These results indicate the existence of distinct cytokine patterns among patients with CaP.
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PMID:Distinct cytokine patterns exist in peripheral blood mononuclear cell cultures of patients with prostate cancer. 1602 40

Most circulating tumor cells die within 24 h of entering the hepatic microvasculature because their arrest initiates an ischemia-reperfusion (I/R) injury that is cytotoxic. Human colorectal carcinomas (CRC) produce the glycoprotein Carcinoembryonic Antigen (CEA) that increases experimental liver metastasis in nude mice. Since CEA induces release of IL-6 and IL-10, we hypothesized that CEA inhibits the I/R injury through a Kupffer cell-mediated cytokine-dependent pathway. We assessed cytokine effects in CRC co-cultured with liver and in vivo. Human CRC prelabeled with fluorescent dyes were incubated with a reoxygenated suspension of ischemic nude mouse liver fragments in a bioreactor. CEA, rhIL-6 or rhIL-10 were either administered to the donor mice prior to hepatic ischemia or during co-culture. Liver donors were athymic nude or iNOS, IL-6 or IL-10 knock out mice. Ischemic-reoxygenated liver kills Clone A CRC through production of nitric oxide (NO) and superoxide anion. Treatment of liver donors with CEA prior to hepatic ischemia inhibited this in vitro cytotoxicity through an IL-10 and Kupffer cell dependent pathway that inhibited NF-kappaB activation, NO production and iNOS upregulation. IL-10 but not IL-6 enhanced CRC survival in nude mouse liver in vivo. Thus, CEA enhanced metastasis by inducing IL-10 to inhibit iNOS upregulation in host liver.
Clin Exp Metastasis 2004
PMID:Carcinoembryonic antigen promotes tumor cell survival in liver through an IL-10-dependent pathway. 1603 16

Melanoma differentiation associated gene-7 (mda-7) was cloned using subtraction hybridization from terminally differentiated human melanoma cells. Based on structural and functional properties, mda-7 is now recognized as interleukin-24 (IL-24), a new member of the expanding IL-10 gene family. Unique properties of mda-7/IL-24 include its ability to selectively induce growth suppression, apoptosis and radiosensitization in diverse human cancer cells, without causing similar effects in normal cells. The utility of mda-7/IL-24, administered by means of a replication-incompetent adenovirus, as a gene therapy for cancer has recently received validation in patients, highlighting an important phenomenon initially observed in pancreatic tumor cells, namely a 'potent bystander apoptosis-inducing effect' in adjacent tumor cells not initially receiving this gene product. We presently investigated the contribution of mda-7/IL-24 secreted by normal cells in mediating this 'bystander effect', and document that normal cells induced to produce mda-7/IL-24 following infection with recombinant adenoviruses expressing this cytokine secrete mda-7/IL-24, which modifies the anchorage-independent growth, invasiveness, survival and sensitivity to radiation of cancer cells that contain functional IL-20/IL-22 receptors, but not in cancer cells that lack a complete set of receptors. Moreover, the combination of secreted mda-7/IL-24 and radiation engenders a 'bystander antitumor effect' not only in inherently mda-7/IL-24 or radiation-sensitive cancer cells, but also in tumor cells overexpressing the antiapoptotic proteins bcl-2 or bcl-x(L) and displaying resistance to either treatment alone. The present studies provide definitive evidence that secreted mda-7/IL-24 from normal cells can induce direct antitumor and radiation-enhancing effects that are dependent on the presence of canonical receptors for this cytokine on tumor cells. Moreover, we now describe a novel means of enhancing mda-7/IL-24's therapeutic potential by targeting normal cells to produce and release this cancer-specific apoptosis-inducing cytokine, a strategy that could be employed as an innovative way of using this unique gene product for treating metastatic disease.
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PMID:Unique aspects of mda-7/IL-24 antitumor bystander activity: establishing a role for secretion of MDA-7/IL-24 protein by normal cells. 1604 51

The pathogenesis of metastasis depends on multiple favorable interactions of tumor cells with host homeostatic mechanisms. Interruption of one or more of these interactions can lead to the inhibition or eradication of cancer metastases. For many years, all efforts to treat cancer concentrated on the inhibition of growth or the destruction of tumor cells. A strategy of both eradication of tumor cells (e.g. by chemotherapy and immunotherapy) and modulation of the host microenvironment (e.g. tumor vasculature and hypoxia) is an additional, relatively novel approach to cancer treatment. Recent advances in our understanding of the biological basis of cancer metastasis open up unprecedented opportunities for translating basic research to clinical treatment of cancer. This research includes the unraveling of the genetic make-up of tumors and genome-wide expression analyses, thereby identifying many potential targets for therapy. Drugs acting on tumor cells which have a metastasis-prone mutational or expression status (by classical or targeted chemotherapy) as well as drugs affecting host-mediated survival pathways must be combined in order to create therapeutic synergy. Therapeutic maneuvers may target receptor tyrosine kinases (EGFR, VEGFR, FGFR), chemokines or G-protein-coupled receptors (CXCR4, CXCR2, EphB2), hypoxia-inducible factor (HIF), and signaling pathways (c-Src, PI3K, Akt, chaperon complexes) in tumor cells. Moreover, stromal and immunological cells and their cytokines coordinate critical pathways that exert important roles in the ability of tumors to invade and metastasize, thus suppressive cytokines (IL-6 and IL-10) and neutralizing specific antibodies might subvert conditions for metastasis.
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PMID:Metastases and their microenvironments: linking pathogenesis and therapy. 1609 51

Despite the radical surgical resection performed in patients with colorectal carcinoma, there is a high rate of tumor recurrence. Over an observation period of 3 years, 18% of the patients in our collective suffered a tumor relapse with local or distinct metastases after initial R0-resection. Some evidence suggests that this may be due to suppression of anti-tumor responses, a phenomenon that might be attributed to regulatory T cells. The aim of our study was to investigate the tumor-specific immune response depending on the UICC stage of patients with colorectal cancer. The cellular immune responses against defined antigens that are overexpressed in most of the patients with colorectal cancer were characterized. For this purpose, the tumor suppressor gene, p53, was chosen as the tumor-associated antigen that exhibits mutations and overexpression in up to 60% of colorectal carcinoma. We observed that p53 induced both IFN-gamma and IL-10 secretion. The predominance of IL-10 production indicated that regulatory T cells directly participate in modulating the anti-tumor immune response. IL-10 levels in the blood as well as the expression of regulatory T-cell specific genes at the tumor site correlate with the UICC stage of the disease. These results may provide an explanation for the poor prognosis and increased recurrence rate in patients with advanced carcinoma.
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PMID:T-cell response to p53 tumor-associated antigen in patients with colorectal carcinoma. 1639 98

CD4+CD25+ regulatory T cells (Treg) that suppress T cell-mediated immune responses may also regulate other arms of an effective immune response. In particular, in this study we show that Treg directly inhibit NKG2D-mediated NK cell cytotoxicity in vitro and in vivo, effectively suppressing NK cell-mediated tumor rejection. In vitro, Treg were shown to inhibit NKG2D-mediated cytolysis largely by a TGF-beta-dependent mechanism and independently of IL-10. Adoptively transferred Treg suppressed NK cell antimetastatic function in RAG-1-deficient mice. Depletion of Treg before NK cell activation via NKG2D and the activating IL-12 cytokine, dramatically enhanced NK cell-mediated suppression of tumor growth and metastases. Our data illustrate at least one mechanism by which Treg can suppress NK cell antitumor activity and highlight the effectiveness of combining Treg inhibition with subsequent NK cell activation to promote strong innate antitumor immunity.
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PMID:CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. 1642 87


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