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)

In our previous studies using gene gun-mediated delivery of interleukin 12 (IL-12) cDNA in vivo, we observed T-cell-mediated regression of established murine tumors and demonstrated the induction of systemic immunity in test animals. In this study, we further characterized the antitumoral and anti-metastatic effect of this gene therapy approach by employing two murine metastatic mammary tumor models: the immunogenic TS/A adenocarcinoma and the weakly immunogenic 4T1 adenocarcinoma. In the TS/A model, gene transfer into the skin overlying an established intradermal tumor with an IL-12 cDNA expression vector resulted in complete tumor regression in 50% of mice followed by the development of immunological memory. In contrast, the growth of the intradermal 4T1 tumors was not affected by the IL-12 gene therapy protocol. However, this treatment resulted in a substantial reduction of spontaneous metastases in the lungs of 4T1 tumor-bearing mice and significantly prolonged their survival time. T cells were not required for this anti-metastatic effect, because it was also observed in nude mice and in mice depleted of CD4+ and CD8+ T cells. Tumor-draining lymph node cells obtained from 4T1 tumor-bearing mice treated with IL-12 cDNA exhibited increased natural killer (NK) activity and produced enhanced levels of interferon-gamma (IFN-gamma) compared with similar mice treated with luciferase cDNA. In addition, in vivo depletion of NK cells or neutralization of IFN-gamma resulted in partial suppression of the anti-metastatic effect of IL-12 gene therapy, suggesting the involvement of both NK cells and IFN-gamma in this effect.
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PMID:Interleukin-12 gene therapy of a weakly immunogenic mouse mammary carcinoma results in reduction of spontaneous lung metastases via a T-cell-independent mechanism. 1088 12

Perforin (pfp) and interferon-gamma (IFN-gamma) together in C57BL/6 (B6) and BALB/c mouse strains provided optimal protection in 3 separate tumor models controlled by innate immunity. Using experimental (B6, RM-1 prostate carcinoma) and spontaneous (BALB/c, DA3 mammary carcinoma) models of metastatic cancer, mice deficient in both pfp and IFN-gamma were significantly less proficient than pfp- or IFN-gamma-deficient mice in preventing metastasis of tumor cells to the lung. Pfp and IFN-gamma-deficient mice were as susceptible as mice depleted of natural killer (NK) cells in both tumor metastasis models, and IFN-gamma appeared to play an early role in protection from metastasis. Previous experiments in a model of fibrosarcoma induced by the chemical carcinogen methylcholanthrene indicated an important role for NK1.1(+) T cells. Herein, both pfp and IFN-gamma played critical and independent roles in providing the host with protection equivalent to that mediated by NK1.1(+) T cells. Further analysis demonstrated that IFN-gamma, but not pfp, controlled the growth rate of sarcomas arising in these mice. Thus, this is the first study to demonstrate that host IFN-gamma and direct cytotoxicity mediated by cytotoxic lymphocytes expressing pfp independently contribute antitumor effector functions that together control the initiation, growth, and spread of tumors in mice.
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PMID:Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. 1113 60

The cytokines interleukin (IL)6 and IL10 appear to be involved in the progression of melanoma because they are secreted by malignant cells and their serum levels are associated with poor survival and with advanced stages of the disease. Antitumour immunity is considered to be a T-cell response, mediated mainly by type 1 cytokines such as IL12 and interferon-gamma (IFNgamma). We evaluated the serum levels of cytokines involved in the host response against tumour (IL12, IFNgamma) and/or the progression of melanoma (IL6, IL10) in 45 melanoma patients with localized and metastatic disease and in 45 controls, using commercially available enzyme-linked immunosorbent assay (ELISA) kits. In the controls, IL6 and IL12 were nearly undetectable, whereas the IL10 and IFNgamma ranges were 0.5-9 pg/ml and 2-4.8 pg/ml, respectively. In the melanoma patients, pathologically high values were found in 44.4% for IL6, in 24.4% for IL10, and in 60% for IL12. Significantly higher values were found for IL6 and IL12, and lower values for IFNgamma. This study highlights a significant difference in serum cytokine profiles between controls and melanoma patients, which is mainly due to the high levels of IL6 and IL12 and the low levels of IFNgamma.
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PMID:Serum imbalance of cytokines in melanoma patients. 1147 28

In a mouse model of prostate cancer, adenovirus-mediated interleukin-12 (Ad.mIL-12) gene therapy resulted in significant growth inhibition of both the injected primary tumor and synchronous metastases. Within 2 days of vector injection, two distinct patterns of apoptosis were detected within the primary tumor, the inhibition of which with a caspase inhibitor substantially negated growth suppression. The dominant pattern displayed localized sheets of apoptotic cells in close association with necrosis containing polymorphic neutrophils (PMNs). Depletion of PMNs resulted in the loss of this pattern of apoptosis and reduced growth suppression. A second major wave of growth suppression within the primary tumor was mediated by an immune response. Natural killer (NK) cell activity was detected within tumor-infiltrating lymphocytes (TIL) by the eighth day post-vector injection, the depletion of which resulted in a significant loss of survival enhancement. A more modest role for T cells was identified, which in the absence of documented cytotoxic T lymphocyte (CTL) activity may be related to a significant reduction in interferon-gamma (IFN-gamma) levels found in mice depleted of T cells, thereby reducing the secondary influences of IFN-gamma. However, depletion of NK cells or T cells had no discernible negative effect on IL-12-mediated anti-metastatic activity. Attention focused on the role of IFN-gamma, observed following Ad.mIL-12 therapy, to mediate the diffuse pattern of apoptosis seen in the primary and metastatic lesions. In vitro studies noted the ability of IFN-gamma to up-regulate tumor cell expression of Fas and FasL to mediate apoptosis, whereas in vivo blockage of Fas/FasL interactions with soluble Fas resulted in a modest reduction in primary tumor growth suppression but complete abrogation within metastatic lesions.
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PMID:Independent contributions of GR-1+ leukocytes and Fas/FasL interactions to induce apoptosis following interleukin-12 gene therapy in a metastatic model of prostate cancer. 1150 92

Synergistic induction of the inducible nitric oxide synthase (NOS II) gene requires a combination of interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). In this study, we determined whether the induction of IFN-gamma was required for NOS II-mediated antitumor activity in vivo. Highly metastatic H7 murine pancreatic adenocarcinoma cells were implanted into the subcutis, footpad, and pancreas of syngeneic IFN-gamma(+/+) and IFN-gamma(-/-) mice. These cells grew and produced metastases and ascites in IFN-gamma(+/+) mice. In sharp contrast, the same tumor cells grew much more aggressively, metastasized more extensively, and produced a larger amount of malignant ascites in IFN-gamma(-/-) mice. Also, induction of IFN-gamma correlated with NOS II gene expression and NO production in IFN-gamma(+/+) injected with the tumor cells but not in IFN-gamma(-/-) mice or IFN-gamma(+/+) mice without tumor challenge. In vitro, only LPS plus IFN-gamma induced a high level of NO production and cytotoxicity against H7 cells. These data suggested that the tumor cells stimulated IFN-gamma secretion from host cells, which in turn stimulated NO production by host cells and suppressed tumor growth and metastasis.
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PMID:Genetic disruption of host interferon-gamma drastically enhances the metastasis of pancreatic adenocarcinoma through impaired expression of inducible nitric oxide synthase. 1168 72

Natural killer (NK) cells may modulate the development of adaptive immune responses, but until now there has been little evidence to support this hypothesis. We investigated the primary and secondary immunity elicited by various tumor cell lines that express CD70 and interact with CD70 ligand (CD27), which is constitutively expressed on NK cells. CD70 expression enhanced primary tumor rejection in vivo as well as T cell immunity against secondary tumor challenge. Primary rejection of major histocompatibility complex (MHC) class I-deficient RMA-S.CD70 tumor cells was mediated by NK cells and perforin- and interferon-gamma-dependent mechanisms. This NK cell-mediated process also efficiently evoked the subsequent development of tumor-specific cytotoxic and T helper type 1 responses to the parental, MHC class I-sufficient, RMA tumor cells. Thus CD27-CD70 interactions provide a key link between innate NK cell responses and adaptive T cell immunity.
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PMID:Induction of tumor-specific T cell memory by NK cell-mediated tumor rejection. 1174 85

Tumor lysate-pulsed dendritic cells were used to generate nodal effector T cells in the murine MCA 205 tumor model. Dendritic cells were derived from bone marrow and cultured in granulocyte-macrophage colony-stimulating factor/interleukin 4 before pulsation with tumor lysate. Multiple subcutaneous administrations of tumor lysate-pulsed dendritic cells (TP-DCs) resulted in an approximately eightfold hypertrophy of the vaccine draining nodes, with an increased influx of dendritic (CD11c+/CD80+) cells and B (B220+) cells. The vaccine-primed lymph node (VPLN) cells were secondarily activated with anti-CD3/interleukin 2 and exhibited specific interferon-gamma release to tumor antigen. The adoptive transfer of TP-DC VPLN cells resulted in regression of established 3-day pulmonary metastases. The antitumor reactivity of TP-DC VPLN cells was comparable to anti-CD3/interleukin 2 activated tumor-draining lymph node cells. However, the admixture of keyhole limpet hemocyanin (KLH) with tumor lysate during pulsation of dendritic cells significantly enhanced the induction of tumor-reactive VPLN cells. Tumor lysate-pulsed dendritic cells can be used as a strategy to generate effector T cells for adoptive immunotherapy.
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PMID:Antitumor reactivity of lymph node cells primed in vivo with dendritic cell-based vaccines. 1175 72

In malignant melanoma, tumor-infiltrating lymphocytes are frequently reactive with melanosomal antigens. Achieving complete remissions by peptide therapy is frequently hampered by metastases evading immune recognition. The tumor microenvironment seems to favor reduced expression of target antigens by melanoma cells. Among candidate factors, interferon-gamma (IFN-gamma) (10(2) to 10(3) U/ml) suppressed expression of antigens MART-1, TRP-1, and gp100 by M14 melanoma cells as shown by immunohistology and fluorescence-activated cell sorting analysis, reducing MART-1 expression by >65%. Northern blot analysis revealed that reduced expression was regulated at the transcriptional level, demonstrating a 79% reduction in MART-1 transcript abundance after 32 hours of IFN-gamma treatment. To evaluate consequences of IFN-gamma exposure for immune recognition, MART-1-responsive T cells were reacted with pretreated HLA-matched melanoma cells. Cytotoxicity was reduced up to 78% by IFN-gamma pretreatment, and was restored by addition of MART-1 peptide AAGIGILTV for 2 hours. Examination of melanoma lesions by quantitative reverse transcriptase-polymerase chain reaction revealed up to 188-fold more abundant IFN-gamma transcripts when compared to control skin. Laser capture microdissection and immunohistology localized most IFN-gamma-producing T cells to the tumor stroma. Reduced MART-1 expression was frequently observed in adjacent tumor cells. Consequently, IFN-gamma may enhance inflammatory responses yet hamper effective recognition of melanoma cells.
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PMID:Interferon-gamma reduces melanosomal antigen expression and recognition of melanoma cells by cytotoxic T cells. 1183 72

Balance of the two types of T helper cells is one of the most important factors for regulation of the immune system. This study examines the production of interleukin (IL)-4, -6, -10, -12, and interferon-gamma by peripheral blood mononuclear cells stimulated with phytohemagglutinin or Staphylococcus aureus. Sixty-one patients, including 25 with gastric and 39 with colorectal cancer, and 39 normal volunteers were entered. The production of IL-12 decreased significantly with advancing disease and was lowest in the patients with distant metastases and cachexia. Compared with normal donors, the production of interferon-gamma decreased in all categories of patients, with no difference among patient groups. Levels of Th2 cytokines, such as IL-4, IL-6, and IL-10, also showed no difference among patient groups. However, production of all these cytokines had increased by 2.5 months after sequential testing in the same cachectic patients. The authors' findings indicate that the induction of Th1 cells seems to be suppressed at a relatively early stage of disease, whereas that of Th2 cells seems to increase in the terminal stage.
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PMID:Decreased production of interleukin-12 and type 2 immune responses are marked in cachectic patients with colorectal and gastric cancer. 1190 52

Clinical trials of recombinant human interleukin-12 (rhIL-12) delivered by intravenous administration have shown dose-limiting toxicities with limited tumor responses at the doses tested. We have previously reported that intratumoral injection of an adenovirus vector expressing murine interleukin-12 (Adv.RSV-mIL-12) was effective in inducing antitumor immune responses, tumor regression, and long-term survival in mice with established metastatic cancer in the liver. We now report additional studies in the same murine tumor model to assess the safety of intratumoral Adv.RSV-mIL-12 injection. At vector doses that were previously shown to be therapeutically effective, no inflammation in the liver or lungs, and no significant elevations in serum creatinine and aminotransferases were seen after vector injection. Serum elevations of IL-12 and interferon-gamma (IFN-gamma) were 17- and 19-fold lower than peak levels after intravenous recombinant IL-12 at the maximal tolerated dose in clinical trials. No elevations in serum proinflammatory cytokines (interleukin-6, tumor necrosis factor-alpha) were noted up to 2 weeks after vector injection. No systemic dissemination of the vector was detected on polymerase chain reaction (PCR) assays at therapeutically effective vector doses. At higher supratherapeutic vector doses of Adv.RSV-mIL-12, however, inflammation in the liver and lungs with elevation in serum aminotransferases were seen, but not in controls injected with the equivalent particle number of an empty adenoviral vector. These results support the cautious testing in patients with hepatic metastases of adenovirus mediated IL-12 gene delivery by intratumoral injection.
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PMID:Intratumoral delivery of adenovirus-mediated interleukin-12 gene in mice with metastatic cancer in the liver. 1193 72


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