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 mechanism of therapeutic activity for recombinant murine interferon-gamma (rMu IFN gamma) in the treatment of metastatic disease was investigated by comparing effector cell augmentation with therapeutic activity in mice bearing experimental lung metastases (B16-BL6 melanoma). Effector cell functions in spleen, peripheral blood, and lung (the tumor-bearing organ) were tested after 1 week and 3 weeks of rMu IFN gamma administration (i.v. three times per week). Natural killer (NK), lymphokine-activated killer (LAK), cytolytic T lymphocyte (CTL) activities against specific and nonspecific targets, and macrophage tumoristatic activity were measured. rMu IFN gamma demonstrated immunomodulatory activity in most assays of immune function. The optimal therapeutic protocol of rMu IFN gamma (2.5 x 10(6) U/kg, three times per week) prolonged survival and decreased the number of pulmonary metastatic foci. This therapeutic activity was correlated with specific CTL activity from pulmonary parenchymal mononuclear cells (PPMC), but not from spleen or blood. Macrophage tumoristatic activity in PPMC also correlated with therapeutic activity, but activity in alveolar macrophages did not. However, therapeutic activity did not correlate with NK or LAK activity at any site. These results demonstrate that the optimal therapeutic protocol is the same as the optimal immunomodulatory dose for pulmonary CTL and macrophage activities. Furthermore, while immunological monitoring may help to optimize treatment protocols, current monitoring procedures that use readily accessible sites, particularly peripheral blood, may not accurately predict the therapeutic efficacy of biological response modifiers in clinical trials.
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PMID:Antitumor response to recombinant murine interferon gamma correlates with enhanced immune function of organ-associated, but not recirculating cytolytic T lymphocytes and macrophages. 840 33

Disseminated malignant melanoma is a very resistant tumor to therapy. Mechanisms of resistance to chemotherapy may be due to glutathione reductase and O6 alkyltransferase, two enzymes especially able to detoxify from alkylation. An interesting model is represented by dacarbazine in the treatment of melanoma with nitrosourea derivatives. Cytokines may come to play an increasing role in the combination with chemotherapy; interferon-alpha and interleukin-2, for example, seem to potentiate the action of chemotherapy in well-designed clinical protocols. Moreover, tumor necrosis factor-alpha was shown to be active in combination therapy with interferon-gamma and chemotherapy when administered by isolation perfusion. Targeting with monoclonal antibodies or melanocyte-stimulating hormone-alpha conjugated to cytotoxic agents represents a promising area. The discovery of a gene, designated MAGE1, coding for a peptide presented by HLA-A1 and able to specifically activate cytotoxic T lymphocytes may represent a unique approach to specific active immunotherapy for melanoma. The interference with integrins and adhesion molecules may play a role in the prevention of metastases. Some preclinical models seem to validate this approach. Current treatment of disseminated malignant melanoma involves chemotherapy often associated with other cytotoxic agents or cytokines, which may potentiate the antitumor effect. Other therapeutic issues reviewed concern targeting and immunotherapy. This review ends with a survey of biologic factors that may constitute new approaches to melanoma therapy.
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PMID:Disseminated melanoma, preclinical therapeutic studies, clinical trials, and patient treatment. 845 23

Recombinant tumor necrosis factor alpha (rTNF alpha) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNF alpha is hampered by severe systemic side effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 10-fold less than the effective dose in animals. Isolated perfusion of the limbs (ILP) allows the delivery of high-dose rTNF alpha in a closed system with acceptable side effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In patients with melanoma-in-transit metastases (stage IIIA or AB), we obtained a 91% complete response rate compared with 52% after ILP with melphalan alone. In unresectable soft tissue sarcomas, this protocol was found to produce a 50% complete response with 87.5% limb salvage, since most tumors became removable. Release of nanograms levels of TNF alpha in the systemic circulation was evident, but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and electively lyses the tumor endothelial cells, while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in man.
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PMID:Administration of high-dose tumor necrosis factor alpha by isolation perfusion of the limbs. Rationale and results. 852 Dec 39

Arginine-derived nitric oxide (NO) has been identified in some tumor cell lines and solid human tumors. The effect of tumor cell NO on tumor biology is poorly understood. The purpose of this study was to investigate the effect of NO production by EMT-6 murine breast cancer cells on tumor cell growth in vitro and subcutaneous tumor growth and experimental pulmonary metastasis in vivo. EMT-6 cells were incubated with endotoxin (LPS, 10 microgram/ml) and interferon-gamma (IFN, 50 U/ml), in the presence or absence of the NO synthase inhibitor, omega-nitro-L-arginine methyl ester (L-NAME, 2 mM), and NO production and cell number were assessed 24 hr later. EMT-6 cells were also treated overnight with LPS/IFN, in the presence or absence of L-NAME, washed and injected either subcutaneously in the dorsal flank (n = 40) or via the tail vein (n = 40) of syngeneic BALB/c mice. Two weeks following tumor cell injection, tumor size and number of pulmonary metastases were assessed. LPS/IFN stimulated NO production in EMT-6 cells and inhibited cell growth in vitro by 50%. L-NAME blocked LPS/IFN stimulation of NO production and restored cell growth to near control levels. When injected into BALB/c mice, LPS/IFN-stimulated tumor cells demonstrated a two-fold increase in subcutaneous tumor growth and experimental pulmonary metastases over control cells. L-NAME reduced tumor size and number of lung metastases to control levels, suggesting that tumor cell NO production was responsible for this effect. In summary, LPS/IFN-stimulated NO production in EMT-6 tumor cells inhibits tumor cell growth in vitro, yet paradoxically augments tumor growth and metastasis in vivo.
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PMID:Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates tumorigenesis and experimental lung metastasis in vivo. 866 Nov 71

Interleukin 12 (IL-12) is a heterodimeric cytokine with a number of biological effects that are consistent with its potential role as an antitumor agent. The antimetastatic and antitumor activities of IL-12 have been demonstrated in a number of murine tumor models. Both the inhibition of established experimental pulmonary or hepatic metastases and a reduction in spontaneous metastases have been achieved by treatment with murine IL-12. Systemic treatment of mice bearing subcutaneous tumors with IL-12 results in tumor growth inhibition, prolongation of survival, and, in some models, tumor regression. The antitumor effect of IL-12 in these models is dose-dependent and can be initiated against well-established tumors. Mice cured of their tumor by IL-12 treatment are specifically immune to rechallenge with the same tumor. A series of experiments have demonstrated that both T-cells and interferon-gamma (IFN-gamma) induction are necessary for the optimal antitumor effects of IL-12. However, the antitumor efficacy of IL-12 has not been observed after exogenous administration of murine IFN-gamma, suggesting that additional factors may be important for the antitumor effects of IL-12. In several tumor models, IL-12 is more active or has a larger therapeutic window than either IL-2 or IFN-alpha, two cytokines with demonstrated antitumor activity against human malignancies. Combining IL-12 with other cytokines or chemotherapeutic drugs can improve antitumor effects.
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PMID:Antitumor activity of interleukin 12 in preclinical models. 876 10

Interleukin 12 (IL-12) has a pivotal role in controlling cell-mediated immunity through a number of important biological activities, such as secretion of interferon-gamma (IFN-gamma). In this review, we report our recent results regarding the antitumor and antimetastatic effects of IL-12. Five intraperitoneal injections of recombinant IL-12 (rIL-12) into mice bearing subcutaneous tumors (CSA1M fibrosarcoma) induced complete tumor regression, irrespective of whether tumors were at early or late stages of growth. Furthermore, IL-12-treated mice that had rejected the primary tumor exhibited complete resistance to rechallenge with the same tumor but did not reject a second syngeneic tumor. Immunohistochemical analyses following IL-12 treatment revealed that CD4+ and CD8+ T-cells had infiltrated the tumor. More importantly, IFN-gamma mRNA expression was observed in fresh tumor masses from tumor-bearing mice receiving IL-12 treatment. The importance of IFN-gamma was further demonstrated by the observation that systemic administration of anti-IFN-gamma monoclonal antibody prior to IL-12 treatment completely abrogated the antitumor effect of IL-12. We next investigated the ability of rIL-12 to modulate the outgrowth of metastatic tumor cells in an ovarian carcinoma (OV-HM) model. This aggressive tumor showed rapid growth of the primary tumor mass, a high incidence of metastases to the lung and lymph nodes, and invasion from the primary subcutaneous site into the peritoneal cavity. At approximately 1 month after tumor implantation, primary tumors in animals without palpable lymph nodes were surgically resected. When examined 2 months later, most animals had developed lymph node and lung metastases. In contrast, rIL-12 injections following tumor resection inhibited the development of metastases in both the lung and lymph nodes. Even in mice showing signs of lymph node metastases or invasion of the abdominal wall before primary tumor resection, rIL-12 administration following tumor resection prevented further invasion into the peritoneal cavity and metastatic tumor cell growth in the lung. Our results demonstrate that administration of rIL-12 to tumor-bearing mice results in tumor regression through mechanisms involving efficient IFN-gamma production by antitumor T-cells at tumor sites in situ and the establishment of a tumor-specific protective immune response. The results also indicate that IL-12 can induce a curative immune response in the face of an aggressive micrometastasizing tumor.
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PMID:Antitumor and antimetastatic effects of interleukin 12. 876 11

We examined the host immune response to the poorly immunogenic B16-BL6 melanoma, which was transduced to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) (450 ng/10(6)/24 h). Tumor growth after subcutaneous inoculation was not significantly altered, although an influx of neutrophils and monocytes/macrophages was evident within tumors and draining lymph nodes (LNs). Immunization with irradiated transduced cells did not induce systemic immunity to the parental tumor. However, vaccination with transduced tumors significantly augmented in vivo sensitization of draining LN cells. These tumor-draining LN (TDLN) cells, when secondarily stimulated in vitro with anti-CD3 monoclonal antibodies and expanded in interleukin-2 (10 U/ml), exhibited greater release of GM-CST and interferon-gamma against tumor compared with TDLN cells from animals with parental tumor. In adoptive immunotherapy, activated LN cells draining transduced tumors mediated significant reductions of the numbers of established pulmonary metastases compared with LN cells draining parental tumor, which were ineffective. In addition, the therapeutic efficacy of LN cells draining transduced tumors was significantly better than LN cells primed in vivo with tumor cells admixed with Corynebacterium parvum, which we have previously described as an approach to generate immune cells. Thus, GM-CSF appears to be an important adjuvant in the induction of tumor immunity.
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PMID:Therapeutic efficacy of T cells derived from lymph nodes draining a poorly immunogenic tumor transduced to secrete granulocyte-macrophage colony-stimulating factor. 878 10

Previously, we reported a case of complete response (CR) of metastatic renal cell carcinoma with inhalant interferon-gamma. This inhalant therapy was considered effective against metastatic lung hilar tumors. On the other hand, metastatic tumors of the peripheral lung field tumor did not respond to the inhalation therapy. We report, a case of metastatic renal cell carcinoma in peripheral lungs showing complete response to continuous subcutaneous administration of interferon alpha and gamma. A 53-year-old woman was admitted to our hospital because of a large palpable mass in the left upper quadrant in March, 1994. Computerized tomographic (CT) scan disclosed a huge renal tumor. To reduce the tumor size, transarterial embolization, and subcutaneous administration of interferon-gamma were performed. In April 1994, the tumor was completely excised. In the post-operative course, multiple metastases were recognized in the lower peripheral lung field, subcutaneous administration of IFN-gamma and inhalation of IFN-gamma were begun, but the tumor size increased in October 1994. She underwent continuous subcutaneous administration of IFN-alpha and gamma. Three months later, the lung tumor disappeared. She has remained tumor-free as of October 1995. We concluded that this therapy may be effective against metastatic renal cell carcinoma in the lungs.
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PMID:[A case study of metastatic renal cell carcinoma in lungs showing complete response to continuous subcutaneous injection of interferon alpha and gamma]. 880 59

We have previously reported that the poorly immunogenic D5 melanoma transduced to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) will elicit immunity in tumor-draining lymph node (TDLN) cells after subcutaneous inoculation. After in vitro activation with anti-CD3 and interleukin-2 (IL-2), these cells acquire in vivo antitumor reactivity to wild-type tumor in the adoptive immunotherapy of pulmonary metastases. Using monoclonal antibodies, depletion of CD4+ or CD8+ T cells immediately after the adoptive transfer of activated TDLN cells revealed that both subsets could mediate the regression of tumor in the absence of exogenous IL-2 administration. CD8+ cells were more potent than CD4+ cells in mediating tumor regression on a per cell basis. We found that the exogenous administration of IL-2 enhanced the antitumor efficacy of CD4+ T cells. Purified CD4+ and CD8+ TDLN cells that were activated separately in culture released GM-CSF and interferon-gamma in response to wild-type tumor in vitro and mediated tumor regression in vivo. Last, the induction of either immune CD4+ or CD8+ T-cell subset during growth of the GM-CSF-secreting melanoma was found to be unaffected by the depletion of the alternate T-cell subset before tumor inoculation. These findings demonstrate that both CD4+ and CD8+ T cells can independently acquire therapeutic reactivity and presumably recognize two separate epitopes involved in tumor rejection.
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PMID:Concurrent induction of CD4+ and CD8+ T cells during tumor growth with antitumor reactivity in adoptive immunotherapy. 908 86

We have previously demonstrated that the growth of weakly immunogenic murine sarcomas leads to the induction of immunologically specific pre-effector cells in tumor-draining lymph nodes (TDLN). The in vitro activation of TDLN cells with anti-CD3 monoclonal antibodies (mAbs) and interleukin-2 (IL-2) resulted in the acquisition of effector function as measured by tumor regression in the adoptive immunotherapy of pulmonary metastases. Further studies were performed to characterize the mechanisms associated with in vivo tumor reactivity mediated by activated TDLN cells. By positive selection, CD4+ and CD8+ T cells were purified and activated by the anti-CD3/IL-2 method. CD8+, but not CD4+, cells manifested tumor-specific granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-gamma) release in vitro, and elicited tumor regression in vivo. By contrast, only activated CD4+ were found to release significant amounts of IL-2 in response to tumor antigen but did not mediate tumor regression in vivo. Mixing the two purified populations enhanced the antitumor activity of the CD8+ T cells. In culture, IL-2 was found to augment the relative amount of tumor-specific release of GM-CSF and IFN-gamma by activated TDLN cells. We found that the tumor-specific release of GM-CSF and IFN-gamma by activated lymphocytes was strongly associated with the in vivo therapeutic efficacy of these cells. Evidence in support of this included the following: (1) cytokine release of TDLN derived after different durations of tumor growth correlated with tumor reactivity in adoptive transfer studies, (2) cytokine release of T cells derived from different lymphoid organs corresponded with tumor reactivity in adoptive transfer, and (3) in vivo administration of neutralizing mAb to IFN-gamma and GM-CSF significantly inhibited the antitumor reactivity of TDLN cells. These studies document the contributory roles of IFN-gamma, GM-CSF, and IL-2 released by activated CD4+ and CD8+ T cells involved in tumor regression.
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PMID:Different cytokine profiles released by CD4+ and CD8+ tumor-draining lymph node cells involved in mediating tumor regression. 910 38


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