UMLS:C0027627 - FACTA Search

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 present study investigates the ability of recombinant interleukin 12 (rIL-12) to modulate the growth of a primary tumor as well as the outgrowth of metastatic tumor cells in an ovarian carcinoma (OV-HM) model. This aggressive tumor displayed rapid growth of the primary tumor mass, high incidence of metastases to lung and lymph nodes, and invasion from the primary s.c. site to the peritoneal cavity. Starting 12 days after s.c. tumor cell implantation, several i.p. injections of rIL-12 at 2-3 day intervals resulted in regression of growing tumors. These treated mice did not show signs of metastases or tumor recurrence at the original site. One month after tumor implantation, untreated mice did not have visible lung metastasis, but some did have palpable lymph nodes. At this stage, the primary tumors of 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 after tumor resection inhibited the development of metastases in both lung and lymph nodes. This contrasted with the failure of IL-2 to prevent metastases. Even for mice already showing signs of lymph node metastases or invasion of the abdominal wall, rIL-12 administration after tumor resection prevented further invasion to the peritoneal cavity and growth of metastatic tumor cells in lung. It was somewhat surprising that the IL-12 treatment of animals after 1 month of tumor growth without resection also resulted in complete tumor regression, as well as eradication of micrometastasis that would have occurred before the treatment. Moreover, they exhibited resistance to a rechallenge with the same tumor but not with a second tumor. Thus, this tumor system provides a relevant model to clinical situations in terms of treatment of advanced tumors and metastases. These results also indicate that IL-12 can induce a curative immune response, even in the face of an aggressive micrometastasizing tumor.
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PMID:Administration of recombinant interleukin 12 prevents outgrowth of tumor cells metastasizing spontaneously to lung and lymph nodes. 767 Dec 53

It has recently been demonstrated that in vivo administration of murine interleukin 12 (IL-12) to mice results in augmentation of cytotoxic natural killer (NK)/lymphocyte-activated killer cell activity, enhancement of cytolytic T cell generation, and induction of interferon gamma secretion. In this study, the in vivo activity of murine IL-12 against a number of murine tumors has been evaluated. Experimental pulmonary metastases or subcutaneous growth of the B16F10 melanoma were markedly reduced in mice treated intraperitoneally with IL-12, resulting in an increase in survival time. The therapeutic effectiveness of IL-12 was dose dependent and treatment of subcutaneous tumors could be initiated up to 14 d after injection of tumor cells. Likewise, established experimental hepatic metastases and established subcutaneous M5076 reticulum cell sarcoma and Renca renal cell adenocarcinoma tumors were effectively treated by IL-12 at doses which resulted in no gross toxicity. Local peritumoral injection of IL-12 into established subcutaneous Renca tumors resulted in regression and complete disappearance of these tumors. IL-12 was as effective in NK cell-deficient beige mice or in mice depleted of NK cell activity by treatment with antiasialo GM1, suggesting that NK cells are not the primary cell type mediating the antitumor effects of this cytokine. However, the efficacy of IL-12 was greatly reduced in nude mice suggesting the involvement of T cells. Furthermore, depletion of CD8+ but not CD4+ T cells significantly reduced the efficacy of IL-12. These results demonstrate that IL-12 has potent in vivo antitumor and antimetastatic effects against murine tumors and demonstrate as well the critical role of CD8+ T cells in mediating the antitumor effects against subcutaneous tumors.
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PMID:Antitumor and antimetastatic activity of interleukin 12 against murine tumors. 810 30

Interleukin 12 (IL-12) enhances lysis mediated by NK- and lymphokine activated killer (LAK) cells. It also causes proliferation of IL-2 stimulated T and NK cells in vitro. For these IL-2 complementing properties murine pulmonary metastases of a coloncarcinoma line were treated with IL-12 and IL-2 or with the individual agents. Results were compared to sham treated controls. IL-2 alone mediated significant tumor reduction but provoked pulmonary edema and concomittand toxicity, graded in three steps. IL-12 combined with an IL-2 dose reduced by 81% still resulted in significant antitumoral activity. Toxicity, however, was not discernable from sham treated controls. IL-12 thus appears as an attractive cytokine for combination with IL-2 in antitumor therapy. Particularly treatment of tumors, like gastrointestinal tract cancers, so far mainly resistant to cell mediated antitumor therapy, might profit from this approach.
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PMID:Addition of interleukin 12 to low dose interleukin 2 treatment improves antitumor efficacy in vivo. 852 51

Particle-mediated (gene gun) in vivo delivery of the murine interleukin 12 (IL-12) gene in an expression plasmid was evaluated for antitumor activity. Transfer of IL-12 cDNA into epidermal cells overlying an implanted intradermal tumor resulted in detectable levels (266.0 +/- 27.8 pg) of the transgenic protein at the skin tissue treatment site. Despite these low levels of transgenic IL-12, complete regression of established tumors (0.4-0.8 cm in diameter) was achieved in mice bearing Renca, MethA, SA-1, or L5178Y syngeneic tumors. Only one to four treatments with IL-12 cDNA-coated particles, starting on day 7 after tumor cell implantation, were required to achieve complete tumor regression. This antitumor effect was CD8+ T cell-dependent and led to the generation of tumor-specific immunological memory. By using a metastatic P815 tumor model, we further showed that a delivery of IL-12 cDNA into the skin overlying an advanced intradermal tumor, followed by tumor excision and three additional IL-12 gene transfections, could significantly inhibit systemic metastases, resulting in extended survival of test mice. These results suggest that gene gun-mediated in vivo delivery of IL-12 cDNA should be further developed for potential clinical testing as an approach for human cancer gene therapy.
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PMID:Gene gun-mediated skin transfection with interleukin 12 gene results in regression of established primary and metastatic murine tumors. 869 8

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

A major goal of tumor immunotherapy is the effective eradication of established metastases associated with the induction of a T cell-mediated protective immunity. We achieved this in a poorly immunogenic murine neuroblastoma model by gene therapy with a single chain interleukin 12 (scIL-12) fusion protein that assures equal expression of its p35 and p40 subunits. Thus, NXS2 hybrid neuroblastoma cells (C1300 x dorsal root ganglion cells), which form experimental bone marrow and liver metastases in syngeneic A/J mice, were transduced with a gene encoding murine interleukin 12, monomerized by introduction of a protein linker between the p35 and p40 protein chains of this heterodimeric cytokine. We demonstrate for the first time that subcutaneous vaccination with these transduced cells induces a protective immunity, as indicated by the complete absence of liver and bone marrow metastasis after challenge with NXS2 wild-type tumor cells. Furthermore, vaccination of animals with established liver and bone marrow metastases completely eradicated liver metastases and suppressed bone marrow metastases. The local and systemic immune response against scIL-12-transduced NXS2 cells is largely dependent on CD8(+) T cells. This was demonstrated in vivo by depletion of immunocompetent A/J mice with monoclonal anti-CD4 and anti-CD8 antibodies and in vitro by specific major histocompatibility complex, class I-restricted CD8(+) T cell-mediated killing of NXS2 and their parental C1300 neuroblastoma cells. In conclusion, we demonstrate successful anti-tumor immunotherapy with an scIL-12 fusion protein that could facilitate clinical application of interleukin 12 gene therapy.
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PMID:Gene therapy with a single chain interleukin 12 fusion protein induces T cell-dependent protective immunity in a syngeneic model of murine neuroblastoma. 948 10

The aim of this study was to evaluate the safety profile of s.c. administered recombinant human interleukin 12 (rHuIL-12). Pharmacokinetics and pharmacodynamics of rHuIL-12 and any evidence of antitumor effect were also considered. Ten pretreated patients with progressive metastatic melanoma were enrolled in this pilot study. Patients received a fixed dose of rHuIL-12 (0.5 microgram/kg) for two identical 28-day cycles, with injections given on days 1, 8, and 15 of each cycle. In case of any evidence of response or disease stabilization, the treatment was continued for two further 28-day cycles. Toxicity mainly consisted of a flu-like syndrome. Transient increases in transaminasemia (6 of 10 patients) and triglyceridemia (8 of 10 patients) were observed. Peak serum IL-12 levels were reached 8-12 h after the first injection in all patients; no serum IL-12 was detectable in 6 of 9 evaluable patients after the last injection of the second cycle. No antibody response to rHuIL-12 could be detected in any of the patients. A marked, transient reduction in circulating CD8+ and CD16+ lymphocytes and neutrophils was observed after the first administration and high levels of serum IFN-gamma and IL-10 were detected in all patients within 24-48 h. Tumor shrinkage, not reaching partial or complete remission, involved the regression of s.c. nodules (2 of 3 patients), superficial adenopathies (1 of 3 patients), and hepatic metastases (1 of 3 patients); regressions were detected after the first cycle of treatment and were maintained in spite of progression at different sites. s.c. rHuIL-12 treatment was well tolerated and had marked effects on immune parameters and potential antitumor activity.
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PMID:Pilot study of subcutaneous recombinant human interleukin 12 in metastatic melanoma. 951 55

Despite the well-demonstrated involvement of both interleukin 2 (IL-2) and interleukin 12 (IL-12) in the activation of host anti-cancer response, the knowledge of IL-2-IL-12 interactions has still to be better investigated. This study was performed to evaluate the effects of subcutaneous (s.c.) low-dose IL-2 on IL-12 secretion in metastatic cancer patients. The study included 19 evaluable metastatic renal cell cancer patients, who received s.c. low-dose IL-2 (6 MIU day(-1) for 6 days per week for 4 weeks) as a first-line immunotherapy of their metastatic disease. Serum levels of IL-12 were measured using an enzyme immunoassay on venous blood samples collected before the immunotherapy and at 1-week intervals. The clinical response consisted of partial response (PR) in four and stable disease (SD) in eight patients, whereas the other seven patients progressed. Mean serum levels of IL-12 observed in the overall patients significantly increased in response to IL-2 injection. Moreover, by evaluating IL-12 variations in relation to the clinical response, a marked significant increase in IL-12 mean values occurred in patients with response or SD, whereas the progressing patients showed a significant decline in IL-12 levels during IL-2 administration. Finally, IL-12 mean pretreatment values observed in patients who progressed were significantly higher than those seen in non-progressing patients. This study shows that low-dose IL-2 immunotherapy of cancer may stimulate the in vivo release of IL-12, and it would suggest that IL-2-induced IL-12 enhancement is associated with a favourable prognosis.
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PMID:In vivo stimulation of IL-12 secretion by subcutaneous low-dose IL-2 in metastatic cancer patients. 966 74

Interleukin 12 (IL-12) is a disulfide-linked heterodimer molecule produced predominantly by professional antigen presenting cells. It promotes the induction of sundry biological effects with significant relevance to antitumor immunity, such as enhancing a T(H)1 helper response, an in vivo antiangiogenic effect, induction of adhesion molecules that assist in lymphocyte homing to sites of tumor growth, and a direct stimulatory effect on both T-cells and NK cells. We tested the efficacy of an antimetastatic vaccine composed of autologous murine D122 cells transfected with both subunits of IL-12 cDNA to express biologically-active IL-12 molecule. Expression of IL-12 by D122 cells significantly reduced their tumorigenicity and metastatic potential in immunocompetent syngeneic hosts. Furthermore, vaccination of mice with 2 x 10(6) irradiated IL-12-transfected D122 cells engendered a protective CTL response which rejected a subsequent challenge with parental D122 cells and eradicated lung micrometastasis in animals whose primary tumors have been surgically removed. The antitumor effects of IL-12 were mediated primarily by its ability to induce gammaIFN expression in vivo. CD8+ T-cells as well as NK cells were crucial in the execution of the antitumor effects of IL-12. These results suggest that autologous tumor cells expressing IL-12 by gene transfer are a potent antitumor vaccine able to induce a systemic immune response against poorly immunogenic and spontaneously metastatic tumors.
Clin Exp Metastasis 1998 Oct
PMID:Antimetastatic vaccination against Lewis lung carcinoma with autologous tumor cells modified to express murine interleukin 12. 993 9

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