UMLS:C0598934 - FACTA Search

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Query: UMLS:C0598934 (tumor growth)
58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of granulocyte/macrophage colony-stimulating factor (GM-CSF) gene transfer on the tumorigenicity and immunogenicity of 2 different murine tumor lines was determined. Transduction of B16 melanoma cells with the GM-CSF gene rendered the cells more immunogenic. In contrast, transduction of NG4TL4 fibrosarcoma in FVB/N mice (NG) with the GM-CSF gene showed increased tumorigenicity in a high producer line (NG-MGh). The parent NG or NG-MG cells induced the same level of cytotoxic T-lymphocyte (CTL) response and the same magnitude of tumor transplantation immunity. However, the proliferation of the NG-MGh cells was increased 2- to 10-fold. There was no increase in apoptosis in the NG cells and there was no increase of NG-MGh cells in S-phase, hence the increase of the proliferative activity appeared to be indeed inherent to the cells. Mixing the splenocytes from the NG-MGh tumor bearers with the NG tumor cells did not increase tumorigenicity but totally inhibited the growth of the NG tumor, indicating that suppressor cells were not present. Mixing 10,000 rad X-irradiated NG-MGh cells with viable NG tumor cells resulted in 3- to 10-fold increased NG tumor growth rate. The in vitro proliferation of NG cells was increased by adding both GM-CSFs and macrophages and not by either one alone, suggesting that interaction between macrophages and GM-CSFs resulted in the production of tumor growth enhancing factor(s). Our findings suggest that transduction of NG tumor cells with the GM-CSF gene increases tumorigenicity, which is attributed both to an increased inherent proliferative ability of the tumor cells and to the in vivo production of a tumor growth enhancing factor(s) at the tumor site.
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PMID:Paradoxical effect of GM-CSF gene transfer on the tumorigenicity and immunogenicity of murine tumors. 945 9

We have examined antitumor effect of human esophageal carcinoma cells (T.Tn) which were retrovirally transduced to express mouse granulocyte macrophage-colony stimulating factor (mGM-CSF) gene. Nude mice inoculated with T.Tn cells secreting mGM-CSF developed small tumors but the tumors regressed spontaneously, although the proliferation in vitro of transduced cells was not different from that of wild-type cells. In contrast, the tumor of T.Tn cells transduced with human GM-CSF grew as that of wild-type cells, since murine GM-CSF receptors do not bind to human GM-CSF. Histological examination of the regressing tumor of mGM-CSF-producing T.Tn cells revealed predominant infiltration of inflammatory cells including macrophages. In addition, local injection of mGM-CSF-producing T.Tn cells into the established wild-type tumors significantly induced the retardation of subsequent wild-type tumor growth, suggesting that T-cell independent local response plays a crucial role in destroying tumor cells.
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PMID:Induction of antitumor effect on human esophageal carcinoma cells by the retroviral expression of granulocyte macrophage-colony stimulating factor gene. 945 56

IFN-gamma production is dramatically reduced in T cells from mice bearing large mammary tumors. This inhibition of IFN-gamma gene expression occurs mostly in CD4+ T cells, as determined by ELISA and reverse transcriptase-PCR. The effects of known mammary tumor factors in normal T cells and its subsets were evaluated. Pretreatment with granulocyte-macrophage CSF resulted in increased IFN-gamma levels by T cells, while PGE2 pretreatment equally decreased the levels of this cytokine in CD4+ and CD8+ T cells from normal mice. Interestingly, phosphatidyl serine (PS) down-regulated the IFN-gamma production of CD4+, but not that of CD8+, T cells. Methylation analysis indicated that the CpG dinucleotide in SnaBI site of the IFN-gamma 5' promoter flank region was hypermethylated in CD4+, but not in CD8+, T cells of large tumor bearers and of normal mice pretreated with PS. Electrophoresis mobility shift assay using an oligonucleotide probe corresponding to the IFN-gamma promoter core region sequence showed a greatly reduced binding of a 90-kDa nuclear protein in CD4+ T cells from tumor bearers and in those from PS-pretreated normal mice. Since IL-2 production is not affected in either CD4+ or CD8+ T cells from tumor bearers, these studies indicate that IFN-gamma production can be regulated independently from that of other type 1 cytokines in vivo. Our data further suggest that PS is involved in IFN-gamma gene down-regulation during mammary tumorigenesis and contributes to the generalized immunosuppression associated with tumor growth.
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PMID:CD4+, but not CD8+, T cells from mammary tumor-bearing mice have a down-regulated production of IFN-gamma: role of phosphatidyl serine. 951 Jan 74

In this study, we provide direct evidence that the magnitude and nature of the immune response to a DNA vaccine can be differentially regulated by codelivery of various mouse cytokine genes. Mice immunized with a hepatitis B virus (HBV) DNA vaccine and the IL-12 or IFN-gamma gene exhibited a significant enhancement of Th1 cells and increased production of anti-HBV surface IgG2a Ab, as well as a marked inhibition of Th2 cells and decreased production of IgG1 Ab. In contrast, coinjection of the IL-4 gene significantly enhanced the development of specific Th2 cells and increased production of IgG1 Ab, whereas Th1 differentiation and IgG2a production were suppressed. Coinjection of the IL-2 or the granulocyte-macrophage-CSF gene enhanced the development of Th1 cells, while the development of Th2 cells was not affected, and the production of IgG1 and IgG2a Ab were both increased. The CTL activity induced by HBV DNA vaccination was most significantly enhanced by codelivery of the IL-12 or IFN-gamma gene, followed by the IL-2 or granulocyte-macrophage-CSF gene, whereas codelivery of the IL-4 gene suppressed the activity. When challenged with HBV surface Ag (HBsAg)-expressing syngeneic tumors, significant reduction of tumor growth was observed in mice that were coadministered the IL-12 gene but not the IL-4 gene. Taken together, these results demonstrate that application of a cytokine gene in a DNA vaccine formulation can influence the differentiation of Th cells as well as the nature of an immune response and may thus provide a strategy to improve its prophylactic and therapeutic efficacy.
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PMID:Development of Th1 and Th2 populations and the nature of immune responses to hepatitis B virus DNA vaccines can be modulated by codelivery of various cytokine genes. 957 May 50

Interleukin-12 (IL-12), a naturally occurring cytokine, has demonstrated antitumor activity in several murine solid tumors. The Lewis lung carcinoma was used to study the most effective scheduling of recombinant murine interleukin-12 (rmIL-12) administration with fractionated radiation therapy. The effect of the schedule of rmIL-12 administration alone or along with a 1- or 2-week fractionated radiation therapy regimen was examined. Beginning rmIL-12 prior to or at the same time as radiation therapy and extending rmIL-12 through the radiation regimen and beyond produced the longest tumor growth delays. Those treatment regimens which were most effective against the primary tumor were also most effective in decreasing the number of lung metastases on day 20. To further assess the immunotherapeutic effects from rmIL-12 administration, the efficacy of rmIL-12 with fractionated radiation therapy delivered to a right hind-limb tumor was measured as tumor growth delay in an unirradiated left hind-limb tumor. There was some difference in the tumor growth delay between the unirradiated tumor in the animals bearing an irradiated tumor in the contralateral leg, and the tumors in animals receiving rmIL-12 only. Recombinant murine granulocyte-macrophage-colony stimulating factor (rmGM-CSF) was also an antitumor agent active against the Lewis lung carcinoma and produced an additive effect in combination with fractionated radiation therapy in this tumor. rmIL-12 was a radiation sensitizer in the Lewis lung carcinoma. When rmIL-12 (45-microg/kg) and rmGM-CSF (45 microg/kg) were administered together with fractionated radiation therapy, a marked increase in tumor growth delay resulted. This treatment combination also nearly ablated lung metastases on day 20 in these animals. These results may serve as a useful guide in developing clinical protocols, including rmIL-12 and fractionated radiation therapy.
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PMID:Optimal scheduling of interleukin-12 and fractionated radiation therapy in the murine Lewis lung carcinoma. 957 83

The annual incidence of malignant melanoma is estimated at 10-12 per 100,000 inhabitants in countries of central Europe and the United States, and alarmingly there has been a dramatic upward trend in that estimate. The B16 murine melanoma is a rapidly growing metastatic tumor of spontaneous origin, as are human malignant melanomas. Melanoma cells produce specific antigens which are uniquely different from normal cellular antigens, and the expression of such antigens is the cornerstone for preparation of anti-melanoma vaccines. One major problem in evaluating the effectiveness of vaccination and other biologic therapies is the variability of experimental tumor models. A new metastatic model of experimental melanoma which was developed in our laboratory imitates the major clinical stages of malignant metastatic melanoma: stage I, primary (local) tumor growth and bone marrow invasion; stage II, regional lymph node involvement; and stage III, metastasis to distant organs, such as the lungs. This model has been used successfully for screening vaccines constructed in our laboratory. Immunization with formalinized vaccines (of extracellular antigens, intact melanoma cells, or B700 antigen) or irradiated vaccines (of intact melanoma cells) partially inhibit primary melanoma tumor growth, reduce metastasis to regional lymph nodes and lungs, and significantly increase mean survival time. These anti-tumor effects were improved when polyvalent and monovalent vaccines were combined with IL-2 therapy. We also compared the immunogenic activity of vaccines made from B16 melanoma cells transfected with genes encoding murine IL-2 or GM-CSF, and effects on tumor bearing mice were compared with or without therapy using the corresponding lymphokines. In sum, comparison of antibody production, growth of primary melanoma tumors, number of surviving mice, mean survival time, and percent of mice with lung metastases, showed that the best course of immunotherapy involves vaccination of mice with irradiated B16 melanoma cells transfected to secrete GM-CSF, coupled with GM-CSF therapy.
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PMID:A new mouse model of experimental melanoma for vaccine and lymphokine therapy. 966 34

PIXY321, a granulocyte-macrophage colony-stimulating factor/interleukin 3 (GM-CSF/IL-3) genetically engineered hybrid, has shown greater biological activity in stimulating committed myeloid progenitors than either GM-CSF or IL-3 in vitro, in vivo, and in patients treated with high-dose chemotherapy. However, one concern is that PIXY321 may stimulate the proliferation of malignant cells which have functional GM-CSF or IL-3 receptors. Therefore, using a human tumor cloning assay, we have tested the effects of several concentrations of PIXY321 ranging from 0.1 to 100 ng/ml on tumor cells taken directly from 98 patients with solid tumors and Hodgkin's or non-Hodgkin's lymphomas. Of the 34 evaluable specimens, including 15 breast cancers, 5 ovarian cancers, 5 lung cancers, and 9 lymphomas, none showed stimulation of tumor growth. Interestingly, a significant inhibition of the tumor proliferation was seen in one breast cancer and in one large cell immunoblastic non-Hodgkin's lymphoma after continuous exposure of PIXY321. In conclusion, the use of PIXY321 to reduce myelosuppression after high-dose chemotherapy appears unlikely to result in stimulation of the growth of malignant cells in patients with lymphoma or cancers of the breast, lung, and ovary.
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PMID:Effects of PIXY321, a granulocyte-macrophage colony-stimulating factor/interleukin 3 fusion protein, on human tumor colony-forming units taken directly from patients. 981 21

The antitumoral activity of recombinant canarypox virus vectors (ALVAC) expressing murine interleukin 12 (IL-12) was evaluated in the syngeneic, nonimmunogenic murine mammary adenocarcinoma model (TS/A). Seven-day preestablished subcutaneous tumors (5- to 6-mm mean diameters) were injected on days 7, 10, 14, 17, 21, and 24 with the vector ALVAC-IL12 at 2.5 x 10(5) TCID50 (50% tissue culture infective dose). Total tumor regression occurred in 40 to 50% of the treated mice. Furthermore, 100% of the cured mice were protected against a contralateral subsequent challenge with the TS/A parental cells on day 28. The ALVAC-IL12 treatment is not effective in nude mice, suggesting the critical role of T cells. CD4 and CD8 T cells infiltrated the tumors treated with ALVAC-IL12 in the BALB/c model. Furthermore, in vivo depletion of CD4+ T cells totally abrogated the induction of the long-term antitumoral immune response by ALVAC-IL12. Interestingly, some tumor growth inhibition was also observed with ALVAC-betaGal treatment and a vaccinal effect was found in 33% of the treated animals, suggesting an adjuvant effect of the vector itself. Other ALVAC vectors expressing murine cytokines (IL-2, GM-CSF, IFN-gamma) were evaluated in the same model. Major antitumoral activity was observed with ALVAC-GM-CSF. However, a combination of ALVAC-GM-CSF and ALVAC-IL12 had no synergistic effect. These results suggest that in vivo gene transfer with canarypox virus expressing IL-12 may provide an effective and safe strategy for the treatment of human cancers.
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PMID:Canarypox virus-mediated interleukin 12 gene transfer into murine mammary adenocarcinoma induces tumor suppression and long-term antitumoral immunity. 985 12

Human and murine squamous cell carcinomas (SCC) have been reported to produce proinflammatory cytokines IL-1alpha, IL-6, GM-CSF, and IL-8 or KC. Production of individual members of the proinflammatory cytokine family has been associated with increased tumor growth or metastasis in a variety of neoplasms. In this study, we determined whether the expression of these cytokines occurs as a result of the events of cellular transformation or culture, or is promoted by interaction of neoplastic cells with factors or cells in the host environment. We compared the expression of proinflammatory cytokines following the spontaneous transformation of murine keratinocytes in vitro, and following the formation of tumors and metastases from these transformed keratinocytes in syngeneic recipients in vivo. Using sensitive ELISA assays, we found that cultures of the in vitro transformed Balb/c SCC line Pam 212 do not produce elevated levels of proinflammatory cytokines IL-1alpha, IL-6, GM-CSF and KC, indicating that transformation or culture alone is insufficient to account for the level of cytokine expression detected in patient and experimental tumors. In contrast, Pam reisolates from primary and metastatic tumors were obtained which constitutively produce markedly elevated levels of cytokines IL-1alpha, IL-6, KC and GM-CSF. The increase in the expression of these cytokines by SCC in vivo occurred independent of T and B lymphocyte-mediated immunity, since increases in expression of the cytokines was observed in lines reisolated from immunodeficient athymic nude and SCID Balb/c congenic mice. The increased expression of cytokines appeared to result from additional events in vivo, rather than due to selection of a pre-existing cytokine-producing subpopulation, since clones of the parental cell line expressed lower cytokine levels than cloned reisolates, and clones of the non-secreting parental cell line that formed tumors in vivo secreted elevated levels of cytokines following reisolation. We conclude that the development of SCC that express proinflammatory cytokines is promoted by tumor-host interaction(s) that are independent of specific T and B cell immunity.
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PMID:The host environment promotes the development of primary and metastatic squamous cell carcinomas that constitutively express proinflammatory cytokines IL-1alpha, IL-6, GM-CSF, and KC. 993 12

Tumor-specific TCR can serve as an effective target for active immunotherapy of T cell malignancies. Using the murine T cell tumor model C6VL, vaccination with C6VL TCR protected mice from a subsequent lethal dose of tumor cells. This study characterizes the immune mechanisms involved in the tumor protection, and the influence of immunologic adjuvants in inducing a protective immune response. Immune responses induced by TCR vaccines formulated with various adjuvants: QS-21, IL-12, SAF-1, CD40L, and GM-CSF were compared. QS-21, IL-12, and SAF-1 biased the humoral immune response toward Th1-type, reflected by the induction of IgG2a and IgG2b anti-C6VL TCR Abs. CD40L and GM-CSF exclusively produced IgG1 Abs, reflecting a Th2-type immune response. In our tumor model system, only vaccines containing adjuvants that induced a Th1-type immune response favored tumor protection. Furthermore, we demonstrated that CD8+ T cells were necessary and sufficient for tumor protection using anti-CD8 mAb depletion and adoptive cell transfer experiments. Transfer of hyperimmune serum containing anti-C6VL TCR Abs into na ive mice had modest anti-tumor effects and was not sufficient to prevent tumor growth. TCR-vaccinated B cell-deficient mice were not protected against C6VL tumor, and tumor protection was not completely restored after hyperimmune serum transfer. Thus, B cells may serve as important APCs in inducing a protective immune response. Based on these results future TCR vaccines should be designed to maintain native TCR conformation, as well as induce a strong Th1-type immune response.
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PMID:TCR vaccines against T cell lymphoma: QS-21 and IL-12 adjuvants induce a protective CD8+ T cell response. 997 1

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