UMLS:C0677930 - FACTA Search

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Query: UMLS:C0677930 (primary tumor)
20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclophosphamide (Cy) is an alkylating agent widely used in cancer chemotherapy. It has a bimodal effect on the immune system, depending on the dose and schedule of administration. We have previously demonstrated that a single low dose of Cy has an antimetastatic effect, achieved through immunomodulation, in lymphoma bearing rats. Such a treatment reduced the splenic production of IL-10, TGF-beta, and NO, restoring the lymphoproliferative capacity. A shift from immunosuppression to immunopotentiation induced by low-dose Cy treatment was mainly mediated by a decrease in IL-10 production. The present study focused on the analysis of the modulation of type-1 cytokine levels by treatment with a single low dose of Cy and the effect these cytokines (IL-2 and IFN-gamma) and IL-10 have on primary tumor and metastatic cell growth. Our results suggest that a single low dose of Cy induces a Th2/Th1 shift in the cytokine profile of lymphoma-bearing rats, which may be responsible for its antimetastatic effect. A direct action of IL-10 as a growth factor and IFN-gamma as a cytotoxic factor on metastatic cells is also shown.
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PMID:Th2/Th1 switch induced by a single low dose of cyclophosphamide in a rat metastatic lymphoma model. 1180 22

To enhance the NK population induced by Herpes Simplex virus thymidine kinase (HSV-tk) gene transduction and ganciclovir (GCV) treatment, adenovirus-mediated (Ad) expression of IL-12 was added to Ad.HSV-tk + GCV as combination gene therapy. This approach resulted in improved local and systemic growth suppression in a metastatic model of mouse prostate cancer (RM-1). In vitro assay of tumor infiltrating lymphocytes noted superior lysis of both RM-1 and Yac-1 targets with combination therapy, but in vivo depletion of NK cells only negatively impacted on systemic growth inhibition. TUNEL assay of primary tumors noted induction of apoptosis between two and four times higher than controls lasting for 6-8 days post-vector injection. After demonstrating that Ad.HSV-tk/GCV and Ad.mIL-12-induced IFN-gamma independently up-regulated expression of FasL and Fas, respectively, studies examined tumor cell-mediated death through Fas/FasL-induced apoptosis as a mechanism of primary tumor growth suppression. In vitro, combination therapy at low vector doses resulted in synergistic growth suppression, which could be negated by the addition of anti-FasL antibody. In vivo co-inoculation of an adenovirus expressing soluble Fas resulted in combination therapy-treated tumors, which were three times larger than expected, and a reduction in apoptosis to baseline levels. In FasL knockout mice, combination therapy maintained the superior results experienced in wild-type mice, indicating that tumor cell, not host cell FasL, was responsible for Fas transactivation. Therefore, the combination of Ad.HSV-tk/GCV + Ad.mIL-12 results in enhanced local growth control via apoptosis due to tumor cell expression of Fas and FasL and improved anti-metastatic activity secondary to a strong NK response.
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PMID:A novel bystander effect involving tumor cell-derived Fas and FasL interactions following Ad.HSV-tk and Ad.mIL-12 gene therapies in experimental prostate cancer. 1194 76

Costimulation of tumor T cells by B7.1 has been shown to be important for eliciting cell-mediated anti-tumor immunity. We constructed a stable B7.1 gene transfectant of a poorly immunogenic murine sarcoma, Moloney murine sarcoma virus-induced tumor cell line (MMSV). This transfectant, MMSV-B7.1, failed to produce any tumor development in syngeneic mouse models. When MMSV-B7.1 was simultaneously injected with wild-type MMSV, about half of the coinjected mice remained tumor free and displayed an increase in T cell population, upregulation of the mRNA level of various cytokines such as IL-4, IL-5, IL-10, IL-13, IL-15 and IFN-gamma, and complete rejection of reinjected MMSV. To investigate whether MMSV-B7.1 demonstrates any vaccinal effect, the transfectant was injected following the surgical removal of the primary tumor mass. Following a re-challenge with wild-type MMSV, all vaccinated mice maintained their tumor free status and displayed a rapid recovery of down-regulated cytokine levels. The results suggest that B7.1 vaccination after tumor removal might be useful for the prevention of tumor recurrence.
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PMID:Tumor removal enhances immunity induced by B7.1. 1210 46

IFN-gamma is a pleiotropic cytokine that plays an important role in regulating the growth of primary tumors. Although numerous studies of the effects of IFN-gamma on primary-solid-tumor growth have been performed and several potential mechanisms for its efficacy have been proposed, it remains unclear how IFN-gamma modulates tumor progression and whether it exerts its effects indirectly via host cells or directly by interacting with tumor cells. Using the well-characterized mouse metastatic mammary carcinoma 4T1 in a postsurgery setting, IFN-gamma-deficient mice were found to have significantly shorter survival time relative to wild-type mice, demonstrating that IFN-gamma is also a critical component in regulating innate immunity to metastatic disease. Experiments quantifying lung and liver metastasis indicate that decreased survival of IFN-gamma-deficient mice is attributable to increased metastatic disease. To determine whether IFN-gamma is acting directly on the tumor cells, IFN-gamma-nonresponsive 4T1 cells were generated by transfection (4t1/IRt). Metastasis experiments with 4T1/IRt demonstrated that IFN-gamma mediates its effects via host-derived cells, rather than by directly affecting tumor growth. To identify the population of cells responsible for IFN-gamma efficacy, perforin-deficient, T-cell subset-depleted, natural killer cell-depleted, or carrageenan-treated phagocytic cell-depleted mice were inoculated with 4T1 and assessed for primary tumor growth and metastatic disease. None of the conditions altered primary tumor growth; however, the carrageenan treatment significantly increased metastatic disease in the liver and lungs. Survival experiments in 4T1-inoculated, carrageenan-treated mice confirmed that the elimination of phagocytic cells significantly reduces survival time and yields a survival phenotype comparable with IFN-gamma deficiency. Therefore, IFN-gamma is a critical component of innate immunity to metastatic mammary carcinoma that probably mediates its effects via host-derived phagocytic cells.
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PMID:Interferon-gamma-dependent phagocytic cells are a critical component of innate immunity against metastatic mammary carcinoma. 1215 47

4-1BB (CD137) is a member of the TNFR superfamily (TNFRSF9). T cell expression of 4-1BB is restricted to activated cells, and cross-linking has been shown to deliver a costimulatory signal. Here we have shown that treatment of tumor-bearing mice with agonistic 4-1BB-specific Abs can lead to T cell-mediated tumor rejection. In vivo mAb depletion experiments demonstrated that this rejection requires CD8(+) cells but not CD4(+) or NK cells. Both IFN-gamma- and CD40-mediated signals were also required, because no benefit was observed on treatment with 4-1BB mAb in mice in which the genes for these molecules had been knocked out. Interestingly, 4-1BB-mediated stimulation of immune responses in CD40L(-/-) mice is effective (although at a reduced level), and may suggest the existence of an alternative ligand for CD40. Additional experiments in IL-15(-/-) mice indicate that IL-15 is not required for either the generation of the primary tumor-specific immune response or the maintenance of the memory immune response. In contrast, the presence of CD4 cells during the primary immune response appears to play a significant role in the maintenance of effective antitumor memory. Finally, in mice in which the number of dendritic cells had been expanded by Fms-like tyrosine kinase3 ligand treatment, the antitumor effects of 4-1BB ligation were enhanced.
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PMID:4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T cells in a CD40-dependent manner. 1216 1

Colorectal cancer is one of the most common fatal malignancies in the United States, with an incidence second only to lung cancer. The liver is the most common site of colorectal metastases and frequently the only affected organ once the primary tumor has been surgically removed. The only potentially curative treatment for metastatic colorectal cancer in the liver is surgery, although most patients are not eligible for resection. We have therefore, evaluated the therapeutic efficacy of dendritic cells (DCs) engineered to express IL-12 in a liver metastasis model. Direct administration of DCs into the portal vein significantly inhibited the growth of established MC38 colon carcinoma in the liver in C57BL/6 mice. This effect was accompanied by an intratumoral accumulation of CD4+, CD8+, and NLDC-145+ immune effector cells, and also resulted in a systemic immune response as determined by enhanced production of IFN-gamma by T lymphocytes isolated from both spleen and draining lymph nodes. Evaluation of homing of Cy3-labeled DCs following the portal vein injection confirmed their distribution in the liver and lymphoid tissue. Thus, a local delivery of DCs transduced with the IL-12 gene can not only inhibit colorectal tumor growth in vivo but also mount systemic antitumor immune responses. This approach is likely to improve the outcome of immunotherapy for metastatic colorectal cancer since high numbers of tumor-associated DCs positively correlate with a more favorable prognosis. Simultaneous local gene therapy with IL-12 will further improve clinical efficacy without placing the patient at risk for systemic toxicity.
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PMID:Local administration of IL-12-transfected dendritic cells induces antitumor immune responses to colon adenocarcinoma in the liver in mice. 1244 Feb 25

Tumor cells, injected s.c., were maintained until spontaneous metastases to the lungs were established in all of the mice. Mice were then treated with a single dose of cytokine-encapsulated biodegradable microspheres injected directly into primary s.c. tumors to achieve a local and sustained release of interleukin 12 (IL-12), granulocyte-macrophage colony-stimulating factor (GM-CSF), or a combination of these cytokines to the tumor microenvironment. The s.c. tumors were surgically excised 6 days after microsphere injections, and the mice were monitored for recurrence of the primary tumor, survival, and progression of metastatic disease. Combined neoadjuvant treatment with IL-12 and GM-CSF microspheres was superior to all other treatments in reducing the recurrence of primary tumors, enhancing postoperative survival, and suppressing established metastatic disease. Long-term survival analysis demonstrated that intratumoral injection of IL-12 + GM-CSF-loaded microspheres resulted in the complete cure of disseminated disease in the majority of the animals. The addition of systemic low-dose IL-2 therapy to the treatment protocol resulted in the loss of the antitumor activity induced by IL-12 + GM-CSF treatment. In vivo lymphocyte subset depletions established that both T- and natural killer-cell subsets were required for the suppression of primary and metastatic tumors. Long-term, tumor-specific T-cell activity was demonstrated by immunohistochemical analysis of metastatic lesions, IFN-gamma enzyme-linked immunosorbent spot (ELISPOT) assays and tumor challenge studies. These results establish that neoadjuvant in situ tumor immunotherapy with IL-12 + GM-CSF microspheres induces both innate and adaptive antitumor immune responses resulting in the eradication of disseminated disease.
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PMID:Cancer immunotherapy with interleukin 12 and granulocyte-macrophage colony-stimulating factor-encapsulated microspheres: coinduction of innate and adaptive antitumor immunity and cure of disseminated disease. 1249 67

Alterations in the surface expression of HLA class I molecules have been described as a strategy of tumors to evade recognition by cytotoxic T cells. We detected complete loss of HLA class I antigen presentation for 2 tumor cell lines from 1 melanoma patient, the first originated from a regional lymph node lesion diagnosed simultaneously with the primary tumor and the second established 8 months later from a metastatic pleural effusion sample. Antigen presentation was not inducible with IFN-gamma but could be restored after transfection of tumor cells with b2m cDNA, indicating a defect in b2m expression. Analysis of the nature of this defect revealed that it originated from at least 2 mutational events affecting both copies of the b2m gene: a microdeletion of 498 bp in one b2m gene, including its entire exon 1, and a macrodeletion involving the entire copy of the second b2m gene. Microsatellite analysis pointed to the macrodeletion by demonstrating LOH for several specific markers on the long arm (q) of chromosome 15. Structural imbalance of 15q was verified by FISH. FISH studies also indicated the coexistence of a structurally abnormal variant of chromosome 15q with 2 apparently entire chromosomes 15q harboring the homozygous b2m microdeletion. Block of b2m expression in tumor cells builds a barrier to immunotherapy of cancer patients, and its early incidence should be of major consideration in the development and design of immunotherapeutic strategies.
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PMID:Complete loss of HLA class I antigen expression on melanoma cells: a result of successive mutational events. 1251 95

While human prostate cancers and cell lines express Fas, most of these cell lines are resistant to Fas-mediated death. In the present studies we addressed the ability of IFN-gamma to influence Fas-mediated cell death in prostate cancer cells. In vitro exposure of the human cell lines LNCaP and PC3 and the mouse cell line RM-1 to agonist anti-Fas antibody and/or soluble Fas ligand resulted in killing of only PC3 cells. However, preincubation with IFN-gamma resulted in synergistic killing in all three cell lines. In vitro treatment of RM-1 with a replication-incompetent adenovirus expressing mouse FasL (Ad.FasL) resulted in maximal cell kill near 40%, which correlated with baseline Fas expression. The addition of IFN-gamma enhanced cell kill to a degree consistent with the resulting higher levels of Fas and maintained synergistic killing at very low doses of vector. Co-inoculation of orthotopic RM-1 primary tumors with Ad.mFasL and an adenovirus expressing mouse IL-12 (Ad.mIL-12) to drive host production of IFN-gamma negated the survival advantage of Ad.mIL-12 alone. However, the staggered injection of Ad.mIL-12 and Ad.FasL achieved almost threefold higher levels of apoptosis in primary tumor tissue and doubled median survival. Therefore, IFN-gamma is capable of bestowing increased sensitivity to Fas-mediated cell death in prostate cancer cells and, in a gene therapy approach, may define a powerful tool to treat prostate cancers.
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PMID:IFN-gamma sensitization of prostate cancer cells to Fas-mediated death: a gene therapy approach. 1259 6

Interferon-gamma is thought to be essential for the regulation of antitumor reactions. However, the degree of responsiveness of malignant cells to IFN-gamma may have a profound influence on the overall efficacy of an antitumor response. In this study, we examined the molecular basis by which IFN-gamma differentially sensitized human primary and metastatic colon carcinoma cells to Fas-mediated apoptosis. To that end, we analyzed IFN-gamma-induced gene expression at the genome scale, followed by an analysis of the expression and function of specific genes associated with IFN-gamma- and Fas-mediated signaling. We found that although both cell populations exhibited a similar gene expression profile at the genome scale in response to IFN-gamma, the expression intensities of the IFN-gamma-regulated genes were much greater in the primary tumor. Noteworthily, two genes, one involved in IFN-gamma-mediated signaling, IFN consensus sequence-binding protein (ICSBP), and one involved in Fas-mediated signaling, caspase-1, were clearly shown to be differentially induced between the two cell lines. In the primary tumor cells, the expression of ICSBP and caspase-1 was strongly induced in response to IFN-gamma, whereas they were weakly to nondetectable in the metastatic tumor cells. Functional studies demonstrated that both caspase-1 and ICSBP were involved in Fas-mediated apoptosis following IFN-gamma sensitization, but proceeded via two distinct pathways. This study also reports for the first time the expression of ICSBP in a nonhemopoietic tumor exhibiting proapoptotic properties. Overall, in a human colon carcinoma cell model, we identified important functional contributions of two IFN-gamma-regulated genes, ICSBP and caspase-1, in the mechanism of Fas-mediated death.
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PMID:Coordinate regulation of IFN consensus sequence-binding protein and caspase-1 in the sensitization of human colon carcinoma cells to Fas-mediated apoptosis by IFN-gamma. 1279 66

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