Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although malignant mesothelioma is not a classically immunogenic cancer, there is abundant evidence for immune recognition. The relative ease of obtaining tumor tissue makes mesothelioma ideal for studying surrogate biomarkers such as lymphocytic infiltration or expression of transduced genes. There is evidence that malignant mesothelioma patients as well as asbestos-exposed persons without mesothelioma have impaired immune responsiveness. Substantial progress has been made in animal models using several biological and immunological techniques, but clinical application has been problematic. Systems studied have included lysis by interleukin-2 (IL-2)-activated lymphokine-activated killer (LAK) cells, tumor necrosis factor-alpha (TNF-alpha), a p16-expressing adenovirus vector, suicide gene therapy using the herpes simplex virus-tyrosine kinase (HSV-tk) followed by ganciclovir, and immunomodulatory gene therapy with IL-2, IL-4, interferon-gamma (IFN-gamma), IFN-alpha, TNF-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and IL-1beta transfected into tumors. Vaccinia virus has been studied as a vector for cytokine gene transfer. Suicide gene therapy has been combined with a tumor vaccine. The University of Western Australia is initiating a pilot study of autologous vaccination in malignant mesothelioma. Novel agents under study include the angiogenesis inhibitors SU5416, bevacizumab, and thalidomide. ZD1839, an orally administered, highly selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, is being tested in a phase II trial. Since platelet-derived growth factor (PDGF) is thought to be an autocrine growth factor for mesothelioma STI-571 (Gleevec; Novartis, Basel, Switzerland), a highly selective inhibitor of the PDGF receptor tyrosine kinase, is being tested in a phase II trial. The development of more active cytotoxic combinations in this disease should facilitate further studies of chemoimmunotherapy. It seems likely that no single treatment modality will be effective by itself.
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PMID:New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents. 1183 73

We established a new lung cancer cell line, designated Y-ML-1B, from a lung cancer of a 70-year-old Japanese man with leukocytosis and thrombocytosis. Before surgical resection, the white blood cell and platelet counts were elevated to 34,400/mm3 and 668,000/mm3, respectively, and the granulocyte colony-stimulating factor (G-CSF) level in the serum was increased at 141 pg/mL. The primary tumor showed an undifferentiated morphology with large cells and induced extensive thickening of the pleura in the right hemithorax. The Y-ML-1B cells grow as a monolayer, with a doubling time of 19 hours, and are tumorigenic in nude mice, which showed a morphology similar to the primary tumor in xenografts. Analysis of the supernatant of cell culture medium of Y-ML-1B showed elevated levels of G-CSF and other cytokines such as interleukin (IL)-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF), consistent with the high levels detected in the patient's serum. Cytogenetic analysis revealed aneuploidy of greater than 56 in metaphases with many structural abnormalities. Mutation analysis of the tumor suppressor genes showed that Y-ML-1B is inactivated in TP53 and RASSF1A, but not in p14(ARF), p16(INK4A), or RB. Neither activating mutations of KRAS or NRAS nor amplification of MYC or MDM2 were detected. Y-ML-1B expressed N-cadherin but not E-cadherin. This newly established cell line might serve as a useful model for studying the molecular pathogenesis for large cell cancers of the lung which express high levels of cytokines.
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PMID:Establishment of a large cell lung cancer cell line (Y-ML-1B) producing granulocyte colony-stimulating factor. 1237 11

Augmenting antitumor immunity is a promising way to enhance the potency of oncolytic adenoviral therapy. Granulocyte-macrophage colony-stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific CD8(+) cytotoxic T-lymphocytes. Serotype 5 adenoviruses (Ad5) are commonly used in cancer gene therapy. However, expression of the coxsackie-adenovirus receptor is variable in many advanced tumors and preclinical data have demonstrated an advantage for replacing the Ad5 knob with the Ad3 knob. Here, a 5/3 capsid chimeric and p16-Rb pathway selective oncolytic adenovirus coding for GMCSF was engineered and tested preclinically. A total of 21 patients with advanced solid tumors refractory to standard therapies were then treated intratumorally and intravenously with Ad5/3-D24-GMCSF, which was combined with low-dose metronomic cyclophosphamide to reduce regulatory T cells. No severe adverse events occurred. Analysis of pretreatment samples of malignant pleural effusion and ascites confirmed the efficacy of Ad5/3-D24-GMCSF in transduction and cell killing. Evidence of biological activity of the virus was seen in 13/21 patients and 8/12 showed objective clinical benefit as evaluated by radiology with Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Antiadenoviral and antitumoral immune responses were elicited after treatment. Thus, Ad5/3-D24-GMCSF seems safe in treating cancer patients and promising signs of efficacy were seen.
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PMID:Treatment of cancer patients with a serotype 5/3 chimeric oncolytic adenovirus expressing GMCSF. 2066 27