The Experts below are selected from a list of 1272 Experts worldwide ranked by ideXlab platform
Judah Folkman - One of the best experts on this subject based on the ideXlab platform.
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adenovirus mediated delivery of a soluble form of the vegf receptor flk1 delays the growth of murine and human pancreatic adenocarcinoma in mice
Surgery, 2002Co-Authors: Jennifer F Tseng, Judah Folkman, Filip Farnebo, Oliver Kisker, Christian M Becker, Calvin J Kuo, Richard C MulliganAbstract:Abstract Background. Because pancreatic adenocarcinoma is poorly responsive to chemoTherapy and radiation Therapy, novel treatments such as Antiangiogenic Gene Therapy may have use in the adjuvant treatment of this malignancy. We evaluated the antitumor effects of the in vivo administration of an adenovirus vector encoding a soluble form of Flk1 (Flk1-Fc), a receptor for vascular endothelial growth factor, in 3 murine models of pancreatic adenocarcinoma. Methods. In a first model, immunocompetent C57Bl/6 mice were injected subcutaneously with Panc02 murine pancreatic adenocarcinoma cells before treatment. In a second model, immunodeficient severe combined immunodeficiency mice were injected subcutaneously with BxPc-3 human pancreatic adenocarcinoma cells before treatment. In a third model, C57Bl/6 mice were injected with Panc02 cells through an intrasplenic route before treatment, in an effort to model metastatic disease. In each model, half the tumor-bearing mice were injected intravenously with 109 Flk1-Fc adenovirus particles and half with control adenovirus. Results. In subcutaneous tumor models, Ad Flk1-Fc-treated animals were found to have 75% smaller murine and 78% smaller human pancreatic tumor volumes, relative to tumor volumes of Ad Fc-treated animals, 6 weeks after vector administration. In animals injected with tumor through the intrasplenic route, pathologic and histologic analyses made 10 days after injection of tumor revealed hepatic, pancreatic, and splenic tumors, together with a desmoplastic response consistent with pathologic findings in human pancreatic cancer. Cohorts of these tumor-bearing mice treated with Ad Flk1-Fc demonstrated significantly longer survival and decreased liver replacement with tumor at the time of death, relative to animals treated with Ad Fc. Conclusion. A recombinant adenovirus encoding soluble Flk-1 inhibited pancreatic tumor growth in mice. These studies suggest that the delivery of Gene products such as Flk1-Fc through in vivo Gene transfer may be useful in the future treatment of patients with pancreatic cancer. (Surgery 2002;132:857-65.)
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Antiangiogenic Gene Therapy
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Judah FolkmanAbstract:The authors (1) laid the foundation for this experiment by previously showing that a single injection of soluble Tie2 receptor protein into a rat cutaneous window reduced tumor vascular length by 40% …
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viral vector targeted Antiangiogenic Gene Therapy utilizing an angiostatin complementary dna
Cancer Research, 1998Co-Authors: Toshihide Tanaka, Judah Folkman, Howard A FineAbstract:Despite recent advances in neurosurgery, radiation, and chemoTherapy, the prognosis of patients with malignant gliomas remains dismal. Based on the observation that solid tumor growth is angiogenic dependent, and gliomas are among the most angiogenic of all tumors, therapeutic strategies aimed at inhibiting angioGenesis are theoretically attractive. Angiostatin, an internal peptide fragment of plasminogen, has recently been shown to potently inhibit endothelial proliferation in vitro and tumor growth in vivo. Long-term systemic delivery of proteins, however, poses a number of difficult logistic and pharmacological problems and may not be necessary or optimal for treating locally aggressive tumors such as gliomas. We now demonstrate that retroviral and adenoviral vectors that transduce the angiostatin cDNA can be used to inhibit endothelial cell growth in vitro and angioGenesis in vivo. Vector-mediated inhibition of tumor-associated angioGenesis results in increased apoptotic tumor cell death, leading to inhibition of tumor growth. These studies support a potential role of vector-mediated transduction of the cDNA encoding angiostatin as a potential novel therapeutic strategy for the treatment of malignant brain tumors and confirm the antitumor activity of angiostatin and the concept of dormancy Therapy.
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expression of angiostatin cdna in a murine fibrosarcoma suppresses primary tumor growth and produces long term dormancy of metastases
Journal of Clinical Investigation, 1998Co-Authors: Evelyn Flynn, Michael S Oreilly, Yihai Cao, Blair Marshall, Judah FolkmanAbstract:Tumor growth and metastasis are angioGenesis dependent. Previously, we reported that angiostatin, a potent angioGenesis inhibitor, produced by a primary Lewis lung carcinoma suppressed its growth of lung metastases (O'Reilly, M.S., L. Holmgren, Y. Shing, C. Chen, R.A. Rosenthal, M. Moses, W.S. Lane, Y. Cao, E.H. Sage, and J. Folkman. 1994. Cell. 79:315-328). Now we show that a shift of balance of tumor angioGenesis by Gene transfer of a cDNA coding for mouse angiostatin into murine T241 fibrosarcoma cells suppresses primary and metastatic tumor growth in vivo. Implantation of stable clones expressing mouse angiostatin in C57Bl6/J mice inhibits primary tumor growth by an average of 77%. After removal of primary tumors, the pulmonary micrometastases in approximately 70% of mice remain in a microscopic dormant and avascular state for the duration of the experiments, e.g., 2-5 mo. The tumor cells in the dormant micrometastases exhibit a high rate of apoptosis balanced by a high proliferation rate. Our study, to our knowledge, for the first time shows the diminished growth of lung metastases after removal of the primary tumor, suggesting that metastases are self-inhibitory by halting angioGenesis. Our data may also provide a novel approach for cancer Therapy by Antiangiogenic Gene Therapy with a specific angioGenesis inhibitor.
Savio L C Woo - One of the best experts on this subject based on the ideXlab platform.
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adenovirus mediated Gene transfer of endostatin in vivo results in high level of transGene expression and inhibition of tumor growth and metastases
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Bernhard Sauter, Olivier Martinet, Weijian Zhang, John Mandeli, Savio L C WooAbstract:Inhibition of angioGenesis has been shown to be an effective strategy in cancer Therapy in mice. However, its widespread application has been hampered by difficulties in the large-scale production of the Antiangiogenic proteins. This limitation may be resolved by in vivo delivery and expression of the Antiangiogenic Genes. We have constructed a recombinant adenovirus that expresses murine endostatin that is biologically active both in vitro, as determined in endothelial cell proliferation assays, and in vivo, by suppression of angioGenesis induced by vascular endothelial growth factor 165. Persistent high serum levels of endostatin (605-1740 ng/ml; mean, 936 ng/ml) were achieved after systemic administration of the vector to nude mice, which resulted in significant reduction of the growth rates and the volumes of JC breast carcinoma and Lewis lung carcinoma (P < 0.001 and P < 0.05, respectively). In addition, the endostatin vector treatment completely prevented the formation of pulmonary micrometastases in Lewis lung carcinoma (P = 0.0001). Immunohistochemical staining of the tumors demonstrated a decreased number of blood vessels in the treatment group versus the controls. In conclusion, the present study clearly demonstrates the potential of vector-mediated Antiangiogenic Gene Therapy as a component in cancer Therapy.
Steven K Libutti - One of the best experts on this subject based on the ideXlab platform.
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Antiangiogenic Gene Therapy of cancer utilizing a recombinant adenovirus to elevate systemic endostatin levels in mice
Cancer Research, 2000Co-Authors: Andrew L Feldman, Nicholas P Restifo, Richard H Alexander, David L Bartlett, Prem Seth, Steven K LibuttiAbstract:Gene Therapy represents a possible alternative to the chronic delivery of recombinant Antiangiogenic proteins to cancer patients. Inducing normal host tissues to produce high circulating levels of these proteins may be more effective than targeting Antiangiogenic Genes to tumor tissue specifically. Previously reported Gene Therapy approaches in mice have achieved peak circulating endostatin levels of 8–33 ng/ml. Here we report plasma endostatin levels of 1770 ng/ml after administration of a recombinant adenovirus. Growth of MC38 adenocarcinoma, which is relatively resistant to adenoviral infection, was inhibited by 40%. These findings encourage Gene delivery approaches that use the host as a “factory” to produce high circulating levels of Antiangiogenic agents.
Richard C Mulligan - One of the best experts on this subject based on the ideXlab platform.
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adenovirus mediated delivery of a soluble form of the vegf receptor flk1 delays the growth of murine and human pancreatic adenocarcinoma in mice
Surgery, 2002Co-Authors: Jennifer F Tseng, Judah Folkman, Filip Farnebo, Oliver Kisker, Christian M Becker, Calvin J Kuo, Richard C MulliganAbstract:Abstract Background. Because pancreatic adenocarcinoma is poorly responsive to chemoTherapy and radiation Therapy, novel treatments such as Antiangiogenic Gene Therapy may have use in the adjuvant treatment of this malignancy. We evaluated the antitumor effects of the in vivo administration of an adenovirus vector encoding a soluble form of Flk1 (Flk1-Fc), a receptor for vascular endothelial growth factor, in 3 murine models of pancreatic adenocarcinoma. Methods. In a first model, immunocompetent C57Bl/6 mice were injected subcutaneously with Panc02 murine pancreatic adenocarcinoma cells before treatment. In a second model, immunodeficient severe combined immunodeficiency mice were injected subcutaneously with BxPc-3 human pancreatic adenocarcinoma cells before treatment. In a third model, C57Bl/6 mice were injected with Panc02 cells through an intrasplenic route before treatment, in an effort to model metastatic disease. In each model, half the tumor-bearing mice were injected intravenously with 109 Flk1-Fc adenovirus particles and half with control adenovirus. Results. In subcutaneous tumor models, Ad Flk1-Fc-treated animals were found to have 75% smaller murine and 78% smaller human pancreatic tumor volumes, relative to tumor volumes of Ad Fc-treated animals, 6 weeks after vector administration. In animals injected with tumor through the intrasplenic route, pathologic and histologic analyses made 10 days after injection of tumor revealed hepatic, pancreatic, and splenic tumors, together with a desmoplastic response consistent with pathologic findings in human pancreatic cancer. Cohorts of these tumor-bearing mice treated with Ad Flk1-Fc demonstrated significantly longer survival and decreased liver replacement with tumor at the time of death, relative to animals treated with Ad Fc. Conclusion. A recombinant adenovirus encoding soluble Flk-1 inhibited pancreatic tumor growth in mice. These studies suggest that the delivery of Gene products such as Flk1-Fc through in vivo Gene transfer may be useful in the future treatment of patients with pancreatic cancer. (Surgery 2002;132:857-65.)
Calvin J Kuo - One of the best experts on this subject based on the ideXlab platform.
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selective intratumoral amplification of an Antiangiogenic vector by an oncolytic virus produces enhanced antivascular and anti tumor efficacy
Molecular Therapy, 2006Co-Authors: Stephen H Thorne, Betty Y Y Tam, David H Kirn, Christopher H Contag, Calvin J KuoAbstract:The development of effective cancer Therapy will require the simultaneous targeting of multiple steps in tumor development. We have previously described an Antiangiogenic Gene Therapy vector, Ad Flk1-Fc, which expresses a soluble VEGF receptor capable of inhibiting tumor angioGenesis and growth. We have also described an oncolytic virus, dl922/947, whose replication and subsequent cytotoxicity are restricted to cancer cells with a loss of the G1–S cell cycle checkpoint. Here we have optimized methods for combining these therapies, yielding significantly greater anti-tumor effects than the respective monotherapies. In cultured tumor lines, co-infection with both Ad Flk1-Fc and dl922/947 allowed replication and repackaging of the replication-deficient Ad Flk1-Fc and enhanced soluble VEGF receptor expression. Similar repackaging and increased Gene expression were demonstrated in vivo using bioluminescence imaging studies. Finally, coadministration of these therapeutic viral therapies in vivo produced significantly enhanced anti-tumor effects in colon HCT 116 and prostate PC-3 xenografts in mice. This increased therapeutic benefit correlated with replication of Ad Flk1-Fc viral genomes, increased intratumoral levels of Flk1-Fc protein, and decreased microvessel density, consistent with enhanced Antiangiogenic activity.
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adenovirus mediated delivery of a soluble form of the vegf receptor flk1 delays the growth of murine and human pancreatic adenocarcinoma in mice
Surgery, 2002Co-Authors: Jennifer F Tseng, Judah Folkman, Filip Farnebo, Oliver Kisker, Christian M Becker, Calvin J Kuo, Richard C MulliganAbstract:Abstract Background. Because pancreatic adenocarcinoma is poorly responsive to chemoTherapy and radiation Therapy, novel treatments such as Antiangiogenic Gene Therapy may have use in the adjuvant treatment of this malignancy. We evaluated the antitumor effects of the in vivo administration of an adenovirus vector encoding a soluble form of Flk1 (Flk1-Fc), a receptor for vascular endothelial growth factor, in 3 murine models of pancreatic adenocarcinoma. Methods. In a first model, immunocompetent C57Bl/6 mice were injected subcutaneously with Panc02 murine pancreatic adenocarcinoma cells before treatment. In a second model, immunodeficient severe combined immunodeficiency mice were injected subcutaneously with BxPc-3 human pancreatic adenocarcinoma cells before treatment. In a third model, C57Bl/6 mice were injected with Panc02 cells through an intrasplenic route before treatment, in an effort to model metastatic disease. In each model, half the tumor-bearing mice were injected intravenously with 109 Flk1-Fc adenovirus particles and half with control adenovirus. Results. In subcutaneous tumor models, Ad Flk1-Fc-treated animals were found to have 75% smaller murine and 78% smaller human pancreatic tumor volumes, relative to tumor volumes of Ad Fc-treated animals, 6 weeks after vector administration. In animals injected with tumor through the intrasplenic route, pathologic and histologic analyses made 10 days after injection of tumor revealed hepatic, pancreatic, and splenic tumors, together with a desmoplastic response consistent with pathologic findings in human pancreatic cancer. Cohorts of these tumor-bearing mice treated with Ad Flk1-Fc demonstrated significantly longer survival and decreased liver replacement with tumor at the time of death, relative to animals treated with Ad Fc. Conclusion. A recombinant adenovirus encoding soluble Flk-1 inhibited pancreatic tumor growth in mice. These studies suggest that the delivery of Gene products such as Flk1-Fc through in vivo Gene transfer may be useful in the future treatment of patients with pancreatic cancer. (Surgery 2002;132:857-65.)