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Biotech / Medical : Introgen Therapeutics -- Ignore unavailable to you. Want to Upgrade?

To: zeta1961 who wrote (494)	3/5/2006 9:08:15 PM
From: zeta1961	Read Replies (1) \| Respond to of 802

mda7+Avastin preclinical..this is an oral Abstract Number: 251 Presentation Title: Translational and functional inhibition of VEGF by Ad-mda7 and bevacizumab results in enhanced anti-tumor activity against lung cancer. Presentation Start/End Time: Sunday, Apr 02, 2006, 8:00 AM -12:00 PM Location: Exhibit Hall, Washington Convention Center Poster Section: 24 Poster Board Number: 27 Author Block: Satoshi Inoue, Amanda Hartman, Cynthia D. Branch, Corazan Bucana, Sunil Chada, Rajagopal Ramesh. The University of Texas, Houston, TX, Introgen Therapeutics, Houston, TX A humanized monoclonal antibody against VEGF, Bevacizumab (Avastin; Genentech, CA) has demonstrated reduced tumor angiogenesis and growth. However, Bevacizumab treatment does not induce complete tumor regression. Therefore, additional treatment strategies need to be incorporated in combination with Bevacizumab to achieve tumor regression. We have shown melanoma differentiation associated gene-7 (MDA-7) protein exerts a potent antiangiogenic activity in vitro and in vivo. In the present study we evaluated the therapeutic effects of Bevacizumab in combination with Ad-mda7 using lung cancer as a model. Treatment of lung tumor cells (H1299, A549) with non-cytotoxic dose of Ad-mda7 (1000 vp/cell) or Bevacizumab showed inhibition of VEGF with no effect on tumor cell growth. However, treatment of tumor cells with Ad-mda7 plus Bevacizumab resulted in enhanced inhibition of VEGF as determined by ELISA. Furthermore, a significant (P < 0.05) inhibition of human umbilical vein endothelial cells (HUVEC) cell proliferation was observed when tissue culture supernatant from Ad-mda7 plus Bevacizumab-treated tumor cells was added to HUVEC compared to HUVEC proliferation treated with culture supernatant from Ad-mda7- or Bevacizumab-treated tumor cells. These results showed that both Ad-mda7 and Bevacizumab effectively inhibit VEGF albeit via different mechanisms. Ad-mda7 inhibited VEGF at a transcriptional level regulated by the Src pathway; Bevacizumab inhibited VEGF by preventing its binding to its receptors (VEGFR) expressed in HUVEC. We next conducted animal experiments using subcutaneous H1299 lung tumor xenograft model to determine whether Ad-mda7 combined with Bevacizumab enhances tumor growth suppression. Tumor-bearing mice were treated with PBS, Ad-luc, Ad-mda7, Bevacizumab, Bevacizumab plus Ad-luc or Bevacizumab plus Ad-mda7. Ad-luc or Ad-mda7 was administered intratumorally (5 X 109 vp/dose) and Bevacizumab intraperitoneally (5 mg/Kg). Treatment was given twice a week for a total of four weeks and tumor growth measured. A significant tumor growth inhibition was observed in mice that were treated with Ad-mda7 plus Bevacizumab compared to tumor growth inhibition in mice that were treated with Ad-mda7, Bevacizumab or Ad-luc plus Bevacizumab. Furthermore, in approximately 70% of the Ad-mda7 plus Bevacizumab-treated mice the tumors completely regressed. Tumor regression was not observed in other treatment groups. Molecular analysis of tumors showed Ad-mda7 plus Bevacizumab treatment enhanced tumor cell apoptosis, effectively inhibited VEGF and reduced angiogenesis as determined by western blotting and immunohistochemsitry. In conclusion, Ad-mda7 plus Bevacizmab treatment significantly increases the antitumor activity against human lung cancer cells and can be potent treatment strategy for advanced lung cancer.

To: zeta1961 who wrote (494)	3/9/2006 9:46:57 PM
From: Jibacoa	Read Replies (1) \| Respond to of 802

Since you are looking at some of M.D. Anderson's presentations, look also at their " New Ideas Fuel Next Generation Gene Therapy Research." emaxhealth.com Among interesting results: A virus for the brain. Take a look at the results of Delta-24-RGD While the point is taken, researchers at M. D. Anderson who last year cured brain cancer in mice were amazed because no one had ever before tested a drug that had any effect on malignant glioma, the most deadly of brain cancers. Testing a gene therapy in mice, likened to a "viral smart bomb," the M. D. Anderson scientists found only empty cavities and scar tissue where human glioma tumors had once been. The therapy, known as Delta-24-RGD, had moved like waves throughout the brains of the mice, killing the cancer while leaving normal tissue intact. While the treatment employs an adenovirus, it does not seem to produce toxic effects in the brain, say researchers. In fact, the mice tested were considered clinically cured of their brain tumors with little known side effects. These animal tests, reported last year, were considered so promising that the National Cancer Institute moved immediately to produce, in its own labs, a clinical-grade version of the therapy, and scientists with the FDA began collaborating. "We have never seen this kind of response before with any other treatment tested in either animals or humans," says the lead author of that study, Juan Fueyo, M.D., an assistant professor in the Department of Neuro-Oncology. A clinical trial testing Delta-24-RGD treatment in brain cancer patients is expected to begin in summer, 2006. Neurosurgeon Frederick Lang, M.D., will insert a catheter into participants' brain tumors, inject Delta-24-RGD and then wait two weeks to remove the tumor. It will then be closely examined to see how much was destroyed by the virus. "Biologic viral therapy like this may be just what we need to treat a complex disease like cancer," says Lang, who co-authored Feuyo's study. "Cancer can be devious in that it does everything possible to evade destruction. But viruses are equally tricky in their quest to invade cells and propagate." This trial is just part of an ongoing larger "platform" of research that is continually refining Delta-24-RGD therapy, says Charles Conrad, M.D., an associate professor in the Department of Neuro-Oncology who works with Fueyo, Lang and others on the "Delta team." They have already created a second and now a third generation of the therapy, each of which is proving more adept in infecting cancer cells and disarming them. One idea is to insert genes into the viral smart bomb that will switch on chemotherapy drugs. This way, a patient could receive an inert form of a chemotherapy drug that would be non-toxic to normal cells, but would be activated by the Delta virus when it spreads in cancer cells. "We would deliver the gene that activates the chemotherapy drug only to tumor cells," says Conrad. Another strategy they are working on is to embed the virus into a specialized stem cell that could travel undetected through the blood-brain barrier and home to what it "sees" as a wound - a tumor. The team, which includes other international and national investigators, also is exploring adapting Delta-24-RGD to other cancer types, such as colon cancer. Questions remain, however, as to whether the therapy will evoke a systemic immune response and just how the virus will be able to spread given physical barriers - such as bones or cavities - that are just a natural part of the body's interior. Many solid tumors also contain areas of dead tissue, which could stop the virus's ability to replicate. Finally, researchers are concerned about the issue that has dogged all adenovirus vectors - that, below the neck as it were, a patient could mount an immune response that would blunt the effectiveness of the therapeutic virus. "We will have our proof of principle in treating gliomas," says Conrad. "If it is safe, and shows some benefit, we will want to try it in other cancers."