CancerCompass message board discussion started by Gdpawel on 7/2/2007 http://www.cancercompass.com/message-board/message/all,13992,0.htm Wed, 23 Jul 2008 00:00:00 GMT Wed, 23 Jul 2008 00:00:00 GMT http://backend.userland.com/rss RSS.NET: http://www.rssdotnet.com/ A microvascular viability assay for anti-angiogenesis-related drugs<p>Angiogenesis is essential for the growth and metastasis (spread) of cancer. A growing tumor requires nutrients and oxygen, which helps it grow, invade nearby tissue, and metastasize. To reach these nutrients, the tumor builds new blood vessels. In fact, growing tumors can become inactive if they can't find a new supply of nutrients.<p>Angiogenesis starts when cancer cells produce a variety of growth factors and other activators (biologic molecules that begin a process). Growth factors cause endothelial cells (the cells that line blood vessels) to produce chemicals that break down the nearby tissue and the extracellular matrix (the spaces between cells). Then, the endothelial cells divide into more cells and begin building new blood vessels. Other elements, such as stromal cells (cells that form connective tissue), provide structural support for the new blood vessels.<p>Because angiogenesis is necessary in the growth and spread of cancer, each part of the angiogenesis process is a potential target for new cancer therapies. The assumption is that if a drug can stop the tumor from receiving the supply of nutrients, the tumor will "starve" and die.<p>Anti-angiogenesis drugs work by blocking the activity of vascular endothelial growth factor (VEGF) to prevent the growth of new capillaries into the tumor and thereby sustain tumor growth. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF.<p>VEGF causes angiogenesis by attaching to special receptors (proteins on the outside of cancer cells that act like doorways), and this action starts a series of chemical reactons inside the cell. Because VEGF is so important to angiogenesis, it is a target of new cancer treatments.<p>Since tumor growth is dependent on angiogenesis, and angiogenesis is dependent on VEGF, a drug like Avastin directly binds to VEGF to directly inhibit angiogenesis. Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. Tumors which secrete relatively low levels of VEGF might be more susceptible to an agent like Avastin which works by blocking VEGF (Avastin "sensitive" tumors). It potently inhibits the formation of new blood vessels.<p>Vatalanib (PTK/ZK) is a small molecule tyrosine kinase inhibitor with broad specificity that targets all VEGF receptors (VEGFR), the platelet-derived growth factor receptor, and c-KIT. It is a multi-VEGFR inhibitor designed to block angiogenesis and lymphangiogenesis by binding the intracellular kinase domain of all three VEGFRs, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). Vatalanib is a targeted drug that inhibits the activity of all known receptors that bind VEGF. The drug potently inhibits the formation of new blood vessels (angiogenesis).<p>In some cases, these and other drugs, kill tumor cells without killing microvascular cells in the same time frame. In other cases they kill microvascular cells without killing tumor cells. In yet other cases they kill both types of cells or neither type of cells. The ability of these agents to kill tumor and/or microvascular cells in the same tumor specimen is highly variable among the different agents.<p>A major modification of the DISC (cell death) assay allows for the study of anti-microvascular drug effects of standard and targeted agents, such as Avastin, Nexavar and vatalanib. The Microvascularity Viability Assay is based upon the principle that microvascular (endothelial and associated) cells are present in tumor cell microclusters obtained from solid tumor specimens. The assay which has a morphological endpoint, allows for visualization of both tumor and microvascular cells and direct assessment of both anti-tumor and anti-microvascular drug effect. CD31 cytoplasmic staining confirms morphological identification of microcapillary cells in a tumor microcluster.<p>The principles and methods used in the Microvascularity Viability Assay include: 1. Obtaining a tissue, blood, bone marrow or malignant fluid specimen from an individual cancer patient. 2. Exposing viable tumor cells to anti-neoplastic drugs. 3. Measuring absolute in vitro drug effect. 4. Finding a statistical comparision of in vitro drug effect to an index standard, yielding an individualized pattern of relative drug activity. 5. Information obtained is used to aid in selecting from among otherwise qualified candidate drugs.<p>It is the only assay which involves direct visualization of the cancer cells at endpoint, allowing for accurate assessment of drug activity, discriminating tumor from non-tumor cells, and providing a permanent archival record, which improves quality, serves as control, and assesses dose response in vitro.<p>Photomicrographs (below) of the assay can show that some clones of tumor cells don't accumulate the drug. These cells won't get killed by it. The Assay measures the net effect of everything which goes on (Whole Cell Profiling methodology). Are the cells ultimately killed, or aren't they?<p>This kind of technique exists today and might be very valuable, especially when active chemoagents are limited in a particular disease, giving more credence to testing the tumor first. After all, cutting-edge techniques can often provide superior results over tried-and true methods that have been around for many years.<p>Source: Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007http://weisenthal.org/slide.057.jpg http://weisenthal.org/slide.058.jpg Gdpawel Mon, 02 Jul 2007 00:00:00 GMT AngioRxT Microvascular Viability / Angiogenesis AssayResearch has shown that controlling production of new blood vessels can restrict tumor growth, often prolonging the life of the cancer patient. Perhaps the most widely-used anti-angiogenic agent to emerge to date is a drug called Avastin. Avastin was approved by the FDA for use in combination with intravenous 5-fluorouracil-based chemotherapy for first-line treatment of patients with metastatic colorectal cancer. However, Avastin has also shown activity in many other solid tumor types such as breast, lung, and ovarian cancers. As with most targeted-therapy drugs, Avastin does not necessarily benefit every patient and it is expensive. Further, no test currently exists that shows reliably who will benefit from it.The Weisenthal Cancer Group has developed an assay for microvasacular viability (M.V.V.) to identify potential responders to Avastin, Nexavar, Sutent, and other anti-angiogenic drugs and to assess previously unanticipated direct and potentiating anti-angiogenic effects of targeted therapy drugs such as Tarceva and Iressa. Prior to development of the M.V.V. assay it was thought that the lack of an intact tumor micro-vasculature would prevent in vitro drug studies in disaggregated tissues. However, it was discovered that endothelial cells are present in tumor microclusters and it appears that drug effect upon these cells can be assessed in the M.V.V. assay. The M.V.V. assay is being offered currently to selected Weisenthal Cancer Group clients on a research basis and as an adjunct to either a Weisenthal Cancer Group standard CytoRxTM assay or an EGFRxT tyrosine kinase assay.http://weisenthalcancer.com/Professionals%20Pages/AngioRxPro http://weisenthalcancer.com/Patient%20Pages/QuickFacts.htm Gdpawel Sat, 10 Nov 2007 00:00:00 GMT