Sorafenib has hit the press release circuit since it has been found that it is effective for hepatocellular carcinoma. It is a inhibitor that is currently licensed for treatment of renal cell carcinoma, when cytokines have failed or are unsuitable, although the improvement in overall survival is not significant vs placebo. Sorafenib inhibits VEGF receptor 2 & 3, c-kit, raf kinase and PDGF. Sounds like a basket of significant cancer related genes. Just thought I would also post some of the mouse data from a study with 786-0 subcutaneous tumour model that shows some inhibition of tumour growth.
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Microvascular Viability Assay for anti-angiogenesis-related drugs
In some cases 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.
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 others. 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.
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.
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.
Photomicrographs 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 (Funtional Profiling methodology). Are the cells ultimately killed, or aren't they?
Over the past few years, researchers have put enormous efforts into genetic profiling as a way of predicting patient response to targeted therapies. However, no gene-based test can discriminate differing levels of anti-tumor activity occurring among different targeted therapy drugs. Nor can an available gene-based test identify situations in which it is advantageous to combine a targeted drug with other types of cancer drugs. So far, only "functional profiling" has demonstrated this critical ability.
Not only is this an important predictive test that is available today, but it is also a unique tool that can help to identify newer and better drugs, evaluate promissing drug combinations, and serve as a "gold standard" correlative model with which to develop new DNA, RNA and protein-based tests that better predict for drug activity.
This assay was presented at the 41st Annual Meeting of the European Society for Clinical Investigation in Uppsala, Sweden on April 18, 2007. Literature citation: Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007
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