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Avastin Largely Safe for Patients With Type of Advanced Lung

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Avastin Largely Safe for Patients With Type of Advanced Lung Cancer

TUESDAY, July 20 (HealthDay News) -- The cancer drug Avastin, when used in combination with standard chemotherapy, is safe and can effectively treat an advanced form of one of the most common lung cancers, researchers report.

Previously it had been thought that this combination might have serious adverse side effects, including life-threatening bleeding, for patients with non-squamous non-small-cell lung tumors. However, this phase 4 trial, which used Avastin (bevacizumab) plus chemotherapy in a large population found these problems were minimal.

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Dentists Torrance

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Published online 21 November 2010 | Nature | doi:10.1038/news.2010.623

http://www.nature.com/news/2010/101121/ ... 0.623.html

About the most key statement in the article (when it comes to treatment) is, "most people agree that a single pathway is not going to do it." When you get rid of VEGF with Avastin, the body cranks out other types of blood vessel growth/survival factors.

The problem with Avastin is the same thing that was a problem with AZT for HIV/AIDS. Early results, then rapid resistance. Solution was combination therapy to attack different targets. With cancer, it's going to take combination antivascular therapy to make a difference.

Tumor vasculature needs VEGF to survive. Avastin removes VEGF, killing blood vessels. But other proangiogenic factors can substitute: FGF, PDGF, ephrin A1, angioprotein 1, IL-8 etc. We need to attack these other targets, as well.

If you can achieve this, then you may not even need the other drugs, which don't get into the tumor so well. But angiogenic attack provides true selective toxicity, something which is sorely lacking with all of the other treatments.

Perhaps Avastin "sensitive" tumors secrete relatively low levels of VEGF. Tumors which secrete relatively low levels of VEGF might be more susceptible to an agent which works by blocking VEGF.

As the article mentions "vascular mimicry," something I've written about on the board previously, there are multiple ways by which tumors can evolve that are independent of VEGF and independent of angiogenesis.

Tumors can acquire a blood supply by angiogenesis, co-option of existing blood vessels and vasculogenic mimicry. All must be inhibited to consistently starve tumors of oxygen.

While vasculogenic mimicry - some types of cancers form channels that carry blood, but are not actual blood vessels - with co-option, instead of growing new blood vessels, tumor cells can just grow along existing blood vessels. This process cannot be stopped with drugs that inhibit new blood vessel formation.

The consistent and specific cure or control of cancer will require developing and using a set of drugs, given in combination, targeted to patterns of normal cellular machinery related to proliferation and invasiveness.

A sufficient number of independent methods of cell killing must be employed so that it is too improbable for a cancer cell to evolve that can escape death or inactivation. It must examine every cell in the body and must do so for a prolonged period of time.

Given the current state of the art, cell-based in vitro drug sensitivity testing (with functional profiling) could be of significant clinical value. One aspect of a functional profiling assay is that microvascular viability can measure dead microvascular cells in tissue, fluid and peripheral blood specimens to identify potential responders to anti-angiogenic drugs (Avastin, Nexavar, Sutent) and to assess direct and potentiating anti-angiogenic effects of tyrosine kinase targeted therapy drugs (Tarceva, Iressa).

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The AngioRx microvascular viability assay a laboratory test which identifies anti-angiogenic drug activity in live tumor microclusters. The test is capable of discriminating anti-tumor effect from anti-angiogenic effect in the same mixed-cell population. It is the only known technology which discriminates the effects of different types of anti-angiogenic drugs within the same class of drugs and within different classes of drugs, and is capable of identifying synergistic effects among different angiogenic and non-angiogenic drugs in specific drug combinations.

Drugs are tested against fresh human tumor microclusters, with 96 hour drug exposures and multiple functional profiling endpoints (MTT, DISC, resazurin and/or ATP). Functional Profiling consists of a combination of a morphologic (structure) endpoint (DISC) and two or more metabolic (cell metabolism) endpoints (MTT, resazurin, ATP) at the cell "population" level. Additional drug concentrations for the targeted/angiogenic agents, some of which have very steep dose response relationships.

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 Sutent. The microvascular 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. The morphologic endpoint information is gathered by examining the state of hundreds of individual cells. The metabolic endpoints measure the combined metabolism of all cells present in the culture (whole cell population profiling). CD31 cytoplasmic staining confirms morphological identification of microcapillary cells in a tumor microcluster.

The principles and methods used in the microvascular 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 (Functional Tumor Cell Profiling methodology). Are the cells ultimately killed, or aren't they?

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.

Bibliography relevant to AngioRx/Microvascular Viability (MVV) assay

1. Weisenthal, L. M. Patel,N., Rueff-Weisenthal, C. (2008). "Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood." J Intern Med 264: 275-287, 2008. doi: 10.1111/j.1365-2796.2008.01955.x

2. Weisenthal, L., Lee,DJ, and Patel,N. (2008). Antivascular activity of lapatinib and bevacizumab in primary microcluster cultures of breast cancer and other human neoplasms. ASCO 2008 Breast Cancer Symposium. Washington, D.C.: Abstract # 166.

3. Weisenthal, L. M. (2010). Antitumor and anti-microvascular effects of sorafenib in fresh human tumor culture in comparison with other putative tyrosine kinase inhibitors. J Clin Oncol 28, 2010 (suppl; abstr e13617)

4. Weisenthal, L., H. Liu, Rueff-Weisenthal, C. (2010). "Death of human tumor endothelial cells in vitro through a probable calcium-associated mechanism induced by bevacizumab and detected via a novel method." Nature Precedings 28 May 2010.

5. Eur J Clin Invest, Volume 37 (suppl. 1):60, 2007

6. Nagourney, R.A. Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)

7. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117

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