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Angiogenesis & Low Dose Chemotherapy


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Giving low doses of several drugs every day by mouth. There would be no needles and the side effects are expected to be mild. Unlike standard chemotherapy, which is given in high doses to kill as many cancer cells as possible, the lower-dose regimen is meant to attack the blood vessels that feed the tumor. Tumors create their own supply lines by secreting substances that stimulate the formation of new blood vessels and researchers suspect that frequent low doses of certain drugs may disrupt the growth of those new vessels, starving the tumor.

The treatment includes small daily doses of standard chemotherapy drugs and two other drugs that have been found to inhibit the formation of new blood vessels, called angiogenesis. One is Celebrex and the other is Thalidomide. It is offered only to people who have no other options, who have advanced tumors that standard treatment cannot cure or those for whom standard chemotherapy has quit working.

Women with advanced breast or ovarian cancer are being given smaller, more frequent doses of chemotherapy to reduce side effects. It is hoped that low-dose treatment may help other cancer patients, not just those who are considered terminal. It may work just as well or even better, maybe through this ability to cause an anti-angiogenesis effect.

This approach to treatment is based on something that can frequently occur in people, when a tumor becomes resistant to chemotherapy and high doses stop working. It is believed that angiogenesis plays a role. Angiogenesis is essential to the survival of many tumors. Many chemotherapy drugs, in addition to killing tumor cells, also fight angiogenesis. But, if these medicines stop angiogenesis, chemotherapy should work better than it does. Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy, so if cancer cells become drug resistant, these medicines should still be able to shrink tumors by destroying their blood supply.

The reason chemotherapy was not stopping angiogenesis was that chemotherapy is usually given in big doses, with breaks of several weeks between doses to let the body recover. During the breaks, the tumor's blood vessels could grow back. By giving chemotherapy more often, at lower doses, it might prevent the regrowth of blood vessels and kill the tumor or at least slow its growth.

It is especially important to study low-dose therapies now because they are being used increasingly in clinics. Doses, timing and combinations all need to be worked out. Doctors need to find out whether the treatments can make patients live longer and whether tumors will eventually outsmart the drugs and find ways to survive even without angiogenesis.

For further information about clinical trials, refer to the National Cancer Institute's website: http://cancertrials.nci.nih.gov

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Guest pat mc

Greg:

I read your post and then read your wife's story (from your profile link). You have my sympathy and thank you so much for sharing. I will look into low dose chemo. What you say makes a lot of sense.

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The October 2005 issue of Ultrasound in Medicine and Biology reports that researchers at the University of Pennsylvania School of Medicine are studying the use of ultrasound to disrupt the vessels supplying blood and nutrition to tumors, much like cancer treatment utilizing anti-angiogenic therapies. After all, cutting-edge techniques can often provide superior results over tried-and-true methods that have been around for many years.

This approach is in keeping with the latest studies of cancer treatment utilizing antiangiogenic therapies, in which they look for ways to stop the growth of vessels supplying blood and nutrition to tumors, rather than develop methods to kill tumor cells themselves. In the future, treatments with ultrasound either alone or in combination with chemotherapeutic agents could be used to treat cancers.

Nobody believed Judah Folkman when, in the 1960s, he claimed that the growth of cancers could be stopped, even reversed, by blocking the tiny vessels that feed them blood. Over the years, however, he has survived peer rejection of his theory, and gone on to develop drugs that did what he predicted they would do. The angiogenesis-blocker boom is on.

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Hi, I was on the thalidomide and cpt-11 trial and it did nothing for my cancer. Thalidomide also works very slowly. The PTK and Xeloda was very effective for me and that was an angiogenesis and low dose chemo. I also plan to ask my oncologist the next time I see him about the sensitivity testing.

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  • 1 year later...

Angiogenesis is the formation of new blood vessels. Although this process is normal in the growth of development of children, it happens rarely in adults. For example, angiogenesis occurs during the healing of a deep cut. Otherwise, angiogenesis in adults is usually part of a disease process such as cancer.

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.

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.

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.

The role of VEGF

Vascular endothelial growth factor (VEGF) is an important activator of angiogenesis. Like the name indicates, VEGF causes endothelial cells to grow. Research has shown that oncogenes (genes that help cancer cells grow), cytokines (substances produced by the immune system), and hypoxia (a low-oxygen environment, which is common in tissues around solid tumors) can all directly or indirectly activate VEGF, thereby starting angiogenesis.

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 reactions inside the cell. Because VEGF is so important to angiogenesis, it is a target of new cancer treatments. For example, the drug bevacizumab (Avastin) blocks a receptor for VEGF.

In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF.

Current therapies

Drugs that are designed to stop angiogenesis are called angiogenesis inhibitors or antiangiogenesis agents. Typically, these drugs are given with other types of therapy, such as traditional chemotherapy. Angiogenesis inhibitors act in the following ways:

Blocking the growth of endothelial cells

Stopping the chemical process that breaks down the extracellular matrix

Preventing the action of VEGF and other similar growth factors that can cause angiogenesis

Blocking general processes in the body that indirectly lead to angiogenesis, such as inflammation

The following drugs are two common examples of angiogenesis inhibitors being used to treat cancer. For more information about these and other cancer drugs, please talk to your doctor.

Thalidomide (Thalomid) appears to stop endothelial cells from forming new blood vessels and is a treatment for multiple myeloma and other types of cancer. However, it is harmful to fetuses, so women who are pregnant or plan to become pregnant should not take thalidomide. Lenalidomide (Revlimid), a drug that is similar to thalidomide, is potentially more active than thalidomide and is being tested in clinical trials.

Bevacizumab (Avastin) is a monoclonal antibody, which is a substance produced in the laboratory that attaches to specific places on the surface of cancer cells. This drug blocks VEGF receptors and is approved to treat metastatic colorectal cancer. It is also being tested in a variety of other local and metastatic cancers.

Many other angiogenesis inhibitors are being tested in clinical trials to treat a variety of cancers, including colorectal cancer, multiple myeloma, renal cell carcinoma (a kidney cancer), liver cancer, Kaposi's sarcoma, leukemia, lymphoma, lung cancer, prostate cancer, and pancreatic cancer.

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  • 6 months later...

A microvascular viability assay for anti-angiogenesis-related drugs

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.

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.

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.

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.

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.

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.

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).

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.

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.

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 (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?

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.

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

http://weisenthal.org:80/slide.057.jpg

http://weisenthal.org:80/slide.058.jpg

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