Antiangiogenic drugs impede chemotherapy-stimulated tumor recovery
September 8, 2008
Scientists have gained new insight into a mechanism whereby chemotherapy may actually assist the rapid regrowth of tumors after treatment. The research, published by Cell Press in the September issue of the journal Cancer Cell, also helps to explain why a combination of traditional chemotherapy with drugs that block formation of new blood vessels might impede the devastating tumor recovery that often follows cancer therapy.
"Chemotherapy remains the most commonly employed form of systemic cancer treatment. However, although partial or complete shrinkage of tumor mass is frequently induced in chemotherapy-responsive tumors, survival benefits of such responses can be compromised by rapid regrowth of the drug-treated tumors," says senior study author Dr. Robert S. Kerbel from the University of Toronto.
Clinical trials have indicated that drugs that inhibit the growth of blood vessels, called antiangiogenic drugs, can sometimes enhance the effectiveness of traditional chemotherapy. For example, coadministration of the antiangiogenic drug bevacizumab with the chemotherapeutic agent paclitaxel improves survival benefits for metastatic breast cancer and small cell lung cancer. In contrast, coadministration of bevacizumab with gemcitabine for treatment of pancreatic cancer does not increase the effectiveness of chemotherapy alone.
"Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy," says author Dr. Yuval Shaked. Drs. Kerbel, Shaked, and colleagues had previously shown that treatment with a type of cytotoxic-like agent known as a vascular disrupting agent (VDA) induces rapid mobilization of cells called circulating endothelial progenitors (CEPs) from the bone marrow compartment that helps the tumor to regrow blood vessels and thereby recover from treatment.
The researchers built on this earlier observation by analyzing whether different, conventional chemotherapeutic drugs had variable abilities to impact CEP mobilization and whether antiangiogenic drugs could block chemotherapy-induced CEP responses and hence amplify their effectiveness. They found that paclitaxel rapidly induced CEP mobilization whereas gemcitabine did not. They went on to show that pharmacological inhibition of CEP mobilization by combination treatment with an antiangiogenic drug or treatment of mutant mice deficient in CEPs resulted in enhanced antitumor effects mediated by paclitaxel but not gemcitabine.
"Our results provide a new perspective regarding the impact that conventional chemotherapy can have on tumor angiogenesis and hence how combination with antiangiogenic drugs may amplify the antitumor effects of chemotherapy," explains Dr. Kerbel. "Further, our findings provide a potential explanation of why not all chemotherapy drugs will necessarily have their efficacy enhanced by the addition of an antiangiogenic agent when the mechanism involves blunting CEP mobilization acutely induced by the chemotherapy drug."
Source: Cell Press
Jun 23, 2009 |
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Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels and have a remarkable ability to divide and migrate. The creation of new blood vessels occurs by a series of sequential steps. An endothelial cell forming the wall of an existing small blood vessel (capillary) becomes activated, secretes enzymes that degrade the extracellular matrix (the spaces between the cells), invades the matrix, and begins dividing. Eventually, strings of new endothelial cells organize into hollow tubes, creating new networks of blood vessels that make tissue growth and repair possible.
Most of the time endothelial cells lie dormant. But when needed, short bursts of blood vessel growth occur in localized parts of tissues. New capillary growth is tightly controlled by a finely tuned balance between factors that activate endothelial cell growth and those that inhibit it.
About 15 proteins are known to activate endothelial cell growth and movement. At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and basic fibroblast growth factor (bFGF), are expressed by many tumors and seem to be important in sustaining tumor growth.
It is generally true that tumors with higher densities of blood vessels are more likely to metastasize and are correlated with poorer clinical outcomes. Also, the shedding of cells from the primary tumor begins only after the tumor has a full network of blood vessels. In addition, both angiogenesis and metastasis require matrix metalloproteinases, enzymes that break down the surrounding tissue (the extracellular matrix), during blood vessel and tumor invasion.
Research 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 has been the drug Avastin. It is increasingly being realized that circulating microvascular cells may be important markers for a wide variety of cancers.
Avastin works by choking off the blood vessels that provide a tumor with oxygen and nutrients (angiogenesis). 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 to produce chemicals that break down the nearby tissue and the extracellular matrix. 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.
The assumption is that if a drug can stop the tumor from receiving the supply of nutrients, the tumor will "starve" and die. However, there are so many agents out there now, doctors have a confusing array of choices. They don't know how to mix them together in the right order.