Anti-Angiogenic Drugs: A Chemotherapy?

Although all forms of cancer therapy aim to rid the body of malignant tumors, they are not always completely successful. Devastating side effects can occur, which can permanently effect the patient's quality of life Such life-altering side effects occur in many people who have undergone chemotherapy.

Chemotherapy works essentially by killing rapidly dividing cells. In this seemingly innocent mode of action, lies a fatal drawback. Cells that are dividing fast are found not only in tumors but also in hair follicles and other important regions of the body such as the bone marrow, the gastrointestinal tract, and the reproductive system including the mammary and prostate glands. In fact, cells dividing rapidly are formed in healing processes throughout the whole body. Since chemotherapy has no way of distinguishing healthy dividing cells from actively dividing cancerous cells, it can seriously harm the body. In most instances of chemotherapy, the affected healthy cells are treated with proper medication to ensure that ordinary functioning is regained. Sometimes, however, the medications fail to save the patients' lives. Even those who survive cancer often have to deal with the negative aftermath of chemotherapy. People suffer from symptoms like mouth dryness, loss of hair, loss of appetite, and malfunctioning of the body's senses. Some people, for example, think pepper tastes sweet, because of impaired taste receptors on the tongue after receiving chemotherapy. Even more importantly, chemotherapy can impair intellect. This cognitive impairment is often referred to as chemobrain.

Tim Ahles, a researcher at the Dartmouth-Hitchcock Medical School, studied 57 people who underwent surgical treatment for cancer and 71 who underwent chemotherapy. Through a standardized test conducted 5 years later, he showed that those who underwent chemotherapy exhibited greater brain damage when compared to those who were treated with surgery. This finding clearly proves that chemotherapy can have negative effects on the brain. He also found that it didn't stem from a depressed state of mind, or a desolate and desperate outlook on life. According to Christina Meyers, a professor of neuropsychology at the M.D. Anderson Cancer Center in Houston, TX, chemotherapeutical agents can cause body cells to release cytokines which enter the brain and impair cognitive functioning. What role do cytokines play in cognitive impairment? Interestingly, these cytokines are also released by cancer cells themselves even before treatment. It is the cytokines that need to be eliminated. Sedatives and steroids given along with the drugs only exacerbate the situation, making cognitive impairment even worse.

Angiogenesis and Tumor Growth:

Given the potential damage that chemotherapy can cause, it is no wonder that several other modes of "cell assassination" have come into play. One such mode of treatment is anti-angiogenetic drug therapy. Angiogenesis is a physiological process by which new blood vessels develop from preexisting vessels. It can lead to neovascularization, the formation of functional microvascular networks in tissue not normally vascularized or vascularized with a red blood cell perfusion. One possible mechanism for neovascularization can be intussusception, the splitting of blood vessels to form new ones.1 Angiogenesis is vital, because it allows tissue growth, whether in adults during menstrual cycles and the healing of wounds, or most significantly during fetal development. In addition, angiogenesis can play a role in pathology.

Anti-Angiogenesis and the New Drugs:

Cancerous cells divide in an uncontrolled fashion forming aggregates called tumors. Once the immune system is unable to effectivly attack these small clusters of tumor cells, they begin to grow into larger tumors. The tumor forms its own new blood vessels, which allows it to develop into a larger mass of cells. It also begins to release growht factors like Vascular Endothelial Growth Factor (VEGF) which further promotes neovascularization. The newly-formed blood vessels feed the tumor nutrients, and oxygen as well as transport waste materials to the outside of the tumor. In this way angiogenesis enhances cancer.

Once the tumor grows in size, individual cells begin branching out of the tumor. They travel through the blood stream and the lymph, and dock at different sites in the body. Here, they again begin to divide and form new tumors called secondary tumors. This process is called metastasis.

Research has shown that tumor cells, when subjected to treatment like chemotherapy or radiation therapy, adapt quickly to the changed environment because of their genomic instability. There is a high rate of mutation in tumors, and particular DNA mutations in cancerous cells modify the cells' nature in a manner similar to that shown by Lederberg et al. in the famous Lederberg Replicating Experiment giving these cells resistance to drugs and therapies.

As explained by the American Medical Association, "Anti-angiogenesis is a form of targeted therapy that uses drugs or other substances to stop tumors from making new blood vessels. Without a blood supply, tumors can't grow." Anti-angiogeneic drugs act by impeding growth of the endothelial cells inside the tumor, which inturn prevent proliferation of the tumor. So these target the blood vessels which in turn impede development of epithelial cells in the tumor.

Anti-angiogenetic drugs such as Avastin (Bevacizumab), target endothelial cells as opposed to tumor cells. By ensuring that cancerous cells are suppressed in their native stages itself, this proves to be much more effective than targeting tumor cells once formed and functional. According to the American Cancer Society, anti-angiogenesis therapy is safer than chemotherapy, mostly because of the virtual absence of chemobrain, which can seriously handicap one's ability to think clearly.

Avastin was the first anti-angiogenic drug developed for cancer therapy, first approved for use in 2004. Incidentally, it was also the first anti-angiogenic drug aproved by the FDA. It is an antibody that targets the VEGF that is released by growing tumor cells, inhibiting it. According to the Avastin website, "AVASTIN®, in combination with intravenous 5-fluorouracil-based chemotherapy, is indicated for first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum."

Conclusion:

Although the use of anti-angiogenetic drugs in cancer treatment strategy is still in its infacny, they have a great potential . The anti-angiogenesis approach bears fewer side effects and is generally a less risky mode of treatment. Anti-angiogenetic drugs pose no risk of a chemobrain and subsequent brain damage or of the Alzheimer's disease for some genetically predisposed patients. As research goes on, we can today hope with greater trust that our loved ones will be saved from the throes of cancerous pain.

References:

Can "chemobrain" be mitigated?' Dartmouth Medicine. Summer 2005. 6 Jun 2007.

"Neovascularization." Online Medical Dictionary. Center for Cancer Education. 12 Dec 1998. 6 Jun 2007.

This experiment showed that bacteria develop resistance to antibiotics such as penicillin, when exposed to

antibiotical environments for prolonged periods of time.

"What Is Anti-angiogenesis treatment?" American Cancer Society. 30 Nov 2006. 3 Jun 2007.

Home page. Avastin (Bevacizumab). 3 Jun 2006.

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- Written by Srinivas Chivukula

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