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A novel drug derived from the bark of the Pacific yew tree may help prevent renarrowing of arteries after balloon angioplasty, a common medical procedure used to treat coronary artery disease, especially after heart attacks.
Scientists at the National Institute on Aging's (NIA) Gerontology Research Center in Baltimore, Maryland have completed initial research into the activity of this drug (taxol) in arteries of rats and report on it in the April 1995 issue of the Journal of Clinical Investigation. By replicating the effects of balloon angioplasty in rats and then administering taxol, the researchers were able to study the beneficial effects of the drug at the damaged arterial sites.
Taxol, which has been used successfully in cancer treatment, may also be useful at less toxic levels in coronary heart disease patients. Despite significant advances in medical and surgical procedures which help patients with coronary heart disease live longer, 30 to 50 percent of patients receiving angioplasty experience a renarrowing of the arteries (restenosis). This makes them prone to other cardio-vascular complications, including heart attacks.
Dr. Edward Lakatta, Acting Scientific Director of the NIA and an author on the paper warns, "The effects of balloon angioplasties on older patients are of particular concern due to the 12 to 17 percent of people over 65 who are rehospitalized for a repeat angioplasty. Angioplasty procedures alone cost this Nation close to $255 million a year in Medicare fees."
Restenosis occurs due to unavoidable injuries to blood vessels during the trauma of balloon expansion during angioplasty. These injuries result in a change in the nature of the cells that line the walls of blood vessels. The damage that is done to the cells is seen most prominently in important cellular subunits known as microtubules. These microtubules play a major role in cell division and in maintaining the structural and functional stability of cells. Under stressful conditions such as angioplasty, microtubules can aid in forming lesions in the vessel's walls which lead to angina and heart attacks.
Taxol is used extensively in cancer chemotherapy. The NIA principal investigators, Drs. James Kinsella and Steven Sollott, believe that taxol will be useful in treating the complications of restenosis after angioplasty because in cancer patients it has been shown to induce very stable and nonfunctional chains of microtubules. Since the changes that occur in blood vessel cells after angioplasty mimic the changes seen in cancer cells (abnormal growth, movement, etc.), Drs. Kinsella and Sollott hypothesized that taxol might inhibit restenosis.
Indeed, in rat studies, the investigators saw the beneficial effects of taxol on the cell's microtubules, and the resultant prevention of restenosis. They believe that taxol acted primarily by inhibiting cell movement and changes in cell shape by inducing the microtubules to form long, stable chains. The amounts of taxol used in the rat studies were about 100 times lower than those used in human cancer chemotherapy applications. This means that it may be possible to administer taxol at very low levels, minimizing the toxicity seen when it is used as a chemotherapy agent, but still have it remain effective in preventing restenosis.
According to Dr. Kinsella, "The most likely use of taxol would be to inhibit restenosis after angioplasty by using a local sustained-release delivery system where balloons, similar to those used during angioplasties, deposit taxol at the site of the cell damage." Highly localized applications of taxol would avoid the need for toxic levels of the drug to be administered throughout the body. Dr. Kinsella also notes that the Laboratory of Cardiovascular Science at NIA will be testing the drug on larger animals, such as pigs, that have a cardiovascular system that closely resembles that of humans. They hope to begin these trials later in the year.
In addition to Drs. Kinsella, Sollott, and Lakatta, the research team consists of Linda Cheng, Rebecca R. Pauly, G. Mark Jenkins, Robert Monticone, Masafumi Kuzuya, Jeffrey P. Froehlich, Michael T. Crow, and Eric K. Rowinsky.
The National Institute on Aging, part of the National Institutes of Health, leads the Federal effort supporting basic, clinical, epidemiological, and social research on aging and the special needs of older people.