Paclitaxel may help treat scleroderma

Nov 1 2005

Using a novel model for scleroderma, researchers from Duke University Medical Center have discovered two important insights into this devastating disorder - the anti-cancer drug paclitaxel (Taxol) may prevent the skin thickening and small blood vessel destruction that characterizes the disease.

Also, they found that a patient's own immune system may actually interfere with body's inherent ability to repair damage, and in particular, damage to small arteries.

The researchers are so encouraged by the results of their experiments in mice that they are in the early planning stages of a clinical trial incorporating their findings in human patients with the disease.

Scleroderma is a chronic degenerative disease that afflicts more than 300,000 Americans, primarily women. The life-threatening disorder is marked by dramatic tissue damage including hardening of the skin, shrinking of muscles, and damage to organs and blood vessels. To date, physicians have been unable to determine what causes the disease, and the available few therapies, serve primarily to relieve symptoms, according to the researchers.

"These new insights are critical clues to understanding a dreadful disease that has so far been impenetrable in terms of what causes it, by what mechanisms it works and why patients get so sick," said cardiologist Pascal Goldschmidt, M.D., senior member of the research team and chairman of Duke's Department of Medicine.

The results of the Duke studies were published in the Nov. 1, 2005, edition of Public Library of Science Medicine. The research was supported by the Scleroderma Research Foundation, San Francisco.

"While we really don't understand what causes scleroderma, we suspect that it may be autoimmune in nature, or that the body's own immune system is involved," said Chunming Dong, M.D., lead author of the paper "Using a novel mouse model, we were able to get a much better understanding of possible mechanisms of the disease that we can use to potentially slow down or reverse the process of tissue damage."

One of the most characteristic effects of the disease is the gradual formation of fibrotic tissue, which leaves patients with disfiguring and painful tightening of the skin. Additionally, the disease tends to slowly destroy small blood vessels and capillaries, which are not only present in skin, but also in internal organs, leaving them vulnerable to function failure.

It is known that the excessive fibrosis seen in scleroderma patients is in part the result of an inappropriate activation of transforming growth factor-beta (TGF-beta), a substance called a cytokine that regulates the intensity and duration of the immune response. Too much TGF-beta activity can occur in the presence of destabilized microtubules, which give structural support to cells and are involved in the movement of genetic material during cell division. When microtubules become destabilized, a complex process ensues which leads to the excessive TGF-beta pathway activation, and consequent accumulation of collagen, the primary component of fibrotic tissue.

"We've learned in our previous studies that the treatment of individual cells with paclitaxel helps stabilize microtubules, thereby blocking the excessive activity of TGF-beta," Dong explained. "So in our latest studies, we were interested in determining whether or not paclitaxel would have any effect on tissue with scleroderma."

For their experiments, the Duke team used mice bred to have no immune system. They transplanted skin samples from humans with and without scleroderma onto the backs of these mice. Some of the skin samples were pre-treated for 30 minutes with paclitaxel.

"We found that the skin samples from scleroderma patients that were pre-treated with paclitaxel prior to transplantation significantly suppressed the activity of TGF-beta and lessened the formation of fibrotic tissue," Dong said.

Just as importantly, the researchers said, the mice that received the skin samples from scleroderma patients exhibited the beginning of new blood vessel formation, a process known as angiogenesis. These new blood vessels were of mouse, and not human, origin. Not only that, the researchers found that the level of angiogenesis in scleroderma skin samples was twice that of skin samples taken from patients without the disease, regardless of whether or not they were pre-treated with paclitaxel.

This finding of enhanced angiogenesis in scleroderma skin samples is important for two reasons, the researchers said.

First, one of the known side effects seen in cancer patients who take paclitaxel at much higher doses is an unwanted amplification of fibrosis and anti-angiogenesis. Since these two processes were not seen at the much lower doses of paclitaxel used in these experiments, the researchers are encouraged that paclitaxel might be safely used to benefit patients with scleroderma. Further studies are needed to determine optimum dosing, they said.

"Secondly, and just as importantly for our understanding of the disease, it appears that scleroderma skin still has the ability to send signals for repair, which includes the formation of new blood vessels, but for whatever reason, that repair does not occur in the patients, which it did occur in mice," Goldschmidt said.

Goldschmidt believes that mammals, including humans, have an inherent ability to repair damage to tissues. Specifically, according to Goldschmidt, specialized cells in the bone marrow known as vascular progenitor cells can be summoned to the site of blood vessel damage and contribute to the appropriate repairs. In scleroderma patients, this balance between damage and repair is skewed toward damage, with patients' smaller vessels slowly being destroyed and replaced by fibrotic tissue.

Going into the experiments, the researchers hypothesized that there were three possibilities to explain why the skin of scleroderma patients cannot trigger an angiogenic response: the skin is unable to send signals to the bone marrow; the signals are present but for some reason the bone marrow cannot respond; or lastly, the skin sends the signal to the bone marrow, which produces progenitor cells, but the immune system destroys the cells before they reach the site of damage.

"The results of this study rules out the first hypothesis, since the skin was clearly able to send the signal for angiogenesis, which did occur" Goldschmidt said. "The next step is to try to further define the underlying mechanism for the lack of blood vessels."

The researchers said that the answer is probably a combination of the last two factors.

"After the repeated vascular injury suffered by patients with scleroderma, it could be that the supply of progenitor cells becomes exhausted or that the produced cells are incompetent" Dong said. "Or, it could be that once the progenitor cells do leave the bone marrow, they are continually exposed to a noxious environment in the form of auto-antibodies so that they are unable to form new blood vessels."