New research in a murine model points to the ability of low-dose paclitaxel (Taxol®) to modulate transforming growth factor-beta (TGF-ß) and lessen fibrosis in systemic sclerosis (SSc) patients, findings that also provide additional clues to the pathogenesis of the disease, according to a study appearing in the November 1, 2005, edition of Public Library of Science Medicine.¹

The investigators transplanted skin samples from humans with and without SSc onto the backs of severe combined immunodeficient mice, including samples that had been pretreated for 30 minutes with 2 mM paclitaxel. They found that the skin samples from SSc patients that were pretreated with paclitaxel prior to transplantation significantly suppressed the activity of TGF-ß and lessened the formation of fibrotic tissue. The results indicate that treatment with paclitaxel at lower doses may have a therapeutic benefit for SSc patients, modulated via TGF-ß signaling.

"As far as Taxol is concerned, we still have a long way to go, and we still need to find out whether Taxol at low doses would have other adverse effects on a patient," lead study author Chunming Dong, MD, of the division of cardiology at Duke University Medical Center in Durham, North Carolina, tells CIAOMed. "But we are one step closer [to a potential new therapy] and this paper provides the basis to undergo a preliminary clinical trial using taxol," he says.

Previous studies have shown that the treatment of individual cells with paclitaxel helps stabilize microtubules, thereby blocking the excessive activity of TGF-ß.
 
Important findings regarding angiogenesis in scleroderma

According to the study findings, the mice that received the skin samples from SSc patients exhibited the beginning of angiogenesis. These new blood vessels were of mouse, and not human, origin. Moreover, the level of angiogenesis in scleroderma skin grafts showed a twofold increase in neovessel formation compared with samples taken from patients without the disease, regardless of whether they were pretreated with paclitaxel.

This finding of enhanced angiogenesis in scleroderma skin samples is important for two reasons, Dr. Dong and colleagues point out. First, one of the known side effects seen in cancer patients who take paclitaxel at much higher doses is an amplification of fibrosis and antiangiogenesis. The researchers reported that they are encouraged that paclitaxel might be safely used to benefit SSc patients, since these two processes were not observed at the considerably lower doses of paclitaxel used in this trial. Further studies are needed to determine optimum dosing, they said.

"These findings indicate that low-dose paclitaxel may potentially help keep in check the fibrotic process associated with SSc, without adversely affecting the vascular component of the disease," the study authors conclude.

The investigators, including a team from the division of rheumatology at Johns Hopkins University in Baltimore, Maryland, noted that the SSc skin grafts in the mice, but not the human, SSc comparator group maintained the ability to send signals for repair, which includes new blood vessel formation, pointing to the origin of neovascular cells in the bone marrow of the recipient mice.

The study authors explained that mammals, including humans, have an inherent ability to repair damage to tissues. Specifically, vascular progenitor cells can be summoned to the site of blood vessel damage and contribute to the appropriate repairs. In scleroderma patients, however, this balance is skewed toward damage, with patients' smaller vessels slowly being destroyed and replaced by fibrotic tissue. Dr. Dong and colleagues hypothesized that either the skin is unable to send signals to the bone marrow, that the signals are present but the bone marrow cannot respond, or that 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 first hypothesis was ruled out, as the skin was clearly able to send the signal for angiogenesis, which did occur, so the next step is to try to further define the underlying mechanism for the lack of blood vessels.

"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," Dr. Dong says. "It could be that once the progenitor cells leave the bone marrow, they are continually exposed to a noxious environment in the form of autoantibodies, so they are unable to form new blood vessels."

Going forward, the SCOT (Scleroderma Cyclophosphamide or Transplantation) study, which is currently enrolling patients, should provide further answers and insights into the cause and best treatments for this vexing disorder. "We are hoping that SCOT will offer more insights on the cause of the angiogensis process," Dr. Dong tells CIAOMed.

 Reference

1. Liu X, Zhu S, Wang T, et al. Paclitaxel modulates TGF-β signaling in scleroderma skin grafts in immunodeficient mice. PloS Med. 2005;2:e354.