Gleevec Touted as Possible Treatment for Systemic Sclerosis

ERLANGEN, Germany, Dec. 28 -- Gleevec (imatinib mesylate), the cancer drug, may be useful in blocking the pathways involved in systemic sclerosis, according to researchers here.

But the findings -- in vitro and in experimental animals -- only form "the molecular background for controlled clinical trials" in humans, according to Jrg Distler, M.D., of the University of Erlangen-Nuremberg.

Gleevec, better known for its effect on chronic myelogenous leukemia and gastrointestinal stromal tumors, exerts selective dual inhibition of the transforming growth factor-? (TGF-?) and platelet-derived growth factor (PDGF) pathways, Dr. Distler and colleagues noted in the January issue of Arthritis & Rheumatism.

Both pathways play central roles in the pathogenesis of systemic sclerosis, which is characterized by progressive tissue fibrosis that can affect the skin, vasculature, gastrointestinal tract, and other organs, the researchers said.

Using fibroblast cultures from five patients with systemic sclerosis and six healthy sex- and age-matched controls, the researchers stimulated the tissue with TGF- and PDGF, followed by incubation with Gleevec.

Both TGF- and PDGF increased levels of profibrotic proteins in the extracellular matrix - including COL1A1, COL1A2, and fibronectin 1 -- but Gleevec inhibited protein production in a dose-dependent manner in both systemic sclerosis and normal dermal fibroblasts, the researchers found.

For example:

• At a concentration of 0.01 micrograms per milliliter, Gleevec down-regulated COL1A1 by 15%.
• At 0.1 micrograms per milliliter, the protein was down-regulated by 63%.
• And the greatest reduction (84%) occurred at a concentration of 1.0 micrograms per milliliter.

In some cases, the researchers said, synthesis of extracellular matrix proteins was reduced to below baseline levels.

The researchers also induced dermal fibrosis in experimental mice using the anti-neoplastic Blenoxane (bleomycin) and showed that Gleevec prevented the induction of fibrosis at doses that could be achieved in humans, 50 mg/kg² and 150 mg/kg² daily.

There were no apparent toxicities in the animals, the researchers said, consistent with the knowledge that in humans Gleevec is a well-tolerated small molecule.

They concluded that Gleevec "is a highly promising candidate for the treatment of fibrotic diseases" like systemic sclerosis.

The report is "of considerable interest," especially because years of research has failed to find antifibrotic agents to treat systemic sclerosis, said Frank Wollheim, M.D., Ph.D., of Lund University Hospital in Sweden, in an accompanying editorial.

He pointed out that the German team again assumed that the doses used correspond to those used in the clinical setting. "This may seem surprising considering that 50-150 mg/kg is a far higher dose than the 200-400 mg/day used in patients," he noted.

"In addition, the experimental conditions enabled study of imatinib mesylate as a prevention, but not as a treatment. Clearly, more extensive animal studies of imatinib mesylate, e.g., using bleomycin-induced pulmonary fibrosis or the recently developed PDGF model of systemic sclerosis, as well as studies assessing its efficacy as a treatment of existing fibrosis in addition to its efficacy as a preventive agent, are needed," adding that "it is well known that extrapolation from animal models can be disappointing."

He also pointed out that "although relatively well tolerated, imatinib mesylate is not free from serious adverse reactions, in particular, liver toxicity. Edema and dyspnea are also relatively common, and a recent report described cases of severe heart failure."

Only controlled clinical trials in select patients with a high probability of progression will show whether Gleevec really works, he cautioned, but the study offers "realistic hope" that the medication will be a useful advance in the treatment of systemic sclerosis.