Protection Against Pulmonary Fibrosis Promises More Efficient Radiotherapy

Pulmonary fibrosis is a progressive terminal disease which involves scarring of the lung as a result of proliferation of fibrous connective tissue. Thickening of the tissue increasingly restricts breathing. The disease may arise spontaneously or be triggered by drugs or pollutants or evolve as a dreaded side effect of radiotherapy or chemotherapy of lung cancer. Scientists of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now discovered that specific inhibition of platelet-derived growth factor (PDGF) signaling may significantly attenuate radiation induced pulmonary fibrosis.

A team of researchers headed by Dr. Amir Abdollahi and PD Dr. Dr. Peter Huber has shown that cells react to irradiation by releasing the PDGF growth factor. It binds to and activates a receptor molecule on the surface of connective tissue cells which are thus induced to grow and start the development of fibrosis. The scientists proceeded to investigate whether substances belonging to a group called kinase inhibitors are able to prevent activation of the PDGF receptor and thus reduce the fibrotic process.

Mice that were treated with one of three different kinase inhibitors after receiving high radiation doses survived significantly longer than untreated animals. Using both magnetic resonance imaging and histological investigations the scientists were able to show that the lungs of the treated animals revealed fewer signs of fibrosis.

“This encourages us to investigate kinase inhibitors in radiotherapy patients, too", said Peter Huber, commenting the results. Frequently, the risk of pulmonary fibrosis makes it impossible to treat tumors with sufficiently high radiation doses. With the protection of the new substances it may be possible to irradiate tumors with the necessary dose and thus to improve the chances of cure for cancer patients. The scientists think that the substances may also be used in the treatment of spontaneous fibrosis, even though already existing fibrosis cannot be reversed.

The good news is that these findings can be used for the benefit of patients with unusual swiftness. Among the three kinase inhibitors studied, there is a well-known substance that has already passed all stages of drug approval: Glivec is a new drug that has been used successfully for treating certain types of leukemias and tumors of the gastrointestinal tract.

Publication: Amir Abdollahi, Minglun Li, Gong Ping, Christian Plathow, Sophie Domhan, Fabian Kiessling, Leslie B. Lee, Gerald McMahon, Hermann-Josef Gröne, Kenneth E. Lipson, and Peter E. Huber: Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. Journal of Experimental Medicine, 2005, 201:925