Inhibition of radiation-induced skin fibrosis with imatinib.
OBJECTIVE
Dermal fibrosis is a disabling late toxicity of radiotherapy. Several lines of evidence suggest that overactive signaling via the Platelet-derived growth factor receptor-beta (PDGFR-β) and V-abl Abelson murine leukemia viral oncogene homolog 1 (cAbl) may be etiologic factors in the development of radiation-induced fibrosis. We tested the hypothesis that imatinib, a clinically available inhibitor of PDGFR-β, Mast/stem cell growth factor receptor (c-kit) and cAbl, would reduce the severity of dermal fibrosis in a murine model.


METHODS
The right hind legs of female C3H/HeN mice were exposed to 35 Gy of X-rays. Cohorts of mice were maintained on chow formulated with imatinib 0.5 mg/g or control chow for the duration of the experiment. Bilateral hind limb extension was measured serially to assess fibrotic contracture. Immunohistochemistry and biochemical assays were used to evaluate the levels of collagen and cytokines implicated in radiation-induced fibrosis.


RESULTS
Imatinib treatment significantly reduced hind limb contracture and dermal thickness after irradiation. Immunohistochemical studies demonstrated a substantial reduction in PDGFR-β phosphorylation. We also observed reduced Transforming Growth factor-β (TGF-β) and collagen expression in irradiated skin of imatinib-treated mice, suggesting that imatinib may suppress the fibrotic process by interrupting cross-talk between these pathways.


CONCLUSIONS
Taken together, these results support that imatinib may be a useful agent in the prevention and treatment of radiation-induced dermal fibrosis.
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Jason A
JA
Horton
Eun Joo
EJ
Chung
Kathryn E
KE
Hudak
Anastasia
A
Sowers
Angela
A
Thetford
Ayla O
AO
White
James B
JB
Mitchell
Deborah E
DE
Citrin
D000818:Animals; D001549:Benzamides; D005260:Female; D005355:Fibrosis; D000068877:Imatinib Mesylate; D051379:Mice; D008809:Mice, Inbred C3H; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D011837:Radiation-Protective Agents; D053773:Transforming Growth Factor beta1; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta; D016315:Proto-Oncogene Proteins c-abl