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8327

Radiation-Induced Craniofacial Bone Growth Inhibition: Investigation of the Mechanisms and Cytoprotection in Vitro

Artur M. Gevorgyan, MD, Giorgio La Scala, MD, Balram Sukhu, PhD, Ivan Yeung, PhD, Peter C. Neligan, MD, Cho Y. Pang, PhD, and Christopher R. Forrest, MD.

Purpose: Radiotherapy for head and neck cancer in children results in severe inhibition of craniofacial bone growth. Previously, the infant rabbit orbito-zygomatic complex (OZC) was established as an animal model and the efficacy of cytoprotection using Amifostine (Ethyol, WR-2721) was demonstrated. The purpose of this study was to investigate the effects of radiation and the efficacy of Amifostine in diminishing the radiation damage in different osteoblastic cells.

Methods: Seven-week old rabbits were irradiated with 0-15 Gy to both OZC with and without Amifostine (300mg/kg, intravenously, 20 minutes before radiation). Primary cell cultures were developed from OZC periostea. Cultured rabbit calvarial osteoblasts and MC3T3-E1 mouse osteoblastic cells were irradiated in vitro (0-10 Gy) with and without pre-treatment with WR-2721 or WR-1065 (active metabolite; 10-310-6 M, 30 minutes before irradiation). Cultures were tested for osteoblast survival, proliferation, differentiation (alkaline phosphatase, collagen type I, mineralization) and cell cycle arrest.

Results: In all cultures, radiation resulted in significant (p<0.05), dose-dependent inhibition of proliferation and differentiation. Pre-treatment with Amifostine significantly (p<0.05) improved these parameters in the OZC periosteal cells. In the rabbit calvarial culture, pre-treatment with both Amifostine and its active metabolite did not result in significant cytoprotection. In MC3T3-E1 osteoblastic cells, 10-4M WR-1065 was significantly though marginally protective.

Conclusion: Radiation consistently resulted in a dose-dependent inhibition of cell growth and function in all cell cultures. Amifostine effects varied depending on cell origin and differentiation state. Current research focuses on elucidation of the molecular mechanisms of radiation damage and cytoprotection in mouse calvarial osteoblasts.


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