Radiotherapy is employed as adjunctive treatment for childhood malignancies, but its use in a growing limb frequently results in crippling limb length discrepancy or angular deformity. Our initial work has established an in vivo model for radiation effects on the growth plate and documented sparing of growth plate function by fractionation and the radioprotectants amifostine [WR-2721], pentoxifylline, misoprostol, selenium, and IL-1a. Even used in combination, these pre-radiation treatments have provided incomplete reversal of the damaging effects of irradiation. Our studies using in vivo immunohistochemical, histomorphometric, and stereologic techniques have suggested that the potential for recovery following growth plate injury is driven by PTHrP primarily, and by FGF2 and TGF-b secondarily. This results initially in accumulation of matrix followed closely by appearance of regenerative proliferative clones, the restoration of which appears to be directly related to reduction of limb length discrepancy. However, the potential for further improvements in growth plate radiation recovery appears to lie in combining radioprotectant with radiorecovery approaches, and the latter has not been investigated in the growth plate. Our first specific aim is to use laser microdissection and molecular biology techniques to test the hypotheses that growth plate radiorecovery is driven initially by PTHrP with its downstream signaling cascade and that the consequent regenerative clones are comprised of normally functioning chondrocytes derived from reserve zone chondrocytes. Our second specific aim is to test both in vitro and in vivo the hypothesis that stimulating the depressed PTHrP axis after radiotherapy will improve growth plate recovery. The third specific aim is to test the hypothesis that combination therapy using radioprotection and radiorecovery strategies will provide significantly better growth plate function than either strategy alone. The long term objectives of this project are to identify a combination strategy of radioprotection and radiorecovery that will act by complementary mechanisms upon the growth plate to maintain as close to normal growth plate function as possible during needed radiotherapy treatment.
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