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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083892-07
Application #
7388969
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Prasanna, Pat G
Project Start
1999-12-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2011-02-28
Support Year
7
Fiscal Year
2008
Total Cost
$245,011
Indirect Cost
Name
Upstate Medical University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
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Wang, Yan; Zhang, Mingliang; Middleton, Frank A et al. (2007) Connective tissue growth factor and insulin-like growth factor 2 show upregulation in early growth plate radiorecovery response following irradiation. Cells Tissues Organs 186:192-203
Zhang, Mingliang; Wang, Yan; Middleton, Frank A et al. (2007) Growth plate zonal microarray analysis shows upregulation of extracellular matrix genes and downregulation of metalloproteinases and cathepsins following irradiation. Calcif Tissue Int 81:26-38

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