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 #
5R01CA083892-06
Application #
7214629
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Prasanna, Pat G
Project Start
1999-12-01
Project End
2009-02-28
Budget Start
2007-03-23
Budget End
2008-02-29
Support Year
6
Fiscal Year
2007
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
Margulies, B S; DeBoyace, S D; Damron, T A et al. (2015) Ewing's sarcoma of bone tumor cells produces MCSF that stimulates monocyte proliferation in a novel mouse model of Ewing's sarcoma of bone. Bone 79:121-30
Pritchard, Meredith R; Horton, Jason A; Keenawinna, Lihini S et al. (2010) Microarray analysis of irradiated growth plate zones following laser microdissection shows later importance of differentially expressed genes during radiorecovery. Cells Tissues Organs 192:240-9
Bush, Peter G; Pritchard, Meredith; Loqman, Mohamad Y et al. (2010) A key role for membrane transporter NKCC1 in mediating chondrocyte volume increase in the mammalian growth plate. J Bone Miner Res 25:1594-603
Damron, Timothy A; Zhang, Mingliang; Pritchard, Meredith R et al. (2009) Microarray cluster analysis of irradiated growth plate zones following laser microdissection. Int J Radiat Oncol Biol Phys 74:949-56
Zhang, Mingliang; Pritchard, Meredith R; Middleton, Frank A et al. (2008) Microarray analysis of perichondral and reserve growth plate zones identifies differential gene expressions and signal pathways. Bone 43:511-20
Horton, Jason A; Bariteau, Jason T; Loomis, Richard M et al. (2008) Ontogeny of skeletal maturation in the juvenile rat. Anat Rec (Hoboken) 291:283-92
Damron, Timothy A; Horton, Jason A; Pritchard, Meredith R et al. (2008) Histomorphometric evidence of growth plate recovery potential after fractionated radiotherapy: an in vivo model. Radiat Res 170:284-91
Margulies, Bryan S; Damron, Timothy A; Allen, Matthew J (2008) The differential effects of the radioprotectant drugs amifostine and sodium selenite treatment in combination with radiation therapy on constituent bone cells, Ewing's sarcoma of bone tumor cells, and rhabdomyosarcoma tumor cells in vitro. J Orthop Res 26:1512-9
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

Showing the most recent 10 out of 21 publications