Radiotherapy is frequently employed as adjunctive treatment for childhood bone and soft-tissue malignancies, but its use in a growing limb frequently results in crippling limb length discrepancy or angular deformity. Little is known regarding growth plate function in the face of radiotherapy alone and even less regarding the effects of radioprotectant strategies. Our preliminary work in rats documented sparing of growth plate function by fractionation and additional sparing by the radioprotectant amifostine (WR-2721). Members of our research team have defined the differential growth of the normal rat growth plate as a function of multiple parameters of chondrocyte kinetics, but this analysis has not been used in the study of the irradiated growth plate. Our initial histomorphometric studies in an animal model suggest the hypothesis that irradiation of the growth plate results in several events: transiently decreased growth and proliferation, early chondrocyte apoptosis, maintenance of some bone growth by increased matrix production, and subsequent return of actively proliferating cellular clones --all of which can be improved by radioprotectant treatment. The first specific aim is to test the above mechanistic hypothesis by measuring chondrocyte kinetics and key immunohistochemical markers in the growth plate using our established unilateral hind limb x-irradiation model in the growing rat. The second specific aim, using the same research design, is to test the hypothesis that the free radical scavenger amifostine maintains proliferation and decreases apoptosis when given immediately preceding irradiation, and that it acts in an additive fashion with dose fractionation. The third specific aim is to test the hypotheses that misoprostol (a radioprotectant known to improve DNA repair) and IL-1 (a radioprotectant known to induce cycling of primitive progenitor cells) will each result in growth plate protection from irradiation by a mechanism unique from and additive to that of fractionation and amifostine. The long-term objectives of this project are to identify radioprotectants, which act by different and complementary mechanisms upon the growth plate, to test these radioprotectants in combination with fractionation and thereby develop strategies that will ultimately permit safer and more effective radiotherapy for malignancies in the growing child.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083892-03
Application #
6604191
Study Section
Radiation Study Section (RAD)
Program Officer
Prasanna, Pat G
Project Start
2001-07-20
Project End
2005-03-31
Budget Start
2003-07-01
Budget End
2005-03-31
Support Year
3
Fiscal Year
2003
Total Cost
$239,400
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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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

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