GROWTH PLATE CELLULAR FUNCTION FOLLOWING RADIOTHERAPY

放射治疗后生长板细胞功能

• 批准号: 6514235
• 负责人: TIMOTHY A DAMRON
• 金额: $ 23.94万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-20 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514235
• 关键词: DNA repair; X ray; apoptosis; cell proliferation; chemoprevention; chondrocytes; epiphysis; fibroblast growth factor; free radical scavengers; genetic markers; immunocytochemistry; interleukin 1; laboratory rat; limbs; parathyroid hormone related protein; pharmacokinetics; radiation protection; radioprotective agents; transforming growth factors; tumor necrosis factor alpha

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.

放射治疗经常被用作儿童骨骼和软组织恶性肿瘤的辅助治疗，但其在生长中的肢体中的使用经常会导致严重的肢体长度差异或成角畸形。 对于单独放射治疗时生长板的功能知之甚少，对于放射防护策略的效果更是知之甚少。 我们在大鼠身上的初步工作记录了通过分级分离和放射防护剂氨磷汀 (WR-2721) 的额外保护对生长板功能的保护。我们的研究小组成员已将正常大鼠生长板的差异生长定义为软骨细胞动力学多个参数的函数，但该分析尚未用于辐照生长板的研究。 我们最初在动物模型中进行的组织形态计量学研究表明，生长板的照射会导致几个事件：暂时减少生长和增殖、早期软骨细胞凋亡、通过增加基质产生来维持一些骨生长，以及随后活跃增殖的细胞克隆的回归。 ——所有这些都可以通过辐射防护治疗来改善。第一个具体目标是通过使用我们在生长大鼠中建立的单侧后肢 X 射线照射模型测量生长板中的软骨细胞动力学和关键免疫组织化学标记物来测试上述机制假设。第二个具体目标，使用相同的研究设计，是检验以下假设：自由基清除剂氨磷汀在照射前立即给予时可维持增殖并减少细胞凋亡，并且它通过剂量分割以累加方式发挥作用。 第三个具体目标是测试以下假设：米索前列醇（一种已知可改善 DNA 修复的放射防护剂）和 IL-1（一种已知可诱导原始祖细胞循环的放射防护剂）将各自通过一种独特的机制保护生长板免受辐射。以及分馏和氨磷汀的添加剂。该项目的长期目标是确定放射防护剂，它们通过不同和互补的机制作用于生长板，与分割结合测试这些放射防护剂，从而制定最终允许对恶性肿瘤进行更安全、更有效的放射治疗的策略。成长中的孩子。