GROWTH FACTOR ALTERATION OF RADIATION RESPONSE IN TUMORS

放射治疗未能实现局部和区域肿瘤控制 仍然是许多解剖部位的重要问题， 对生存产生负面影响。 出现了临床和 实验室证据表明，肿瘤克隆原增殖期间， 放射治疗过程显著损害这种局部控制。 最近的原位研究表明，多达一半的人类 癌细胞有可能在5个或更少的时间内使其细胞数量增加一倍， 天 因此，在最初的治疗中存活下来的细胞可能会迅速 重新填充肿瘤导致更差的控制。 拟议方案将 评估可能的战略，以克服快速增长的负面影响， 在这些癌症中的扩散。 五个协调项目将 评估三种可能的治疗策略， 增殖：改变分级，使用S期特异性 放射增敏剂以及生物和/或药理学 减缓或抑制细胞分裂的修饰剂。 项目I将研究细胞抑制药物和生物制剂的作用 正常和恶性肿瘤的放射损伤与修复 乳腺和前列腺上皮细胞。 项目II将检查卤化 人肿瘤细胞系和异种移植物中的嘧啶代谢 目的是优化放射增敏和评价 调节细胞动力学以提高肿瘤细胞的比例 敏感。 抗雌激素治疗对放射治疗的影响 将研究MCF-7人乳腺癌异种移植物的反应 在强调治疗结果的项目III中， 激素抗性肿瘤和MCF-7异种移植物对 在没有增殖的情况下进行分次放疗。 项目四 包括最先进的计算机分析， 放射治疗的临床结果，其中增殖率在 将导出肿瘤和/或放射敏感性因子。 同一电视节目 将使用从所有其他项目获得的参数对结果进行建模， 包括项目V的临床测量，以帮助设计 实验室实验和临床方案。 项目五将寻求 建立肿瘤动力学和局部控制率之间的相关性，以及 启动旨在改变肿瘤细胞增殖的临床试验 和/或放射敏感性 包括使用卤代嘧啶类似物，加速 分级或细胞抑制疗法。

Failure to achieve local and regional tumor control with radiation therapy remains a significant problem for a number of anatomic sites and can have a negative impact upon survival. There is emerging clinical and laboratory evidence that proliferation of tumor clonogens during the course of radiation treatment significantly impairs such local control. Recent in situ studies suggest that as many as half of all human carcinomas have the potential to double their cell number in five or fewer days. Thus, cells that survive the initial treatments might rapidly repopulate a tumor, leading to poorer control. The proposed Program will evaluate potential strategies for overcoming the negative impact of rapid proliferation in these cancers. The five coordinated Projects will evaluate three potential treatment strategies for dealing with proliferation: altered fractionation, use of S-phase specific radiosensitizers, and the use of biological and/or pharmacological modifiers that slow or inhibit cell division. Project I will investigate the effects of cytostatic drugs and biologicals on radiation damage and repair in primary human normal and malignant breast and prostate epithelial cells. Project II will examine halogenated pyrimidine metabolism in human tumor cell lines and xenografts with the goal of optimizing radiosensitization and evaluating mechanisms of modulating cell kinetics to enhance the proportion of tumor cells sensitized. The influence of antiestrogen treatment on the radiation response of MCF-7 human breast carcinoma xenografts will be investigated in Project III with an emphasis on treatment outcome, the emergence of hormone resistant tumors and the response of MCF-7 xenografts to fractionated radiotherapy in the absence of proliferation. Project IV consists of state-of-the art computer analysis of published and emerging clinical results in radiotherapy, from which rates of proliferation in tumors and/or radiosensitivity factors will be derived. The same programs will model results using parameters obtained from all other Projects, including clinical measurements from Project V to help in design of both laboratory experiments and clinical protocols. Project V will seek to establish correlations between tumor kinetics and local control rates, and initiate clinical trials designed to modify tumor cell proliferation and/or radiosensitivity via kinetic-specific treatment modifications including the use of halogenated pyrimidine analogs, accelerated fractionation or cytostatic therapy.