GROWTH FACTOR ALTERATION OF RADIATION RESPONSE IN TUMORS

未能通过放射治疗实现局部和区域肿瘤控制 仍然是许多解剖部位的一个重大问题，并可能 对生存的负面影响。出现了新的临床和 实验室证据表明，肿瘤克隆性细胞在 放射治疗的疗程显著损害了这种局部控制。 最近的现场研究表明，多达一半的人类 癌症有可能在5个或更少的时间内使其细胞数量翻一番 几天。因此，在最初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。拟议的计划将 评估克服快速反应的负面影响的潜在战略 在这些癌症中的增殖。五个协调一致的项目将 评估三种潜在的治疗策略以应对 增殖：改变分级，使用S相特异性 放射增敏剂以及生物和/或药物的使用 延缓或抑制细胞分裂的修饰物。 项目I将调查细胞抑制药物和生物制品的效果 原发人体正常与恶性辐射损伤与修复的研究 乳腺和前列腺上皮细胞。项目二将审查卤素 人肿瘤细胞系和异种移植瘤中的嘧啶代谢 优化放射增敏的目标和评价机制 调节细胞动力学以提高肿瘤细胞比例 敏化。抗雌激素治疗对辐射的影响 MCF-7人乳腺癌异种移植瘤的疗效观察 在强调治疗结果的项目III中，出现了 激素抵抗肿瘤及MCF-7移植瘤对激素抵抗的反应 在没有增殖的情况下进行分割放射治疗。项目IV 包括对已出版和新兴的最先进的计算机分析 放射治疗的临床结果，由此导致的增殖率 肿瘤和/或放射敏感性因子将会衍生出来。同样的计划 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，以帮助设计这两个 实验室实验和临床方案。项目V将寻求 建立肿瘤动力学和局部控制率之间的关联，以及 启动旨在改变肿瘤细胞增殖的临床试验 和/或通过动力学特异性治疗改进的放射敏感性 包括使用卤化的嘧啶类似物，加速 分割或细胞抑制疗法。

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.