MODIFYING XENOGRAFT RADIOSENSITIVITY BY CHEMOTHERAPY

通过化疗改变异种移植物的放射敏感性

基本信息

批准号：
2848719
负责人：
RALPH E. DURAND
金额：
$ 5万
依托单位：
BRITISH COLUMBIA CANCER AGENCY
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-04-01 至 1998-09-30
项目状态：
已结题

项目摘要

Our long-term goal in this competing renewal application continues to be the improved treatment of human solid tumors. As in the initial three years of this project, we will explore combination chemotherapy- radiotherapy treatments of human tumor xenografts, but with approaches and goals that are, to our knowledge, unique to this laboratory: using conventional chemotherapeutic agents to modulate tumor blood flow and/or cellular metabolism, thereby Increasing the radiosensitivity of tumor cell subpopulations. During the requested funding interval, we intend to determine the extent and nature of hypoxia and other microenvironmental anomalies in several types of xenografted human tumors growing in immunocompromised mice, and to test four common chemotherapeutic agents (carboplatin, CCNU, cyclophosphamide, and 5-fluorouracil) as radiation modifiers. We hypothesize that appropriate time and dose schedules will produce radiosensitization, altered blood flow, metabolic perturbations leading to reoxygenation, and/or preferential cytotoxicity. The therapeutic potential of the combination treatments will be assessed using fluorescence-activated cell sorting techniques to isolate and differentially determine the clonogenic potential of hypoxic versus aerobic cell subpopulations from the xenografts. These studies will be complemented by variations of the comet assay aimed at determining the growth fraction, and the hypoxic fraction of the tumors and isolated subpopulations. Concurrently, drug-induced changes in blood flow will be quantified at the macroscopic level with laser Doppler flowmetry, and at the microregional level with image analysis techniques. The potential and reliability of a new flow cytometric method for quantifying transient blood flow, based on dual labeling with thymidine analogues, will also be determined. Oxygen utilization rates will be measured for cells in situ using an innovative fluorescent staining procedure. We anticipate that our integrated results will, at the very least, provide novel information concerning the nature and role of hypoxia in the in vivo action and interaction of carboplatin, CCNU, cyclophosphamide and 5- fluorouracil with radiation; at best, new treatment schemes entirely feasible for immediate clinical testing will be suggested.

我们在此次竞争续签应用中的长期目标继续是改善了人类实体瘤的治疗。就像最初的三个在这个项目的几年中，我们将探索组合化疗 - 人类肿瘤异种移植物的放疗治疗，但采用方法和据我们所知，该实验室独有的目标：使用常规的化学治疗剂调节肿瘤血流和/或细胞代谢，从而增加肿瘤细胞的放射敏感性亚群。在请求的资金间隔中，我们打算确定缺氧和其他微环境异常的性质异种移植的类型在免疫功能低下的小鼠中生长的人类肿瘤，以及测试四种常见的化学治疗剂（Carboplatin，CCNU，环磷酰胺和5-氟尿嘧啶作为辐射修饰符。我们假设适当的时间和剂量时间表将产生放射敏化，血流改变，代谢扰动导致重氧和/或优先的细胞毒性。将评估组合治疗的治疗潜力使用荧光激活的细胞分选技术来分离和差异确定缺氧与异种移植物的有氧细胞亚群。这些研究将是与旨在确定的彗星测定法的变化相辅相成生长部分以及肿瘤的低氧部分和分离亚群。同时，药物引起的血流变化将是用激光多普勒流量指定在宏观水平上定量，并在带有图像分析技术的微区水平。潜力和用于量化瞬态的新流式细胞术方法的可靠性基于胸苷类似物的双重标记的血流也将是决定。将在原位测量细胞的氧气利用率使用创新的荧光染色程序。我们预计我们的综合结果至少将提供关于缺氧在体内的性质和作用的新信息卡铂，CCNU，环磷酰胺和5-的作用和相互作用荧光素带辐射；充其量，新的治疗方案完全是将提出可行的临床测试。