MODIFYING XENOGRAFT RADIOSENSITIVITY

改变异种移植物的放射敏感性

• 批准号: 2097414
• 负责人: RALPH E. DURAND
• 金额: $ 13.09万
• 依托单位: BRITISH COLUMBIA CANCER AGENCY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-04-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2097414
• 关键词: adenocarcinoma; athymic mouse; biological response modifiers; blood flow measurement; cell line; cis platinum compound; colon neoplasms; combination cancer therapy; cytotoxicity; disease /disorder model; doxorubicin; drug interactions; drug metabolism; drug screening /evaluation; flow cytometry; hypoxia; laboratory mouse; lomustine; mitomycin C; neoplasm /cancer chemotherapy; neoplasm /cancer transplantation; nonhuman therapy evaluation; oxygen consumption; oxygen tension; radiation sensitivity; radiosensitizer; xenotransplantation

Local failure remains a major problem for radiotherapy of human solid tumors, and at least a part of tumor radioresistance is generally agreed to be linked to hypoxia. Clinical approaches to overcoming the problem of hypoxic tumor cells have generally been directed toward improving tumor oxygenation and developing better hypoxic cell radiosensitizers. In the laboratory, however, new considerations suggest that tumor hypoxia may present a therapeutic opportunity, and considerable effort is now directed toward developing agents with specific toxicity to hypoxic cells. While intriguing, the practicality of either reducing or exploiting tumor hypoxia nonetheless remains questionable for human disease, largely due to uncertainty regarding the nature of hypoxia in human tumors, and lack of availability of appropriate modifying agents suitable for clinical use. Our ongoing studies with spheroids in vitro, recently extended to human xenografts in vivo, have revealed that a number of agents capable of modifying tumor hypoxia are already in clinical use: common cancer chemotherapeutic drugs. Our intent in this project is to test selected drugs as radiation modifiers in human tumor xenografts in mice, by identifying time and dose schedules which 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 study hypoxic versus aerobic cell subpopulations from the xenografts. 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. Oxygen utilization rates will be measured for cells in situ using an innovative fluorescent staining procedure. Using conventional cancer chemotherapy drugs for the specific purpose of modifying the amount and degree of tumor hypoxia is, to the applicant's knowledge, unique to this laboratory. We consequently 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 cisplatin, doxorubicin, mitomycin-C and CCNU with radiation; at best, new treatment schemes entirely feasible for immediate clinical testing will be suggested.

局部失败仍然是人类固体放疗的主要问题 通常同意肿瘤，至少一部分肿瘤放射线 与缺氧有关。 克服问题的临床方法 缺氧性肿瘤细胞通常用于改善肿瘤 氧合和发展更好的低氧细胞放射敏剂。 在 但是，实验室的新考虑表明肿瘤缺氧可能 提出治疗机会，现在要指导大量的努力 致力于发育对低氧细胞具有特异性毒性的剂。 尽管 有趣的是减少或利用肿瘤缺氧的实用性 尽管如此，仍然对人类疾病仍然值得怀疑，这主要是由于 关于人类肿瘤中缺氧性质的不确定性以及缺乏 适用于适合临床使用的适当修饰剂。 我们正在进行的体外球体研究，最近扩展到人类 体内异种移植物已显示许多能够 修改肿瘤缺氧已经在临床中：常见癌症 化学治疗药物。 我们在这个项目中的目的是测试选定的 药物作为小鼠人类肿瘤异种移植物中的辐射修饰剂，通过 识别产生放射敏化的时间和剂量时间表， 血流改变，代谢扰动导致重氧， 和/或优先的细胞毒性。 治疗潜力 将使用荧光激活的细胞评估组合处理 分类技术分离和差异研究低氧与 异种移植物的有氧细胞亚群。 同时，药物 诱导的血流变化将在宏观水平上进行量化 用激光多普勒流量仪，并在微区域级别与图像 分析技术。 将测量细胞的氧气利用率 原位使用创新的荧光染色程序。 使用 常规癌症化疗药物的特定目的 修改肿瘤缺氧的数量和程度是申请人的 知识，该实验室独有的知识。 因此，我们期望我们的 综合结果至少将提供新的信息 关于缺氧在体内作用中的性质和作用以及 顺铂，阿霉素，丝裂霉素-C和CCNU与辐射的相互作用； 充其量，新的治疗方案完全可行，可立即进行临床 将建议进行测试。