MODIFYING XENOGRAFT RADIOSENSITIVITY

改变异种移植物的放射敏感性

• 批准号: 3200950
• 负责人: RALPH E. DURAND
• 金额: $ 12.35万
• 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/3200950
• 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 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.

局部失效仍然是人体实体放射治疗的一个主要问题 肿瘤，并且至少有一部分肿瘤的放射抗性被普遍认为 与缺氧有关。 克服该问题的临床方法 缺氧的肿瘤细胞通常被用来改善肿瘤 氧合和开发更好的缺氧细胞放射增敏剂。 在 然而，实验室新的考虑表明肿瘤缺氧可能 提供了一个治疗机会，现在正在投入大量努力 致力于开发对缺氧细胞具有特定毒性的药物。 尽管 有趣的是，减少或利用肿瘤缺氧的实用性 尽管如此，对于人类疾病仍然存在疑问，这主要是由于 关于人类肿瘤缺氧性质的不确定性，以及缺乏 适合临床使用的适当修饰剂的可用性。 我们正在进行体外球体研究，最近扩展到人类 体内异种移植，已经揭示了许多能够 改变肿瘤缺氧已在临床使用：常见癌症 化疗药物。 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的辐射调节剂， 确定产生放射增敏作用的时间和剂量表， 血流改变，代谢紊乱导致再氧合， 和/或优先的细胞毒性。 的治疗潜力 将使用荧光激活细胞评估联合治疗 分离和区别研究缺氧与缺氧的分类技术 来自异种移植物的需氧细胞亚群。 同时，药物 引起的血流变化将在宏观水平上量化 使用激光多普勒血流计，并在微区域水平上使用图像 分析技术。 将测量细胞的氧气利用率 使用创新的荧光染色程序进行原位染色。 使用 用于特定目的的常规癌症化疗药物 改变肿瘤缺氧的量和程度是申请人的 知识，是本实验室独有的。 因此，我们预计我们的 综合结果至少将提供新颖的信息 关于缺氧在体内作用的性质和作用以及 顺铂、阿霉素、丝裂霉素-C 和 CCNU 与辐射的相互作用； 充其量，新的治疗方案对于立即临床完全可行 将建议进行测试。