HYPERTHERMIC SENSITIZERS AND RADIOTHERAPY

这项建议的目的是确定如何高温 可以最有效地用于治疗癌症， 通过使用热疗结合放射治疗 致敏剂，一种化合物，将提高更大的杀伤力， 癌细胞加热 由于几类药物被证明是优秀的， 细胞培养研究中的热致敏剂和放射增敏剂， 如果在体外， 这些发现将被明确定义的体内肿瘤证实， 具体网站。 实验将用两种体内肿瘤系统进行。 它们是生长在C3 H肌内的RIF-1纤维肉瘤 小鼠和Fischer大鼠脑内生长的9 L胶质肉瘤， 都是高度抗辐射的肿瘤 两类药物将被 测试的是（i）酸性pH热敏剂（氯尼达明和棉酚） 和（ii）缺氧细胞热敏剂（5-硫代-D-葡萄糖， 罗丹明-123和并环戊二烯内酯）。 初步研究将是 旨在确定加热的最佳时间和顺序， 通过测量肿瘤的药代动力学、pH和血流量来测定药物 和正常组织（皮肤和脑）。 肿瘤的终点 反应将是肿瘤再生，肿瘤治愈和单细胞 克隆形成测定。 第二阶段的研究将确定 三效联合增敏比 肿瘤组织的放射、热、药物治疗。 的 研究的最后阶段是确定正常组织 急性和晚期联合效应的耐受性 模态 这项研究的意义将是确定关键的放射生物学 选择性改善治疗指数的因素 热辐射联合治疗放射抵抗性肿瘤 人类肿瘤，如软组织肉瘤和恶性脑肿瘤 肿瘤的

The objective of this proposal is to determine how hyperthermia can be used most effectively in the treatment of cancer in combination with radiation through the use of hyperthermic sensitizer, a compound that would enhance greater killing of cancer cells by heat. Since several classes of drugs are shown to be both excellent hyperthermic sensitizer and radiosensitizer in cell culture studies, substantial therapeutic gain might be anticipated, if in vitro findings are to be confirmed with well defined in vivo tumors of specific sites. Experiments will be carried out with two in vivo tumor system. They are RIF-1 fibrosarcoma growing intramuscularly in C3H mice and 9L gliosarcoma growing intracerebrally in Fischer rats, both highly radio-resistant tumors. Two classes of drugs to be tested are (i) acidic pH thermosensitizer (lonidamine and gossypol) and (ii) hypoxic cell thermosensitizer (5-thio-D-glucose, rhodamine-123 and pentalenolactone). The initial studies will be directed to determine the optimum time and sequence of heat and drugs by measuring pharmacokinetics, pH and blood flow of tumor and normal tissues (skin and brain). The end points for tumor response will be tumor regrowth, tumor cure and single cell clonogenic assays. The second phase of study will be to determine thermosensitizer enhancement ratio of three way combined treatment of radiation, heat and drugs for tumor tissues. The final phase of the study will be to determine the normal tissue tolerance of both acute and late effects of the combined modality. Significance of the study will be to identify key radiobiological factors that would selectively improve therapeutic index of the combined heat and radiation in the treatment of radioresistant human tumors, such as soft tissue sarcoma and malignant brain tumors.