HYPERTHERMIA AND CHEMOTHERAPY ON TUMOR AND NORMAL TISSUE

热疗显著增加化疗所致的细胞毒性 对肿瘤和正常组织都适用。因此，正常的组织损伤限制了 这一强大的抗癌疗法的应用。鉴于此， 对潜在有效疗法的严重限制，有 令人惊讶的是，很少有关于急性正常组织反应的研究 局部/局部或全身热化疗，无研究 晚期正常组织反应。这样做的总体目标是 持续的研究是建立一种最佳的热化疗 对正常组织提供最小损伤的治疗方案 最大限度地切除肿瘤。大鼠纤维肉瘤的反应将是 用作肿瘤模型。我们假设已知的血管，代谢， 肿瘤和正常组织之间的pH和修复差异可能是 在保持抗肿瘤作用的同时减少正常组织损伤 效果。我们建议利用肿瘤和肿瘤之间的这些差异 通过首先建立正常组织的剂量反应曲线 局部/区域和全身性加热与 顺铂、阿霉素、博莱霉素及其各自的单药 毒性较低的类似物。我们将首先量化正常组织对 热化疗；然后我们将使用药代动力学和生化 优化药物/热疗计划的药理学研究，以减少 正常组织毒性、保留抗肿瘤联合药效 治疗敏感肿瘤并显示出对抗耐药的活性 肿瘤。已知可降低特定药物毒性的保护性化合物 在常温下进行体温过高和药物测试 进一步提高综合治疗的治疗指数。 从这些研究中学到的信息将被应用于Rational 一种用于临床的多药化疗热疗方案的设计 癌症患者。

Hyperthermia significantly increases chemotherapy induced cytotoxicity for both tumor and normal tissue. Thus, normal tissue injury limits the application of this powerful anti-cancer therapy. in the light of this serious restriction to a potentially effective therapy, there are surprisingly few studies of acute normal tissues reaction to chemotherapy with either local/regional or systemic heat, and no studies of late normal tissue response. The general objective of this continuing research is to establish an optimal thermo-chemotherapy treatment regiment that provides both minimal injury to normal tissue with maximum tumor ablation. The response of a rat fibrosarcoma will be used as a tumor model. We hypothesize that known vascular, metabolic, pH and repair differences between tumors and normal tissues may be exploited to reduce normal tissue damage while maintaining anti-tumor effect. We propose to utilize these dissimilarities between tumor and normal tissues by first establishing dose response curves of local/regional and systemic heat administered simultaneously with the single agents cisplatin, doxorubicin, bleomycin and their respective less toxic analogs. We will first quantitate normal tissue response to the thermochemotherapy; we will then use pharmacokinetic and biochemical pharmacologic studies to optimize drug/heat schedules in order to reduce normal tissue toxicities, retain anti-tumor efficacy of the combined therapy in sensitive tumors and demonstrate activity against resistant tumors. Protective compounds known to reduce specific drug toxicities at normal temperature will then be tested with hyperthermia and drugs to further increase the therapeutic index of the combined modality therapy. Information learned from these studies will be applied to the rational design of a multi-agent chemotherapy-hyperthermia therapy to be used in cancer patients.