OPTIMIZING CANCER CHEMOTHERAPY

描述：(申请者摘要)一种很有希望的方法 热疗联合热疗治疗转移性结直肠癌 用化疗来克服癌症中的耐药性。全身 热疗(WBH)具有增加化疗的独特潜力 对系统性疾病的疗效；然而，狭隘的治疗指数 限制了其在临床上的广泛应用。系统的优化设计 WBH与药物联合应用方案提高治疗指数 到目前为止，一直是一种试错的方法。 指导合并计划的客观生物标志物是 需要的。申请人和其他人观察到WBH以及5- 氟尿嘧啶(5-FU)，增强肿瘤细胞的死亡能力 细胞凋亡(程序性细胞死亡)。申请人假设 诱导剂诱导的细胞凋亡和/或坏死对于最终 肿瘤和正常组织的反应。她进一步推论说 综合治疗可以通过安排WBH的药物治疗来优化， 由两种药物诱导的不同能力引导 与正常组织相比，肿瘤组织中的细胞凋亡和/或坏死。为了测试 这些假设，申请人建议检查的结果 各种静脉输注(PIF)5-FU，既有长效、低剂量的 温度WBH(LL-WBH，40.0摄氏度，8小时)和短持续时间， 高温WBH(SH-WBH，41.5℃，2小时) Ward结肠癌活体实验。她将首先确定是否有 在药物和热诱导的细胞凋亡和/或 肿瘤和正常组织(肠道和血液)之间的坏死 系统)通过量化细胞凋亡和/或 由以下原因引起的坏死(如发病时间、高峰和持续时间) 单独的特工。然后，她将尝试利用肿瘤方面的差异 和正常组织的凋亡/坏死参数来指导组合 日程表。根据她的初步数据，她将安排 以细胞凋亡峰为导向的5-FU/WBH组合， 对合成组合诱导参数进行量化 肿瘤组织和正常组织中的细胞凋亡/坏死。她将会把 动力学参数与治疗指数的关系。然后她会决定 在优化方案中，细胞凋亡和/或坏死是否可以 此外还被一种凋亡/坏死修饰剂改变， 重组人肿瘤坏死因子-α。

DESCRIPTION: (Applicant's Abstract) A promising approach to the treatment of metastatic colorectal carcinoma is to combine hyperthermia with chemotherapy to overcome drug resistance in the cancer. Whole body hyperthermia (WBH) has a unique potential to increase chemotherapy efficacy against systemic disease; however, a narrow therapeutic index has limited its widespread clinical application. Optimization of the combination schedule of WBH with drugs to enhance the therapeutic index has heretofore been a trial and error approach. An objective biological marker to guide the combination schedule is needed. The applicant and others have observed that WBH, as well as 5- fluorouracil (5- FU), enhance the ability of tumor cells to die via apoptosis (programmed cell death). The applicant hypothesizes that agent-induction of apoptosis and/or necrosis is critical to the ultimate response of tumor and normal tissue. She further theorizes that combined modality therapy can be optimized by scheduling a drug with WBH, guided by the differential capacity of the two agents to induce apoptosis and/or necrosis in tumor compared to normal tissues. To test these hypotheses, the applicant proposes to examine the results of various intravenous infusional (PIF) 5-FU with both long-duration, low- temperature WBH (LL-WBH, 40.0 degrees C for 8 hours) and short-duration, high-temperature WBH (SH-WBH, 41.5 degrees C for 2 hours) using the rat Ward colon carcinoma in vivo. She will first determine whether there is a measurable difference in drug- and heat-induced apoptosis and/or necrosis between tumor and normal tissue (the gut and hematological systems) by quantitating the kinetic parameters of apoptosis and/or necrosis (e.g. time of onset, peak and duration) induced by the individual agents. She will then try to exploit differences in tumor and normal tissue apoptosis/necrosis parameters to guide combination schedules. Based on her preliminary data, she will schedule combinations of 5-FU/WBH using peaks of apoptosis as guides, quantitating resultant combination-induced parameters of apoptosis/necrosis in tumor and normal tissues. She will correlate the kinetic parameters with the therapeutic index. She will then determine whether, in the optimized regimen, apoptosis and/or necrosis can be additionally altered by an apoptosis/necrosis-modifying agent, recombinant human tumor necrosis factor-alpha.