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.
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