Mohamed Faheez, Stuart O Anthony, Glehen Olivier, Urano Muneyasu, Sugarbaker Paul H
The Washington Cancer Institute, Washington Hospital Center, 106 Irving Street, NW, # 3900N, Washington, DC 20010, USA.
Cancer Chemother Pharmacol. 2006 Dec;58(6):719-24. doi: 10.1007/s00280-006-0229-2. Epub 2006 Apr 14.
Hyperthermia enhances the cytotoxicity of some chemotherapeutic agents. Both clinical and laboratory studies suggest melphalan may be an important drug when hyperthermia is added to chemotherapy treatments. Factors that may modify the thermal enhancement of melphalan were studied to optimize its clinical use with hyperthermia.
The tumor studied was an early-generation isotransplant of a spontaneous C3Hf/Sed mouse fibrosarcoma, Fsa-II. All studies were performed under supervision of the Animal Care and Use Committee. Hyperthermia was administered by immersing the tumor-bearing foot into a constant temperature water bath. Four factors were studied: duration of hyperthermia, sequencing of hyperthermia and melphalan, intensity of hyperthermia, and tumor size. To study duration of hyperthermia tumors were treated at 41.5 degrees C for 30 or 90 min immediately after intraperitoneal administration of melphalan. For sequencing of hyperthermia and melphalan, animals received hyperthermia treatment of tumors for 30 min at 41.5 degrees C immediately after drug administration, both immediately and 3 h after administration of drug or only at 3 h after administration of drug. Intensity of hyperthermia was studied using heat treatment of tumors for 30 min at 41.5 or 43.5 degrees C immediately following drug administration. Effect of tumor size was studied by delaying experiments until three times the tumor volume (113 mm3) was observed. Treatment of tumors was for 30 min at 41.5 degrees C immediately following drug administration. Tumor response was studied by the mean tumor growth time.
Hyperthermia in the absence of melphalan had a small but significant effect on tumor growth time at 43.5 degrees C but not at 41.5 degrees C. Hyperthermia at 41.5 degrees C immediately after melphalan administration doubled mean tumor growth time at 30 min and caused a threefold increase at 90 min (P=0.0002) when compared to tumors treated with melphalan alone at room temperature. Application of hyperthermia for one-half hour immediately following drug administration was the most effective in delaying tumor growth. No significant difference in mean tumor growth time was observed with an increase in temperature from 41.5 to 43.5 degrees C. For large tumors heat alone and melphalan alone caused a moderate increase in tumor growth delay. These effects in large tumors were greatly increased by a combination of chemotherapy and hyperthermia.
From our data it would appear that the administration of intraperitoneal melphalan immediately prior to 90 min of heat at 41.5 degrees C may optimize anti-neoplastic activity. These data may be useful in formulating clinical protocols in which melphalan and heat are combined.
热疗可增强某些化疗药物的细胞毒性。临床和实验室研究均表明，当热疗与化疗联合应用时，美法仑可能是一种重要药物。为优化美法仑与热疗联合的临床应用，对可能影响美法仑热增强作用的因素进行了研究。
所研究的肿瘤是自发C3Hf/Sed小鼠纤维肉瘤Fsa-II的早期同基因移植瘤。所有研究均在动物护理与使用委员会的监督下进行。通过将荷瘤足浸入恒温水浴中进行热疗。研究了四个因素：热疗持续时间、热疗与美法仑的给药顺序、热疗强度和肿瘤大小。为研究热疗持续时间，在腹腔注射美法仑后立即将肿瘤在41.5℃下处理30或90分钟。对于热疗与美法仑的给药顺序，动物在给药后立即、给药后立即和3小时或仅在给药后3小时接受在41.5℃下对肿瘤进行30分钟的热疗。在给药后立即使用41.5或43.5℃对肿瘤进行30分钟的热处理来研究热疗强度。通过将实验推迟至观察到肿瘤体积增大至三倍（113立方毫米）来研究肿瘤大小的影响。在给药后立即在41.5℃下对肿瘤进行3分钟的处理。通过平均肿瘤生长时间来研究肿瘤反应。
在无美法仑的情况下，43.5℃的热疗对肿瘤生长时间有微小但显著的影响，而41.5℃时则无影响。与在室温下仅用美法仑治疗的肿瘤相比，在美法仑给药后立即进行41.5℃的热疗使平均肿瘤生长时间在30分钟时加倍，在90分钟时增加了两倍（P = 0.0002）。给药后立即进行半小时的热疗在延迟肿瘤生长方面最有效。温度从4上升到43.5℃时，平均肿瘤生长时间无显著差异。对于大肿瘤，单纯热疗和单纯美法仑均使肿瘤生长延迟有适度增加。化疗与热疗联合可使大肿瘤的这些作用大大增强。
从我们的数据来看，在41.5℃下进行90分钟热疗之前立即腹腔注射美法仑可能会优化抗肿瘤活性。这些数据可能有助于制定美法仑与热疗联合的临床方案。
