Wiedemann G J, Siemens H J, Mentzel M, Biersack A, Wössmann W, Knocks D, Weiss C, Wagner T
Department of Internal Medicine, Medical University of Lübeck, Germany.
Cancer Res. 1993 Sep 15;53(18):4268-72.
The influence of tumor temperature (28, 32, 37, 39, 41, or 43 degrees C for 1 h) on the therapeutic efficacy of i.v. single bolus injections of ifosfamide (IFO) (32, 65, 125, or 250 mg/kg body weight) in human tumor xenografts (MX1 breast carcinoma) grown in nude mice (n = 240) was studied. Tumor temperature was controlled by water bath immersion. Sixty days after treatment the percentage of tumor-free survival was determined. For example, at 37 degrees C IFO in a dose of 65 mg/kg body weight led to 10% tumor-free survival in the treated animals. At 43 degrees C the same dose resulted in 60% tumor-free survival. A clear drug dose- and temperature-dependent increase of the therapeutic efficacy of an active oxazaphosphorine compound was also demonstrated in vitro. The concentrations of IFO and of 4-hydroxyifosfamide in blood and tumors at different body temperatures (controlled by water bath immersion) were determined over 120 min and WBC counts were obtained. The half-lives and the areas under the curve for IFO in blood were not significantly different at 37 degrees C and 41 degrees C. Since the half-life of IFO depends mainly on hepatic metabolism, the similarity of half-lives and of areas under the curve for IFO at 37 degrees C and 41 degrees C indicates a constant activation rate. However, significantly lower plasma concentrations of the activated drug at a liver (body) temperature of 41 degrees C, compared with 37 degrees C, were found, indicating a higher elimination rate. The concentration of the activated drug in the tumors within the initial 60 min at 41 degrees C, however, exceeded by > 2-fold that at 37 degrees C. The bone marrow toxicity of the same drug dose did not significantly increase with body temperature.
研究了肿瘤温度（28、32、37、39、41或43摄氏度，持续1小时）对静脉单次大剂量注射异环磷酰胺（IFO）（32、65、125或250毫克/千克体重）治疗裸鼠（n = 240）体内人肿瘤异种移植瘤（MX1乳腺癌）疗效的影响。通过水浴浸泡控制肿瘤温度。治疗60天后测定无瘤生存率。例如，在37摄氏度时，65毫克/千克体重剂量的IFO使治疗动物的无瘤生存率达到10%。在43摄氏度时，相同剂量导致60%的无瘤生存率。体外实验也证明了活性氧氮磷杂环化合物的治疗效果明显呈现药物剂量和温度依赖性增加。在120分钟内测定了不同体温（通过水浴浸泡控制）下血液和肿瘤中IFO及4-羟基异环磷酰胺的浓度，并获取了白细胞计数。37摄氏度和41摄氏度时，IFO在血液中的半衰期和曲线下面积无显著差异。由于IFO的半衰期主要取决于肝脏代谢，37摄氏度和41摄氏度时IFO半衰期及曲线下面积的相似性表明活化速率恒定。然而，发现41摄氏度肝脏（身体）温度下活化药物的血浆浓度明显低于37摄氏度时，这表明消除速率更高。然而，41摄氏度时最初60分钟内肿瘤中活化药物的浓度比37摄氏度时高出2倍以上。相同药物剂量的骨髓毒性并未随体温显著增加。
