Los G, Smals O A, van Vugt M J, van der Vlist M, den Engelse L, McVie J G, Pinedo H M
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam.
Cancer Res. 1992 Mar 1;52(5):1252-8.
The purpose of this study was to optimize the treatment of cancers restricted to the peritoneal cavity by combining i.p. chemotherapy with abdominal hyperthermia. In vitro experiments demonstrated that the uptake of carboplatin into CC531 tumor cells was increased at temperatures higher than 41.5 degrees C at dose levels of 5 and 50% cell kill. Carboplatin-DNA adduct formation and cytotoxicity, however, were already increased at temperatures of about 40 degrees C, indicating that carboplatin-DNA adduct formation and consequently cytotoxicity could be enhanced by mild hyperthermia (temperatures in the range of 39-41.5 degrees C). CC531 tumor bearing rats were treated i.v. and i.p. with carboplatin (6.15 mg/kg) in combination with regional hyperthermia of the abdomen (41.5 degrees C for 1 h). The mean temperature was 41.5 +/- 0.3 degrees C (SD) in the peritoneal cavity and 40.5 +/- 0.3 degrees C in the esophagus. Enhanced platinum concentrations were found in peritoneal tumors (factor 3) and in kidney, liver, spleen, and lung (a factor 2 average), after the combined i.v. or i.p. carboplatin-hyperthermia treatment. Pharmacokinetic data of i.p. CBDCA combined with hyperthermia demonstrated an increased tumor exposure for total and ultrafiltered platinum in plasma. The areas under the concentration x time curve for total platinum at 37 degrees C and 41.5 degrees C were 69 and 210 microM/h, respectively; for ultrafiltered platinum these values were 47 and 173 microM/h. This may have been due to a slower elimination of platinum from the blood at the higher temperature (t1/2 beta for total platinum 99 and 156 min at 37 and 41.5 degrees C, respectively). The direct exposure of the tumor via the peritoneal fluid appeared to diminish, since the area under the curve for total platinum was lower at 41.5 degrees C than at 37 degrees C (576 microM/h versus 1255 microM/h, respectively). Our results indicate that the advantage of adding hyperthermia is caused by an increased drug exposure of the tumor via the circulation. This was supported by the fact that platinum concentrations in peritoneal tumors after carboplatin treatment at elevated temperatures were similar for the i.p. and i.v. routes.
本研究的目的是通过腹腔内化疗与腹部热疗相结合来优化对局限于腹膜腔的癌症的治疗。体外实验表明，在细胞杀伤率为5%和50%的剂量水平下，当温度高于41.5摄氏度时，卡铂在CC531肿瘤细胞中的摄取量会增加。然而，卡铂 - DNA加合物的形成和细胞毒性在约40摄氏度时就已经增加，这表明轻度热疗（温度在39 - 41.5摄氏度范围内）可增强卡铂 - DNA加合物的形成，进而增强细胞毒性。给携带CC531肿瘤的大鼠静脉内和腹腔内注射卡铂（6.15毫克/千克），并对腹部进行区域热疗（41.5摄氏度，持续1小时）。腹腔内平均温度为41.5±0.3摄氏度（标准差），食管温度为40.5±0.3摄氏度。在静脉内或腹腔内联合卡铂 - 热疗后，在腹膜肿瘤中发现铂浓度升高（3倍），在肾脏、肝脏、脾脏和肺中也升高（平均2倍）。腹腔内注射卡铂联合热疗的药代动力学数据表明，血浆中总铂和超滤铂的肿瘤暴露增加。37摄氏度和41.5摄氏度时总铂的浓度 - 时间曲线下面积分别为69和210微摩尔/小时；超滤铂的这些值分别为47和173微摩尔/小时。这可能是由于在较高温度下铂从血液中的消除较慢（总铂的β半衰期在37摄氏度和41.5摄氏度时分别为99和156分钟）。由于41.5摄氏度时总铂的曲线下面积低于37摄氏度时（分别为576微摩尔/小时和1255微摩尔/小时），通过腹膜液对肿瘤的直接暴露似乎减少。我们的结果表明，添加热疗的优势是由于肿瘤通过循环增加了药物暴露。这一事实得到了支持，即在高温下卡铂治疗后，腹膜肿瘤中铂浓度对于腹腔内和静脉内给药途径相似。
