Pestieau S R, Stuart O A, Chang D, Jacquet P, Sugarbaker P H
The Washington Cancer Institute, Washington Hospital Center, Washington, DC 20010, USA.
Tumori. 1998 Nov-Dec;84(6):706-11. doi: 10.1177/030089169808400619.
Gemcitabine (2'-2' difluorodeoxycytidine) has been shown to possess a broad spectrum of antitumor activity against various malignancies, particularly pancreatic carcinoma. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal (i.p.) chemotherapy over intravenous (i.v.) chemotherapy is the high drug concentration that can be achieved locally. In addition, the cytotoxic effect of several anticancer agents can be enhanced by hyperthermia. Using a rat model, this study was designed to compare i.p. vs i.v. gemcitabine and to evaluate the effect of hyperthermia on i.p. gemcitabine.
In the first phase of this study, 18 Sprague Dawley rats were given a single dose of gemcitabine then randomized into three groups according to dose and route of delivery of chemotherapy (12.5 mg/kg--i.v., 12.5 mg/kg--i.p. or 125 mg/kg--i.p.). In a separate experiment (phase 2), 12 Sprague Dawley rats were given a continuous i.p. perfusion of gemcitabine (12.5 mg/kg in 150 mL total perfusate) and randomized into two groups according to the temperature of the peritoneal perfusate (normothermic or hyperthermic). During the course of both experiments, peritoneal fluid and blood were sampled using a standardized protocol. At the end of the procedure the rats were sacrificed and all urine was extracted. Selected tissue samples were taken from rats in the second phase of the study. The concentration of gemcitabine in all samples was determined by high performance liquid chromatography (HPLC).
When gemcitabine was delivered at 12.5 mg/kg (phase 1) the area under the curve (AUC) was significantly higher with i.p. administration as compared to i.v. administration (P = 0.001). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 12.5+/-3.2 for i.p. delivery as opposed to 0.2+/-0.2 for i.v. delivery (P = 0.0002). The AUC ratio for i.p. gemcitabine at 125 mg/kg was 26.8+/-5.8. Although there was no significant difference in drug concentrations between samples from the normothermic and hyperthermic groups, all tissue samples (except stomach) in the hyperthermic group exhibited increased gemcitabine concentrations.
These experiments demonstrated that the exposure of peritoneal surfaces to gemcitabine is significantly increased with i.p. gemcitabine. Intraabdominal hyperthermia had no significant effect on the pharmacokinetics of i.p. gemcitabine but there was evidence of increased absorption of gemcitabine in most intraabdominal tissues. Due to the likelihood of a high incidence of microscopic residual disease after resection of a pancreatic carcinoma, clinical studies to evaluate i.p. hyperthermic gemcitabine may be indicated.
吉西他滨（2'-2'二氟脱氧胞苷）已显示出对多种恶性肿瘤具有广泛的抗肿瘤活性，尤其是胰腺癌。对于发生在腹腔内的癌症，腹腔内（i.p.）化疗相对于静脉内（i.v.）化疗的优势在于可以在局部实现高药物浓度。此外，热疗可增强几种抗癌药物的细胞毒性作用。本研究使用大鼠模型，旨在比较腹腔内与静脉内给予吉西他滨，并评估热疗对腹腔内给予吉西他滨的影响。
在本研究的第一阶段，给18只Sprague Dawley大鼠单次给予吉西他滨，然后根据化疗的剂量和给药途径随机分为三组（12.5mg/kg——静脉内、12.5mg/kg——腹腔内或125mg/kg——腹腔内）。在另一个单独的实验（第二阶段）中，给12只Sprague Dawley大鼠持续腹腔内灌注吉西他滨（12.5mg/kg，共150mL灌注液），并根据腹腔灌注液的温度（常温或热疗）随机分为两组。在两个实验过程中，使用标准化方案采集腹腔液和血液样本。实验结束时处死大鼠并提取所有尿液。从研究第二阶段的大鼠中采集选定的组织样本。通过高效液相色谱法（HPLC）测定所有样本中吉西他滨的浓度。
当以12.5mg/kg给予吉西他滨时（第一阶段），腹腔内给药的曲线下面积（AUC）与静脉内给药相比显著更高（P = 0.001）。腹腔内给药的AUC比值（AUC腹腔液/AUC血浆）为12.5±3.2，而静脉内给药为0.2±0.2（P = 0.0002）。125mg/kg腹腔内给予吉西他滨的AUC比值为26.8±5.8。尽管常温组和热疗组样本之间的药物浓度没有显著差异，但热疗组的所有组织样本（除胃外）吉西他滨浓度均升高。
这些实验表明，腹腔内给予吉西他滨可显著增加腹腔表面对吉西他滨的暴露。腹腔内热疗对腹腔内给予吉西他滨的药代动力学没有显著影响，但有证据表明大多数腹腔内组织中吉西他滨的吸收增加。由于胰腺癌切除术后微小残留疾病的发生率可能较高，因此可能需要进行评估腹腔内热疗吉西他滨的临床研究。
