Giaccone G, Linn S C, Welink J, Catimel G, Stieltjes H, van der Vijgh W J, Eeltink C, Vermorken J B, Pinedo H M
Department of Medical Oncology, University Hospital Vrije, HV 1081 Amsterdam, The Netherlands.
Clin Cancer Res. 1997 Nov;3(11):2005-15.
Forty-two patients with advanced solid tumors were entered into a dose-finding study of the combination of doxorubicin with the cyclosporin analogue SDZ PSC 833 (PSC), given by oral route. Patients received PSC at escalating doses, ranging from 2.5 to 25 mg/kg/day, for 5 days, in doses given every 12 h. Doxorubicin was given by i.v. push on day 3 of PSC administration, 4 h after the morning dose of PSC. Pharmacokinetic analyses of PSC and doxorubicin were performed. A total of 38 patients received a combination of PSC and doxorubicin, and 27 received doxorubicin alone in the first course. The major toxicity of the combination was hematological and was significantly more severe than that with doxorubicin alone; severe myelosuppression was already observed at the first PSC dose level, which required doxorubicin dose reduction from 50 to 35 mg/m2. At all dose levels of PSC, up to 17.5 mg/kg/day, there were at least two patients with grade 3 or 4 hematological toxicity, which was manageable in less heavily pretreated patients. A further PSC dose escalation was performed to 25 mg/kg/day, together with doxorubicin, at a further reduced dose of 20 mg/m2. At this dose, central nervous system toxicity became the most relevant side effect. The increase of toxicity in the combined treatment was supported by a significant increase of the area under the plasma concentration-time curve to infinity of doxorubicin (54%) and a 10-fold increase of the area under the plasma concentration-time curve to infinity of doxorubicinol. The pharmacological interaction was not dependent on the plasma concentration of PSC. The total body clearance of doxorubicin decreased by 30%. PSC plasma concentrations of >1 microM at the time of doxorubicin administration were, in general, found at a dose of 7.5 mg/kg/day or higher. One patient had a partial response. In conclusion, PSC plasma concentrations that can revert multidrug resistance in experimental models could be achieved in patients who have solid tumors and who are treated with doxorubicin. However, a marked pharmacological interaction was found between doxorubicin and PSC, which led to substantial increase in hematological toxicity and required marked reduction of the doxorubicin dose. Further study of PSC may be warranted, in association with the investigation of P-glycoprotein expression and concentration of drugs in the tumor tissues.
42例晚期实体瘤患者进入一项阿霉素与环孢素类似物SDZ PSC 833（PSC）联合用药的剂量探索研究，采用口服给药。患者接受剂量递增的PSC，范围为2.5至25mg/kg/天，持续5天，每12小时给药一次。阿霉素在PSC给药第3天上午剂量后4小时静脉推注。对PSC和阿霉素进行了药代动力学分析。共有38例患者接受了PSC与阿霉素的联合治疗，27例患者在第一个疗程中单独接受了阿霉素治疗。联合用药的主要毒性为血液学毒性，且明显比单独使用阿霉素时更严重；在PSC的第一个剂量水平就已观察到严重的骨髓抑制，这需要将阿霉素剂量从50mg/m²降至35mg/m²。在PSC的所有剂量水平，直至17.5mg/kg/天，至少有两名患者出现3级或4级血液学毒性，在预处理较轻的患者中这种毒性是可控的。进一步将PSC剂量递增至25mg/kg/天，同时将阿霉素剂量进一步降至20mg/m²。在此剂量下，中枢神经系统毒性成为最主要的副作用。联合治疗中毒性的增加得到了阿霉素血浆浓度-时间曲线下面积至无穷大显著增加（54%）以及阿霉素醇血浆浓度-时间曲线下面积至无穷大增加10倍的支持。药物相互作用不依赖于PSC的血浆浓度。阿霉素的总体清除率降低了30%。在阿霉素给药时，PSC血浆浓度>1μM一般出现在剂量为7.5mg/kg/天或更高时。1例患者出现部分缓解。总之，在接受阿霉素治疗的实体瘤患者中，可以达到在实验模型中能逆转多药耐药的PSC血浆浓度。然而，发现阿霉素与PSC之间存在显著的药物相互作用，这导致血液学毒性大幅增加，且需要显著降低阿霉素剂量。可能有必要进一步研究PSC，并结合对P-糖蛋白表达和肿瘤组织中药物浓度的研究。
