Fuhrman G M, Cromeens D M, Newman R A, Cleary K R, Carrasco C H, Wright K C, Guercio S, Guercio A, Curley S A
Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Surg Oncol. 1994 Feb;3(1):17-25. doi: 10.1016/0960-7404(94)90020-5.
Tumour resistance to chemotherapeutic drugs through expression of the multidrug resistance phenotype is a major impediment in the treatment of hepatic malignancies. We performed hepatic arterial infusion of verapamil (at a dose known to block P-glycoprotein activity) and doxorubicin combined with complete hepatic venous isolation and extracorporeal chemofiltration in non-tumour-bearing pigs with normal livers to evaluate the pharmacology and toxicology of this drug combination. The complete hepatic venous isolation-chemofiltration system significantly reduced system exposure to both verapamil and doxorubicin (P < 0.01). Hepatic arterial infusion of verapamil (2 mg/kg) alone did not result in hepatocellular toxicity. However, the combination of verapamil and doxorubicin (3 mg/kg or 5 mg/kg) produced significant elevations in liver enzymes (P < 0.01), and gross histological evidence of liver damage in 90% of the treated animals. The results of this study indicate that hepatic arterial infusion of verapamil and doxorubicin, in an attempt to improve treatment response in unresectable liver tumours expressing the multidrug resistance phenotype, may not be tolerated by patients with limited hepatic reserve.
肿瘤通过表达多药耐药表型对化疗药物产生抗性是肝恶性肿瘤治疗中的主要障碍。我们在肝脏正常的非荷瘤猪中进行了维拉帕米（以已知可阻断P-糖蛋白活性的剂量）和阿霉素的肝动脉灌注，并结合完全肝静脉隔离和体外化学滤过，以评估这种药物组合的药理学和毒理学。完全肝静脉隔离-化学滤过系统显著降低了维拉帕米和阿霉素的全身暴露量（P < 0.01）。单独肝动脉灌注维拉帕米（2 mg/kg）未导致肝细胞毒性。然而，维拉帕米和阿霉素（3 mg/kg或5 mg/kg）联合使用导致肝酶显著升高（P < 0.01），并且在90%的受试动物中出现了肝脏损伤的大体组织学证据。本研究结果表明，试图改善对表达多药耐药表型的不可切除肝肿瘤的治疗反应而进行的维拉帕米和阿霉素肝动脉灌注，肝储备有限的患者可能无法耐受。
