Advani R, Saba H I, Tallman M S, Rowe J M, Wiernik P H, Ramek J, Dugan K, Lum B, Villena J, Davis E, Paietta E, Litchman M, Sikic B I, Greenberg P L
Stanford University Medical Center, Stanford, CA, USA.
Blood. 1999 Feb 1;93(3):787-95.
A potential mechanism of chemotherapy resistance in acute myeloid leukemia (AML) is the multidrug resistance (MDR-1) gene product P-glycoprotein (P-gp), which is often overexpressed in myeloblasts from refractory or relapsed AML. In a multicenter phase II clinical trial, 37 patients with these poor risk forms of AML were treated with PSC 833 (Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ), a potent inhibitor of the MDR-1 efflux pump, plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). Pharmacokinetic (PK) interactions of etoposide and mitoxantrone with PSC were anticipated, measured in comparison with historical controls without PSC, and showed a 57% decrease in etoposide clearance (P =.001) and a 1.8-fold longer beta half-life for mitoxantrone in plasma (P <.05). The doses of mitoxantrone and etoposide were substantially reduced to compensate for these interactions and clinical toxicity and in Cohort II were well tolerated at dose levels of 4 mg/m2 mitoxantrone, 40 mg/m2 etoposide, and 1 g/m2 C daily for 5 days. Overall, postchemotherapy marrow hypoplasia was achieved in 33 patients. Twelve patients (32%) achieved complete remission, four achieved partial remission, and 21 failed therapy. The PK observations correlated with enhanced toxicity. The probability of an infectious early death was 36% (4 of 11) in patients with high PK parameters for either drug versus 5% (1 of 20) in those with lower PK parameters (P =.04). P-gp function was assessed in 19 patients using rhodamine-123 efflux and its inhibition by PSC. The median percentage of blasts expressing P-gp was increased (49%) for leukemic cells with PSC-inhibitable rhodamine efflux compared with 17% in cases lacking PSC-inhibitable efflux (P =.004). PSC-MEC was relatively well tolerated in these patients with poor-risk AML, and had encouraging antileukemic effects. The Eastern Cooperative Oncology Group is currently testing this regimen versus standard MEC chemotherapy in a phase III trial, E2995, in a similar patient population.
急性髓系白血病（AML）化疗耐药的一种潜在机制是多药耐药（MDR-1）基因产物P-糖蛋白（P-gp），其在难治性或复发性AML的成髓细胞中常过度表达。在一项多中心II期临床试验中，37例具有这些不良风险形式AML的患者接受了PSC 833（伏司朴达；诺华制药公司，新泽西州东哈嫩）治疗，PSC 833是一种强效的MDR-1外排泵抑制剂，联合米托蒽醌、依托泊苷和阿糖胞苷（PSC-MEC）。预期并测量了依托泊苷和米托蒽醌与PSC的药代动力学（PK）相互作用，与无PSC的历史对照相比，依托泊苷清除率降低了57%（P = 0.001），米托蒽醌在血浆中的β半衰期延长了1.8倍（P < 0.05）。米托蒽醌和依托泊苷的剂量大幅降低以补偿这些相互作用和临床毒性，在队列II中，剂量水平为米托蒽醌4 mg/m²、依托泊苷40 mg/m²和阿糖胞苷每日1 g/m²共5天时耐受性良好。总体而言，33例患者化疗后出现骨髓发育不全。12例患者（32%）达到完全缓解，4例达到部分缓解，21例治疗失败。PK观察结果与毒性增强相关。两种药物PK参数高的患者感染性早期死亡概率为36%（11例中的4例），而PK参数低的患者为5%（20例中的1例）（P = 0.04）。使用罗丹明-123外排及其被PSC抑制的情况对19例患者的P-gp功能进行了评估。与缺乏PSC可抑制外排的病例中17%相比，具有PSC可抑制罗丹明外排的白血病细胞中表达P-gp的母细胞中位百分比增加（49%）（P = 0.004）。PSC-MEC在这些高危AML患者中耐受性相对良好，并具有令人鼓舞的抗白血病作用。东部肿瘤协作组目前正在一项III期试验E2995中，在类似患者群体中测试该方案与标准MEC化疗的疗效对比。
