Adamson P C
Pharmacology and Experimental Therapeutics Section, National Cancer Institute, Bethesda, MD 20892.
Leukemia. 1994;8 Suppl 3:S22-5.
This review will summarize the rationale for pursuing investigations into the use of retinoids for pediatric patients with cancer, describe the phase I results of all-trans-retinoic acid (ATRA) in children, and discuss the results of a series of preclinical and clinical pharmacokinetic studies of ATRA. The prognosis for children with advanced stage neuroblastoma, the most common extracranial solid tumor of childhood, has remained poor despite significant increases in the intensity of multi-modality therapy. Observations that neuroblastoma has the potential in vivo to differentiate into the more mature neuronal phenotype of a ganglioneuroma or to spontaneously regress, combined with the ability of ATRA to induce differentiation of neuroblastoma cell lines in vitro, suggests that neuroblastoma may be a prime candidate for a retinoid-based approach to differentiation therapy. We previously performed a standard pediatric phase I trial of ATRA and defined the maximum tolerated dose (MTD) in children to be 60 mg/m2/day, significantly lower than the MTD in adult patients. Pharmacokinetic results revealed that the plasma half-life of ATRA was short (45 min) relative to 13-cis-RA (12-24 h), and that plasma drug exposure decreased significantly by day 28 of daily drug administration. Preclinical studies using an i.v. formulation of ATRA in a Rhesus monkey pharmacokinetic model then demonstrated that ATRA is eliminated by a capacity-limited (saturable) process. This elimination process was rapidly induced within the first week of daily i.v. ATRA administration, and suggested that an intermittent schedule of drug administration might allow for down-regulation of the elimination process. These pre-clinical studies formed the basis for investigating whether an intermittent schedule of ATRA administration would allow for repeated periods of relatively higher plasma drug concentrations. Preliminary results of two clinical trials using intermittent schedules of administration suggest that this approach may result in significantly higher plasma drug exposure over time. Plans to study the role of intermittent schedules of ATRA administration in pediatric phase II trials in patients with neuroblastoma are underway.
本综述将总结对癌症患儿使用维甲酸进行研究的理论依据，描述全反式维甲酸（ATRA）在儿童中的I期试验结果，并讨论一系列ATRA的临床前和临床药代动力学研究结果。尽管多模式治疗强度显著增加，但晚期神经母细胞瘤（儿童最常见的颅外实体瘤）患儿的预后仍然很差。有观察表明，神经母细胞瘤在体内有分化为更成熟的神经节神经瘤神经元表型或自发消退的潜力，再加上ATRA在体外诱导神经母细胞瘤细胞系分化的能力，提示神经母细胞瘤可能是基于维甲酸的分化治疗的主要候选对象。我们之前进行了一项标准的儿科ATRA I期试验，并确定儿童的最大耐受剂量（MTD）为60mg/m²/天，显著低于成年患者的MTD。药代动力学结果显示，相对于13-顺式维甲酸（12 - 24小时），ATRA的血浆半衰期较短（45分钟），并且在每日给药第28天时血浆药物暴露量显著下降。随后在恒河猴药代动力学模型中使用静脉注射ATRA制剂进行的临床前研究表明，ATRA通过容量限制（饱和）过程消除。在每日静脉注射ATRA给药的第一周内，这种消除过程迅速诱导产生，这表明间歇性给药方案可能会使消除过程下调。这些临床前研究为研究ATRA间歇性给药方案是否能实现相对较高血浆药物浓度的重复给药周期奠定了基础。两项使用间歇性给药方案的临床试验的初步结果表明，随着时间推移，这种方法可能会导致显著更高的血浆药物暴露量。目前正在计划研究ATRA间歇性给药方案在神经母细胞瘤患儿II期试验中的作用。
