Reynolds C P, Lemons R S
Developmental Therapeutics Section, Division of Hematology-Oncology, Children's Hospital of Los Angeles, University of Southern California, Keck School of Medicine, Los Angeles, California, USA.
Hematol Oncol Clin North Am. 2001 Oct;15(5):867-910. doi: 10.1016/s0889-8588(05)70256-2.
In vitro studies that showed RA could cause growth arrest and differentiation of myelogenous leukemia and neuroblastoma led to clinical trials of retinoids in APL and neuroblastoma that increased survival for both of those diseases. In the case of APL, ATRA has been the drug of choice, and preclinical and clinical data support direct combinations of ATRA with cytotoxic chemotherapy. For neuroblastoma, a phase I study defined a dose of 13-cis-RA, which was tolerable in patients after myeloablative therapy, and a phase III trial that showed postconsolidation therapy with 13-cis-RA improved EFS for patients with high-risk neuroblastoma. Preclinical studies in neuroblastoma indicate that ATRA or 13-cis-RA can antagonize cytotoxic chemotherapy and radiation, so use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. A limitation on the antitumor benefit of ATRA in APL is the marked decrease in drug levels that occurs during therapy as a result of induction of drug metabolism, resulting in a shorter drug half-life and decreased plasma levels. Although early studies sought to overcome the pharmacologic limitations of ATRA therapy in APL, the demonstration that ATO is active against APL in RA-refractory patients has led to a focus on studies employing ATO. Use of 13-cis-RA in neuroblastoma has avoided the decreased plasma levels seen with ATRA. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cis-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase I trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development.
体外研究表明，维甲酸（RA）可导致骨髓性白血病和神经母细胞瘤生长停滞并分化，这促使针对急性早幼粒细胞白血病（APL）和神经母细胞瘤开展了维甲酸类药物的临床试验，结果这两种疾病的生存率均有所提高。就APL而言，全反式维甲酸（ATRA）一直是首选药物，临床前和临床数据均支持将ATRA与细胞毒性化疗直接联合使用。对于神经母细胞瘤，一项I期研究确定了13 - 顺式维甲酸的剂量，该剂量在清髓治疗后的患者中是可耐受的，一项III期试验表明，对高危神经母细胞瘤患者进行巩固治疗后使用13 - 顺式维甲酸可改善无事件生存期（EFS）。神经母细胞瘤的临床前研究表明，ATRA或13 - 顺式维甲酸可拮抗细胞毒性化疗和放疗，因此在神经母细胞瘤中，13 - 顺式维甲酸的使用仅限于细胞毒性化疗和放疗完成后的维持治疗。ATRA在APL中抗肿瘤疗效的一个局限性是，治疗期间由于药物代谢的诱导，药物水平显著下降，导致药物半衰期缩短和血浆水平降低。尽管早期研究试图克服ATRA治疗APL的药理学局限性，但三氧化二砷（ATO）对维甲酸难治性APL患者有效的证明，使得研究重点转向了使用ATO的研究。在神经母细胞瘤中使用13 - 顺式维甲酸避免了出现ATRA时所见到的血浆水平下降情况。神经母细胞瘤在13 - 顺式维甲酸治疗期间或之后出现的复发性疾病，很可能是由于肿瘤细胞对维甲酸介导的分化诱导产生了耐药性。对13 - 顺式维甲酸和ATRA耐药的神经母细胞瘤细胞系研究表明，它们可能对细胞毒性维甲酸芬维A胺敏感，在某些情况下还对其侧支超敏。芬维A胺诱导肿瘤细胞产生细胞毒性而非分化，其作用独立于维甲酸受体，在最初的I期试验中耐受性良好。芬维A胺单独使用以及与神经酰胺调节剂联合使用的临床试验正在开展中。
