Reynolds C Patrick, Matthay Katherine K, Villablanca Judith G, Maurer Barry J
Division of Hematology-Oncology, Children's Hospital of Los Angeles and The University of Southern California Keck School of Medicine, Los Angeles, CA 90054, USA.
Cancer Lett. 2003 Jul 18;197(1-2):185-92. doi: 10.1016/s0304-3835(03)00108-3.
Retinoids are derivatives of vitamin A that include all trans-retinoic acid (ATRA), 13-cis-retinoic acid, (13-cis-RA), and fenretinide (4-HPR). High levels of either ATRA or 13-cis-RA can cause arrest of cell growth and morphological differentiation of human neuroblastoma cell lines, and phase I trials showed that higher and more sustained drug levels were obtained with 13-cis-RA relative to ATRA. A phase III randomized trial showed that high-dose, pulse therapy with 13-cis-RA given after completion of intensive chemoradiotherapy (with or without autologous bone marrow transplantation) significantly improved event-free survival in high-risk neuroblastoma. The cytotoxic retinoid 4-HPR achieved multi-log cell kills in neuroblastoma cell lines resistant to ATRA and 13-cis-RA, and a pediatric phase I trial has shown it to be well tolerated. Cytotoxicity of 4-HPR is mediated at least in part by increasing tumor cell ceramide levels and combining 4-HPR with ceramide modulators increased anti-tumor activity in pre-clinical models. Thus, further clinical trials of 4-HPR in neuroblastoma, and of 4-HPR in combination with ceramide modulators, are warranted.
维甲酸是维生素A的衍生物，包括全反式维甲酸（ATRA）、13-顺式维甲酸（13-cis-RA）和芬维A胺（4-HPR）。高水平的ATRA或13-顺式维甲酸均可导致人神经母细胞瘤细胞系的细胞生长停滞和形态分化，I期试验表明，相对于ATRA，13-顺式维甲酸可获得更高且更持久的药物水平。一项III期随机试验表明，在强化放化疗（有或无自体骨髓移植）完成后给予高剂量脉冲式13-顺式维甲酸治疗，可显著提高高危神经母细胞瘤的无事件生存率。细胞毒性维甲酸4-HPR在对ATRA和13-顺式维甲酸耐药的神经母细胞瘤细胞系中实现了多对数级的细胞杀伤，一项儿科I期试验表明其耐受性良好。4-HPR的细胞毒性至少部分是通过增加肿瘤细胞神经酰胺水平介导的，在临床前模型中，将4-HPR与神经酰胺调节剂联合使用可增强抗肿瘤活性。因此，有必要对4-HPR在神经母细胞瘤中的应用以及4-HPR与神经酰胺调节剂联合应用进行进一步的临床试验。
