Fenretinide activity in retinoid-resistant oral leukoplakia
Fenretinide activity in retinoid-resistant oral leukoplakia
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DOI：
10.1158/1078-0432.ccr-05-2636
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发表时间：
2006-05-15
影响因子：
11.5
通讯作者：
Lotan, R
中科院分区：
文献类型：
--
作者：
Lippman, SM;Lee, JJ;Lotan, R
目的：验证维甲酸N-（4-羟基苯基）维甲酸（芬维甲酸）在天然类维甲酸耐药口腔白斑患者中可能通过受体不依赖的细胞凋亡和受体依赖作用发挥临床活性的假设，这是该假设在任何体内环境中的首次验证。实验设计：一项II期试验，在口服白斑患者中使用芬维甲酸（200mg /d，疗程3个月），这些患者对之前的天然类维生素A治疗没有反应（从头耐药）或有反应后复发（获得性耐药）。我们通过末端脱氧核苷酸转移酶介导的缺口末端标记原位DNA片段分析细胞凋亡。结果：我们收集了35例可评估的类维甲酸耐药口腔白斑患者，12例（34.3%）对芬维甲酸有部分反应（95%置信区间，19.2-52.4%），反应与对天然类维甲酸获得性耐药相关（P = 0.015， Fisher精确检验）。9名应答者在停用芬瑞啶的9个月内出现进展。毒性很小，依从性很好。平均凋亡值（SE）从基线时的0.35%（0.25%）上升至3个月时的1.18% (0.64%)（P = 0.001，符号检验）；这种增加与临床反应无关。3个月平均血清芬维甲酸（0.23 μ mol/L）和N-（4-甲氧基苯基）维甲酸（0.57 μ mol/L）浓度升高与视黄醇浓度降低相关[Spearman相关系数分别为-0.57 （P = 0.001）和-0.43 (P = 0.01)]。结论：低剂量芬维甲酸在类维甲酸耐药口腔白斑中具有临床活性，且细胞凋亡有小幅增加。
Purpose: To test the hypothesis that the retinamide N- (4-hydroxyphenyl)retinamide (fenretinide) would be clinically active potentially via receptor-independent apoptosis and receptor-dependent effects in natural retinoid-resistant oral leukoplakia patients-the first test of this hypothesis in any in vivo setting.Experimental Design: A phase II trial of fenretinide (200 mg/d for 3 months) in oral leukoplakia patients who had not responded (de novo resistance) or who had responded and then relapsed (acquired resistance) to previous treatment with natural retinoids. We analyzed apoptosis via the terminal deoxynucleotidyl transferase - mediated nick end labeling in situ DNA fragmentation assay.Results: We accrued 35 evaluable patients with retinoid-resistant oral leukoplakia, 12 (34.3%) had partial responses to fenretinide (95% confidence interval, 19.2-52.4%), and response was associated with acquired resistance to natural retinoids (P = 0.015, Fisher's exact test). Nine responders progressed within 9 months of stopping fenretinide. Toxicity was minimal and compliance was excellent. Mean apoptosis values (SE) increased from 0.35% (0.25%) at baseline to 1.18% (0.64%) at 3 months (P = 0.001, sign test); this increase did not correlate with clinical response. The increases in 3-month mean serum concentrations of fenretinide (0.23 mu mol/L) and N- (4-methoxyphenyl)retinamide (0.57 mu mol/L) correlated with decreased retinol concentrations [Spearman correlation coefficient of -0.57 (P = 0.001) and -0.43 (P = 0.01), respectively].Conclusions: Low-dose fenretinide was clinically active and produced a small increase in apoptosis in retinoid-resistant oral leukoplakia.