Clifford J L, Sabichi A L, Zou C, Yang X, Steele V E, Kelloff G J, Lotan R, Lippman S M
Department of Clinical Cancer Prevention The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Epidemiol Biomarkers Prev. 2001 Apr;10(4):391-5.
Superficial bladder cancer is a major target for chemoprevention. Retinoids are important modulators of epithelial differentiation and proliferation and are effective in the treatment and prevention of several epithelial cancers. One class of compounds, the retinamides, is structurally similar to other retinoids but have the added feature of being potent apoptosis inducers. Among these, fenretinide (N-[4-hydroxyphenyl]retinamide), or 4HPR, has promise for bladder cancer chemoprevention and is currently under Phase III study in this setting. In addition to 4HPR, there are several new structurally related phenylretinamides bearing hydroxyl, carboxyl, or methoxyl residues on carbons 2, 3, and 4 of the terminal phenylamine ring [designated N-(2-hydroxyphenyl)retinamide, N-(3-hydroxyphenyl)retin amide, N-(2-carboxyphenyl)retin- amide, N-(3-carboxyphenyl)retin amide, N-(4-carboxy- phenyl)retinamide, and N-(4-methoxyphenyl)retinamide, respectively]. The objective of this study was to compare the growth inhibitory and apoptotic effects of these phenylretinamides with 4HPR in human bladder transitional cell cancer-derived cell lines of varying histological grade (RT4, grade 1; UM-UC9 and UM-UC10, grade 3; and UM-UC14, grade 4) by cell counting, cell cycle fluorescence-activated cell sorter analysis and a dual stain apoptosis assay. All of the seven phenylretinamides reduced cell number, altered the cell cycle distribution, and induced apoptosis when administered at a concentration of 10 microM, which is within the pharmacologically achievable range. Although the relative potencies of the phenylretinamides varied depending on the cell line, N-(3-hydroxy phenyl)retin- amide was the most active with significantly greater growth inhibition than 4HPR in all of the four cell lines. These in vitro findings warrant further study of these novel phenylretinamides, which may have potential as preventive or therapeutic agents in transitional cell cancer.
浅表性膀胱癌是化学预防的主要目标。维甲酸是上皮细胞分化和增殖的重要调节剂，在多种上皮性癌症的治疗和预防中有效。一类化合物，视黄酰胺，在结构上与其他维甲酸相似，但具有强效凋亡诱导剂这一额外特性。其中，芬维A胺（N-[4-羟基苯基]视黄酰胺），即4HPR，有望用于膀胱癌的化学预防，目前正处于该适应症的III期研究阶段。除了4HPR，还有几种新的结构相关的苯基视黄酰胺，在末端苯胺环的2、3和4位碳原子上带有羟基、羧基或甲氧基残基[分别命名为N-(2-羟基苯基)视黄酰胺、N-(3-羟基苯基)视黄酰胺、N-(2-羧基苯基)视黄酰胺、N-(3-羧基苯基)视黄酰胺、N-(4-羧基苯基)视黄酰胺和N-(4-甲氧基苯基)视黄酰胺]。本研究的目的是通过细胞计数、细胞周期荧光激活细胞分选分析和双染凋亡检测，比较这些苯基视黄酰胺与4HPR对不同组织学分级的人膀胱移行细胞癌衍生细胞系（RT4，1级；UM-UC9和UM-UC10，3级；以及UM-UC14，4级）的生长抑制和凋亡作用。当以10微摩尔的浓度给药时，所有七种苯基视黄酰胺均减少了细胞数量，改变了细胞周期分布并诱导了凋亡，该浓度在药理学可达到的范围内。尽管苯基视黄酰胺的相对效力因细胞系而异，但N-(3-羟基苯基)视黄酰胺活性最高，在所有四个细胞系中均具有比4HPR显著更强的生长抑制作用。这些体外研究结果值得对这些新型苯基视黄酰胺进行进一步研究，它们可能具有作为移行细胞癌预防或治疗药物的潜力。
