Hsieh T C, Wu J M
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla 10595, USA.
Prostate. 1997 Oct 1;33(2):97-104. doi: 10.1002/(sici)1097-0045(19971001)33:2<97::aid-pros3>3.0.co;2-j.
Although fenretinide (4-HPR) is currently being evaluated in a phase II clinical study for the chemoprevention of prostate cancer [Greenwald et al.: CA 45:31-49, 1995], the mechanism underlying its antineoplastic activity has not been elucidated.
Androgen-dependent human prostatic LNCaP cells cultured with fetal bovine serum (FBS) were treated with 4-HPR and evaluated for effects on cell growth and cell cycle phase distribution, induction of apoptosis, and changes in proliferating cell nuclear antigen (PCNA), prostate-specific antigen (PSA), and androgen receptor (AR) levels.
LNCaP cells treated with 4-HPR for 6 days showed 82-95% suppression of cell growth, with accompanying time- and dose-dependent downregulation of PCNA, a partial arrest in G1 phase of the cell cycle, and a marked increase in the percentage of apoptotic cells. Apoptosis was demonstrated by the characteristic DNA fragmentation pattern seen on agarose gels, and by flow cytometric analysis. 4-HPR-induced prostate-specific phenotype changes included significant downregulated expression of both intracellular and secreted forms of PSA, which were preceded by a reduction of AR expression.
These data suggest that 4-HPR acts as a pleiotropic effector of prostate cell growth and specific gene expression.
尽管目前正在进行一项关于非那瑞提（4-HPR）预防前列腺癌的II期临床研究[格林沃尔德等人：《癌症》45:31 - 49，1995]，但其抗肿瘤活性的潜在机制尚未阐明。
用胎牛血清（FBS）培养的雄激素依赖型人前列腺LNCaP细胞用4-HPR处理，并评估其对细胞生长、细胞周期阶段分布、凋亡诱导以及增殖细胞核抗原（PCNA）、前列腺特异性抗原（PSA）和雄激素受体（AR）水平变化的影响。
用4-HPR处理6天的LNCaP细胞显示细胞生长受到82 - 95%的抑制，同时PCNA呈时间和剂量依赖性下调，细胞周期在G1期部分停滞，凋亡细胞百分比显著增加。通过琼脂糖凝胶上特征性的DNA片段化模式以及流式细胞术分析证实了凋亡。4-HPR诱导的前列腺特异性表型变化包括细胞内和分泌形式的PSA表达均显著下调，且在此之前AR表达降低。
这些数据表明4-HPR是前列腺细胞生长和特定基因表达的多效性效应物。
