Brewer Molly, Wharton J Taylor, Wang Jian, McWatters Amanda, Auersperg Nelly, Gershenson David, Bast Robert, Zou Changping
Department of Gynecologic Oncology, University of Texas, The M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Gynecol Oncol. 2005 Aug;98(2):182-92. doi: 10.1016/j.ygyno.2005.01.051.
Epithelial ovarian cancer has the highest mortality rate among the gynecologic cancers. The synthetic retinoid, N-(4-hydroxyphenyl) retinamide (4-HPR), has been used in the chemoprevention of ovarian cancer. However, the effectiveness of its application for different populations has been questioned because of the genetic differences among normal, high risk, and women with cancer.
To explore the similarities and the differences in 4-HPR effects on different ovarian epithelial cells which mimic different populations of women, normal ovarian surface epithelium to represent the normal population of women, immortalized ovarian surface epithelium to represent premalignant changes, and cells derived from ovarian cancer cells to represent malignant changes were used as in vitro models.
Normal ovarian surface epithelial cells, immortalized ovarian surface epithelial cells, and ovarian cancer cells were incubated for different intervals with increasing concentrations of 4-HPR. Growth inhibition, the fraction of apoptotic cells, the expression of apoptosis-related genes, including p53, p16, p21, and caspase-3, and mitochondrial permeability transition were measured before and after 4-HPR treatment.
Treatment with 4-HPR produced growth inhibition and apoptosis in a dose-dependent manner for all 3 cell types. 4-HPR produced the strongest activation of the p53 pathway in normal ovarian epithelial (NOE) cells, while it caused the largest increase in MPT in the cancer cells, suggesting a different mechanism for growth inhibition and/or apoptosis in these cell lines. 4-HPR, at a concentration of 10 muM, had a maximal effect on caspase-3 activity at 72 h in normal cells and at 48 h in immortalized and cancer cells, although the effects were modest.
Normal ovarian surface epithelial cells, immortalized ovarian surface epithelial cells, and ovarian cancer cells showed a differential response to 4-HPR. Although the same endpoints of growth inhibition and apoptosis induction were present in response to 4-HPR, these endpoints may be regulated through different pathways.
Clinical trials with higher concentrations of 4-HPR should prove beneficial.
上皮性卵巢癌在妇科癌症中死亡率最高。合成维甲酸N-(4-羟苯基)视黄酰胺（4-HPR）已用于卵巢癌的化学预防。然而，由于正常人群、高危人群和癌症女性之间的基因差异，其在不同人群中的应用效果受到质疑。
为探讨4-HPR对模拟不同女性群体的不同卵巢上皮细胞的作用异同，采用体外模型，以正常卵巢表面上皮代表正常女性群体，永生化卵巢表面上皮代表癌前病变，卵巢癌细胞衍生细胞代表恶性病变。
将正常卵巢表面上皮细胞、永生化卵巢表面上皮细胞和卵巢癌细胞与浓度递增的4-HPR孵育不同时间。在4-HPR处理前后，测量生长抑制、凋亡细胞比例、凋亡相关基因（包括p53、p16、p21和caspase-3）的表达以及线粒体通透性转换。
4-HPR处理对所有3种细胞类型均产生剂量依赖性的生长抑制和凋亡。4-HPR在正常卵巢上皮（NOE）细胞中对p53途径的激活最强，而在癌细胞中引起最大的线粒体通透性转换增加，提示这些细胞系中生长抑制和/或凋亡的机制不同。4-HPR浓度为10μM时，对正常细胞72小时、永生化细胞和癌细胞48小时的caspase-3活性有最大影响，尽管影响较小。
正常卵巢表面上皮细胞、永生化卵巢表面上皮细胞和卵巢癌细胞对4-HPR表现出不同反应。尽管4-HPR诱导生长抑制和凋亡的终点相同，但这些终点可能通过不同途径调节。
更高浓度4-HPR的临床试验应证明是有益的。
