Cobleigh M A
Rush-Presbyterian St. Luke's Medical Center, Chicago, IL.
Leukemia. 1994;8 Suppl 3:S59-63.
Preclinical studies make fenretinide attractive for prevention and treatment of breast cancer. It inhibits mammary gland end bud formation in developing animals. Carcinogen-induced mammary cancer is suppressed by fenretinide, both at early and late stages of carcinogenesis, in young and mature rats. Fenretinide causes regression of invasive rat mammary cancer. Cytostatic activity has been demonstrated against human breast cancer cell lines. Autocrine stimulation of human breast cancer cell lines by tgf-alpha, insulin-like growth factors I and II is significantly abrogated by fenretinide. The human half-life is 24 hours. Absorption is markedly affected by meal content. Serum levels of 1 mM are achieved at doses of 200 mg/day. This dose significantly suppresses serum IGF-I levels in women. This concentration is capable of suppressing human breast cancer growth in vitro. A 3-day drug holiday is given each month in order to restore serum retinol levels. Under these circumstances, fenretinide is well tolerated. A phase III trial evaluating the efficacy of fenretinide for breast cancer prevention in high-risk women has been completed. Tamoxifen enhances the effectiveness of fenretinide in carcinogenesis models. The combination can be safely administered to women. A phase III adjuvant trial of tamoxifen, with or without fenretinide will be conducted in the United States.
临床前研究表明，芬维A胺在乳腺癌的预防和治疗方面具有吸引力。它能抑制发育中动物的乳腺终末芽形成。在年轻和成熟大鼠中，芬维A胺在致癌作用的早期和晚期均能抑制致癌物诱导的乳腺癌。芬维A胺可使侵袭性大鼠乳腺癌消退。已证实其对人乳腺癌细胞系具有细胞生长抑制活性。芬维A胺能显著消除人乳腺癌细胞系中由转化生长因子α、胰岛素样生长因子I和II引起的自分泌刺激。其在人体内的半衰期为24小时。吸收情况受食物成分的显著影响。每日服用200毫克剂量时，血清浓度可达1毫摩尔。该剂量能显著降低女性血清中胰岛素样生长因子I的水平。此浓度在体外能够抑制人乳腺癌生长。每月给予3天的停药期以恢复血清视黄醇水平。在这种情况下，芬维A胺耐受性良好。一项评估芬维A胺对高危女性预防乳腺癌疗效的III期试验已完成。他莫昔芬可增强芬维A胺在致癌模型中的有效性。二者联合用药对女性安全。美国将开展一项他莫昔芬联合或不联合芬维A胺的III期辅助试验。
