Zanardi S, Serrano D, Argusti A, Barile M, Puntoni M, Decensi A
Department of Medical and Preventive Oncology, E.O. Ospedali Galliera, Mura delle Cappuccine 14, 16128 Genoa, Italy.
Endocr Relat Cancer. 2006 Mar;13(1):51-68. doi: 10.1677/erc.1.00938.
Retinoids have been studied as chemopreventive agents in clinical trials due to their established role in regulating cell growth, differentiation and apoptosis in preclinical models. Experimental evidence suggests that retinoids affect gene expression both directly, by activating and/or repressing specific genes, and indirectly, by interfering with different signal transduction pathways. Induction of apoptosis is a unique feature of fenretinide, the most widely studied retinoid in clinical trials on breast cancer chemoprevention due to its selective accumulation in breast tissue and to its favourable toxicological profile. In a phase III breast cancer prevention trial, fenretinide showed a durable trend to a reduction of second breast malignancies in premenopausal women. This pattern was associated with a favourable modulation of circulating IGF-I and its main binding protein (IGF-binding protein-3, IGFBP-3), which have been associated with breast cancer risk in premenopausal women in different prospective studies. In a subsequent biomarker study on premenopausal women who had participated in the phase III trial, high IGF-I and low IGFBP-3 baseline levels were found to predict second breast cancer risk, although the magnitude of their changes during treatment did not fulfil the requirements for suitable surrogate end-point biomarkers. In postmenopausal women, fenretinide did not reduce second breast cancer incidence, nor did it induce significant modulation of the IGF system. Similarly, fenretinide was not found to affect risk biomarkers significantly in early postmenopausal women on hormone replacement therapy, who are at increased risk of developing breast cancer. Biomarker studies of fenretinide alone or in combination with different nuclear receptor ligands are being conducted. In particular, clinical trials of fenretinide and tamoxifen have proved to be feasible, and this combination appears to be safe and well tolerated in high-risk women, especially when low-dose tamoxifen is employed. Novel retinoid X receptor-selective retinoids, or rexinoids, have been shown to suppress the development of breast cancer in several animal models with minimal toxicity, and are being intensively studied either alone or in combination with selective oestrogen receptor modulators, both in vitro and in vivo. The rexinoid, bexarotene, has recently been approved for the treatment of patients with cutaneous T-cell lymphoma, and a biomarker trial with bexarotene in women with high breast cancer risk is currently underway.
由于维甲酸在临床前模型中具有调节细胞生长、分化和凋亡的既定作用，因此在临床试验中作为化学预防剂进行了研究。实验证据表明，维甲酸通过激活和/或抑制特定基因直接影响基因表达，并通过干扰不同的信号转导途径间接影响基因表达。诱导凋亡是芬维A胺的独特特征，由于其在乳腺组织中的选择性积累及其良好的毒理学特征，它是乳腺癌化学预防临床试验中研究最广泛的维甲酸。在一项III期乳腺癌预防试验中，芬维A胺显示出绝经前女性继发性乳腺恶性肿瘤减少的持久趋势。这种模式与循环中的胰岛素样生长因子-I（IGF-I）及其主要结合蛋白（胰岛素样生长因子结合蛋白-3，IGFBP-3）的有利调节有关，在不同的前瞻性研究中，它们与绝经前女性的乳腺癌风险相关。在一项对参与III期试验的绝经前女性进行的后续生物标志物研究中，发现高IGF-I和低IGFBP-3基线水平可预测继发性乳腺癌风险，尽管它们在治疗期间的变化幅度未达到合适替代终点生物标志物的要求。在绝经后女性中，芬维A胺既没有降低继发性乳腺癌的发病率，也没有对IGF系统产生显著调节作用。同样，在接受激素替代疗法的绝经后早期女性中，未发现芬维A胺对风险生物标志物有显著影响，这些女性患乳腺癌的风险增加。正在进行单独使用芬维A胺或与不同核受体配体联合使用的生物标志物研究。特别是，芬维A胺和他莫昔芬的临床试验已被证明是可行的，这种联合用药在高危女性中似乎是安全且耐受性良好的，尤其是使用低剂量他莫昔芬时。新型视黄酸X受体选择性维甲酸，即类视黄醇X受体激动剂，已在几种动物模型中显示出以最小的毒性抑制乳腺癌的发展，并且正在单独或与选择性雌激素受体调节剂联合进行深入的体外和体内研究。类视黄醇X受体激动剂贝沙罗汀最近已被批准用于治疗皮肤T细胞淋巴瘤患者，目前正在进行一项针对乳腺癌高风险女性的贝沙罗汀生物标志物试验。
