Pharmacogenomics of tamoxifen and aromatase inhibitors
Pharmacogenomics of tamoxifen and aromatase inhibitors
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DOI：
10.1002/cncr.23192
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发表时间：
2008-02-01
期刊：
影响因子：
6.2
通讯作者：
Ingle, James N.
中科院分区：
文献类型：
--
作者：
Ingle, James N.
在乳腺癌女性患者的治疗选择中，焦点几乎完全集中在肿瘤的特征上，例如雌激素受体（ER）和HER-2。直到最近，基本上没有注意到主机和她的基因组成，因为它涉及到不同药物的代谢。药物遗传学在乳腺癌管理中的第一个真实的临床应用涉及他莫昔芬生物转化为活性抗癌代谢物。关于他莫昔芬代谢为活性代谢物4羟基-N-去甲基-他莫昔芬（内昔芬）的新信息已经出现。Endoxifen是一种代谢物，具有抗肿瘤活性和对ER的亲和力，与4-羟基-他莫昔芬相似，但通常以更高的浓度存在。CYP 2D 6在内昔芬的代谢中起核心作用，1项已发表的研究表明，CYP 2D 6的基因型差异和CYP 2D 6抑制剂的使用对接受他莫昔芬治疗的女性的结局有影响。芳香化酶抑制剂是乳腺癌治疗中的主要药物。芳香化酶基因已被重新测序，功能基因组学已被确定的非同义编码单核苷酸多态性，显示活性水平显着下降。这些发现与CYP 19基因的遗传变异在芳香酶抑制剂的活性中可能是重要的假设是一致的。目前，研究的重点是在接受芳香酶抑制剂治疗乳腺癌的妇女中检查药效学和药代动力学途径中的多个基因（因此是药物基因组学）。
In selection of therapy for women with breast cancer, the focus has been almost exclusively on the characteristics of the tumor, eg, estrogen receptor (ER) and HER-2. Until recently, essentially no attention has been paid to the host and her genetic makeup as it relates to the metabolism of different drugs. The first real clinical application of pharmacogenetics in breast cancer management relates to tamoxifen's biotransformation to active anticancer metabolites. New information has arisen on the metabolism of tamoxifen to the active metabolite, 4 hydroxy-N-desmethyl-tamoxifen (endoxifen). Endoxifen is a metabolite with antitumor activity and affinity for the ER that is similar to 4-hydroxy-tamoxifen, but 1 that is normally present in substantially higher concentrations. CYP2D6 plays a central role in the metabolism to endoxifen and 1 published study shows that genotypic differences in CYP2D6 and use of CYP2D6 inhibitors has an impact on outcomes of women treated with tamoxifen. The aromatase inhibitors represent a major class of drugs in the armamentarium against breast cancer. The aromatase gene has been resequenced and functional genomics have been performed on the identified nonsynonymous coding single nucleotide polymorphisms showing significant decreases in levels of activity. These findings are consistent with a hypothesis that genetic variation in the CYP19 gene might be important in the activity of aromatase inhibitors. Currently, the emphasis is on examining multiple genes (thus pharmacogenomics) in pharmacodynamic and pharmacokinetic pathways in women receiving aromatase inhibitors for breast cancer.