Molecular mechanisms of gefitinib-induced rash formation: Gefitinib augments lipogenesis and steroidgenesis in sebaceous glands

吉非替尼诱导皮疹形成的分子机制：吉非替尼增强皮脂腺的脂肪生成和类固醇生成

基本信息

批准号：
22590506
负责人：
SATO Takashi
金额：
$ 2.75万
依托单位：
Tokyo University of Pharmacy and Life Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

项目摘要

A small-molecule tyrosine kinase inhibitor, gefitinib, which targets the ligand-binding domain of epidermal growth factor receptors, exhibits anti-tumorigenic activity in patients with advanced non-small cell lung cancer. Many patients treated with gefitinib develop an acne-like rash on the face and upper body. Although acne is characterized as a functional disorder in sebaceous glands and pilosebaceous units, there have been no reports to date that gefitinib may modulate sebum production in sebaceous glands. In the present study, a mass spectrometry analysis revealed that orally administrated gefitinib was detectable in a pustule from a patient treated with gefitinib but not ones from four acne patients. In addition, gefitinib augmented the production of triacylglycerols (TG), the major sebum component, and perilipin, a sebocytic differentiation marker, in human and hamster sebocytes. Furthermore, gefitinib facilitated steroidogenesis in both hamster and human sebocytes. Therefore, these results provide novel evidence that gefitinib exists in the hair follicle of the skin after its oral administration and directly facilitates sebum production by the augmentation of TG production. Moreover, the augmentation of sebum production is likely to due to the increases of androgen synthesisin sebocytes. These findings will help to increase the clinical understanding of the side effects of gefitinib, and improve the QOL of patients being treated with gefitinib

针对表皮生长因子受体的配体结合域的小分子酪氨酸激酶抑制剂Gefitinib在晚期非小细胞肺癌患者中表现出抗肿瘤活性。许多接受吉非替尼治疗的患者在面部和上半身会出现类似痤疮的皮疹。尽管痤疮的特征是皮脂腺和多叶胶质单元中的功能障碍，但迄今为止尚无报道称吉非替尼可能会调节皮脂腺中皮脂产生。在本研究中，质谱分析表明，可以在脓毒症患者的脓疱中检测到口服的吉非替尼，但未从四名痤疮患者的患者中检测到。此外，吉非替尼增强了人和仓鼠皮脂细胞中三酰甘油（TG），主要皮脂成分的产生（TG），主要皮脂成分和果皮细胞分化标记物的产生。此外，吉非替尼促进了仓鼠和人脂肪细胞中的类固醇生成。因此，这些结果提供了新的证据，表明吉非替尼口服后，皮肤的毛囊存在于皮肤的毛囊中，并直接通过TG产生的增强来促进皮脂产生。此外，皮脂产生的增强可能是由于雄激素合成细胞的增加所致。这些发现将有助于增加对吉非尼副作用的临床理解，并改善用吉非迪治疗的患者的QoL