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帕博西尼(PD 0332991):靶向乳腺癌中的细胞周期机制。

Palbociclib (PD 0332991) : targeting the cell cycle machinery in breast cancer.

作者信息

Rocca Andrea, Farolfi Alberto, Bravaccini Sara, Schirone Alessio, Amadori Dino

机构信息

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Department of Medical Oncology , Meldola , Italy +39 0543 739100 ; +39 0543 739151 ;

出版信息

Expert Opin Pharmacother. 2014 Feb;15(3):407-20. doi: 10.1517/14656566.2014.870555. Epub 2013 Dec 26.

Abstract

INTRODUCTION

The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway, governing the cell cycle restriction point, is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy. Palbociclib (PD 0332991) , a potent and selective inhibitor of CDK4 and CDK6, inhibits proliferation of several Rb-positive cancer cell lines and xenograft models.

AREAS COVERED

The basic features and abnormalities of the cell cycle in breast cancer are described, along with their involvement in estrogen signaling and endocrine resistance. The pharmacological features of palbociclib, its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated, and its clinical development in breast cancer described. A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years.

EXPERT OPINION

The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy. Further, potentially useful combinations are those with drugs targeting mitogenic signaling pathways, such as HER2- and PI3K-inhibitors. Combination with chemotherapy seems more problematic, as antagonism has been reported in preclinical models. The identification of predictive factors, already explored in preclinical studies, must be further refined and validated in clinical trials.

摘要

引言

细胞周期蛋白D - 细胞周期蛋白依赖性激酶4和6(CDK4/6) - 视网膜母细胞瘤(Rb)通路控制着细胞周期限制点,在乳腺癌中经常发生改变,是抗癌治疗的一个潜在相关靶点。帕博西尼(PD 0332991)是一种强效且选择性的CDK4和CDK6抑制剂,可抑制多种Rb阳性癌细胞系和异种移植模型的增殖。

涵盖领域

描述了乳腺癌细胞周期的基本特征和异常情况,以及它们在雌激素信号传导和内分泌抵抗中的作用。接着阐述了帕博西尼的药理学特性、其在乳腺癌临床前模型中的活性以及反应的潜在决定因素,并描述了其在乳腺癌中的临床开发情况。通过PubMed以及近年来主要癌症大会的会议记录对该主题进行了文献检索。

专家观点

帕博西尼与内分泌药物联合使用是一种非常有前景的治疗方法,目前正在进行III期临床试验以确认其疗效。此外,与靶向有丝分裂信号通路的药物(如HER2和PI3K抑制剂)联合使用可能会有帮助。与化疗联合使用似乎问题更多,因为在临床前模型中已报道存在拮抗作用。在临床前研究中已经探索的预测因素的识别,必须在临床试验中进一步完善和验证。

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