肿瘤药学
腫瘤藥學
종류약학
ANTI-TUMOR PHARMACY
2014年
2期
86-96
,共11页
HDAC抑制剂%激酶抑制剂%多靶点药物%靶向治疗%肿瘤治疗
HDAC抑製劑%激酶抑製劑%多靶點藥物%靶嚮治療%腫瘤治療
HDAC억제제%격매억제제%다파점약물%파향치료%종류치료
HDAC inhibitors%Kinase inhibitors%Multi-target agents%Targeted therapy%Cancer therapy
肿瘤的发生和发展涉及多个信号传导通路。研究表明，多靶点抗癌药物可提高单靶点抗癌药物的治疗效果，并降低耐药性，是抗癌药物研发的重要研究方向。目前，多靶点抗癌药物的设计是其研发的主要挑战之一。组蛋白去乙酰化酶（histone deacetylases，HDACs）与肿瘤的发生密切相关，其抑制剂可以降低肿瘤细胞凋亡的阈值，具有广泛的抗肿瘤活性，并且可与多种抗肿瘤药物联合使用发挥协同作用。目前，已有2个HDAC抑制剂被美国FDA批准用于治疗皮肤T-细胞淋巴瘤，分别是Vorinostat（SAHA）和Romidepsin（FK228），还有多个HDAC抑制剂如PXD-101（Phase II）、LBH589（Phase III）、MS-275（Phase II）等尚处于临床研究阶段。本文主要对基于HDAC抑制剂的多靶点抗癌药物的设计思路和生物活性进行综述。
腫瘤的髮生和髮展涉及多箇信號傳導通路。研究錶明，多靶點抗癌藥物可提高單靶點抗癌藥物的治療效果，併降低耐藥性，是抗癌藥物研髮的重要研究方嚮。目前，多靶點抗癌藥物的設計是其研髮的主要挑戰之一。組蛋白去乙酰化酶（histone deacetylases，HDACs）與腫瘤的髮生密切相關，其抑製劑可以降低腫瘤細胞凋亡的閾值，具有廣汎的抗腫瘤活性，併且可與多種抗腫瘤藥物聯閤使用髮揮協同作用。目前，已有2箇HDAC抑製劑被美國FDA批準用于治療皮膚T-細胞淋巴瘤，分彆是Vorinostat（SAHA）和Romidepsin（FK228），還有多箇HDAC抑製劑如PXD-101（Phase II）、LBH589（Phase III）、MS-275（Phase II）等尚處于臨床研究階段。本文主要對基于HDAC抑製劑的多靶點抗癌藥物的設計思路和生物活性進行綜述。
종류적발생화발전섭급다개신호전도통로。연구표명，다파점항암약물가제고단파점항암약물적치료효과，병강저내약성，시항암약물연발적중요연구방향。목전，다파점항암약물적설계시기연발적주요도전지일。조단백거을선화매（histone deacetylases，HDACs）여종류적발생밀절상관，기억제제가이강저종류세포조망적역치，구유엄범적항종류활성，병차가여다충항종류약물연합사용발휘협동작용。목전，이유2개HDAC억제제피미국FDA비준용우치료피부T-세포림파류，분별시Vorinostat（SAHA）화Romidepsin（FK228），환유다개HDAC억제제여PXD-101（Phase II）、LBH589（Phase III）、MS-275（Phase II）등상처우림상연구계단。본문주요대기우HDAC억제제적다파점항암약물적설계사로화생물활성진행종술。
Cancer is a multi-genetic disease arising from the accumulation of different genetic alterations affecting genes that control cell proliferation and/or apoptosis. There is a general agreement that molecules interfering simultaneously with multiple receptors might be more effective and less adaptive to resistance than single target agents. The design of multi-target anti-tumor drugs has become one of the major challenges in the research and development of multi-target agents. Histone deacetylases (HDACs) expressions were associated with the occurrence and development of cancer. HDAC inhibitors were pan anticancer agents. They could lower the apoptotic threshold of tumor cells, and be combined with a variety of anticancer agents to exert synergistic antitumor effects. So far, two HDAC inhibitors, Vorinostat (SAHA) and Romidepsin (FK228), have been ap-proved by US FDA for the treatment of cutaneous T cell lymphoma (CTCL). Several HDAC inhibitors like PXD-101 (Phase II), LBH589 (Phase III), MS-275 (Phase II) were being studied in clinic. Here we mainly reviewed the design of multi-target agents that based on the structure of HDAC inhibitors and their biological activities.
