PROTEIN KINASE ANTAGONISTS--PRECLINICAL AND CLINICAL STUDIES

蛋白激酶拮抗剂——临床前和临床研究

• 批准号: 2464490
• 负责人: E SAUSVILLE
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2464490
• 关键词: MCF7 cell; antineoplastics; apoptosis; cell cycle; cis platinum compound; clinical research; clinical trial phase I; cyclins; drug screening /evaluation; enzyme inhibitors; enzyme substrate; flavones; human subject; low angle X ray diffraction analysis; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic cell; neoplastic growth; oncoproteins; pharmacokinetics; phosphorylation; protein kinase; radiosensitizer; retinoblastoma protein

This research will define the cellular basis for differential or selective inhibition of neoplastic cell growth by the protein kinase antagonists flavopiridol and UCN-01, with special focus on cell cycle arrest and apoptosis; determine the biochemical basis for, and consequences of, flavopiridol's and UCN-01's respective action on the cyclin dependent kinase(CDK) family of cell cycle regulatory molecules; and define pharmacodynamic endpoints in vitro and in vivo for use in clinical trials with flavopiridol and UCN-01. In the past year, this project has examined the capacity of a series of flavopiridol analogs to inhibit CDK2, for which crystals for X-ray diffraction could be generated by Dr. Kim (UC Berkeley). It was subsequently possible to diffuse deschloro flavopiridol into CDK2 crystals, and actually demonstrate the drug's presence in the ATP binding site (Proc. Natl. Acad Sci. 93, 2735, 1996). We also demonstrated that flavopiridol could potently inhibit CDK 2 as well as CDK4, and that cells arrested in G1 by flavopiridol show dephosphorylation of the retinoblastoma tumor suppressor protein (pRb), a known substrate of CDKs 2 and 4 (Cancer Res. 56, 2973, 1996). We are currently conducting a Phase I Trial with continuous infusion flavopiridol. We have demonstrated that UCN-01 can abrogate the G2 checkpoint in irradiated cells. Exposure to UCN-01 results in apparent sensitization to both radiation or cisplatin. This effect is most evident, in a MCF7/papilloma E6 transfected in cells with altered (vs wt) p53 function (J. Natl. Cancer Inst 88, 956, 1996). We have recently also opened a Phase I trial of UCN-01.

这项研究将确定差异或选择性的细胞基础， 蛋白激酶拮抗剂对肿瘤细胞生长的抑制 flavopiridol和UCN-01，特别关注细胞周期阻滞， 细胞凋亡;确定的生化基础，和后果， flavopiridol和UCN-01各自对细胞周期蛋白依赖性 细胞周期调节分子的CDK家族;并定义 用于临床试验的体外和体内药效学终点 flavopiridol和UCN-01。在过去的一年里，该项目审查了 一系列flavopiridol类似物抑制CDK 2的能力， 金博士（UC）可以生成哪些用于X射线衍射的晶体 Berkeley）。随后可以扩散去氯黄吡啶醇， 转化为CDK 2晶体，实际上证明了药物的存在， ATP结合位点（Proc.美国科学院93，2735，1996）。我们也 表明flavopiridol可以有效地抑制CDK 2， CDK 4，Flavopiridol阻滞在G1期的细胞表现出去磷酸化 视网膜母细胞瘤肿瘤抑制蛋白（pRb），一种已知的底物， CDK 2和4（Cancer Res.56，2973，1996）。我们目前正在进行一项 持续输注flavopiridol的I期试验。 我们已经证明 UCN-01可以消除辐照细胞中的G2检查点。暴露 UCN-01导致对辐射或 顺铂这种效应在转染MCF 7/乳头状瘤E6的细胞中最为明显。 在具有改变的（相对于wt）p53功能的细胞中（J. Natl.癌症研究所88，956， 1996年）的报告。我们最近还开始了UCN-01的I期试验。