PROTEIN KINASE ANTAGONISTS--PRECLINICAL AND CLINICAL STUDIES

这项研究将确定差异或选择性的细胞学基础 蛋白激酶拮抗剂对肿瘤细胞生长的抑制作用 黄烷醇和UCN-01，特别关注细胞周期停滞和 细胞凋亡；确定生物化学基础和后果， 黄烷醇和Ucn-01‘S对细胞周期蛋白依赖性的作用 激酶(CDK)家族的细胞周期调节分子；并定义 用于临床试验的体内外药效学终点 加入黄烷醇和UCN-01。在过去的一年里，这个项目审查了 一系列黄烷醇类似物抑制CDK2的能力 金博士(UC)可以产生哪些用于X射线衍射的晶体 伯克利)。随后有可能扩散地氯黄烷醇。 进入CDK2晶体，并实际证明药物存在于 三磷酸腺苷结合位点(过程娜塔莉。阿卡德科学公司。93、2735、1996)。我们也 结果表明，黄烷醇对CDK2有明显的抑制作用。 CDK4，且被黄吡啶醇阻滞于G1期细胞显示去磷酸化 视网膜母细胞瘤肿瘤抑制蛋白(PRB)，已知的底物 CDKs 2和4(癌症研究56,2973,1996)。我们目前正在进行一项 持续输注黄烷醇的I期试验。我们已经证明了 UCN-01可以消除受辐射细胞中的G2检查点。暴露量 对UCN-01有明显的辐射敏化作用 顺铂。这种影响在MCF7/乳头状瘤E6细胞中最为明显 在p53功能改变(与wt)的细胞中(J.Natl.癌症研究所88,956， 1996年)。我们最近还开始了UCN-01的第一阶段试验。

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.