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Cell cycle and diseases

细胞周期与疾病

基本信息

批准号：
13043012
负责人：
KOHSAKA Hitoshi
金额：
$ 47.74万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2005
项目状态：
已结题

项目摘要

Intra-articular gene transfer of cyclin-dependent kinase inhibitors (CDKI) to suppress synovial cell cycling has shown efficacy in treating animal models of rheumatoid arthritis (RA). CDKIs also modulate immune function via a CDKindependent pathway. Accordingly, systemic administration of small molecules that inhibit. CDK might ameliorate arthritis. In order to address this issue, alvocidib (flavopiridol), known to be tolerated clinically for treating cancers, and also a newly synthesized CDK4/6-selective inhibitor were tested for anti-arthritic effects. In vitro, they inhibited proliferation of human and mouse synovial fibroblasts without inducing apoptosis. In vivo, treatment of collagen-induced arthritis (CIA) mice with alvocidib suppressed synovial hyperplasia and joint destruction while serum concentrations of anti-type II collagen (Cll) antibodies and proliferative responses to Cll were maintained. Treatment was effective even when therapeutically administered. Treated mice developed arthritis after termination of treatment. Thus, immune responses to Cll were unimpaired. The same treatment ameliorated arthritis induced by K/BxN serum transfer to lymphocyte-deficient mice. Similarly, the CDK4/6-selective inhibitor suppressed CIA. Both small molecule (sm) CDK inhibitors were effective in treating animal models of RA not by suppressing lymphocyte function. We believe that smCDK inhibitors hold promise as a new class of anti-rheumatic drugs that inhibit a distinct phase of rheumatoid pathogenesis

细胞周期蛋白依赖性激酶抑制剂（CDKI）的关节内基因转移抑制滑膜细胞循环在治疗类风湿性关节炎（RA）动物模型中显示出疗效。CDKIs也通过不依赖cdk的途径调节免疫功能。因此，系统管理的小分子，抑制。CDK可能会改善关节炎。为了解决这一问题，我们对临床已知可耐受治疗癌症的alvocidib （flavopiridol）和一种新合成的cdk4 /6选择性抑制剂的抗关节炎作用进行了测试。在体外，它们抑制人和小鼠滑膜成纤维细胞的增殖，但不诱导细胞凋亡。在体内，用alvocidib治疗胶原诱导关节炎（CIA）小鼠可抑制滑膜增生和关节破坏，同时维持血清抗II型胶原（Cll）抗体浓度和对Cll的增殖反应。即使是治疗性的治疗也是有效的。治疗小鼠在终止治疗后出现关节炎。因此，对Cll的免疫反应未受损。同样的治疗可以改善K/BxN血清转移到淋巴细胞缺陷小鼠引起的关节炎。同样，cdk4 /6选择性抑制剂抑制CIA。两种小分子（sm） CDK抑制剂均不通过抑制淋巴细胞功能有效治疗RA动物模型。我们相信smCDK抑制剂有望成为一类新的抗风湿病药物，抑制类风湿发病的一个不同阶段