Phase II study of flavopiridol in mantle cell lymphoma and DLBCL

黄吡醇是通过合成过程获得的，但它的化学结构与从印度本土植物Dysoxylum binectariferum中获得的产品相同。当黄吡醇首次被发现时，它被认为是一种酪氨酸激酶拮抗剂，但随后，它被证明通过抑制细胞周期蛋白依赖性激酶（CDK）1和CDK2来可逆地抑制生长[1,2]。黄吡醇通过改变酪氨酸残基的磷酸化，以及通过与ATP[3]的竞争性抑制而拮抗CDK1和CDK2活性，诱导细胞周期抑制。基于这些初步观察，研究人员假设黄吡醇对肿瘤体积最小的快速分裂肿瘤系统有效。我们现在知道黄吡醇还有许多其他靶点，包括套细胞淋巴瘤中过度表达的周期蛋白D-1复合体和周期蛋白h。此外，在淋巴瘤细胞系中的研究已经证明黄吡醇对活化的B细胞（ABC）型细胞系和NF-kappa B下调具有活性[4,5]。

Flavopiridol is obtained from a synthetic process, but its chemical structure is identical to a product obtained from an indigenous plant in India called Dysoxylum binectariferum. When flavopiridol was first discovered, it was considered to be a tyrosine kinase antagonist but subsequently, it was shown to reversibly inhibit growth via inhibition of cyclin-dependent kinase (CDK)1 and CDK2[1, 2]. Flavopiridol induced cell cycle inhibition by altering phosphorylation of tyrosine residues as well as antagonizing CDK1 and CDK2 activity as a result of competitive inhibition with ATP[3]. Based on these initial observations, investigators hypothesized that flavopiridol would be effective in rapidly dividing tumor systems where a minimum volume of tumor exists. We now know that flavopiridol has a number of additional targets that include the cyclin D-1 complex over-expressed in mantle cell lymphoma and cyclin H. In addition, studies in lymphoma cell lines have demonstrated activity against activated B-cell (ABC) type cell lines and NF-kappa B down-regulation[4, 5].