Phase II study of flavopiridol in mantle cell lymphoma and DLBCL

Flavopiridol是从合成过程中获得的，但其化学结构与从印度本土植物Dysoxylum binectariferum中获得的产品相同。首次发现flavopiridol时，认为它是一种酪氨酸激酶拮抗剂，但随后发现它可通过抑制细胞周期蛋白依赖性激酶（CDK）1和CDK 2可逆地抑制生长[1，2]。Flavopiridol通过改变酪氨酸残基的磷酸化以及拮抗CDK 1和CDK 2活性（作为与ATP竞争性抑制的结果）诱导细胞周期抑制[3]。基于这些初步观察结果，研究人员假设flavopiridol将有效地快速分裂肿瘤系统，其中存在最小体积的肿瘤。我们现在知道，flavopiridol还有许多其他的靶点，包括在套细胞淋巴瘤中过度表达的细胞周期蛋白D-1复合物和细胞周期蛋白H。此外，在淋巴瘤细胞系中的研究已经证明了对活化B细胞（ABC）型细胞系和NF-κ B下调的活性[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].