Phase II study of flavopiridol in mantle cell lymphoma and DLBCL

黄烷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八角莲中获得的产品相同。当黄烷醇第一次被发现时，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[1，2]而可逆地抑制生长。通过改变酪氨酸残基的磷酸化，以及由于与ATP的竞争抑制而拮抗CDK1和CDK2的活性，黄曲醇诱导细胞周期抑制[3]。基于这些初步观察，研究人员推测，在肿瘤体积最小的地方，黄烷醇将有效地快速分割肿瘤系统。我们现在知道，黄烷醇还有许多额外的靶点，包括在套细胞淋巴瘤和周期蛋白H中过表达的细胞周期蛋白D-1复合体。此外，对淋巴瘤细胞株的研究表明，它对激活的B细胞(ABC)型细胞株具有活性，并下调核因子-kappa B[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].