Seventy-two hour continuous infusion flavopiridol in relapsed and refractory mantle cell lymphoma
Seventy-two hour continuous infusion flavopiridol in relapsed and refractory mantle cell lymphoma
复制标题
DOI：
10.1080/10428190290016908
复制
发表时间：
2002-04-01
影响因子：
2.6
通讯作者：
Shipp, MA
中科院分区：
文献类型：
--
作者：
Lin, TS;Howard, OM;Shipp, MA
细胞周期调节蛋白Cyclin D1在95-100%的套细胞淋巴瘤(MCL)中过度表达，是一个潜在的治疗靶点。黄吡哆醇抑制细胞周期蛋白依赖性激酶(CDK)4-细胞周期蛋白D1复合体，并诱导淋巴瘤细胞系的凋亡。之前的I期临床研究已经证明，这种药物可以安全地在人类身上使用，这促使进一步评估黄烷醇作为MCL的单一药物。10例复发或难治性MCL患者，既往接受过一种化疗方案，给予黄吡酯50 mg/m(2)/d，72h持续静脉滴注，每14d一次。治疗耐受性良好，只有一名患者出现III-IV级非血液毒性。然而，没有临床反应；尽管接受了治疗，3名患者保持了病情稳定，7名患者在两个月内表现出病情进展。在复发和难治性MCL中，单药以50 mg/m(2)/d持续滴注72 h效果不佳。最近使用人血浆进行的体外研究表明，为了达到临床疗效，可能需要更高的血浆药物水平。对黄烷醇的体外研究表明，该试剂与DNA损伤化合物具有协同作用。作为临床药物的进一步研究应该集中在可供选择的给药方案和化合物在联合化疗方案中的潜在用途。
The cell cycle regulatory protein cyclin D1, which is over-expressed in 95-100% of mantle cell lymphomas (MCL), is a potential therapeutic target. Flavopiridol inhibits the cyclin-dependent kinase (CDK)4-cyclin D1 complex and induces apoptosis in lymphoma cell lines. Previous phase I clinical studies had demonstrated that this drug could be safely administered in humans, prompting further evaluation of flavopiridol as a single agent in MCL. Ten patients with relapsed or refractory MCL, who had received one prior chemotherapy regimen, were treated with flavopiridol 50 mg/m(2)/day given as a 72 h continuous intravenous infusion every 14 days. Treatment was well tolerated, and only one patient developed grade III-IV non-hematologic toxicity. However, there were no clinical responses; despite therapy, three patients maintained stable disease, and seven patients demonstrated progressive disease within two months. In relapsed and refractory MCL, flavopiridol is ineffective as a single agent given by 72 h continuous infusion at 50 mg/m(2)/day. Recent in vitro studies using human plasma suggest that higher plasma drug levels may be necessary to achieve clinical efficacy. In vitro studies of flavopiridol indicate that the agent is synergistic with DNA-damaging compounds. Further investigation into flavopiridol as a clinical agent should focus on alternative dosing schedules and the compound's potential use in combination chemotherapeutic regimens.