Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias.
Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias.
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DOI：
10.1007/s00280-013-2249-z
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发表时间：
2013-10
影响因子：
3
通讯作者：
Bannerji, Rajat
中科院分区：
文献类型：
--
作者：
Gojo, Ivana;Sadowska, Mariola;Walker, Alison;Feldman, Eric J.;Iyer, Swaminathan Padmanabhan;Baer, Maria R.;Sausville, Edward A.;Lapidus, Rena G.;Zhang, Da;Zhu, Yali;Jou, Ying-Ming;Poon, Jennifer;Small, Karen;Bannerji, Rajat
在临床前研究中，Dinaciclib抑制细胞周期蛋白依赖性激酶1、2、5和9的治疗指数优于flavopiridol。本研究评估了dinaciclib在临床和体外急性白血病中的活性。复发性/难治性急性髓性白血病成人患者（n = 14）和急性淋巴细胞白血病成人患者（n = 6）接受dinaciclib 50 mg/m2输注治疗，每21天输注2小时。大多数患者循环原始细胞显著但短暂减少;然而，按照该方案未实现缓解。最常见的毒性反应为胃肠道反应、疲乏、转氨酶升高以及肿瘤溶解综合征的临床和实验室表现，其中1例患者死于急性肾衰竭。Dinaciclib的药代动力学显示快速（2小时）达到最大浓度，消除/分布相较短。药效学研究表明，在dinaciclib输注后4小时，患者外周血单核细胞中Mcl-1表达的体内抑制和PARP裂解的诱导，但24小时后效果消失，与临床结局无关。相关的体外研究表明，在临床可达到的浓度下，长时间暴露于dinaciclib可改善白血病细胞杀伤。虽然dinaciclib 2小时推注给药未表现出持久的临床活性，但药代动力学和药效学数据支持在急性白血病患者的未来试验中探索延长输注时间表。 本文的在线版本（doi：10.1007/s 00280 -013-2249-z）包含补充材料，可供授权用户使用。
Dinaciclib inhibits cyclin-dependent kinases 1, 2, 5, and 9 with a better therapeutic index than flavopiridol in preclinical studies. This study assessed the activity of dinaciclib in acute leukemia both in the clinic and in vitro. Adults with relapsed/refractory acute myeloid leukemia (n = 14) and acute lymphoid leukemia (n = 6) were treated with dinaciclib 50 mg/m2 given as a 2-h infusion every 21 days. Most patients had dramatic but transient reduction in circulating blasts; however, no remissions were achieved on this schedule. The most common toxicities were gastrointestinal, fatigue, transaminitis, and clinical and laboratory manifestations of tumor lysis syndrome, including one patient who died of acute renal failure. Dinaciclib pharmacokinetics showed rapid (2 h) achievement of maximum concentration and a short elimination/distribution phase. Pharmacodynamic studies demonstrated in vivo inhibition of Mcl-1 expression and induction of PARP cleavage in patients’ peripheral blood mononuclear cells 4 h after dinaciclib infusion, but the effects were lost by 24 h and did not correlate with clinical outcome. Correlative in vitro studies showed that prolonged exposures to dinaciclib, at clinically attainable concentrations, result in improved leukemia cell kill. While dinaciclib given as a 2-h bolus did not exhibit durable clinical activity, pharmacokinetic and pharmacodynamic data support the exploration of prolonged infusion schedules in future trials in patients with acute leukemias. The online version of this article (doi:10.1007/s00280-013-2249-z) contains supplementary material, which is available to authorized users.
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影响因子：
3.2
作者：
Gorlick R;Kolb EA;Houghton PJ;Morton CL;Neale G;Keir ST;Carol H;Lock R;Phelps D;Kang MH;Reynolds CP;Maris JM;Billups C;Smith MA
通讯作者：
Smith MA
影响因子：
2.7
作者：
Karp JE;Blackford A;Smith BD;Alino K;Seung AH;Bolaños-Meade J;Greer JM;Carraway HE;Gore SD;Jones RJ;Levis MJ;McDevitt MA;Doyle LA;Wright JJ
通讯作者：
Wright JJ
影响因子：
45.3
作者：
Lin, Thomas S.;Ruppert, Amy S.;Byrd, John C.
通讯作者：
Byrd, John C.
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
20.3
作者：
Karp, Judith E.;Smith, B. Douglas;Rudek, Michelle A.
通讯作者：
Rudek, Michelle A.