Mechanistic Investigation of Bone Marrow Suppression Associated with Palbociclib and its Differentiation from Cytotoxic Chemotherapies
Mechanistic Investigation of Bone Marrow Suppression Associated with Palbociclib and its Differentiation from Cytotoxic Chemotherapies
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DOI：
10.1158/1078-0432.ccr-15-1421
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发表时间：
2016-04-15
影响因子：
11.5
通讯作者：
Sacaan, Aida I.
中科院分区：
文献类型：
--
作者：
Hu, Wenyue;Sung, Tae;Sacaan, Aida I.
目的：Palbociclib（PD-0332991）是首个获批用于治疗转移性乳腺癌的选择性细胞周期蛋白依赖性激酶（CDK）4/6抑制剂。血液学效应，尤其是中性粒细胞减少症，是palbociclib在人体中的剂量限制性不良事件。实验设计：在大鼠和犬的毒理学研究中，发现palbociclib治疗后出现可逆的血液学效应和骨髓细胞减少。为了了解血液学毒性发生的机制，并进一步将其与细胞毒性化疗药物引起的骨髓毒性区分开来，使用人骨髓单个核细胞（hBMNC）进行体外试验。这项研究表明，palbociclib诱导的骨髓抑制是通过细胞周期阻滞发生的，在临床相关浓度下没有细胞凋亡，没有谱系特异性，并且在palbociclib停药后可逆。与此相反，化疗药物（紫杉醇和阿霉素）的治疗导致DNA损伤和细胞凋亡的hBMNC中的细胞死亡。在存在或不存在抗雌激素的情况下，palbociclib处理的hBMNC在palbociclib停药后均未衰老并恢复增殖，与药理学静止一致。相反，乳腺癌细胞MCF-7在palbociclib或抗雌激素药物联合治疗后出现衰老，并在抗雌激素药物存在下保持停滞状态。结论：Palbociclib可引起可逆的骨髓抑制，与细胞毒性化疗药物引起的细胞凋亡明显不同。该研究还将Palbociclib对正常骨髓细胞的细胞周期阻滞作用与在乳腺癌细胞中观察到的衰老作用进行了区分。这些结果阐明了palbociclib诱导的骨髓毒性的机制，并支持临床风险管理。(C)2015年AACR。
Purpose: Palbociclib (PD-0332991) is the first selective cyclin-dependent kinase (CDK) 4/6 inhibitor approved for metastatic breast cancer. Hematologic effects, especially neutropenia, are dose-limiting adverse events for palbociclib in humans.Experimental Design: Reversible hematologic effects and bone marrow hypocellularity have been identified in toxicology studies in rats and dogs after palbociclib treatment. To understand the mechanism by which the hematologic toxicity occurs, and to further differentiate it from the myelotoxicity caused by cytotoxic chemotherapeutic agents, an in vitro assay using human bone marrow mononuclear cells (hBMNC) was utilized.Results: This work demonstrated that palbociclib-induced bone marrow suppression occurred through cell-cycle arrest, with no apoptosis at clinically relevant concentrations, was not lineage-specific, and was reversible upon palbociclib withdrawal. In contrast, treatment with chemotherapeutic agents (paclitaxel and doxorubicin) resulted in DNA damage and apoptotic cell death in hBMNCs. In the presence or absence of the antiestrogen, palbociclib-treated hBMNCs did not become senescent and resumed proliferation following palbociclib withdrawal, consistent with pharmacologic quiescence. The breast cancer cells, MCF-7, conversely, became senescent following palbociclib or antiestrogen treatment with additive effects in combination and remained arrested in the presence of antiestrogen.Conclusions: Palbociclib causes reversible bone marrow suppression, clearly differentiating it from apoptotic cell death caused by cytotoxic chemotherapeutic agents. This study also distinguished the cell-cycle arresting action of palbociclib on normal bone marrow cells from the senescent effects observed in breast cancer cells. These results shed light on the mechanism and support risk management of palbociclib-induced bone marrow toxicity in the clinic. (C) 2015 AACR.