Section of Cytokines and Supportive Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Semin Hematol. 2010 Jul;47(3):249-57. doi: 10.1053/j.seminhematol.2010.03.004.
Thrombocytopenia is a common problem in hematology/oncology patients. In the past two decades a number of thrombopoietic growth factors and related cytokines have become available for clinical investigations. Unfortunately, most of the pleiotropic cytokines have been limited by their modest activity and toxicity profile. The discovery of thrombopoietin (TPO), a key regulator of platelet production, led to the clinical development of two recombinant versions of the molecule: full-length, recombinant human thrombopoietin (rhTPO), and truncated and pegylated, megakaryocyte growth and development factor (Peg-rHuMGDF). Both agents showed significant biologic activity in various clinical settings, including nonmyeloablative chemotherapy, mobilization of progenitors, platelet apheresis, and treatment of thrombocytopenia related to other conditions. Despite promising thrombopoietic activity, the clinical development of the first generation of recombinant TPOs was discontinued due to the neutralizing antibodies observed with PEG-rHuMGDF. This has led to the development of TPO agonists with no sequence homology to TPO, which can bind to the TPO receptors and activate signaling, leading to an increase in platelet production. The clinical experience with the first generation of thrombopoietic agents has provided insight into the biology and future directions for a second generation of thrombopoietic agents in various disorders of thrombocytopenia.
血小板减少症是血液学/肿瘤学患者的常见问题。在过去的二十年中，许多促血小板生成因子和相关细胞因子已可用于临床研究。不幸的是，大多数多效细胞因子因其活性和毒性特征有限而受到限制。血小板生成素（TPO）的发现，是血小板生成的关键调节剂，导致该分子的两种重组版本的临床开发：全长、重组人血小板生成素（rhTPO）和截断和聚乙二醇化、巨核细胞生长和发育因子（Peg-rHuMGDF）。这两种药物在各种临床环境中均表现出显著的生物学活性，包括非清髓性化疗、祖细胞动员、血小板单采术以及治疗与其他情况相关的血小板减少症。尽管促血小板生成活性很有前景，但第一代重组 TPO 的临床开发因 PEG-rHuMGDF 观察到的中和抗体而停止。这导致了与 TPO 没有序列同源性的 TPO 激动剂的开发，它们可以与 TPO 受体结合并激活信号转导，从而导致血小板生成增加。第一代促血小板生成剂的临床经验为各种血小板减少症疾病的第二代促血小板生成剂的生物学和未来方向提供了深入了解。
