Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression
Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression
复制标题
G1T28的临床前特征：一种新的CDK4/6抑制剂，可减少化疗诱导的骨髓抑制
DOI：
10.1158/1535-7163.mct-15-0775
复制
发表时间：
2016-05-01
影响因子：
5.7
通讯作者：
Strum, Jay C.
中科院分区：
文献类型：
--
作者：
Bisi, John E.;Sorrentino, Jessica A.;Strum, Jay C.
化疗引起的骨髓抑制仍然是细胞毒性化疗的主要剂量限制毒性，表现为中性粒细胞减少、淋巴细胞减少、贫血和血小板减少。因此，骨髓抑制是癌症治疗的许多副作用的来源，包括感染、败血症、出血和疲劳，因此需要住院、造血生长因子支持和输血(红细胞和/或血小板)。此外，骨髓抑制引起的临床担忧通常会导致化疗剂量的减少，因此限制了治疗剂量强度，降低了治疗的抗肿瘤效果。目前，治疗骨髓抑制的唯一疗程是生长因子支持，这是次优的。这些治疗是特定血统的，不能保护骨髓免受化疗引起的细胞毒作用的影响，而且每种药物的安全性和毒性都是极其具体的。在这里，我们描述了G1T28的临床前发展，G1T28是一种新的有效和选择性的CDK4/6抑制剂，可以瞬时和可逆地调节小鼠和犬骨髓造血干细胞和祖细胞的增殖，并提供多系保护，免受化疗的血液学毒性。此外，G1T28不会降低细胞毒化疗对RB1缺陷肿瘤的疗效。G1T28目前正在临床开发中，用于减少小细胞肺癌一线和二线治疗中化疗引起的骨髓抑制。(C)2016年AACR。
Chemotherapy-induced myelosuppression continues to represent the major dose-limiting toxicity of cytotoxic chemotherapy, which can be manifested as neutropenia, lymphopenia, anemia, and thrombocytopenia. As such, myelosuppression is the source of many of the adverse side effects of cancer treatment including infection, sepsis, bleeding, and fatigue, thus resulting in the need for hospitalizations, hematopoietic growth factor support, and transfusions (red blood cells and/or platelets). Moreover, clinical concerns raised by myelosuppression commonly lead to chemotherapy dose reductions, therefore limiting therapeutic dose intensity, and reducing the antitumor effectiveness of the treatment. Currently, the only course of treatment for myelosuppression is growth factor support which is suboptimal. These treatments are lineage specific, do not protect the bone marrow from the chemotherapy-inducing cytotoxic effects, and the safety and toxicity of each agent is extremely specific. Here, we describe the preclinical development of G1T28, a novel potent and selective CDK4/6 inhibitor that transiently and reversibly regulates the proliferation of murine and canine bone marrow hematopoietic stem and progenitor cells and provides multilineage protection from the hematologic toxicity of chemotherapy. Furthermore, G1T28 does not decrease the efficacy of cytotoxic chemotherapy on RB1-deficient tumors. G1T28 is currently in clinical development for the reduction of chemotherapy-induced myelosuppression in first-and second-line treatment of small-cell lung cancer. (C)2016 AACR.