Parchment R E, Huang M, Erickson-Miller C L
Division of Pharmacology & Toxicology, Hipple Cancer Research Center, Dayton, Ohio 45439-2092.
Toxicol Pathol. 1993;21(2):241-50. doi: 10.1177/019262339302100217.
Myelosuppression is the dose-limiting side effect for most anti-cancer and many anti-human immunodeficiency virus agents, which can be quantitated with optimized colony-forming assays (granulocyte-macrophage, late erythroid, and megakaryocytic [for murine only] colony-forming units and early erythroid burst-forming units (BFUs)). When applied to new drug development, the assays are used for therapeutic index-based screening (e.g., less myelosuppressive analogues, structure-toxicity studies, new drug leads), interpreting efficacy data from xenotransplant models, and selecting the most accurate animal model for human hematopoietic toxicity. However, other types of assays may be required to identify the mechanism underlying myelosuppression. In clinical trial planning, in vitro colony-forming assays can be used to elucidate schedule dependency of myelotoxicity (which in turn provides clues about mechanism of action), to plan cytokine support, and to estimate dose-escalation effects. The inhibition of colony formation can be measured relative to a compound with known clinical myelotoxicity and schedule dependency to provide some idea of the toxicity expected at particular doses, and the degree of heterogeneity between individuals, during clinical trials. The predictive accuracy of the in vitro data has been proven by validation studies with alkylating agents.
骨髓抑制是大多数抗癌药物和许多抗人类免疫缺陷病毒药物的剂量限制性副作用，可通过优化的集落形成试验进行定量分析（粒细胞-巨噬细胞、晚期红系和巨核细胞[仅适用于小鼠]集落形成单位以及早期红系爆式集落形成单位）。在新药研发中，这些试验用于基于治疗指数的筛选（例如，骨髓抑制作用较小的类似物、结构-毒性研究、新药先导物）、解读异种移植模型的疗效数据以及选择用于人类造血毒性研究的最准确动物模型。然而，可能需要其他类型的试验来确定骨髓抑制的潜在机制。在临床试验规划中，体外集落形成试验可用于阐明骨髓毒性的给药方案依赖性（这反过来可为作用机制提供线索）、规划细胞因子支持以及评估剂量递增效应。相对于具有已知临床骨髓毒性和给药方案依赖性的化合物，可测量集落形成的抑制情况，以了解在临床试验期间特定剂量下预期的毒性以及个体间的异质性程度。体外数据的预测准确性已通过烷化剂的验证研究得到证实。
