Schurig J E, Schlein A, Florczyk A P, Farwell A R, Bradner W T
Exp Hematol. 1985;13 Suppl 16:101-5.
An important objective of new anticancer drug discovery programs is identification of agents that are less myelosuppressive than those currently available. We have developed several animal models to evaluate these drugs for myelosuppression. Our screening model measures changes in neutrophil counts in mice as an indicator of myelosuppression. This model correctly predicted the myelosuppressive effects of 13 (76%) of 17 known agents. Cisplatin, carboplatin, spiroplatin, and marcellomycin caused no reduction in the neutrophil counts, representing four (24%) of 17 false negatives. Our secondary evaluation system is the more labor-intensive murine CFU-C assay on femoral bone marrow cells from drug-treated mice. Known myelosuppressive drugs such as mitomycin C, doxorubicin, and BCNU, as well as the false negatives from the mouse neutropenia model (cisplatin, carboplatin, spiroplatin, and marcellomycin) caused marked inhibition of colony formation 24 h after dosing; bleomycin was inactive. Advanced evaluations are performed using ferrets in which neutrophil counts can be monitored in the same animal for 28 days after treatment. Mitomycin C, doxorubicin, and BCNU caused significant reductions in the neutrophil counts whereas bleomycin had no effect. Importantly, cisplatin and marcellomycin also caused significant reductions in the neutrophil counts. Although the mouse neutropenia model is a rapid assay, there is potential for false-negative predictions. It is important that other test systems be used for more advanced evaluation of drugs identified by this model as being less myelosuppressive than reference drugs. The mouse CFU-C and ferret hematology models are suitable for this purpose in that they can identify the false-negative predictions as well as identify less myelosuppressive drugs such as bleomycin.
新型抗癌药物研发项目的一个重要目标是找到比现有药物骨髓抑制作用更小的药物。我们已经开发了几种动物模型来评估这些药物的骨髓抑制作用。我们的筛选模型通过测量小鼠中性粒细胞计数的变化来作为骨髓抑制的指标。该模型正确预测了17种已知药物中13种（76%）的骨髓抑制作用。顺铂、卡铂、螺铂和马塞洛霉素未导致中性粒细胞计数减少，这17种药物中有4种（24%）出现假阴性结果。我们的二级评估系统是对药物处理小鼠的股骨骨髓细胞进行更耗时的小鼠CFU-C检测。已知的骨髓抑制药物如丝裂霉素C、阿霉素和卡氮芥，以及小鼠中性粒细胞减少模型中的假阴性药物（顺铂、卡铂、螺铂和马塞洛霉素）在给药后24小时均导致集落形成受到显著抑制；博来霉素无活性。使用雪貂进行进一步评估，在处理后的28天内可在同一只动物中监测中性粒细胞计数。丝裂霉素C、阿霉素和卡氮芥导致中性粒细胞计数显著减少，而博来霉素无作用。重要的是，顺铂和马塞洛霉素也导致中性粒细胞计数显著减少。虽然小鼠中性粒细胞减少模型是一种快速检测方法，但存在假阴性预测的可能性。对于该模型鉴定出的骨髓抑制作用比参考药物小的药物，使用其他检测系统进行更深入的评估非常重要。小鼠CFU-C和雪貂血液学模型适用于此目的，因为它们可以识别假阴性预测结果，并识别出骨髓抑制作用较小的药物，如博来霉素。
