Schurig J E, Florczyk A P, Bradner W T
Cancer Chemother Pharmacol. 1986;16(3):243-6. doi: 10.1007/BF00293985.
We evaluated 17 clinically used anticancer drugs for their effects on total WBC and absolute neutrophil counts in BDF1 mice. These drugs were selected from three categories, based on their myelosuppressive effects in man: myelosuppression is dose-limiting; myelosuppression occurs but is not dose-limiting; or myelosuppression does not occur. The ability of each drug to cause myelosuppression in mice was determined by its effect on the neutrophil count 4 days after single-dose treatment. The neutropenic effect of the maximum tolerated dose (LD0-20) of each drug was characterized as marked (greater than 65% decreases), moderate (35%-65% decreases), or minimal (less than 35% decreases) to correspond with the three clinical categories of myelosuppression. The neutropenic effects in mice correctly predicted (true + or true -) the myelosuppressive effects in man for 13 of the 17 drugs (76%). Marcellomycin and the platinum complexes cisplatin, carboplatin, and spiroplatin did not cause neutropenia at maximum tolerated doses. These represent false-negative predictions, since the drugs are myelosuppressive in man. The results with the platinum complexes indicate that this method is not suitable as a means of screening these agents for myelosuppression. Excluding the platinum complexes, the predictions were correct for 12 of 13 drugs (92%). Therefore, this model is considered a good predictor for the myelosuppressive effects of anticancer drugs in man (except platinum complexes) and can be used effectively to screen drugs for this toxicity. However, it is important that drugs identified by this system as being less myelosuppressive than the reference agent(s) be evaluated further, since all the incorrect predictions were false negatives.
我们评估了17种临床使用的抗癌药物对BDF1小鼠白细胞总数和中性粒细胞绝对计数的影响。这些药物根据其对人体的骨髓抑制作用分为三类：骨髓抑制是剂量限制性的；发生骨髓抑制但不是剂量限制性的；或不发生骨髓抑制。每种药物在小鼠中引起骨髓抑制的能力通过单剂量治疗4天后对中性粒细胞计数的影响来确定。每种药物最大耐受剂量（LD0 - 20）的中性粒细胞减少效应被表征为显著（减少大于65%）、中度（减少35% - 65%）或最小（减少小于35%），以对应骨髓抑制的三种临床类别。小鼠中的中性粒细胞减少效应正确预测（真阳性或真阴性）了17种药物中13种（76%）在人体中的骨髓抑制效应。马塞洛霉素和顺铂、卡铂、螺铂等铂类复合物在最大耐受剂量下未引起中性粒细胞减少。这些代表假阴性预测，因为这些药物在人体中具有骨髓抑制作用。铂类复合物的结果表明，这种方法不适合作为筛选这些药物骨髓抑制作用的手段。排除铂类复合物后，13种药物中有12种（92%）的预测是正确的。因此，该模型被认为是预测抗癌药物在人体中（铂类复合物除外）骨髓抑制作用的良好指标，可有效用于筛选具有这种毒性的药物。然而，重要的是，通过该系统鉴定为骨髓抑制作用小于参考药物的药物应进一步评估，因为所有错误预测均为假阴性。
