Gómez Susana G, Bueren Juan A, Faircloth Glynn, Albella Beatriz
PharmaMar, S.A. Polígono Industrial La Mina, Avda de los Reyes, 1. 28770 Colmenar Viejo, Madrid, Spain.
Toxicol In Vitro. 2003 Oct-Dec;17(5-6):671-4. doi: 10.1016/s0887-2333(03)00139-5.
Acute cytotoxic exposure causes decreases in bone marrow progenitors that precedes the neutrophil nadir. Experiments in animal models reveal a relationship between the reduction in granulocyte-macrophage progenitors (CFU-GM) and the decrease in absolute neutrophil count [Toxicol. Pathol. 21 (1993) 241]. Recently, the prevalidation of a model for predicting acute neutropenia by the CFU-GM assay has been reported [Toxicol. In Vitro 15 (2001) 729]. The model was based on prediction of human MTD by adjusting the animal-derived MTD for the differential sensitivity between CFU-GM from animal species and humans. In this study, this model has been applied on a new antitumoral drug, Yondelis (Ecteinascidin; ET-743). Preclinical studies showed that hematotoxicity was the main side effect in mice, being the MTD of 600 microg/m2 [Drugs Future 21 (1996) 1155]. The sensitivity of myeloid progenitors was higher in mice than in humans, with IC90 values of 0.69+/-0.22 nM and 1.31+/-0.21 nM for murine and human CFU-GMs respectively. This study predicts a human MTD of 1145 microg/m2. The reported human MTD of ET-743 given as a 24-h continuous infusion every 3 weeks is 1800 microg/m2 [J. Clin. Oncol. 19 (2001) 1256]. Since our predicted MTD is within fourfold of the actual MTD (the interspecies variation in tolerated dose due to differences in clearance rates, metabolism pathways and infusion rate) the result confirms the profit of the prediction model.
急性细胞毒性暴露会导致骨髓祖细胞减少，且该减少发生在中性粒细胞计数最低点之前。动物模型实验揭示了粒细胞 - 巨噬细胞祖细胞（CFU - GM）减少与绝对中性粒细胞计数降低之间的关系[《毒理病理学》21卷（1993年）第241页]。最近，已有关于通过CFU - GM测定法预测急性中性粒细胞减少模型的预验证报告[《毒理学体外研究》15卷（2001年）第729页]。该模型基于通过调整动物源性最大耐受剂量（MTD）来预测人类MTD，以考虑动物物种和人类CFU - GM之间的差异敏感性。在本研究中，此模型已应用于一种新的抗肿瘤药物Yondelis（埃博霉素；ET - 743）。临床前研究表明，血液毒性是小鼠的主要副作用，MTD为600μg/m²[《药物未来》21卷（1996年）第1155页]。小鼠髓系祖细胞的敏感性高于人类，小鼠和人类CFU - GM的IC90值分别为0.69±0.22 nM和1.31±0.21 nM。本研究预测人类MTD为1145μg/m²。每3周进行一次24小时连续输注时，已报道的ET - 743人类MTD为1800μg/m²[《临床肿瘤学杂志》19卷（2001年）第1256页]。由于我们预测的MTD在实际MTD的四倍以内（由于清除率、代谢途径和输注速率差异导致的种间耐受剂量变化），结果证实了该预测模型的益处。
