Erickson-Miller C L, May R D, Tomaszewski J, Osborn B, Murphy M J, Page J G, Parchment R E
Hipple Cancer Research Center, Dayton, OH 45439, USA.
Cancer Chemother Pharmacol. 1997;39(5):467-72. doi: 10.1007/s002800050600.
20(S)-Camptothecin (CAM), topotecan (TPT, active ingredient in Hycamtin) and 9-amino-20(S)-camptothecin (9AC) are topoisomerase I inhibitors that cause similar dose-limiting toxicities to rapidly renewing tissues, such as hematopoietic tissues, in humans, mice, and dogs. However, dose-limiting toxicity occurs at tenfold lower doses in humans than in mice. The purpose of the current study was to determine whether hematopoietic progenitors of the myeloid lineage from humans, mice, and dogs exhibit the differential sensitivity to these compounds that is evident in vivo.
Drug-induced inhibition of in vitro colony formation by a myeloid progenitor in human, murine, and canine marrow colony-forming unit-granulocyte/macrophage (CFU-GM) provided the basis for interspecies comparisons at concentrations which inhibited colony formation by 50% (IC50) and 90% (IC90).
Murine IC90 values were 2.6-, 2.3-, 10-, 21-, 5.9-, and 11-fold higher than human values for CAM lactone (NSC-94600) and sodium salt (NSC-100880), TPT (NSC-609699), and racemic (NSC-629971), semisynthetic and synthetic preparations (NSC-603071) of 9AC, respectively. In contrast, canine IC90 values were the same as, or lower than, the human IC90 values for all six compounds.
The greater susceptibility of humans and dogs to the myelotoxicity of camptothecins, compared to mice, was evident in vitro at the cellular level. Differential sensitivity between murine and human myeloid progenitors explains why the curative doses of TPT and 9AC in mice with human tumor xenografts are not achievable in patients. Realizing the curative potential of these compounds in humans will require the development of therapies to increase drug tolerance of human CFU-GM at least to a level equal to that of murine CFU-GM. Because these interspecies differences are complicated by species-specific effects of plasma proteins on drug stability, not all in vitro assay conditions will yield results which can contribute to the development of such therapies.
20(S)-喜树碱（CAM）、拓扑替康（TPT，Hycamtin中的活性成分）和9-氨基-20(S)-喜树碱（9AC）是拓扑异构酶I抑制剂，在人类、小鼠和犬类中，它们对快速更新的组织（如造血组织）会引起相似的剂量限制性毒性。然而，人类发生剂量限制性毒性的剂量比小鼠低10倍。本研究的目的是确定人类、小鼠和犬类髓系谱系的造血祖细胞对这些化合物是否表现出在体内明显的差异敏感性。
药物诱导的人、鼠和犬骨髓集落形成单位-粒细胞/巨噬细胞（CFU-GM）中髓系祖细胞体外集落形成的抑制作用，为在抑制集落形成50%（IC50）和90%（IC90）的浓度下进行种间比较提供了基础。
对于CAM内酯（NSC-94600）和钠盐（NSC-100880）、TPT（NSC-609699）以及9AC的外消旋体（NSC-629971）、半合成和合成制剂（NSC-603071），小鼠的IC90值分别比人类的值高2.6倍、2.3倍、10倍、21倍、5.9倍和11倍。相比之下，所有六种化合物的犬类IC90值与人类IC90值相同或更低。
在细胞水平上，体外实验表明人类和犬类比小鼠对喜树碱的骨髓毒性更敏感。小鼠和人类髓系祖细胞之间的差异敏感性解释了为什么用人类肿瘤异种移植小鼠模型中TPT和9AC的治愈剂量在患者中无法达到。要实现这些化合物在人类中的治疗潜力，将需要开发提高人类CFU-GM药物耐受性至少达到小鼠CFU-GM水平的疗法。由于这些种间差异因血浆蛋白对药物稳定性的物种特异性影响而变得复杂，并非所有体外实验条件都能产生有助于开发此类疗法的结果。
