Department of Medicine III, Hematology, Oncology and Transfusion Medicine, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
Invest New Drugs. 2012 Aug;30(4):1396-403. doi: 10.1007/s10637-011-9705-6. Epub 2011 Jul 13.
The novel AKT inhibitor perifosine possesses myelopoiesis-stimulating effects in rodents. We studied the in vitro effects of the novel agents perifosine, bortezomib and lenalidomide in addition to adriamycin against normal human hematopoietic progenitor cells (HPC) using different clonogenic and non-clonogenic assays. All agents inhibited colony-forming unit (CFU) formation, perifosine inhibiting mainly CFU-granulocyte/macrophage formation and the other agents burst-forming unit-erythroid formation. Perifosine combined with lenalidomide or adriamycin tended to act antagonistically in suppressing CFU formation. Despite their inhibition of CFU formation, perifosine, bortezomib and lenalidomide induced only slight or moderate cytotoxicity in CD34(+) selected HPC, as assessed using different assays such as flow cytometry-based detection of activated caspases and immunohistochemistry studies (e.g., Ki-67 staining). In contrast to its myelopoiesis-stimulating effects in rodents, perifosine--like bortezomib and lenalidomide--suppresses the clonogenic potential of HPC from healthy donors in vitro and thus probably plays no role in preventing neutropenia or in shorting its duration after intensive chemotherapy. However, all these novel agents typically induce only slight or moderate suppression of the clonogenic potential or loss of viability of normal HPC at clinically achievable plasma concentrations, assuming that hematoxicity is manageable and functional HPC can be collected after treatment with these compounds.
新型 AKT 抑制剂帕非司他在啮齿类动物中具有刺激骨髓生成的作用。我们研究了新型药物帕非司他、硼替佐米和来那度胺以及阿霉素对正常人类造血祖细胞（HPC）的体外作用，使用了不同的集落形成和非集落形成测定法。所有药物均抑制集落形成单位（CFU）的形成，帕非司他主要抑制 CFU-粒细胞/巨噬细胞的形成，而其他药物则抑制红系爆式集落形成单位的形成。帕非司他与来那度胺或阿霉素联合使用时，在抑制 CFU 形成方面倾向于表现出拮抗作用。尽管帕非司他、硼替佐米和来那度胺抑制 CFU 的形成，但如通过流式细胞术检测活化半胱天冬酶和免疫组织化学研究（例如 Ki-67 染色）等不同测定法评估，其对 CD34+选择的 HPC 仅表现出轻微或中度的细胞毒性。与在啮齿类动物中具有刺激骨髓生成的作用不同，帕非司他——与硼替佐米和来那度胺一样——在体外抑制来自健康供体的 HPC 的集落形成潜力，因此可能不会在预防中性粒细胞减少症或缩短强化化疗后的持续时间方面发挥作用。然而，假设血液毒性是可控制的，并且可以在用这些化合物治疗后收集功能性 HPC，则所有这些新型药物通常仅在临床可达到的血浆浓度下对正常 HPC 的集落形成潜力或活力产生轻微或中度抑制作用。
