Optimization of drug administration order in anti-cancer drug combination therapy in hematopoietic stem cell transplantation

2015 Fiscal Year Final Research Report

• Project/Area Number: 25460203
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Hokkaido University
• Principal Investigator: SUGAWARA Mitsuru 北海道大学, 薬学研究科(研究院), 教授 (60332467)
• Co-Investigator(Kenkyū-buntansha): TAKEKUMA Yoh 北海道大学, 大学院薬学研究院, 准教授 (00396293)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: エトポシド / 細胞周期 / 白血病 / 造血幹細胞移植

Outline of Final Research Achievements

We demonstrated schedule-dependent cytotoxicity of VP-16 and 4-HPC (preactivated form of cyclophosphamide) in K-562 cells. When K-562 cells were pretreated with low concentrations of 4-HCP, cells subsequently exposed to VP-16 showed reduced viability. In contrast, there was no change in the viability of K-562 cells pretreated with low concentrations of VP-16, followed by exposure to 4-HPC. It was shown that 4-HPC caused cell cycle arrest at S phase. It was suggested that since VP-16 have cell cycle specificity for cell killing from early-S to mid-S phase, the effect of VP-16 was increased by pretreatment with 4-HPC. We also demonstrated schedule-dependent cytotoxicity of VP-16 and 4-HPC in P-gp-overexpressed K-562/P-gp cells. Cytotoxicity of VP-16 was enhanced in K-562/P-gp cells that were pretreated with a non-cytotoxic concentration of 4-HPC compared to that of cells not treated with 4-HPC. The findings may lead to improvements in clinical combination chemotherapy.

Free Research Field

薬物動態学