Schedule-dependent cytotoxicity of etoposide (VP-16) and cyclophosphamide in leukemia cell line K-562.
In allogeneic bone marrow transplantation (allo-BMT) in patients with leukemia, the combination of VP-16 and cyclophosphamide (CY) is commonly used for the conditioning regimen. In the present study, we demonstrated schedule-dependent cytotoxicity of VP-16 and CY in K-562 cells. K-562 cells were pretreated with low concentrations (2.5 and 5 µg/mL) of 4-hydroperoxycyclophosphamide (40487S), which is a preactivated analog of CY. It was confirmed that these concentrations did not influence cell viability. Cells subsequently exposed to 0.5-100 µg/mL of VP-16 showed reduced the viability compared to that of control cells not treated with 40487S. In contrast, there was no change in the viability of K-562 cells pretreated with low concentrations (0.5 and 1 µg/mL) of VP-16. It was confirmed that these concentrations did not influence cell viability. Viability of subsequently exposed to 1-20 µg/mL was not different from that of control cells not treated with VP-16. VP-16 caused cell cycle arrest at G₂/M phase. On the other hand, 40487S arrested the cell cycle at S phase. Thymidine-synchronized cells, VP-16 showed cell cycle specificity for cell killing from early-S to mid-S phase. On the other hand, 40487S showed cell cycle-independent cytotoxicity. Exposure of cells to VP-16 after 40487S induced a greater cytotoxic effect on K-562 cells. The findings may lead to improvements in clinical combination chemotherapy.
Laboratory of Pharmacokinetics, Department of Biopharmaceutical Sciences and Pharmacy, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Yuki
Y
Tazawa
Kazunori
K
Matsumura
Yoh
Y
Takekuma
Mitsuru
M
Sugawara
D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage*; D006801:Humans; D020014:K562 Cells; D007938:Leukemia
D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D003520:Cyclophosphamide