title: Schedule-dependent cytotoxicity of Etoposide and cyclophosphamide in P-glycoprotein-expressing human leukemic K-562 cells.
abstract: Combination chemotherapy is often used to treat cancer. Many studies have shown schedule-dependent effects between anticancer drugs. Our previous studies showed that K-562 cells pretreated with non-cytotoxic concentrations of 4-hydroperoxycyclophosphamide (4-HPC), which is a preactivated analog of cyclophosphamide (CY), enhanced the cytotoxicity of etoposide (VP-16). The appearance of cellular resistance to anticancer drugs is a major problem in cancer chemotherapy. P-Glycoprotein (P-gp) plays an important role in drug resistance, and VP-16 is a substrate for this efflux pump. In the present study, we demonstrated schedule-dependent cytotoxicity of VP-16 and CY 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. 4-HPC arrested the cell cycle at S phase. Cells in S phase are most sensitive to VP-16. The results suggest that cell cycle arrest by 4-HPC pretreatment may be responsible for the enhanced cytotoxicity of VP-16. The findings in this study should lead to improvements in clinical combination chemotherapy.
authors.affiliation: Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tazawa
authors.forename: Ippei
authors.initials: I
authors.lastname: Usukubo
authors.forename: Kazuki
authors.initials: K
authors.lastname: Takada
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takekuma
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shibayama
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sugawara
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001692:Biological Transport / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage*; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005047:Etoposide; D003520:Cyclophosphamide; C011272:perfosfamide