title: Inhibition of replication induces non-apoptotic cell death in fibroblast cell lines derived from LEC rats.
abstract: Hydroxyurea (HU), an anticancer drug, inhibits ribonucleoside diphosphate reductase and reduces pool sizes of deoxyribonucleoside triphosphate (dNTP). The reduction of dNTP results in inhibition of DNA replication. The cytotoxic effect of HU was investigated using fibroblast cell lines from LEC rats. LEC rat cells showed significantly higher sensitivity to HU than did cell lines from control WKAH rats. No significant differences were observed between the percentages of apoptotic cells in either LEC or WKAH rat cells that had been treated with HU and those that had not been treated with HU. LEC rat cells also showed significantly higher sensitivity to aphidicolin, which blocks DNA synthesis by inhibiting DNA polymerase alpha, than did WKAH rat cells. In both LEC and WKAH rat cells, intensified bands of p53 protein were observed immediately after treatment with HU. Although the high level of p53 protein persisted in WKAH rat cells until 6 hr post-incubation time after treatment with HU, the level of p53 protein had decreased at 6 hr post-incubation time in LEC rat cells. When the cells were X-irradiated in the absence or presence of HU, the ratio of the surviving fraction without HU to that with HU only slightly increased after X-irradiation in WKAH rat cells. In contrast, the ratio in LEC rat cells significantly increased after X-irradiation in a dose-dependent manner.
authors.affiliation: Department of Veterinary Radiology, School of Veterinary Medicine, Rakuno Gakuen University, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Hayashi
authors.forename: Taku
authors.initials: T
authors.lastname: Hamasu
authors.forename: Daiji
authors.initials: D
authors.lastname: Endoh
authors.forename: Reiko
authors.initials: R
authors.lastname: Shimojima
authors.forename: Toyo
authors.initials: T
authors.lastname: Okui
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects* / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004261:DNA Replication / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D006918:Hydroxyurea / Q000494:pharmacology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays; D014965:X-Rays
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; D006918:Hydroxyurea