Radiosensitization of normal human cells by LY294002: cell killing and the rejoining of DNA and interphase chromosome breaks.
The radiosensitizing effect of a phosphoinositide-3 kinase (PI3K) inhibitor, wortmannin, has been studied rather extensively, but there have been few studies on the radiosensitizing effect of another PI3K inhibitor, LY294002. In this report, we present the radiosensitizing effect of LY294002 using normal human cells. Clonogenic cell survival indicated that LY294002 enhanced the killing effect of gamma-rays in a dose-dependent manner, although this drug by itself did not affect the cell killing. To obtain a 10% cell survival, about one half of the radiation dose was needed when cells were treated with 50 microM LY294002 as compared to cells without the drug. A mild inhibition of repair of DNA double strand breaks (DSBs) was observed in irradiated normal human cells pre-treated with LY294002 (50 microM). At the interphase chromosome level, we also observed an increase in the number of residual breaks when irradiated cells were pre-treated with this drug (about 2-fold at 5 Gy). These results suggest that the inhibition of DSB repair mediated the radiosensitizing effect of LY294002 at the dose level that we used.
Okayasu
Ryuichi
R
International Space Radiation Laboratory, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan. rokayasu@nirs.go.jp
Takakura
Kaoru
K
Poole
Shannon
S
Bedford
Joel S
JS
D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology*; D002875:Chromosomes / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D007700:Kinetics; D009025:Morpholines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013997:Time Factors
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D011838:Radiation-Sensitizing Agents; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one