Modulation of DNA damage by pentoxifylline and alpha-tocopherol in skin fibroblasts exposed to Gamma rays.
Previous in vivo studies showed the combination pentoxifylline (PTX) and alpha-tocopherol was highly efficient in reducing late radiation-induced skin damage. The present work aimed at investigating the molecular and cellular mechanisms involved in the effects of this combination. Primary cultures of confluent dermal fibroblasts were gamma-irradiated in the presence of PTX and trolox (Tx), the water-soluble analogue of alpha-tocopherol. Drugs were added either before or after radiation exposure and were maintained over time. Their antioxidant capacity and their effect on radiation-induced ROS production was assessed together with cell viability and clonogenicity. DNA damage formation was assessed by the alkaline comet assay and by the micronucleus (MN) test. Cell cycle distribution was also determined. The combination of PTX/ Tx was shown to reduce both immediate and late ROS formation observed in cells after irradiation. Surprisingly, decrease in DNA strand breaks measured by the comet assay was observed any time drugs were added. In addition, the micronucleus test revealed that for cells irradiated with 10 Gy, a late significant increase in MN formation occurred. The combination of PTX/Tx was shown to be antioxidant and to decrease radiation-induced ROS production. The observed effects on DNA damage at any time the drugs were added suggest that PTX/Tx could interfere with the DNA repair process.
Laurent
Carine
C
Laboratoire de Dosimétrie Biologique, DRPH/SRBE, Institut de Radioprotection et de Sûreté Nucléaire, F-92262 Fontenay-aux-Roses, France.
Pouget
Jean-Pierre
JP
Voisin
Philippe
P
D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects* / Q000528:radiation effects*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004338:Drug Combinations; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects*; D006801:Humans; D010431:Pentoxifylline / Q000008:administration & dosage*; D011837:Radiation-Protective Agents / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism; D012879:Skin Physiological Phenomena / Q000187:drug effects / Q000528:radiation effects; D024502:alpha-Tocopherol / Q000008:administration & dosage*
D004338:Drug Combinations; D011837:Radiation-Protective Agents; D017382:Reactive Oxygen Species; D004247:DNA; D024502:alpha-Tocopherol; D010431:Pentoxifylline