Examination of irradiated neuroblastoma and neuroepithelial cell lines for the interrelationship between cell survival, micronucleation, apoptosis and DNA repair

[摘要] ENGLISH ABSTRACT:Predictive assays are of key importance in clinical radiotherapy, chemotherapyand toxicology. Prior to exposing malignant tissues to irradiation or drugs inthe clinic, a good understanding of the damage response to the cytotoxic agentis required. Such information is necessary for effective planning and treatment.Regrettably however the methods which detect DNA damage, namelymicronucleus, apoptosis and DNA repair assays do not rank cells according totheir intrinsic survival response to cytotoxic agents. The application ofpredictive assays based on micronuclei and apoptosis in the clinic thereforeremains unreliable. Using a panel of 7 neuroblastoma and 6 neuroepithelialcell lines, it is shown that damage assays also do not rank cell lines accordingto cell survival. However, radiosensitivity can be reconstructed frommicronuclei formation and apoptosis, and a new parameter, cell death due tosmall deletions, chromosome aberrations and misrepair. The interrelationshipsbetween radiation-induced micronuclei, apoptosis and repair is complex andvaries between cell lines. Micronuclei formation and apoptosis areexponentially interrelated. This suggests that these cell inactivation pathwaysare strongly correlated. Evidence exists to show that the expression ofapoptosis and micronuclei is influenced by the extent of DNA double-strandbreak repair within the first 2 hours after irradiation. Cell lines which repairmore damage in the first 2 hours express more micronuclei and less apoptosis.Micronuclei formation and apoptosis and are not significantly correlated withthe 20 hours slow repair component. There is however a strong correlation between 20 hours of repair and radiosensitivity, with the more radioresistantcell lines being more repair proficient. This suggests that the 2 hours (fast)DNA repair component is more error prone, and that cells lines repairing moredamage late after irradiation tend to show better survival. In conclusion,micronuclei formation, apoptosis and DNA repair are strictly cell type specificand are not suitable for predicting radiosensitivity in terms of cell survival.However, these assays are very useful for studies on the influences of dosemodifying agents i.e. oxygen tension, radiation modality, pH, cytotoxicsensitisers and radiation protectors which alter cellular responses and provideinsight into damage mechanisms.

[发布机构] Stellenbosch University