Analysis of adaptive response to bleomycin and mitomycin C |
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| Institution: | 1. CONICET – Subsecretaría de Cultura de Neuquén – Museo Carmen Funes, Av. Córdoba 55, Plaza Huincul, Neuquén, Argentina;2. CONICET – Instituto de Investigación en Paleobiología y Geología, Sede Alto Valle-Valle Medio-Universidad Nacional de Río Negro, Av. Roca 1242, Gral. Roca, Río Negro, Argentina;3. UNED, Senda del Rey 9, 28040, Madrid, Spain;4. University of Alberta, CW405 Biological Sciences Building, Edmonton, Alberta, Canada;1. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK;2. Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK;3. Institute for Systems Biology, Seattle, WA 98109, USA;4. Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands;5. Faculty of Medicine, Joint Research Centre for Computational Biomedicine, RWTH Aachen University, Aachen 52057, Germany;6. Department of EEMCS, Delft University of Technology, Delft 2628 CD, the Netherlands;7. Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA;8. Genetically Defined Diseases and Genomics, Bristol-Myers Squibb Research and Development, Hopewell, NJ 08534, USA;9. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet 08908, Barcelona, Catalonia, Spain;10. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;11. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA;12. Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, Barcelona 08003, Spain;13. Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Catalonia, Spain;14. Department of Physiological Sciences II of the School of Medicine, University of Barcelona, L’Hospitalet 08908, Barcelona, Catalonia, Spain;15. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA;16. Cancer Genomics Netherlands, Uppsalalaan 8, Utrecht 3584CT, the Netherlands |
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| Abstract: | Genetic instability resulting from the disturbances in various mechanisms of DNA-repair is the characteristic feature of cancer cells. One of the possibilities to evaluate the effectiveness of DNA-repair system is the adaptive response (AR) analysis. The AR is a phenomenon by which cells exposed to low, non-genotoxic doses of a mutagen become significantly resistant to a subsequent higher dose of the same or another genotoxic agent. Generally, it is postulated that AR is related to a reduction of damage by the induction of free radical detoxification and/or DNA-repair systems.The existence of various DNA-repair mechanisms poses the question whether there are differences in AR induced by chemicals causing DNA-damage that requires different pathways for its repair. In this paper we present the study on the AR induced by two chemical mutagens, bleomycin (BLM) and mitomycin C (MMC), which differ in their action on DNA. BLM is a radiomimetic agent causing mainly single-strand breaks (SSB) and double-strand breaks (DSB) and, thus, inducing chromosomal aberrations (CA). MMC is a potent bifunctional mutagen acting as an alkylating agent, causing DNA cross-links and inducing sister chromatid exchanges (SCEs).The protective effect induced by low doses of tested chemicals was analysed in whole blood human lymphocytes using cytogenetic endpoints (CA for BLM and SCE for MMC, respectively) as a measure of chromosomal instability. There was a significant difference between the protective effects induced by BLM and MMC in the lymphocytes of the same group of donors. The pre-treatment with a low dose of BLM-induced almost 50% decrease in the frequency of CA induced by challenging dose (CD), while the protective effect of MMC was below 20%. The higher AR induced by BLM may be related to the repair processing of BLM-induced DNA-damages. There was also a variability in ARs among individuals, which may reflect the differences in individual DNA-repair capacity. |
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