Differential sensitivity of double minute chromosomes to hydroxyurea treatment in cultured methotrexate-resistant mouse cells |
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| Institution: | 1. Laboratory of Structural Biology, Graduate School of Systems Life Sciences, Hakozaki 6-10-1, Fukuoka 812-8581, Japan;2. Laboratory of Biochemistry, Department of Bioscience and Biotechnology, Graduate School, Faculty of Agriculture, Kyushu University, Hakozaki 6-10-1, Fukuoka 812-8581, Japan;3. Department of Health and Nutrition Sciences, Faculty of Health and Social Welfare Science, Nishikyushu University, 4490-9 Ozaki, Kanzaki-machi, Kanzaki-shi, Saga 842-8585, Japan;1. School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA;2. Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA;1. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA;2. Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA;3. Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA;1. Department of Medical Biochemistry and Cell Biology, University of Gothenburg, P.O. Box 440, 405 30 Gothenburg, Sweden;2. Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27514, USA;3. Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany;4. Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;5. Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0QQ, UK;6. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden;1. Immunology Program, Infectious Diseases Service, Department of Medicine, Lucille Castori Center for Microbes Inflammation and Cancer, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;2. Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;3. Electron Microscopy Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;4. Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;5. Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA;6. Summer Undergraduate Research Program, Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;7. Science Research Program, Ossining High School, Ossining, NY 10562, USA |
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| Abstract: | Treating mammalian cells with continuous sub-lethal doses of Hydroxyurea (HU) causes the loss of double minute chromosomes (DMs) containing amplified oncogenes in culture. Recently, we have shown that treating glioblastoma multiforme cells in culture with low doses of HU causes the loss of DMs containing epidermal growth factor receptor genes. Loss of amplified EGFR genes was accompanied by cessation of growth, and greatly decreased tumorigenicity. To further study HU-induced elimination of DMs we have now followed the fate of dihydrofolate reductase gene (DHFR) amplifying DMs in methotrexate-resistant mouse cells during simultaneous treatment with both MTX and HU. We report that in the presence of both HU and MTX, the amplified genes decreased to 25% of starting levels in the first week of treatment, but that ultimately the cells become resistant to HU and reamplify the DHFR gene. We also report that some DHFR amplifying DMs are much more sensitive to HU than others. This study demonstrates that HU does not simply increase the rate of passive loss of DMs. |
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