A free-radical hypothesis for the instability and evolution of genotype and phenotype in vitro.
It has been known for several decades that cultured murine cells undergo a defined series of changes, i.e., an in vitro evolution, which includes crisis, spontaneous transformation ('immortalization'), aneuploidy, and spontaneous neoplastic transformation. These changes have been shown to be caused by the in vitro environment rather than an inherent instability of the murine phenotype or genotype. Serum amine oxidases were recently identified as a predominant cause of crisis. These enzymes generate hydrogen peroxide from polyamine substrates that enter the extracellular milieu. This finding implicates free-radical toxicity as the underlying cause of in vitro evolution. We propose an oxyradical hypothesis to explain each of the stages of in vitro evolution and discuss its significance for cytotechnology and long-term cultivation of mammalian cell types.
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Division of Pharmacology & Toxicology, Hipple Cancer Research Center, Dayton, Ohio 45439-2092.
Natarajan
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D000782:Aneuploidy; D000818:Animals; D001769:Blood; D016923:Cell Death; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D002478:Cells, Cultured / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016922:Cellular Senescence; D003470:Culture Media / Q000633:toxicity*; D016895:Culture Media, Serum-Free; D005609:Free Radicals; D005838:Genotype; D051379:Mice; D008954:Models, Biological; D009857:Oncogenes; D009928:Organ Specificity; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000097:blood / Q000633:toxicity*; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors
D003470:Culture Media; D016895:Culture Media, Serum-Free; D005609:Free Radicals; D010088:Oxidoreductases; D010100:Oxygen