Cell cycle defect in connection with oxygen and iron sensitivity in Fanconi anemia lymphoblastoid cells.
Fanconi anemia (FA) is an autosomal recessive disorder involving progressive pancytopenia, skeletal malformations, and a predisposition to leukemia. The in vitro growth of FA fibroblasts is impaired, due to a defective G2 phase traverse of the cell cycle. Analyzing the cell cycle of lymphoid cell lines (LCLs) obtained from peripheral blood of FA patients by transformation with Epstein-Barr virus, we found a similar G2 phase defect, which was dependent upon the oxygen concentration. In addition, FA cells exhibited hypersensitivity toward cis-dichlorodiammineplatinum and mitomycin C, and moderate sensitivity toward trans-dichlorodiammineplatinum. FA cells, however, showed no elevated sensitivity toward paraquat, an intracellular generator of superoxide radicals, or cumene hydroperoxide, a model organic peroxide. Chelating iron with low concentrations of o-phenanthrolin improved cell proliferation and G2 phase transit of FA cells at 20% oxygen, but little at 5% oxygen. LCL cultures from healthy subjects were inhibited in their proliferation rate at all concentrations of o-phenanthrolin. Exposure to excess iron, on the other hand, was very toxic to FA cells at 20%, but less toxic at 5% oxygen. In conclusion, the FA mutation leads to a cell cycle defect, which is expressed in cultures of lymphoid cells from FA patients, and involves hypersensitivity toward bifunctional alkylating agents, oxygen, and iron.
Poot
M
M
Department of Human Genetics, University of Würzburg, Germany.
Gross
O
O
Epe
B
B
Pflaum
M
M
Hoehn
H
H
D000477:Alkylating Agents / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000276:immunology; D002461:Cell Line, Transformed / Q000166:cytology / Q000378:metabolism / Q000821:virology; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004996:Ethidium; D005199:Fanconi Anemia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005456:Fluorescent Dyes; D016193:G1 Phase / Q000276:immunology; D016195:G2 Phase / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000502:physiology; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism; D008297:Male; D008677:Metaphase / Q000276:immunology; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000494:pharmacology; D016196:S Phase / Q000276:immunology; D012680:Sensitivity and Specificity
D000477:Alkylating Agents; D005456:Fluorescent Dyes; D017382:Reactive Oxygen Species; D004247:DNA; D007501:Iron; D004996:Ethidium; D001973:Bromodeoxyuridine; D010100:Oxygen