The metabolic basis of deoxyuridine cytotoxicity. Studies of cultured human lymphoblasts.
The metabolic consequences of deoxyuridine treatment in four cultured human lymphoblast lines (CCRF-CEM, RPMI-8402, JM, and BALM) were studied by cell growth experiments, flow cytometry, and measurement of 2'-deoxyribonucleoside triphosphate (dNTP) levels. DNA perturbations occurred in all lymphoblast lines, but there was no significant impairment of RNA synthesis. The DNA perturbations in CCRF-CEM, RPMI-8402, and BALM cells reflected inhibition of DNA synthesis, and the associated dNTP changes were consistent with ribonucleotide reductase inhibition or, specifically in BALM cells, with DNA alpha-polymerase inhibition. JM cells treated with an intermediate concentration of deoxyuridine developed a block at the G1/S boundary which was deoxyuridine concentration-dependent, but not specific for deoxyuridine (it was also seen with thymidine treatment) and not related to DNA synthesis inhibition. There were no idiosyncratic dNTP effects accompanying the G1/S boundary block, and the responsible metabolic mechanism remains to be determined.
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism; D003857:Deoxyuridine / Q000633:toxicity*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D012313:RNA / Q000378:metabolism; D013997:Time Factors
D003854:Deoxyribonucleotides; D012313:RNA; D004247:DNA; D003857:Deoxyuridine