Preferential stimulation of iododeoxyuridine phosphorylation by 5'-aminothymidine in human bladder cancer cells in vitro.
5'-Aminothymidine represents a novel class of compounds capable of antagonizing the feedback inhibition which normally regulates thymidine kinase. As a consequence, the uptake of iododeoxyuridine, a substrate of thymidine kinase, can be substantially increased by 5'-aminothymidine. in this study the phosphorylation, uptake, and cytotoxicity of iododeoxyuridine was markedly enhanced by 5'-aminothymidine in three human bladder cancer cell lines, T24, HT1197 and 647V. In contrast, neither the uptake nor the toxicity of iododeoxyuridine was increased by 5'-aminothymidine in normal human urothelial cells propagated in vitro. Although 30 microM 5'-aminothymidine increased the uptake of 3 microM iododeoxyuridine 4- to 5-fold in the HT1197 and 647V cells and 2.5-fold in the T24 cells, no stimulation was produced in the normal urothelial cells. The modulation of iododeoxyuridine uptake was associated with parallel changes in the inhibition of cellular replication. The cytotoxicity of iododeoxyuridine was strongly augmented by 5'-aminothymidine in the HT1197 and 647V cells, modestly increased in the T24 cells, and unchanged in the normal urothelial cells. The degree to which iododeoxyuridine phosphorylation was stimulated did not correlate with cellular replication rates or with intracellular thymidine triphosphate concentrations. Iododeoxyuridine uptake was markedly increased in the HT1197 (doubling time = 52 h) and 647V (doubling time = 24 h) cells, moderately in the rapidly growing cells T24 (doubling time = 20 h), and minimally in the normal urothelial cells which doubled every 32 h. In exponentially growing cells the thymidine triphosphate pools were approximately 18 microM in the normal cells and about 21, 24, and 35 microM in the HT1197, T24, and 647V cells, respectively. The use of 5'-aminothymidine and other compounds capable of antagonizing feedback inhibition may provide a new means of increasing the efficacy of cytotoxic nucleosides.
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D001692:Biological Transport / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D004357:Drug Synergism; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D007065:Idoxuridine / Q000378:metabolism*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013937:Thymidine Kinase / Q000378:metabolism; D013942:Thymine Nucleotides / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D013942:Thymine Nucleotides; C023821:5-(aminomethyl)-2'-deoxyuridine; D013937:Thymidine Kinase; D007065:Idoxuridine; D013936:Thymidine