{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T15:01:52Z","timestamp":1790002912447,"version":"4.0.1"},"reference-count":35,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2003,7,11]],"date-time":"2003-07-11T00:00:00Z","timestamp":1057881600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2003,10,20]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Adequate intracellular concentrations of ara\u2010CMP, the monophosphorylated derivative of ara\u2010C, are essential for its cytotoxicity. The critical step for ara\u2010CMP formation is intracellular phosphorylation of ara\u2010C by deoxycytidine kinase (dCK). A common nucleoside resistance mechanism is mutation affecting the expression or the specificity of dCK. We describe the ability of a <jats:italic>tert<\/jats:italic>\u2010butyl <jats:italic>S<\/jats:italic>\u2010acyl\u2010thioethyl (SATE) derivative of ara\u2010CMP (UA911) to circumvent ara\u2010C resistance in a dCK\u2010deficient human follicular lymphoma cell line (RL\u2010G). The RL\u2010G cell line was produced by continuous exposure to gemcitabine and displayed low dCK mRNA and protein expression that conferred resistance both to ara\u2010C (2,250\u2010fold) and to gemcitabine (2,092\u2010fold). RL\u2010G cells were able to take up the UA911 pronucleotide by diffusion and metabolize it to the corresponding ara\u2010CMP and ara\u2010CTP nucleotides, exhibiting a 199\u2010fold reduction in resistance ratios, and a similar cell cycle arrest to the parental RL\u20107 cells. Exposures to 10, 50 or 100 \u03bcM concentrations of UA911 produced 160 \u00b1 7, 269 \u00b1 8 and 318 \u00b1 62 pmol ara\u2010CTP\/mg protein in RL\u20107 cells, and 100 \u00b1 12, 168 \u00b1 10 and 217 \u00b1 39 pmol ara\u2010CTP\/mg protein in RL\u2010G cells, respectively. Exposure of RL\u2010G cells to underivatized, radiolabeled ara\u2010C produced no detectable amounts of the active triphosphate metabolites. We conclude that the UA911 pronucleotide is capable of overcoming dCK\u2010mediated resistance. This result can be attributed to the unique cellular metabolism of the SATE pronucleotides giving rise to the intracellular delivery of ara\u2010CMP to dCK\u2010deficient cells. \u00a9 2003 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.11339","type":"journal-article","created":{"date-parts":[[2003,8,22]],"date-time":"2003-08-22T13:36:44Z","timestamp":1061559404000},"page":"149-154","source":"Crossref","is-referenced-by-count":14,"title":["Sensitization of ara\u2010C\u2010resistant lymphoma cells by a pronucleotide analogue"],"prefix":"10.1002","volume":"107","author":[{"given":"Carlos Mar\u00eda","family":"Galmarini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyn L.","family":"Clarke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl 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