Increased cytotoxicity of 2',2'-difluoro-2'-deoxycytidine in human leukemic cell-lines after a preincubation with cyclopentenyl cytosine.
The in vitro modulating effect of Cyclopentenyl cytosine (CPEC) on the metabolism of gemcitabine was studied in lymphocytic and myeloid leukemic cell-lines. In MOLT-3 cells, that were pretreated with CPEC, the incorporation of 2',2'-difluoro-2'-deoxycytidine triphosphate (dFdCTP) into DNA was significantly increased by 57-99% in comparison with cells that were only treated with gemcitabine. The increased incorporation of dFdCTP into DNA in CPEC pretreated cells was paralleled by an increase in apoptotic and necrotic cells of 17-34%. In HL-60 cells that were preincubated with CPEC, increased concentrations of the mono-/di- and triphosphate form of gemcitabine were observed, as well as an increased incorporation of dFdCTP into DNA (+773%). This increased incorporation was paralleled by a significant increase in apoptosis and necrosis. We conclude that CPEC enhances the incorporation of dFdCTP into DNA and thus increases the cytotoxicity of gemcitabine in lymphocytic and myeloid leukemic cell-lines.
Verschuur
A C
AC
Laboratory of Genetic Metabolic Diseases, Division of Clinical Chemistry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Van Gennip
A H
AH
Leen
R
R
Van Kuilenburg
A B P
AB
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D019731:Carbon-Nitrogen Ligases / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D002986:Clinical Trials as Topic; D003562:Cytidine / Q000031:analogs & derivatives* / Q000737:chemistry*; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D009336:Necrosis; D009369:Neoplasms / Q000188:drug therapy*; D013997:Time Factors; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D003841:Deoxycytidine; D003562:Cytidine; C045911:cyclopentenyl cytosine; D004247:DNA; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase; D000093542:Gemcitabine