Comparison of the induction of apoptosis in human leukemic cell lines by 2',2'-difluorodeoxycytidine (gemcitabine) and cytosine arabinoside.
The induction of DNA fragmentation by cytosine arabinoside (araC) and 2',2'-difluorodeoxycytidine (dFdC, gemcitabine) was compared in human leukemic cell lines. For both araC and dFdC this process was time- and concentration-dependent and resulted in loss of clonogenic survival of HL-60 myeloid leukemic cells. There was a marked difference in the potency between these two analogs in inducing apoptosis. A 6 h exposure to 5 microM araC was required to produce DNA laddering in HL-60 cells, whereas dFdC at a concentration 100-fold less (0.05 microM) was sufficient to produce similar results. Pre-incubation of HL-60 cells with staurosporine, a non-specific protein kinase C inhibitor, increased the level of apoptosis induced by a 3 h exposure to araC or dFdC, suggesting the possible involvement of this family of enzymes in this process. Also, dFdC was able to increase the expression of both c-jun and c-fos in Molt-3 leukemic cells with a concentration known to induce apoptosis in this cell line.
Bouffard
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DY
Department of Pharmacology, Université de Montréal, Québec, Canada.
Momparler
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RL
D000470:Alkaloids / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015152:Blotting, Northern; D003561:Cytarabine / Q000494:pharmacology*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos; D016758:Genes, jun; D018922:HL-60 Cells / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019311:Staurosporine; D014407:Tumor Cells, Cultured / Q000187:drug effects; D000093542:Gemcitabine
D000470:Alkaloids; D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D003561:Cytarabine; D003841:Deoxycytidine; D011493:Protein Kinase C; D019311:Staurosporine; D000093542:Gemcitabine