Effects of fludarabine and gemcitabine on human acute myeloid leukemia cell line HL 60: Direct comparison of cytotoxicity and cellular Ara-C uptake enhancement

• Published in: Leukemia research 1996, Vol.20 (1), p.37-45
• Main Authors: Santini, Valeria, D'Ippolito, Gianluca, Bernabei, Pietro Antonio, Zoccolante, Antonella, Ermini, Angela, Rossi-Ferrini, Pierluigi
• Format: Article
• Language: English
• Subjects: acute leukemia; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; arabinosylcytosine; Biological and medical sciences; cell cycle; Cell Division - drug effects; Cell Survival - drug effects; Cytarabine - pharmacokinetics; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Drug Interactions; Fludarabine; gemcitabine; General aspects; HL-60 Cells - drug effects; HL-60 Cells - metabolism; HL-60 Cells - pathology; Humans; Medical sciences; Pharmacology. Drug treatments; Thymidine - metabolism; Vidarabine - analogs & derivatives; Vidarabine - pharmacology
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/0145-2126(95)00106-9

This study was designed to compare the effects of fludarabine and gemcitabine on cytosine arabinoside (Ara-C) uptake and retention, and their specific cytotoxicity on HL 60 human acute myeloid leukemia cells. The leukemic blasts were exposed to either drug at equimolar concentrations (10 μM) for 3 h and further incubated with Ara-C (5 μM), added immediately (day 0) or after an interval of 24 h in which cells were kept in a drug-free medium (day 1). On day 0, leukemic cells exposed to fludarabine 10 μM had a significant ( P < 0.01) increase in Ara-C uptake (297 ± 11 pmol/10 7 cells) with respect to control cells (not pre-treated: 195 ± 10 pmol/10 7 cells). After treatment of leukemic cells with fludarabine, cytoplasmic Ara-C peaked after 180 min of exposure, as well as nuclear bound Ara-C. At the same time, a significant decrease in the number of S-phase leukemic cells, consistent with depressed [ 3H]TdR uptake was observed. Although on day 0 gemcitabine 10 μM did not have potentiating effects on Ara-C uptake, it showed a high degree of intrinsic cytotoxicity as a single agent (clear from cell cycle distribution, [ 3H]TdR uptake, plating efficiency (PE) data and percentage of apoptotic cells). Cells exposed to gemcitabine, on the other hand, showed on day 1 a significant increase in Ara-C uptake (2.4 × control values in the cytoplasmic and 3 × in the nuclear fractions) and a reduced number of S-phase blasts, [ 3H]TdR uptake and PEs, as well as an increased apoptotic cell death. Evidently, it is possible to modulate Ara-C uptake by leukemic cells with gemcitabine. Although this effect is similar to that demonstrated with fludarabine, its kinetics and time of efficacy are different and also, because of its intrinsic higher cytotoxicity and lack of important side effects, gemcitabine could be considered a suitable candidate for Ara-C association therapy in acute leukemia.