All-trans-retinoic acid increases cytosine arabinoside cytotoxicity in HL-60 human leukemia cells in spite of decreased cellular ara-CTP accumulation

摘要: Summary Background: Accumulation of the cytosine arabinoside (ara-C) metabolite ara-C-triphosphate (ara-CTP) in leukemic blast cells is considered to be main determinant ara-C cytotoxicity vitro and vivo. Retinoids such as a//-?ra«.s-retinoic acid (ATRA) have been shown increase sensitivity acute myelogenous (AML) ara-C. To investigate mechanism this sensitisation, hypothesis was tested that ATRA augments cellular ara-CTP levels human-derived leukemia HL-60 cells. Materials methods: The effect 13-cisretinoic on accumulation ara-C-induced apoptosis studied. Ara-CTP were measured by highperformance liquid chromatography (HPLC), tetrazolium (MTT) assay, occurrence DNA fragmentation (gel electrophoresis), cell shrinkage loss (flow cytometry). Results: Pretreatment with (0.01-1 uM) caused a significant decrease intracellular levels; e.g., incubation for 72 hours 1 uM prior one hour 10 reduced 41% ± 4% control. Similar results obtained after preincubation 7J-C/.5-retinoic acid. In spite decreased levels, combination supraadditive augmented apoptosis. Conclusions: At therapeutically relevant concentrations increased induced but augmentation not corollary elevated levels. feasibility treatment optimisation via strategies other than those involving elevation should investigated further.