Altered expression of multidrug resistance (mDR1) gene in cells selected for resistance to 9-ß-D-Arabinofuranosylguanine
(English)Manuscript (preprint) (Other academic)
9-ß-D-Arabinofuranosylguanine (AraG) is an important and relatively new guanine nucleoside analogue that is highly toxic to T-cell maliguancies. Two resistant sublines with low activity of nucleoside phosphorylating enzymes, deoxycytidine kinase (dCK) (50-70% reduction) and deoxyguanosine kinase (dGK, 70-80% reduction), were generated from a MOLT-4 cell line with stepwise-increasing concentrations of AraG. As expected, the resistant sublines were highly cross-resistance to analogues that are activated by dCK and dGK such as cytosine arabinoside, cladribine, and fludarabine. Surprisingly, the resistant cells were siguificantly less sensitive to anthracyclines and podophyllotoxin derivatives resulting from decreased cellular drug accumulation restored by cyclosporin A, as determined by calcein uptake and flow cytometry studies. To clarify the mechanisms of this resistance, the gene expression of various multidrug resistance proteins, e.g. the multidrug resistance gene (mdr1), multidrng resistance-associated protein, lung resistance-associated protein and topoisomerase IIα or IIß were investigated. We found that the resistant cells overexpressed the mdr1 gene, as assessed by a real-time PCR, and contained higher levels of P-glycoprotein, as assessed by western blotting. The expression of other multidrug resistance proteins was not affected in the AraG-resistant sublines. These fmdings may be useful in the clinical trials of AraG singly and in combination with anthracyclines and related agents.
leukaemia, 9-ß-D-arabinofuranosylguanine, multidrug resistance, cytotoxicity
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-80287OAI: oai:DiVA.org:liu-80287DiVA: diva2:546409