Nelarabine resistance of childhood T-cell lymphoblastic leukemia/lymphoma cells

Background : Nelarabine(NEL) is a new purine nucleoside analoguethat has recently become available for both adults and children with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) and T- lymphoblastic lymphoma(T-LBL). We studied the drug resistance profile of eight children with T-ALL/LBL using an in vitro cytotoxic assay including NEL. Furthermore, we tried to establish a NEL resistant T-ALL cell line model to investigate the mechanism of NEL resistance.Results : Four of 8 patients showed a higher 50% lethal concentration (LC50) than the maximum clinical concentration of NEL. There were no correlations in LC50 values between NEL and other drugs. To study the mechanism of NEL resistance, we originally established a nucleoside analogueresistant T-ALL Jurkat cellline model (Jurkat+C) induced by incubation in medium containing cytarabine(AraC) at LC50 of the control. Jurkat+C showed resistance to NEL and Fludarabineas well as AraC but not Daunorubicin. Next, we studied the role of Equivalent Nucleoside Transporter-1 (ENT-1), a major cellular nucleoside transporter, in the acquired drug resistance in Jurkat+C. Nitrobenzylmercaptopurine riboside, an ENT-1- specific inhibitor, showed an inhibitory effect of nucleoside analogueson in vitro toxicity in both Jurkat and Jurkat+C, while no differences in ENT-1 mRNA expression levels between Jurkat and Jurkat+C were found.Conclusions : In vitro NEL resistance was seen in half of the tested childhood T-ALL cells. We could establish the NEL resistant T-ALL cell line model by AraC exposure. ENT-1 may partly act as a transporter of NEL, but not play a key role in AraC induced NEL resistance. This cell line model may be useful to provide a mechanism to explain NEL resistance.