Background : Nelarabine (NEL) is a new purine nucleoside analogue that 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 analogue resistant T-ALL Jurkat cell line model (Jurkat+C) induced by incubation in medium containing cytarabine (AraC) at LC₅₀ of the control. Jurkat+C showed resistance to NEL and Fludarabine as 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 analogues on 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.