Resistance to 1-β-d-Arabinofuranosylcytosine after High-Dose Treatment in Childhood Lymphoblastic Leukemia: Isolation of a Drug Resistant and a Sensitive Cell Line

Abstract

A patient with acute lymphoblastic leukemia refractory to conventional combination chemotherapy schedules was treated with high-dose 1-β-d-arabinofuranosylcytosine (ara-C) (8 doses of 3 g/m²). The patient achieved complete remission but relapsed 6 weeks later. Two cell lines, PER-145 and PER-163, were established from bone marrow samples obtained before and after treatment, respectively. Both cells represent common acute lymphoblastic leukemia cells (CALLA⁺, HLA-DR⁺, sIg^-, cIg^-). Exposure of the two cell lines to ara-C in vitro revealed that the primary line PER-145 is susceptible to ara-C, while cell line PER-163 is more than 1000-fold more resistant (based on 50% inhibitory doses for growth in culture). Moreover, it was observed that ara-C concentrations from 1 to 33 µg/ml resulted in the stimulation of this cell line. Five weeks after his relapse the patient was given another high-dose ara-C course during which the blasts increased by a factor of 10, thus showing a response in vivo similar to that of the PER-163 cells in vitro. This pair of human acute lymphoblastic leukemia cells provides a unique opportunity to investigate the mechanisms underlying the acquired resistance and proliferative response to ara-C.