In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia

Abstract

Summary. Factors that reduce the intracellular concentration of triphosphorylated cytarabine (ara-CTP), the active form of cytarabine (ara-C), may induce chemoresistance in acute myeloid leukaemia (AML) patients. These factors include reduced influx of ara-C by the hENT1 transporter, reduced phosphorylation by deoxycytidine kinase (dCK), and increased degradation by high Km cytoplasmic 5¢-nucleotidase (5NT) and/or cytidine deaminase (CDD). Increased levels of DNA polymerase a (DNA POL) and reduced levels of topoisomerase I (TOPO I) and topoisomerase II (TOPO II) have also been detected in ara-C-resistant cell lines. To determine whether these factors are implicated in clinical ara-C resistance, we analysed the expression of these parameters at diagnosis, using reverse transcription polymerase chain reaction, in the blast cells of 123 AML patients treated with ara-C. At diagnosis, hENT1, dCK, CDD, 5NT, TOPO I, TOPO II, DNA POL and MDR1 were expressed in 83%, 22%, 7%, 37%, 59%, 37%, 39% and 16% of patients respectively. In univariate analysis, patients with expression of 5NT or DNA POL at diagnosis had significantly shorter disease-free survival (DFS). In multivariate analysis, DNA POL positivity and hENT1 deficiency were related to a shorter DFS. In univariate analysis, patients with 5NT-positive blasts had significantly shorter overall survival (OS). In multivariate analysis, shorter OS was related to DNA POL positivity. These results suggest that expression of DNA POL, 5NT and hENT1 at diagnosis may be resistance mechanisms to ara-C in AML patients.

The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia

“…Our results are supported by the fact that hENT1 has been implicated as a crucial factor in ara-C sensitivity in previous studies (Galmarini et al, 2002b, c). Galmarini et al measured hENT1 mRNA expression in adult AML samples and demonstrated that hENT1 deficiency was related to a shorter disease-free survival (Galmarini et al, 2002c). In addition, elevated hENT1 mRNA expression explained the remarkable ara-C sensitivity of infants with MLL gene-rearranged ALL (Stam et al, 2003).…”

Differential gene expression profiles of radioresistant oesophageal cancer cell lines established by continuous fractionated irradiation

“…Protein kinase C is a known tumour metabolite in several proliferation-promoting pathways of EGF receptor signalling. Furthermore, Galmarini et al (2002) reported that CD73-positive acute myeloid leukaemia (AML) patients had worse disease-free survival and overall survival than negative patients, and suggested that CD73 expression might be a mechanism of resistance to cytarabine. To our knowledge, there have been no reports of an association between radioresistance and CD73.…”

Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells

“…21 Nevertheless, in CLL patients, although they show high mRNA levels for hENT1 and hENT2, mRNA amounts do not correlate with ex vivo sensitivity to fludarabine, whereas fludarabine influx does. 18 However, uptake measurements may not be a suitable tool to predict response to treatment in CLL because this technique is complex: it requires the use of radioactive-labeled drug, as well as a large number of cells.…”