Studies on the effect of asparaginase in paediatric leukaemia

• Main Author: Coe, Nicholas
• Published: University of Salford 2010
• Subjects: 618.92
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.535486

Asparaginase, an important agent in the treatment of acute lymphoblastic leukaemia, is thought to cause cell death by depriving lymphoblasts of asparagine. However, because asparaginase also hydrolyses glutamine, a critical fuel for normal lymphocyte function, the mechanism of asparaginase action requires further investigation. Plasma samples from newly diagnosed children who had received either native E. coli or pegylated (PEG)- asparaginase were assayed to determine asparagine and glutamine levels, asparaginase activity and antibody formation to asparaginase. In parallel, in vitro studies of asparagine and glutamine deprivation on growth inhibition, apoptosis and the cell cycle in Molt-4 and NALM-6 cells were compared to the effects of asparaginase. Asparaginase activity in patient samples up to 3 days post treatment (native-treated) and 14 days (PEG- asparaginase) was generally good (> 100 U/L). Asparagine levels were depleted throughout treatment; however, there was large inter-patient variation in the extent of glutamine depletion which was reduced up to 9% of baseline levels. Antibodies were largely undetected in either study. When asparagine or glutamine was depleted after 72 hours in vitro, there was little effect on growth inhibition, apoptosis or cell cycle changes compared to cells treated with asparaginase. Only when asparagine and glutamine were depleted simultaneously to low, clinically relevant levels (3 uM and 50 uM respectively) was there an increase in apoptosis and growth inhibition, but little effect on the cell cycle. This suggests that within these cell populations under stress, a proportion of cells undergo division, some enter apoptosis and some become quiescent, which may allow the whole population to survive. In vivo, this may explain how 'resistant' populations persist, especially if low asparagine and glutamine levels are maintained by mesenchymal cells in the bone marrow. XIV