Studies on the effect of asparaginase in paediatric leukaemia

Coe, N

Abstract

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.
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Citation

Coe, N. Studies on the effect of asparaginase in paediatric leukaemia. (Thesis). Salford : University of Salford

• Thesis Type: Thesis
• Deposit Date: Oct 3, 2012
• Award Date: Jan 1, 2010