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CPX-351 exhibits hENT-independent uptake and can be potentiated by fludarabine in leukaemic cells lines and primary refractory AML

Anderson, Elizabeth; Mehta, Priyanka; Heywood, Jonathan; Rees, Barbara; Bone, Heather; Robinson, Gareth; Reynolds, Darren; Salisbury, Vyv; Mayer, Lawrence

Authors

Priyanka Mehta

Jonathan Heywood

Barbara Rees barbara.rees@uwe.ac.uk

Heather Bone

Gareth Robinson Gareth2.Robinson@uwe.ac.uk
Senior Lecturer in Molecular Microbiology

Vyv Salisbury vyv.salisbury@uwe.ac.uk

Lawrence Mayer



Abstract

© 2018 Elsevier Ltd CPX-351, a liposomal formulation co-encapsulating cytarabine and daunorubicin (DNR) in a synergistic 5:1 M ratio, has shown favourable response in newly diagnosed elderly high-risk AML. This study assessed intracellular ara-CTP levels following in vitro exposure of human immortalised leukaemic cell lines and primary AML blasts to CPX-351, and investigated fludarabine potentiation of intracellular ara-CTP formation from CPX-351. Comparison of intracellular handling of CPX-351 to cytarabine in HL-60 cells indicated slower conversion to ara-CTP for CPX-351, but equivalent cytotoxicity to cytarabine and combined DNR/cytarabine (DA) at 48 h, mostly likely reflecting the need for intracellular liposome processing to release encapsulated drugs. Further assessment demonstrated cytotoxicity of CPX-351 to be superior to DA at 48 and 72 h in cytarabine-resistant THP-1 cells (p < 0.001), and this effect could not be inhibited upon blockade of human equilibrative nucleoside transporter (hENT) function with dipyridamole. Assessment of Flu-CPX in primary blasts from presentation AML patients (n = 5) demonstrated a more rapid and pronounced potentiation of ara-CTP from CPX-351 than in immortalised cell lines, with 4/5 patients showing significant increases in ara-CTP, notably for those that went on to fail induction and relapse treatment in vivo (n = 3). This suggests a favourable impact on patient outcome from Flu-CPX.

Citation

Anderson, E., Mehta, P., Heywood, J., Rees, B., Bone, H., Robinson, G., …Mayer, L. (2018). CPX-351 exhibits hENT-independent uptake and can be potentiated by fludarabine in leukaemic cells lines and primary refractory AML. Leukemia Research, 74, 121-129. https://doi.org/10.1016/j.leukres.2018.08.007

Journal Article Type Article
Acceptance Date Aug 9, 2018
Online Publication Date Aug 11, 2018
Publication Date Nov 1, 2018
Journal Leukemia Research
Print ISSN 0145-2126
Electronic ISSN 1873-5835
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 74
Pages 121-129
DOI https://doi.org/10.1016/j.leukres.2018.08.007
Keywords CPX-351, fludarabine, ara-CTP, E. coli HA1, biosensor
Public URL https://uwe-repository.worktribe.com/output/863406
Publisher URL https://doi.org/10.1016/j.leukres.2018.08.007
Additional Information Additional Information : This is the author's accepted manuscript. The final published version is available here: https://doi.org/10.1016/j.leukres.2018.08.007.

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