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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

Heather Bone

Gareth Robinson Gareth2.Robinson@uwe.ac.uk
Associate Director (Partnerships & Planning)

Vyv Salisbury

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
Deposit Date Aug 13, 2018
Publicly Available Date Mar 28, 2024
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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