Disparate in vivo efficacy of FTY720 in xenograft models of Philadelphia positive and negative B-lineage acute lymphoblastic leukemia.

PloS One
Craig T Wallington-BeddoeLinda J Bendall

Abstract

Most patients with acute lymphoblastic leukemia (ALL) respond well to standard chemotherapy-based treatments. However a significant proportion of patients, particularly adult patients, relapse with the majority dying of leukemia. FTY720 is an immunosuppressive drug that was recently approved for the treatment of multiple sclerosis and is currently under pre-clinical investigation as a therapy for a number of hematological malignancies. Using human ALL xenografts in NOD/SCIDγc(-/-) mice, we show for the first time that three Ph(+) human ALL xenografts responded to FTY720 with an 80 ± 12% (p = 0.048) reduction in overall disease when treatment was commenced early. In contrast, treatment of mice with FTY720 did not result in reduced leukemia compared to controls using four separate human Ph(-) ALL xenografts. Although FTY720 reactivated PP2A in vitro, this reactivation was not required for death of Ph(-) ALL cells. The plasma levels of FTY720 achieved in the mice were in the high nanomolar range. However, the response seen in the Ph(+) ALL xenografts when treatment was initiated early implies that in vivo efficacy may be obtained with substantially lower drug concentrations than those required in vitro. Our data suggest that while...Continue Reading

References

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Citations

Jun 14, 2014·Journal of Pharmaceutical and Biomedical Analysis·Yicheng MaoMitch A Phelps
May 23, 2015·Molecules and Cells·Kazuyuki KitataniToshiro Okazaki
Jan 8, 2015·Frontiers in Oncology·Dorien HaesenVeerle Janssens
Aug 27, 2016·Expert Opinion on Drug Discovery·Sanil BhatiaJulia Hauer
Oct 2, 2015·Journal of Investigative Medicine High Impact Case Reports·Stanley CohanLeah Gaedeke
Mar 26, 2013·British Journal of Haematology·Craig T Wallington-BeddoeLinda J Bendall
Dec 16, 2020·Cancer Control : Journal of the Moffitt Cancer Center·Xianwang WangYingying Lu
Apr 28, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Adam A FriedmanDavid E Fisher
Nov 1, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Katia BeiderArnon Nagler

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Methods Mentioned

BETA
xenograft
xenografts
flow cytometry
light microscopy

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