title: Disparate in vivo efficacy of FTY720 in xenograft models of Philadelphia positive and negative B-lineage acute lymphoblastic leukemia.
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 FTY720 may have potential as a treatment for Ph(+) ALL it will not be a useful agent for the treatment of Ph(-) B-ALL.
authors.affiliation: Westmead Institute for Cancer Research, Westmead Millennium Institute, The University of Sydney, Sydney, Australia.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Wallington-Beddoe
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Don
authors.forename: John
authors.initials: J
authors.lastname: Hewson
authors.forename: Qiao
authors.initials: Q
authors.lastname: Qiao
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Papa
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bradstock
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bendall
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018450:Disease Progression; D004334:Drug Administration Schedule; D000068876:Fingolimod Hydrochloride; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009367:Neoplasm Staging; D010677:Philadelphia Chromosome; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011409:Propylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D054648:Protein Phosphatase 2 / Q000378:metabolism; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011409:Propylene Glycols; D054648:Protein Phosphatase 2; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine