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Initial testing of dasatinib by the pediatric preclinical testing program
Author(s) -
Kolb E. Anders,
Gorlick Richard,
Houghton Peter J.,
Morton Christopher L.,
Lock Richard B.,
Tajbakhsh Mayamin,
Reynolds C. Patrick,
Maris John M.,
Keir Stephen T.,
Billups Catherine A.,
Smith Malcolm A.
Publication year - 2008
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.21368
Subject(s) - dasatinib , medicine , in vivo , imatinib , tyrosine kinase , cancer research , imatinib mesylate , pharmacology , tyrosine kinase inhibitor , myeloid leukemia , ex vivo , cancer , biology , receptor , microbiology and biotechnology
Abstract Background Dasatinib, a dual inhibitor of the src and abl tyrosine kinases, was recently approved by the Federal Drug Administration for the treatment of imatinib mesylate‐resistant chronic myeloid leukemia. Procedures Dasatinib was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 0.1 nM to 1.0 µM and was tested in vivo at a dose of 50 mg/kg administered orally twice daily 5 days per week for 4 weeks for the solid tumor xenografts and once daily for the acute lymphoblastic leukemia (ALL) xenografts. Results Dasatinib was selectively active against the cell lines of the PPTP in vitro panel, reaching an IC 50 in 6 of the 22 lines. The most sensitive were the AML line Kasumi‐1, which has a gain‐of‐function c‐Kit mutation (Asn822Lys), and the rhabdoid tumor line CHLA‐266 (IC 50 approximately 10 nM for each). In the in vivo panel, dasatinib induced significant differences in EFS distribution in 8 of 32 (25%) solid tumor models and 3 of 7 ALL models. Using the time to event activity measure, dasatinib had intermediate activity against 1 of 27 (4%) evaluable solid tumor xenografts and 3 of 7 ALL xenografts. One xenograft in the ALL panel, a Philadelphia chromosome positive (Ph + ) ALL xenograft, demonstrated a complete response. Conclusions Dasatinib was active at low nanomolar concentrations against a small subset of the PPTP's in vitro panel. Dasatinib had limited in vivo activity against the PPTP solid tumor xenografts, but was highly active against a Ph + ALL xenograft and also had anti‐leukemia activity against two other xenografts. Pediatr Blood Cancer 2008;50:1198–1206. © 2007 Wiley‐Liss, Inc.