Initial testing of dasatinib by the pediatric preclinical testing program.
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.


METHODS
Dasatinib was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 0.1 nM to 1.0 microM 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.
Kolb
E Anders
EA
The Children's Hospital at Montefiore, Bronx, New York, USA. eakolb@nemours.org
Gorlick
Richard
R
Houghton
Peter J
PJ
Morton
Christopher L
CL
Lock
Richard B
RB
Tajbakhsh
Mayamin
M
Reynolds
C Patrick
CP
Maris
John M
JM
Keir
Stephen T
ST
Billups
Catherine A
CA
Smith
Malcolm A
MA
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D000069439:Dasatinib; D005260:Female; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib