Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis.
BACKGROUND
Dasatinib is a small molecule kinase inhibitor that has recently been shown to inhibit Src family kinases (SFK) and also has activity against CaP. Of importance to metastatic CaP, which frequently metastasises to bone, SFK are also vital to the regulation of bone remodelling. We sought to determine the ability of dasatinib to inhibit growth of CaP in bone.


METHODS
C4-2B CaP cells were injected into tibiae of SCID mice and treated with dasatinib, alone or in combination with docetaxel. Serum prostate-specific antigen levels, bone mineral density, radiographs and histology were analysed.


RESULTS
Treatment with dasatinib alone significantly lowered sacrifice serum prostate-specific antigen levels compared to control, 2.3+/-0.4 vs 9.2+/-2.1 (P=0.004). Combination therapy improved efficacy over dasatinib alone (P=0.010). Dasatinib increased bone mineral density in tumoured tibiae by 25% over control tumoured tibiae (P<0.001).


CONCLUSIONS
Dasatinib inhibits growth of C4-2B cells in bone with improved efficacy when combined with docetaxel. Additionally, dasatinib inhibits osteolysis associated with CaP. These data support further study of dasatinib in clinical trials for men with CaP bone metastases.
Koreckij
T
T
Department of Urology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
Nguyen
H
H
Brown
L G
LG
Yu
E Y
EY
Vessella
R L
RL
Corey
E
E
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015519:Bone Density / Q000187:drug effects; D001859:Bone Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary*; D045744:Cell Line, Tumor; D000069439:Dasatinib; D000077143:Docetaxel; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010014:Osteolysis / Q000097:blood / Q000188:drug therapy*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology*; D043823:Taxoids / Q000008:administration & dosage; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D043823:Taxoids; D013844:Thiazoles; D000077143:Docetaxel; D019061:src-Family Kinases; D017430:Prostate-Specific Antigen; D000069439:Dasatinib