Preclinical evaluation of sunitinib as a single agent in the prophylactic setting in a mouse model of bone metastases.
BACKGROUND
A substantial number of breast cancer patients are identified as being at high risk of developing metastatic disease. With increasing number of targeted therapeutics entering clinical trials, chronic administration of these agents may be a feasible approach for the prevention of metastases within this subgroup of patients. In this preclinical study we examined whether sunitinib, a multi-tyrosine kinase inhibitor which has anti-angiogenic and anti-resorptive activity, is effective in the prevention of bone metastases.


METHODS
Sunitinib was administered daily with the first dose commencing prior to tumor cell inoculation. Intracardiac injection was performed with MDA-MB23 bone-seeking cells, which were stably transfected with DsRed2. In vivo plain radiography and fluorescent imaging (Berthold NightOwl) was used in the analysis of bone metastases. Histomorphometry was used for the quantification of TRAP+ cells from bone sections and immunohistochemistry was performed using an antibody reactive to CD34 for quantification of microvessel density.


RESULTS
Preventive dosing administration of sunitinib does not inhibit colonization of tumor cells to bone or reduce the size of osteolytic lesions. There was a decrease in the number of TRAP+ cells with sunitinib treatment but this did not reach significance. Sunitinib inhibited tumor growth as determined by imaging of fluorescent tumor area. Immunohistochemical analyses of microvessel density revealed a concomitant decrease in the number of tumor blood vessels.


CONCLUSIONS
The findings suggest that sunitinib can be used as a therapeutic agent for the treatment of bone metastases but as a single agent it is not effective in terms of prevention. Therefore a combination approach with other cytostatic drugs should be pursued.
Department of Gynecology, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
Christian
C
Schem
Dirk
D
Bauerschlag
Sascha
S
Bender
Ann-Christin
AC
Lorenzen
Daniel
D
Loermann
Sigrid
S
Hamann
Frank
F
Rösel
Holger
H
Kalthoff
Claus C
CC
Glüer
Walter
W
Jonat
Sanjay
S
Tiwari
D000135:Acid Phosphatase / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D000077210:Sunitinib; D000071681:Tartrate-Resistant Acid Phosphatase; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D018952:Antigens, CD34; D014408:Biomarkers, Tumor; D007211:Indoles; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D000077210:Sunitinib