Relevance of a new rat model of osteoblastic metastases from prostate carcinoma for preclinical studies using zoledronic acid.
Animal models that mimic osteoblastic metastases associated with prostate carcinoma are required to improve the therapeutic options in humans. A new model was then developed and characterized in immunocompetent rats. The bisphosphonate zoledronic acid (ZOL) was tested to validate this model as a therapeutic application. Rat AT6-1 prostate tumor cells were characterized in vitro at the transcriptional (bone and epithelial markers) and functional (induction of mineralized nodules) levels. The bone lesions induced after their direct injection into the femur bone marrow were characterized by radiography, microscanner and histology analyses. ZOL effects were studied in vivo on bone lesion development and in vitro on AT6-1 cell proliferation, apoptosis and cell cycle analysis. Apart from epithelial markers, AT6-1 cells express an osteoblast phenotype as they express osteoblastic markers and are able to induce mineralized nodule formation in vitro. A disorganization of the trabecular bone at the growth zone level was observed in vivo after intraosseous AT6-1 cell injection as well as cortical erosion. The tumor itself is associated with bone formation as revealed by SEM analysis and polarized light microscopy. ZOL prevents the development of such osteoblastic lesions, related to a direct inhibitory effect on tumor cell proliferation independent of caspase 3 activation, but associated with cell cycle arrest. A new rat model of osteoblastic bone metastases was validated in immunocompetent rats and used to show the relevance of using ZOL in such lesions, as this compound shows bifunctional effects on both bone remodelling and tumor cell proliferation.
Lamoureux
François
F
INSERM, ERI 7, Nantes, France.
Ory
Benjamin
B
Battaglia
Séverine
S
Pilet
Paul
P
Heymann
Marie-Françoise
MF
Gouin
François
F
Duteille
Franck
F
Heymann
Dominique
D
Redini
Françoise
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D016723:Bone Remodeling / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured / Q000187:drug effects; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid