Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats.
Cancer Res
; 62(22): 6538-44, 2002 Nov 15.
Article
en En
| MEDLINE
| ID: mdl-12438248
ABSTRACT
Bisphosphonates (BPs) are used currently in the treatment of patients with bone metastases because these compounds inhibit bone resorption. We examined here the effects of BPs on inhibition of endothelial cell functions in vitro and in vivo. Treatment of endothelial cells with BPs (clodronate, risedronate, ibandronate, and zoledronic acid) reduced proliferation, induced apoptosis, and decreased capillary-like tube formation in vitro. Quantification of blood vessels in bone biopsy specimens from patients with Paget's disease before and after clodronate treatment showed a 40% reduction of the vascularization after BP treatment. However, such a decreased vascularity could be secondary to a reduction of bone resorption. Therefore, the tissue distribution of [14C]BPs in male rats was examined to develop an angiogenesis model in a noncalcified tissue where BPs could accumulate. [14C]BPs (zoledronic acid, ibandronate, and clodronate) not only accumulated in bone but also transiently accumulated in the prostate. The effects of BPs on testosterone-induced revascularization of the prostate gland in castrated rats were then studied. Testosterone in combination with ibandronate or zoledronic acid induced a 17-35% reduction of the prostate weight compared with castrated rats treated with testosterone alone. Blood vessel immunostaining on prostate tissue sections revealed that both ibandronate and zoledronic acid induced a 50% reduction of the revascularization of the prostate gland. Moreover, zoledronic acid did not alter testosterone-induced activity of a luciferase gene reporter construct transfected in androgen-dependent prostatic cells, indicating that this BP did not directly interfere with testosterone. In conclusion, BPs have in vivo antiangiogenic properties, which could be of relevance to improve therapy and prevention of bone metastasis. In addition, our results extend the potential clinical use of BPs to patients with early prostate cancer.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Próstata
/
Testosterona
/
Ácido Etidrónico
/
Neovascularización Fisiológica
/
Inhibidores de la Angiogénesis
/
Difosfonatos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Cancer Res
Año:
2002
Tipo del documento:
Article
País de afiliación:
Francia