Fournier Pierrick, Boissier Sandrine, Filleur Stéphanie, Guglielmi Julien, Cabon Florence, Colombel Marc, Clézardin Philippe
Institut National de la Santé et de la Recherche Médicale, Research Unit 403, Faculty of Medicine Laënnec, Lyon 69372, France.
Cancer Res. 2002 Nov 15;62(22):6538-44.
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.
双膦酸盐（BPs）目前用于治疗骨转移患者，因为这些化合物可抑制骨吸收。我们在此研究了BPs在体外和体内对内皮细胞功能抑制的影响。用BPs（氯膦酸盐、利塞膦酸盐、伊班膦酸盐和唑来膦酸）处理内皮细胞可降低其增殖、诱导凋亡并减少体外毛细血管样管形成。对佩吉特病患者氯膦酸盐治疗前后骨活检标本中的血管进行定量分析，结果显示BP治疗后血管化减少了40%。然而，这种血管减少可能是骨吸收减少的继发结果。因此，研究了[14C]BPs在雄性大鼠体内的组织分布，以建立一个BPs可在其中积累的非钙化组织中的血管生成模型。[14C]BPs（唑来膦酸、伊班膦酸盐和氯膦酸盐）不仅在骨中积累，还短暂地在前列腺中积累。随后研究了BPs对去势大鼠睾酮诱导的前列腺再血管化的影响。与单独用睾酮治疗的去势大鼠相比，睾酮联合伊班膦酸盐或唑来膦酸可使前列腺重量减少17 - 35%。前列腺组织切片上的血管免疫染色显示，伊班膦酸盐和唑来膦酸均使前列腺再血管化减少了50%。此外，唑来膦酸并未改变睾酮诱导的在雄激素依赖性前列腺细胞中转染的荧光素酶基因报告构建体的活性，表明这种BP不会直接干扰睾酮。总之，BPs具有体内抗血管生成特性，这可能与改善骨转移的治疗和预防有关。此外，我们的结果将BPs的潜在临床应用扩展到早期前列腺癌患者。
