Alendronate inhibits intraperitoneal dissemination in in vivo ovarian cancer model.
Alendronate inhibits intraperitoneal dissemination in in vivo ovarian cancer model.
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DOI：
10.1158/0008-5472.540.65.2
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发表时间：
2005-01
期刊：
影响因子：
11.2
通讯作者：
Kae Hashimoto;Ken‐ichirou Morishige;Kenjiro Sawada;M. Tahara;Rikako Kawagishi;Y. Ikebuchi;M. Sakata;K. Tasaka;Y. Murata
中科院分区：
文献类型：
--
作者：
Kae Hashimoto;Ken‐ichirou Morishige;Kenjiro Sawada;M. Tahara;Rikako Kawagishi;Y. Ikebuchi;M. Sakata;K. Tasaka;Y. Murata
卵巢癌的特征是弥漫性腹膜癌变，并且常常有大量腹水。我们之前报道过阿仑膦酸盐（一种含氮双膦酸盐）通过抑制甲羟戊酸途径减弱 Rho 的激活，从而抑制卵巢癌细胞的迁移。然而，阿仑膦酸钠抑制癌细胞对贴壁组织的侵袭以及体内播散性卵巢癌生长的能力仍然存在疑问。我们通过腹腔注射建立了体内卵巢癌模型。无胸腺免疫缺陷小鼠的癌病。在预防模型中，阿仑膦酸钠从肿瘤接种后第二天开始给药，阿仑膦酸钠阻止了间质侵袭，减轻了肿瘤负荷，并抑制了腹水积聚。组织学观察表明，阿仑膦酸钠治疗减少了腹腔间质侵袭。肿瘤，同时抑制腹水中的金属蛋白酶-2活性。这种抗肿瘤作用可能是由于抑制癌细胞迁移和蛋白水解活性所致。在治疗模型中，当肉眼可见的肿瘤已经植入腹膜时，从肿瘤接种后10天开始给予阿仑膦酸钠，抗肿瘤效果较弱，但仍然显着。此外，与未接受治疗的小鼠相比，给予阿仑膦酸钠可降低患有播散性卵巢癌的小鼠的血清 CA-125 水平。阿仑膦酸钠在减少间质侵袭、肿瘤负荷和腹水方面的有效作用表明，它在治疗卵巢癌女性的方案中具有重要价值。
Ovarian cancer is characterized by diffuse peritoneal carcinomatosis and often by large volumes of ascites. We previously reported that alendronate, a nitrogen-containing bisphosphonate, inhibited ovarian cancer cell migration by attenuating the activation of Rho through inhibiting the mevalonate pathway. However, questions remain about the ability of alendronate to inhibit the invasiveness of cancer cells to the adherent tissues and the growth of disseminated ovarian cancer in vivo. We established an in vivo ovarian cancer model with i.p. carcinomatosis in athymic immunodeficient mice. In the prevention model, in which alendronate administration started from the day after tumor inoculation, alendronate prevented the stromal invasion, reduced the tumor burden, and inhibited ascites accumulation. Histologic observation revealed that alendronate treatment decreased the stromal invasion of the i.p. tumor while inhibiting the metalloproteinase-2 activity in ascites. This antitumor effect might result from the inhibition of cancer cell migration and proteolytic activity. In the treatment model, in which alendronate was given from 10 days after tumor inoculation when macroscopic tumors are already implanted in the peritoneum, the antitumor effect was weaker but still significant. Furthermore, alendronate administration decreased the serum CA-125 levels of mice bearing disseminated ovarian cancer compared with those of nontreated mice. The potent effects of alendronate in reducing stromal invasion, tumor burden, and ascites suggest that it will be of value in regimens for treatment of women with ovarian cancer.