Inhibition of prostate cancer metastasis in vivo: a comparison of 1,23-dihydroxyvitamin D (calcitriol) and EB1089.
Inhibition of prostate cancer metastasis in vivo: a comparison of 1,23-dihydroxyvitamin D (calcitriol) and EB1089.
复制标题
DOI：
--
复制
发表时间：
1999-03
期刊：
影响因子：
--
通讯作者：
B. Lokeshwar;G. Schwartz;M. Selzer;K. Burnstein;S. Zhuang;N. Block;L. Binderup
中科院分区：
文献类型：
--
作者：
B. Lokeshwar;G. Schwartz;M. Selzer;K. Burnstein;S. Zhuang;N. Block;L. Binderup
类固醇激素 1,25-二羟基维生素 D [1,25(OH)2D，也称为骨化三醇] 已知可抑制人类前列腺癌细胞的增殖并促进其分化。此外，我们还发现 1,25(OH)2D 在体外显着抑制人前列腺癌细胞的侵袭性（G. G. Schwartz 等人，Cancer Epidemiol. Biomark. Prev., 6: 727-732, 1997）。这些特性支持使用 1,25(OH)2D 作为前列腺癌的分化疗法。然而，1,25(OH)2D在体内的使用受到高钙血症风险的限制。因此，我们在雄激素不敏感的转移性前列腺癌体内模型（大鼠 Dunning MAT LyLu 前列腺癌模型）中比较了 1,25(OH)2D 和 EB1089（一种具有降低钙血作用的 1,25(OH)2D 类似物）的效果。使用皮下注射的哥本哈根大鼠研究肿瘤生长和转移。注射 MAT LyLu 细胞。将 50 只雄性大鼠分为 5 组，每组 10 只。四个实验组接受腹膜内注射。注射低剂量和高剂量的 1,25(OH)2D 和 EB1089（分别为 0.5 和 1.0 微克/千克，低剂量和高剂量）。对照组仅接受媒介物注射。每周测量肿瘤体积三次。每周对大鼠称重。评估肺部转移的数量和高钙血症的程度。与对照组相比，所有实验组的肿瘤体积均明显较小。同样，1,25(OH)2D 和 EB1089 均显着减少了肺转移的数量（病灶数量/肺）。对照大鼠每肺出现 22.7 (+/- 1.98 SE) 个肿瘤灶。用 1,25(OH)2D 和 EB1089 (1.0 microg/kg) 治疗的大鼠分别出现 10.4 (+/- 2.81) 和 7.70 (+/- 1.29) 个肿瘤灶（分别为 P < 0.001 和 P < 0.0001；药物与对照）。与对照组（10.79 +/- 0.1 mg/dl）相比，1,25(OH)2D 和 EB1089 治疗的大鼠血清钙水平均显着升高（P < 0.01）。然而，EB1089 的钙血症显着低于 1,25(OH)2D（12.59 +/- 0.21 mg/dl 对比 14.47 +/- 0.46 mg/dl；1.0 microg/kg；P < 0.001）。用 1,25(OH)2D 治疗的大鼠显示出明显的体重减轻：初始体重的 20.0 +/- 1.9% 和 26.3 +/- 1.7%（分别为低剂量和高剂量，P < 0.001）。使用高剂量 8.4 (+/- 2.9)% 的 EB1089 治疗的大鼠体重减轻明显较低。此外，用低剂量 EB1089 治疗的大鼠体重增加了 5.2 (+/- 3.7) %。总之，1,25(OH)2D 和 EB1089 对体内前列腺癌转移显示出显着且等效的抑制作用。 EB1089 的钙血症明显低于 1,25(OH)2D，并且不会引起严重的体重减轻。这是维生素 D 类似物在体内显着抑制前列腺癌转移且不会产生恶病质或不可接受的高钙血症的第一份报告。
The steroid hormone 1,25-dihydroxyvitamin D [1,25(OH)2D, also known as calcitriol] is known to inhibit the proliferation and to promote the differentiation of human prostate cancer cells. Additionally, we showed that 1,25(OH)2D markedly inhibits the invasiveness of human prostate cancer cells in vitro (G. G. Schwartz et al., Cancer Epidemiol. Biomark. Prev., 6: 727-732, 1997). These properties support the use of 1,25(OH)2D as differentiation therapy in prostate cancer. However, the use of 1,25(OH)2D in vivo is limited by the risk of hypercalcemia. We therefore compared the effects of 1,25(OH)2D and of EB1089, an analogue of 1,25(OH)2D with reduced calcemic effects, in an in vivo model of androgen-insensitive metastatic prostate cancer, the rat Dunning MAT LyLu prostate cancer model. Tumor growth and metastasis were studied using Copenhagen rats given s.c. injections of MAT LyLu cells. Fifty male rats were divided into five groups of 10 rats each. Four experimental groups received i.p. injections of low and high doses of 1,25(OH)2D and EB1089 (0.5 and 1.0 microg/kg, low and high, respectively). A control group received injections of vehicle only. Tumor volumes were measured three times per week. Rats were weighed weekly. The number of metastases to the lungs and the extent of hypercalcemia were evaluated. Compared with controls, tumor volumes were significantly smaller in all experimental groups. Similarly, the number of lung metastases (number of foci/lung) was reduced markedly by both 1,25(OH)2D and EB1089. Control rats developed 22.7 (+/- 1.98 SE) tumor foci per lung. Rats treated with 1,25(OH)2D and with EB1089 (1.0 microg/kg) developed 10.4 (+/- 2.81) and 7.70 (+/- 1.29) tumor foci, respectively (P < 0.001 and P < 0.0001, respectively; drug versus control). Compared with controls (10.79 +/- 0.1 mg/dl), serum calcium levels were significantly elevated in both 1,25(OH)2D and EB1089-treated rats (P < 0.01). However, EB1089 was significantly less calcemic than 1,25(OH)2D (12.59 +/- 0.21 mg/dl versus 14.47 +/- 0.46 mg/dl; 1.0 microg/kg; P < 0.001). Rats treated with 1,25(OH)2D showed marked weight loss: 20.0 +/- 1.9% and 26.3 +/- 1.7% of their initial weight (low and high doses, respectively, P < 0.001). Weight loss was significantly lower in rats treated with EB1089 at the high dose 8.4 (+/- 2.9) %. Moreover, rats treated with low-dose EB1089 gained 5.2 (+/- 3.7) % of their initial weight. In conclusion, 1,25(OH)2D and EB1089 showed marked and equivalent inhibition of prostate cancer metastasis in vivo. EB1089 was significantly less calcemic than 1,25(OH)2D and did not induce severe weight loss. This is the first report of a vitamin D analogue that significantly inhibits prostate cancer metastasis in vivo and that does so without producing cachexia or unacceptable hypercalcemia.