Effects of Seocalcitol (EB1089) on nitrosomethyl urea-induced rat mammary tumors
Effects of Seocalcitol (EB1089) on nitrosomethyl urea-induced rat mammary tumors
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DOI：
10.1023/a:1024962316691
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发表时间：
2003-08-01
影响因子：
3.8
通讯作者：
Binderup, L
中科院分区：
文献类型：
--
作者：
Colston, KW;Pirianov, G;Binderup, L
虽然1，25-二羟维生素D-3是一种有效的细胞分化剂，但由于其诱导高钙血症，因此无法用于癌症预防或治疗。已经开发了在乳腺癌动物模型中抑制肿瘤进展的合成类似物。一种类似物Seocalcitol（EB 1089）已被证明可有效地导致N-甲基-亚硝基脲诱导的大鼠乳腺肿瘤消退。然而，在最有效的口服剂量下，观察到血清和尿钙水平显著升高。为了比较不同的西骨化醇给药方案的功效，将大鼠每周给药6次（1 μ g/kg）或通过间歇给药以达到相同的每周总剂量。西骨化醇的所有给药方案均有效抑制肿瘤进展。每日一次给药比间歇性给药显著更有效，但与血清钙浓度的更大升高相关。为了评价限制钙代谢效应的替代治疗策略，我们评估了使用双膦酸盐限制维生素D诱导的高钙血症的疗效。西骨化醇（2.5 μ g/kg，每日p.o.持续4周）单独给药和与帕米膦酸盐（APD 0.4 mg/kg/天s.c.）或相同剂量的双膦酸盐EB 1053引起实质性肿瘤消退。在联合治疗和单独的西骨化醇治疗之间没有观察到统计学显著差异。与APD或EB 1053的共同治疗并没有限制单独由Seocalcitol诱导的血清钙的升高。停止治疗或给予较低剂量（1 μ g/kg，每周两次）可逆转高剂量西骨化醇诱导的高钙血症、高钙尿症和体重减轻。然而，在大多数动物中维持肿瘤体积的减小。
Although 1,25-dihydroxyvitamin D-3 is a potent cell-differentiating agent, its use in cancer prevention or therapy is precluded because it induces hypercalcemia. Synthetic analogs have been developed which inhibit tumor progression in animal models of breast cancer. One analog, Seocalcitol (EB1089) has been shown to be effective in causing regression of N-methyl-nitrosourea-induced rat mammary tumors. However, at the most effective oral dose, a significant increase in serum and urinary calcium levels were observed. In order to compare the efficacy of different dosing schedules of Seocalcitol, rats were treated either 6 times weekly (1 mug/kg) or by intermittent dosing to achieve the same total weekly dose. All dosing schedules of Seocalcitol were effective in inhibiting tumor progression. Once daily dosing was significantly more effective than intermittent dosing but was associated with a greater rise in serum calcium concentration. In order to evaluate alternative treatment strategies to limit calcemic effects, we assessed the efficacy of limiting vitamin D-induced hypercalcemia using bisphosphonates. Seocalcitol (2.5 mug/kg daily p.o. for 4 weeks) alone and in combination with pamidronate (APD 0.4 mg/kg per day s.c.) or the same dose of the bisphosphonate EB1053 caused substantial tumor regression. No statistically significant difference was seen between combination treatment and Seocalcitol treatment alone. Co-treatment with APD or EB1053 did not limit the rise in serum calcium induced by Seocalcitol alone. Cessation of treatment or administration of a lower dose (1 mug/kg twice weekly) reversed hypercalcemia, hypercalciuria and weight loss induced by high dose Seocalcitol. However, reduction in tumor volume was maintained in the majority of animals.