Wietrzyk Joanna, Pełczyńska Marzena, Madej Janusz, Dzimira Stanisław, Kuśnierczyk Halina, Kutner Andrzej, Szelejewski Wiesław, Opolski Adam
Laboratory of Experimental Anticancer Therapy, Institute of Immunology and Experimental Therapy, 12 R. Weigla St., 53-114 Wrocław, Poland.
Steroids. 2004 Sep;69(10):629-35. doi: 10.1016/j.steroids.2004.05.015.
Many efforts have been made to obtain active and less toxic Vitamin D analogs for new clinical applications. The results of previous studies demonstrated the efficacy and safety of topical treatment of psoriasis with one of these analogs, 1,24-dihydroxyvitamin D(3), tacalcitol (1,24-(OH)(2)D(3)). In the present study, we evaluated the toxicity and antitumor effect of this analog. Lethal toxicity of 1,24-(OH)(2)D(3) after s.c. injection was significantly lower than that of calcitriol. No significant differences were observed in the toxicity of the analogs when administered p.o. Calcium levels in the serum of mice treated with calcitriol were significantly higher (111%) than those in mice treated with 1,24-(OH)(2)D(3) (89%) at 5 day after the first s.c. (10 microg/kg/day) administration in comparison to the control (healthy, untreated animals). Oral administration increased the calcium level by 78% for calcitriol and only to 47% over the control for 1,24-(OH)(2)D(3). Parallel administration of clodronate prevented the calcitriol- and 1,24-(OH)(2)D(3)-induced lethal toxicity and also prevented increase in calcium levels. Single therapy with calcitriol did not affect tumor growth in the 16/C mouse mammary cancer model. In contrary, 1,24-(OH)(2)D(3) alone reduced tumor volume to 41% of control. Cisplatin alone did not affect growth of 16/C tumor in these conditions. The growth of tumors in the presence of cisplatin was inhibited by 1,24-(OH)(2)D(3) but not by calcitriol. Interestingly, the inhibition of tumor growth in cisplatin-treated mice by 1,24-(OH)(2)D(3) was greater, than that observed in mice treated with this analog alone. In conclusion, 1,24-(OH)(2)D(3) revealed higher antitumor and lower calcemic activity and toxicity than calcitriol. Application of biphosphonates along with Vitamin D analogs is sufficient to overcome the calcemic and toxic side effects of the proposed treatment.
为了获得活性更高、毒性更低的维生素D类似物用于新的临床应用，人们已经做出了许多努力。先前的研究结果表明，这些类似物之一1,24 - 二羟基维生素D(3)（他卡西醇，1,24-(OH)(2)D(3)）局部治疗银屑病具有有效性和安全性。在本研究中，我们评估了这种类似物的毒性和抗肿瘤作用。皮下注射后1,24-(OH)(2)D(3)的致死毒性显著低于骨化三醇。口服给药时，这些类似物的毒性未观察到显著差异。与对照组（健康、未治疗的动物）相比，在首次皮下注射（10微克/千克/天）后5天，用骨化三醇治疗的小鼠血清钙水平显著高于用1,24-(OH)(2)D(3)治疗的小鼠（分别为111%和89%）。口服给药时，骨化三醇使钙水平升高78%，而1,24-(OH)(2)D(3)仅比对照组升高47%。同时给予氯膦酸盐可预防骨化三醇和1,24-(OH)(2)D(3)诱导的致死毒性，也可预防钙水平升高。在16/C小鼠乳腺癌模型中，单独使用骨化三醇对肿瘤生长没有影响。相反，单独使用1,24-(OH)(2)D(3)可使肿瘤体积缩小至对照组的41%。在这些条件下，单独使用顺铂对16/C肿瘤的生长没有影响。在有顺铂存在的情况下，1,24-(OH)(2)D(3)可抑制肿瘤生长，但骨化三醇则不能。有趣的是，1,24-(OH)(2)D(3)对顺铂治疗小鼠肿瘤生长的抑制作用比对单独使用该类似物治疗的小鼠观察到的抑制作用更大。总之，1,24-(OH)(2)D(3)显示出比骨化三醇更高的抗肿瘤活性、更低的血钙活性和毒性。双膦酸盐与维生素D类似物联合应用足以克服所提议治疗的高钙血症和毒性副作用。
