Kawa S, Yoshizawa K, Tokoo M, Imai H, Oguchi H, Kiyosawa K, Homma T, Nikaido T, Furihata K
Second Department of Internal Medicine, Shinshu University, School of Medicine, Matsumoto, Japan.
Gastroenterology. 1996 May;110(5):1605-13. doi: 10.1053/gast.1996.v110.pm8613068.
BACKGROUND & AIMS: Effective chemotherapy for pancreatic cancer is urgently needed. The aim of this study was to compare the anti-proliferative activity of a new vitamin D3 analogue, 22-oxa-1,25-dihydroxyvitamin D3 (22-oxa-calcitriol), on pancreatic cancer cells lines with that of 1,25-dihydroxyvitamin D3 (calcitriol) with analysis of vitamin D receptor status.
Antiproliferative effects of both agents were compared using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method and by measuring the tumor size of xenograft inoculated into athymic mice. Vitamin D receptor contents by Scatchard analysis and mutational analysis of receptor complementary DNA were performed.
In vitro, 22-oxa-calcitriol and calcitriol markedly inhibited the proliferation (3 of 9 cell lines) and caused a G1 phase cell cycle arrest by appearance of numerous domes. In vivo, 22-oxa-calcitriol inhibited the growth of BxPC-3 xenografts more significantly than calcitriol without including hypercalcemia. Hs 766T, showing no response to either agent, had the second highest receptor contents with no abnormalities in its primary structure deduced by receptor complementary DNA.
22-oxa-calcitriol may provide a more useful tool for the chemotherapy of pancreatic cancer than calcitriol. Also, the susceptibility of the cell lines to both agents is not well determined by evaluating either the contents or the mutation of vitamin D receptor.
胰腺癌急需有效的化疗方法。本研究旨在比较一种新型维生素D3类似物22-氧杂-1,25-二羟基维生素D3（22-氧杂骨化三醇）与1,25-二羟基维生素D3（骨化三醇）对胰腺癌细胞系的抗增殖活性，并分析维生素D受体状态。
使用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐法并通过测量接种到无胸腺小鼠体内的异种移植物的肿瘤大小，比较两种药物的抗增殖作用。通过Scatchard分析测定维生素D受体含量，并进行受体互补DNA的突变分析。
在体外，22-氧杂骨化三醇和骨化三醇显著抑制增殖（9种细胞系中的3种），并通过出现大量穹窿导致G1期细胞周期停滞。在体内，22-氧杂骨化三醇比骨化三醇更显著地抑制BxPC-3异种移植物的生长，且不引起高钙血症。Hs 766T对两种药物均无反应，其受体含量第二高，其受体互补DNA推导的一级结构无异常。
与骨化三醇相比，22-氧杂骨化三醇可能为胰腺癌化疗提供更有用的工具。此外，通过评估维生素D受体的含量或突变，不能很好地确定细胞系对这两种药物的敏感性。
