Getzenberg R H, Light B W, Lapco P E, Konety B R, Nangia A K, Acierno J S, Dhir R, Shurin Z, Day R S, Trump D L, Johnson C S
Department of Pathology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pennsylvania 15213-2582, USA.
Urology. 1997 Dec;50(6):999-1006. doi: 10.1016/S0090-4295(97)00408-1.
Risk factors for prostate cancer (PCa)-related mortality include old age, black race, and residence in northern latitudes. The objectives of this study are to examine the in vitro and in vivo effects of 1,25-dihydroxycholecalciferol (1,25-D3) and less-hypercalcemic analogues on the Dunning rat prostate adenocarcinoma model.
To evaluate the effect of 1,25-D3 on PCa in vitro, we used the highly metastatic Mat-lylu (MLL) and moderately metastatic R3327-AT-2 (AT-2) Dunning prostate cell lines, and examined effects on growth, clonogenicity, differentiation, and cell cycle. In vivo analysis included examination of the effects of these compounds on tumor growth and metastasis.
Using both the 3-day MTT and 7-day clonogenic assay, 1,25-D3 demonstrated a growth inhibitory effect with a concentration for 50% inhibition (IC50) of approximately 20 microM for both MLL and AT-2. Cell cycle analysis of treated MLL cells (10 microM 1,25-D3 for 48 hours) had 25% more cells in the G0/G1 phase than did control cells. To examine the in vivo effect of 1,25-D3 and the less hypercalcemic vitamin D analogue, Ro25-6760 (or 6760), on MLL PCa growth and metastasis, tumors (5 x 10(5) cells) were implanted subcutaneously into the flank of Copenhagen rats on the same day that treatment was initiated with 1,25-D3 (1 microgram) or 6760 (1 or 5 micrograms); rats received treatment three times a week. After 3 weeks, 1,25-D3 and 6760 (5 micrograms dosing) resulted in an inhibition of tumor volume and a reduction in the number and size of lung metastases.
These preclinical studies demonstrate the profound in vitro, or in vivo, or both antiproliferative and differentiating effects of 1,25-D3 and 6760 on PCa and suggest that these drugs may have potential beneficial effects in the treatment of advanced PCa.
前列腺癌（PCa）相关死亡的风险因素包括老年、黑人种族以及居住在高纬度地区。本研究的目的是研究1,25 - 二羟胆钙化醇（1,25 - D3）及低高钙血症类似物对邓宁大鼠前列腺腺癌模型的体外和体内作用。
为评估1,25 - D3对PCa的体外作用，我们使用了高转移性的Mat - lylu（MLL）和中度转移性的R3327 - AT - 2（AT - 2）邓宁前列腺细胞系，并检测其对生长、克隆形成、分化和细胞周期的影响。体内分析包括检测这些化合物对肿瘤生长和转移的影响。
使用3天的MTT法和7天的克隆形成试验，1,25 - D3对MLL和AT - 2均表现出生长抑制作用，半数抑制浓度（IC50）约为20微摩尔。对处理后的MLL细胞（10微摩尔1,25 - D3处理48小时）进行细胞周期分析，发现处于G0/G1期的细胞比对照细胞多25%。为检测1,25 - D3和低高钙血症维生素D类似物Ro25 - 6760（或6760）对MLL PCa生长和转移的体内作用，在开始用1,25 - D3（1微克）或6760（1或5微克）治疗的同一天，将肿瘤细胞（5×10⁵个细胞）皮下植入哥本哈根大鼠的侧腹；大鼠每周接受三次治疗。3周后，1,25 - D3和6760（5微克剂量）导致肿瘤体积受到抑制，肺转移灶的数量和大小减少。
这些临床前研究证明了1,25 - D3和6760在体外或体内或两者兼具的对PCa的深刻抗增殖和分化作用，并表明这些药物在晚期PCa的治疗中可能具有潜在的有益作用。
