Konety B R, Leman E, Vietmeier B, Arlotti J, Dhir R, Getzenberg R H
Departments of Urology, Pathology and Pharmacology, and the University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J Urol. 2000 Nov;164(5):1812-8.
Although many studies have investigated the role of calcitriol in the growth regulation of normal and cancerous prostates, little is known about its role in early prostatic development. The interactions between calcitriol and androgens, and their actions on the normal prostate have similarly been proposed but not evaluated. Previous studies in our laboratory have revealed that in utero administration of 1,25-dihydroxycholecalciferol or calcitriol can influence prostate growth and differentiation throughout the life of the animal. We further examined the influence of calcitriol on the normal prostate in vitro and in vivo by focusing on early stages of prostatic development.
The effects of calcitriol on the growth of the normal human neonatal prostatic epithelial cell line 267B-1 was determined in the presence and absence of dihydrotestosterone (DHT). We also examined the effect of calcitriol on the growth of maturing rat prostates in vivo. Before puberty 4 groups of rats 27 to 38 days old were treated with vehicle (controls) or calcitriol. When the rats reached adulthood at age 100 to 110 days a control group and a calcitriol group were sacrificed. The other 2 groups were given exogenous DHT for 5 days. For the animals to become adapted to DHT they were kept alive for 1 additional week and sacrificed at about age 120 days.
In vitro studies demonstrated that 267B-1 cells possess vitamin D receptors and their growth was inhibited by calcitriol with an IC50 (concentration resulting in 50% cytotoxicity) of 30 microM. Proliferation of these neonatal prostate cells was also inhibited by calcitriol in the presence of DHT in vitro. Our studies indicate that, although calcitriol was administered at the apparently important prepubertal period, there was no difference in prostatic weights between the control and calcitriol treated rats. Exogenous administration of DHT decreased prostatic weight of control rats but in rats treated with 1,25-dihydroxycholecalciferol DHT did not have any significant effect on prostatic weight. No statistically significant differences were observed in seminal vesicle weights among the different groups of animals. Analysis of the nuclear matrix protein composition of the prostatic tissue showed differences in composition between the DHT, and calcitriol and DHT treated rat prostates.
These studies indicate that calcitriol administered just before puberty does not significantly influence prostatic growth in the presence of endogenous or exogenous administered DHT, and has an inhibitory effect on neonatal prostate epithelial cell growth in vitro in the presence and absence of DHT. Treatment with calcitriol and DHT also results in differences in nuclear matrix protein composition. Prepubertal administration of calcitriol may inhibit the exogenous DHT action in decreasing epithelial growth and stimulating stromal proliferation in the rat prostate.
尽管许多研究探讨了骨化三醇在正常前列腺和癌性前列腺生长调节中的作用，但对其在前列腺早期发育中的作用知之甚少。骨化三醇与雄激素之间的相互作用及其对正常前列腺的作用也已被提出，但尚未得到评估。我们实验室之前的研究表明，子宫内给予1,25 - 二羟胆钙化醇或骨化三醇可影响动物一生的前列腺生长和分化。我们通过关注前列腺发育的早期阶段，进一步研究了骨化三醇在体外和体内对正常前列腺的影响。
在有和没有双氢睾酮（DHT）存在的情况下，测定骨化三醇对正常人新生儿前列腺上皮细胞系267B - 1生长的影响。我们还研究了骨化三醇对体内成熟大鼠前列腺生长的影响。青春期前，将4组27至38日龄的大鼠用赋形剂（对照组）或骨化三醇处理。当大鼠在100至110日龄达到成年时，处死一组对照组和一组骨化三醇处理组。另外两组给予外源性DHT 5天。为使动物适应DHT，使其再存活1周，并在约120日龄时处死。
体外研究表明，267B - 1细胞具有维生素D受体，其生长受到骨化三醇的抑制，IC50（导致50%细胞毒性的浓度）为30 microM。在体外有DHT存在的情况下，骨化三醇也抑制这些新生儿前列腺细胞的增殖。我们的研究表明，尽管在明显重要的青春期前时期给予骨化三醇，但对照组和骨化三醇处理组大鼠的前列腺重量没有差异。外源性给予DHT可降低对照大鼠的前列腺重量，但在1,25 - 二羟胆钙化醇处理的大鼠中，DHT对前列腺重量没有任何显著影响。不同组动物的精囊重量未观察到统计学上的显著差异。对前列腺组织核基质蛋白组成的分析表明，DHT处理组、骨化三醇处理组以及骨化三醇和DHT联合处理组大鼠的前列腺在组成上存在差异。
这些研究表明，青春期前给予骨化三醇在有内源性或外源性DHT存在的情况下不会显著影响前列腺生长，并且在有和没有DHT存在的情况下，对体外新生儿前列腺上皮细胞生长具有抑制作用。骨化三醇和DHT联合处理也导致核基质蛋白组成的差异。青春期前给予骨化三醇可能会抑制外源性DHT在降低大鼠前列腺上皮生长和刺激基质增殖方面的作用。
