褪黑素抑制由 17-β-雌二醇诱发的垂体催乳素瘤的生长

Inhibitory Effect of Melatonin on the Development of Pituitary Prolactin- producing Tumors Induced by 17-β- Estradiol

观察整体条件下褪黑素 (melatonin, MLT)抑制由 17-β-雌二醇 (E2)诱发的垂体催乳素 (prolactin, PRL)瘤的生长，并初步探讨其作用机制。方法以雄性 Sprague- Dawley大鼠皮下埋植 E2药泵，诱发 PRL瘤。实验组大鼠分 5组，在诱瘤之前每日定时分别皮下注射 0.05、 0.25、 0.50、 1.00和 2.00 mg MLT，共 90 d;对照组大鼠皮下注射等体积 4％乙醇－生理盐水。结果 (1)给予 0.05、 0.25、 0.50、 1.00和 2.00 mg MLT处理组 PRL瘤重量分别较对照组降低 25.91％ (P >0.05)、 48.78％ (P< 0.01)、 36.78％ (P< 0.05)、 31.04％ (P >0.05)和 35.22％ (P > 0.05); (2)Northern Blot分析表明，注射 0.05、 0.25、 0.50 mg MLT组 PRL瘤细胞 PRL mRNA表达水平分别比对照组降低 33.67％ (P< 0.05)、 25.51％ (P< 0.05)和 41.84％ (P< 0.01)；原代培养的 PRL瘤细胞原位杂交实验也获得类似结果 ; (3)激光扫描共聚焦显微镜检测结果显示， 0.05、 0.25和 0.50 mg MLT组 PRL瘤细胞 DNA的相对含量分别较对照组降低 40.73％ (P< 0.001)、 51.15％ (P< 0.001)和 60.23％ (P< 0.001); (4)紫外分光光度法测定显示， 0.05、 0.25、 0.50、 1.00和 2.00 mg MLT组血浆过氧化脂质水平分别比对照组降低 26.45％ (P< 0.05)、 23.97％ (

Objective To examine the inhibitory effect of melatonin (MLT) on the development of pituitary prolactin- producing tumors (prolactinoma) induced by 17-β- estradiol (E2), in vivo, and explore MLT′ s oncostatic mechanisms. Methods The prolactinomas were established by implanting E2- laden silastic capsules subcutaneously in Sprague- Dawley male rats. MLT doses 0.05, 0.25, 0.50, 1.00, and 2.00 mg/rat were administrated separately to 5 groups subcutaneously starting seven days prior to tumor induction for 97 days. The matched controls were given equal volumes of 4％ alcohol in saline. Results (1) The prolactinoma weights in 0.05, 0.25, 0.50, 1.00 and 2.00 mg MLT dose groups were 25.91％ (P > 0.05), 48.78％ (P< 0.01), 36.78％ (P< 0.05), 31.04％ (P >0.05) and 35.22％ (P >0.05) respectively which were lower than that of control group; (2) The PRL mRNA levels of prolactinoma in 0.05, 0.25, and 0.50 mg MLT dose groups were 33.67％ (P< 0.05), 25.51％ (P< 0.05) and 41.84％ (P< 0.01) respectively which were lower than that of control group as estimated by Northern Blot, and the in situ hybridization studies; (3) The DNA contents of prolactinoma in 0.05, 0.25 and 0.50 mg MLT dose groups were 40.73％ (P< 0.001), 51.15％ (P< 0.001) and 60.23％ (P< 0.001)respectively which were lower than that of control group by laser scanning confocal microscopy ; (4) Plasma peroxida tive lipid contents in 0.05, 0.25, 0.50, 1.00 and 2.00 mg MLT dose groups were 26.45％ (P< 0.05), 23.97％ (P< 0.05), 47.11％ (P< 0.001), 66.12％ (P< 0.001) and 64.46％ (P< 0.001) respectively which were lower than that of control group. The correlation coefficient between MLT doses and plasma peroxidative lipid contents was－ 0.8257 (P< 0.05). Conclusions MLT in suitable doses is able to inhibit the development of E2- induced prolactinoma by inhibiting the expression of PRL gene and the DNA synthesis. The link between MLT antioxidative action and its inhibitory effect on development of prolactinoma should be further investigated.