Schally A V, Redding T W
Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, New Orleans, LA 70146.
Proc Natl Acad Sci U S A. 1987 Oct;84(20):7275-9. doi: 10.1073/pnas.84.20.7275.
The combination of a long-acting delivery system for the agonist [D-Trp6]luteinizing hormone-releasing hormone ([D-Trp6]LH-RH) with modern somatostatin analogs was studied in the Dunning R-3327H rat prostate cancer model. Microcapsules of [D-Trp6]LH-RH releasing 25 micrograms/day were injected once a month. In the first experiment the adjunct was the somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), administered at a dose of 2.5 micrograms twice a day, and the therapy was continued for 70 days. Tumor volume was significantly decreased by [D-Trp6]LH-RH microcapsules or RC-121 given alone. The combination of microcapsules and analog RC-121 caused a greater inhibition of tumor growth than the single agents. Similar effects were seen when the percent increase in the tumor volume was examined. The inhibition of tumor growth caused by the [D-Trp6]LH-RH microcapsules was greater than that caused by RC-121. The combination of the two agents was again the most effective, resulting in the smallest increase in tumor volume. Tumor weights were much lower in the groups treated with microcapsules or RC-121 alone than in controls. The lowest tumor weights were obtained in the group that received the combination of [D-Trp6]LH-RH microcapsules and RC-121. Similar results were obtained in the second experiment, in which the animals were treated for a period of 83 days with microcapsules containing the somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) that released 5 micrograms/day and were injected twice a month alone or in combination with microcapsules of [D-Trp6]LH-RH. Microcapsules of analog RC-160 given alone significantly decreased tumor growth as measured by the final tumor volume, the percentage change from the initial tumor volume, and the reduction in tumor weight. The inhibition of tumor growth induced by [D-Trp6]LH-RH microcapsules was greater than that caused by RC-160. The most striking decrease in tumor weight and volume was obtained in animals treated with microcapsules of [D-Trp6]LH-RH combined with the delayed delivery system for RC-160. The overall response to the combination therapy could reflect the inhibition by somatostatin analogs of the proliferation of prostate cancer cells through a decrease in growth hormone and prolactin release and interference with endogenous growth factors, in addition to the main effect, which is the suppression by [D-Trp6]LH-RH of the growth of androgen-dependent tumor cells. Our results indicate that somatostatin analogs enhance the inhibitory effects of [D-Trp6]LH-RH on the growth of prostate tumors. The administration of somatostatin analogs in combination with microcapsules of [D-Trp6]LH-RH might improve clinical response in patients with advanced prostate carcinoma.
在邓宁R-3327H大鼠前列腺癌模型中，研究了长效促性腺激素释放激素激动剂[D-色氨酸6]促黄体生成素释放激素（[D-色氨酸6]LH-RH）与现代生长抑素类似物的联合应用。每月注射一次每天释放25微克[D-色氨酸6]LH-RH的微胶囊。在第一个实验中，辅助药物是生长抑素类似物D-苯丙氨酸-半胱氨酸-酪氨酸-D-色氨酸-赖氨酸-缬氨酸-半胱氨酸-苏氨酸-酰胺（RC-121），每天两次，每次剂量为2.5微克，治疗持续70天。单独使用[D-色氨酸6]LH-RH微胶囊或RC-121可使肿瘤体积显著减小。微胶囊与类似物RC-121联合使用对肿瘤生长的抑制作用比单一药物更强。检查肿瘤体积的百分比增加时也观察到类似效果。[D-色氨酸6]LH-RH微胶囊对肿瘤生长的抑制作用大于RC-121。两种药物联合使用再次最为有效，导致肿瘤体积增加最小。单独用微胶囊或RC-121治疗的组的肿瘤重量远低于对照组。接受[D-色氨酸6]LH-RH微胶囊和RC-121联合治疗的组的肿瘤重量最低。在第二个实验中获得了类似结果，在该实验中，动物用每天释放5微克且每月注射两次的含有生长抑素类似物D-苯丙氨酸-半胱氨酸-酪氨酸-D-色氨酸-赖氨酸-缬氨酸-半胱氨酸-色氨酸-酰胺（RC-160）的微胶囊单独或与[D-色氨酸6]LH-RH微胶囊联合治疗83天。单独给予类似物RC-160微胶囊可显著降低肿瘤生长，这通过最终肿瘤体积、相对于初始肿瘤体积的百分比变化以及肿瘤重量的减轻来衡量。[D-色氨酸6]LH-RH微胶囊诱导的肿瘤生长抑制作用大于RC-160。在用[D-色氨酸6]LH-RH微胶囊与RC-160延迟释放系统联合治疗的动物中，肿瘤重量和体积的下降最为显著。联合治疗的总体反应可能反映了生长抑素类似物通过减少生长激素和催乳素释放以及干扰内源性生长因子对前列腺癌细胞增殖的抑制作用，此外，主要作用是[D-色氨酸6]LH-RH对雄激素依赖性肿瘤细胞生长的抑制。我们的结果表明，生长抑素类似物增强了[D-色氨酸6]LH-RH对前列腺肿瘤生长的抑制作用。生长抑素类似物与[D-色氨酸6]LH-RH微胶囊联合给药可能改善晚期前列腺癌患者的临床反应。
