Jungwirth A, Pinski J, Galvan G, Halmos G, Szepeshazi K, Cai R Z, Groot K, Vadillo-Buenfil M, Schally A V
Department of Experimental Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.
Eur J Cancer. 1997 Jun;33(7):1141-8. doi: 10.1016/s0959-8049(97)00072-5.
The aim of this study was to test the antagonist of LH-RH (Cetrorelix), agonist [D-Trp6]LH-RH (triptorelin) and new bombesin antagonists RC-3940-II and RC-3950-II for their effect on the growth of an androgen-independent prostate cancer cell line, DU-145, xenografted into nude mice. Xenografts were grown in male nude mice, and after 4 weeks, the animals were treated either with saline (control) or with one of the analogues. One group of mice was given a combination of Cetrorelix and RC-3950-II. Treatment was given for 4 weeks. Tumour and body weights, and tumour volumes were measured. At sacrifice, tumours were dissected for histological examination and receptor studies. Serum was collected for measurement of hormone levels. The final tumour volume in control animals injected with saline was 577 +/- 155 mm3 and that of animals treated with Cetrorelix only 121.4 +/- 45 mm3 (P < 0.01). Bombesin antagonists RC-3940-II and RC-3950-II also significantly reduced DU-145 tumour volume in nude mice to 84.9 +/- 19.9 and 96.8 +/- 28 mm3, respectively. Agonist [D-Trp6]LH-RH did not significantly inhibit tumour growth. Serum levels of LH were decreased to 0.08 +/- 0.02 ng/ml (P < 0.05) in the Cetrorelix treated group as compared to 1.02 +/- 0.1 ng/ml for the controls, and testosterone levels were reduced to castration levels (0.01 +/- 0.01 ng/ml). Specific receptors for EGF and LH-RH in DU-145 tumours were significantly downregulated after treatment with Cetrorelix, RC-3940-II and RC-3950-II. Although LH-RH could be a local regulator of growth of prostate cancer, the fall in LH-RH receptors is not fully understood and the inhibitory effects of Cetrorelix and bombesin antagonists on DU-145 tumour growth might be attributed at least in part to a downregulation of EHF receptors. Since Cetrorelix and bombesin antagonists inhibit growth of androgen-independent DU-145 prostate cancers, these compounds could be considered for the therapy of advanced prostate cancer in men, especially after relapse.
本研究旨在测试促黄体生成素释放激素（LH-RH）拮抗剂（西曲瑞克）、激动剂[D-色氨酸6]LH-RH（曲普瑞林）以及新型蛙皮素拮抗剂RC-3940-II和RC-3950-II对移植到裸鼠体内的雄激素非依赖性前列腺癌细胞系DU-145生长的影响。将异种移植物接种到雄性裸鼠体内，4周后，动物分别用生理盐水（对照）或其中一种类似物进行处理。一组小鼠给予西曲瑞克和RC-3950-II的组合。治疗持续4周。测量肿瘤和体重以及肿瘤体积。处死时，解剖肿瘤进行组织学检查和受体研究。收集血清以测量激素水平。注射生理盐水的对照动物的最终肿瘤体积为577±155立方毫米，仅用西曲瑞克治疗的动物的肿瘤体积为121.4±45立方毫米（P<0.01）。蛙皮素拮抗剂RC-3940-II和RC-3950-II也显著降低了裸鼠体内DU-145肿瘤体积，分别降至84.9±19.9和96.8±28立方毫米。激动剂[D-色氨酸6]LH-RH未显著抑制肿瘤生长。与对照组的1.02±0.1纳克/毫升相比，西曲瑞克治疗组的促黄体生成素血清水平降至0.08±0.02纳克/毫升（P<0.05），睾酮水平降至去势水平（0.01±0.01纳克/毫升）。用西曲瑞克、RC-3940-II和RC-3950-II治疗后，DU-145肿瘤中表皮生长因子（EGF）和LH-RH的特异性受体显著下调。虽然LH-RH可能是前列腺癌生长的局部调节因子，但LH-RH受体的下降尚未完全了解，西曲瑞克和蛙皮素拮抗剂对DU-145肿瘤生长的抑制作用可能至少部分归因于表皮生长因子受体的下调。由于西曲瑞克和蛙皮素拮抗剂可抑制雄激素非依赖性DU-145前列腺癌的生长，这些化合物可考虑用于男性晚期前列腺癌的治疗，尤其是在复发后。
