Pinski J, Reile H, Halmos G, Groot K, Schally A V
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70146.
Cancer Res. 1994 Jan 1;54(1):169-74.
The effects of somatostatin analogue RC-160 and bombesin/gastrin releasing-peptide (GRP) antagonist RC-3095 were evaluated in Copenhagen rats bearing the anaplastic, androgen-independent Dunning R3327-AT-1 prostatic adenocarcinoma. In the first experiment, RC-160 was given in the form of microcapsules releasing 60 micrograms/day/rat. RC-3095 was administered from implanted Alzet osmotic minipumps liberating 100 micrograms/day/rat. After 32 days, tumor volumes and weights were significantly reduced by RC-160 as compared with the control group. Tumor doubling time in rats treated with RC-160 was significantly longer than in controls. Bombesin/GRP antagonist RC-3095 also significantly reduced tumor volume after 7 days of treatment, but after 18 days the inhibition in tumor volume was no longer significant. Tumor growth was not suppressed by castration. In the second experiment, 3-mm3 fragments of Dunning R-3327-AT-1 tumor were implanted orthotopically into the prostates of Copenhagen rats in order to evaluate the survival time of animals bearing this cancer during treatment with RC-160 released from Alzet osmotic minipumps at a dose of 100 micrograms/day/rat. Treatment with RC-160 significantly (P < 0.05) prolonged the mean survival time of rats by 5.3 days as compared to control animals. In both experiments, therapy with RC-160 significantly decreased serum growth hormone or insulin-like growth factor I levels. In the first experiment, receptor assays on R-3327-AT-1 tumor membranes showed high affinity binding sites for somatostatin, bombesin, and epidermal growth factor. At the end of the treatment, receptors for epidermal growth factor were significantly down-regulated by treatment with RC-160 but not with RC-3095. The binding capacity of bombesin receptors was reduced to nondetectable levels after the treatment with RC-3095. In cell cultures, high affinity binding sites for bombesin/GRP were found on intact Dunning R-3327-AT-1 cells, but receptors for somatostatin could not be detected. Proliferation of the AT-1 cell line was significantly inhibited by antagonist RC-3095. However, no effect on tumor cell growth in vitro was observed with analogue RC-160. Our results demonstrate that somatostatin analogue RC-160 and bombesin/GRP antagonist RC-3095 can inhibit the growth of the androgen-independent Dunning R-3327-AT-1 prostatic cancer in rats, although the remission produced by RC-3095 may be of short duration due to a down-regulation of bombesin receptors. Our work suggests the merit of further investigation as to whether these analogues can induce a possible delay in relapse and prolong survival in prostate cancer.
在患有间变性、雄激素非依赖性邓宁R3327-AT-1前列腺腺癌的哥本哈根大鼠中，评估了生长抑素类似物RC-160和蛙皮素/胃泌素释放肽（GRP）拮抗剂RC-3095的作用。在第一个实验中，RC-160以每天每只大鼠释放60微克的微胶囊形式给药。RC-3095通过植入的Alzet渗透微型泵给药，每天每只大鼠释放100微克。32天后，与对照组相比，RC-160显著降低了肿瘤体积和重量。用RC-160治疗的大鼠肿瘤倍增时间明显长于对照组。蛙皮素/GRP拮抗剂RC-3095在治疗7天后也显著降低了肿瘤体积，但在18天后对肿瘤体积的抑制作用不再显著。去势并未抑制肿瘤生长。在第二个实验中，将3立方毫米的邓宁R-3327-AT-1肿瘤片段原位植入哥本哈根大鼠的前列腺中，以评估在用每天每只大鼠剂量为100微克的从Alzet渗透微型泵释放的RC-160治疗期间患有这种癌症的动物的存活时间。与对照动物相比，用RC-160治疗显著（P<0.05）延长了大鼠的平均存活时间5.3天。在两个实验中，用RC-160治疗均显著降低了血清生长激素或胰岛素样生长因子I水平。在第一个实验中，对R-3327-AT-1肿瘤膜的受体分析显示存在生长抑素、蛙皮素和表皮生长因子的高亲和力结合位点。在治疗结束时，用RC-160治疗可使表皮生长因子受体显著下调，但用RC-3095治疗则无此作用。用RC-3095治疗后，蛙皮素受体的结合能力降低到无法检测的水平。在细胞培养中，在完整的邓宁R-3327-AT-1细胞上发现了蛙皮素/GRP的高亲和力结合位点，但未检测到生长抑素受体。拮抗剂RC-3095显著抑制了AT-1细胞系的增殖。然而，未观察到类似物RC-160对体外肿瘤细胞生长有影响。我们的结果表明，生长抑素类似物RC-160和蛙皮素/GRP拮抗剂RC-3095可以抑制大鼠雄激素非依赖性邓宁R-3327-AT-1前列腺癌的生长，尽管由于蛙皮素受体的下调，RC-3095产生的缓解可能持续时间较短。我们的工作表明，值得进一步研究这些类似物是否可以在前列腺癌中诱导可能的复发延迟并延长生存期。
