Plonowski A, Schally A V, Nagy A, Kiaris H, Hebert F, Halmos G
Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, New Orleans, Louisiana 70112-1262, USA.
Cancer Res. 2000 Jun 1;60(11):2996-3001.
The effectiveness of chemotherapy targeted to somatostatin (SST) receptors based on cytotoxic SST analogue AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to SST carrier octapeptide, was investigated in human renal cell carcinomas (RCCs). SST receptors, which showed high-affinity binding for AN-238, were found in the SW-839 RCC line with sst2A subtype and in the 786-0 RCC line, which expressed the sst5 subtype. CAKI-1 RCC, which does not express sst2A or sst5, was used as a negative control for testing the specificity of SST receptor targeting. Using microsatellite analysis, AN-238 was shown to selectively inhibit the proliferation of 786-0 line, but not the CAKI-1 RCC line in vitro. The effects of three i.v. injections of 150 nmol/kg of AN-238 or AN-201, given on days 1, 8, and 21, were evaluated in groups of nude mice bearing s.c. xenografts of SW-839 and 786-0 RCC. After 5 weeks, the volumes of SW-839 and 786-0 RCC tumors were decreased by 67.2 (P < 0.05) and 78.3% (P < 0.01), respectively, whereas AN-201 had no significant effect on tumor growth. The inhibition of SST receptor-negative CAKI-1 tumors by AN-238 was only marginal. To investigate the efficacy of SST receptor-targeted chemotherapy in metastatic RCC, three i.v. injections of AN-238 or AN-201 at 150 nmol/kg were given at biweekly intervals to nude mice implanted with 786-0 tumors under the renal capsule. After 6 weeks, the weight of orthotopic tumors treated with AN-238 (55.3 +/- 44.3 mg) was significantly lower (87% reduction; P < 0.001) than that in the control group (414.2 +/- 41.0 mg) or in animals given AN-201 (270.2 +/- 603 mg; P < 0.05). Five of six animals (83%), both in the control and the AN-201 group, developed metastases to lymph nodes, but only one of seven mice (14%) given AN-238 showed lymphatic spread. Lung metastases were found in 83% of controls and 50% of AN-201 treated animals, but none occurred in mice treated with AN-238. This study demonstrates that targeted cytotoxic SST analogue AN-238 provides an effective therapy for chemoresistant neoplasms such as RCC. Because most clinical RCCs express SST receptors, this treatment modality might be beneficial to patients with metastatic disease.
基于细胞毒性生长抑素（SST）类似物AN - 238（由与SST载体八肽相连的2 - 吡咯啉阿霉素（AN - 201）组成）的化疗对人肾细胞癌（RCC）的有效性进行了研究。在具有sst2A亚型的SW - 839肾癌细胞系和表达sst5亚型的786 - 0肾癌细胞系中发现了对AN - 238具有高亲和力结合的SST受体。不表达sst2A或sst5的CAKI - 1肾癌细胞用作测试SST受体靶向特异性的阴性对照。使用微卫星分析表明，AN - 238在体外可选择性抑制786 - 0细胞系的增殖，但对CAKI - 1肾癌细胞系无抑制作用。对皮下接种SW - 839和786 - 0肾癌细胞异种移植物的裸鼠组，评估了在第1、8和21天静脉注射三次150 nmol/kg的AN - 238或AN - 201的效果。5周后，SW - 839和786 - 0肾癌细胞肿瘤体积分别减少了67.2%（P < 0.05）和78.3%（P < 0.01），而AN - 201对肿瘤生长无显著影响。AN - 238对SST受体阴性的CAKI - 1肿瘤的抑制作用仅很轻微。为了研究SST受体靶向化疗对转移性肾癌细胞的疗效，对肾包膜下植入786 - 0肿瘤的裸鼠每两周静脉注射三次150 nmol/kg的AN - 238或AN - 201。6周后，接受AN - 238治疗的原位肿瘤重量（55.3±44.3 mg）显著低于对照组（414.2±41.0 mg）或接受AN - 201治疗的动物（270.2±603 mg；P < 0.05），减轻了87%（P < 0.001）。对照组和AN - 201组的六只动物中有五只（83%）发生了淋巴结转移，但接受AN - 238治疗的七只小鼠中只有一只（14%）出现了淋巴转移。对照组83%的动物和接受AN - 201治疗的动物中有50%发生了肺转移，但接受AN - 238治疗小鼠中未出现肺转移。这项研究表明，靶向细胞毒性SST类似物AN - 238为肾癌细胞等化疗耐药肿瘤提供了一种有效的治疗方法。由于大多数临床肾癌细胞表达SST受体，这种治疗方式可能对转移性疾病患者有益。
