Koppan M, Nagy A, Schally A V, Arencibia J M, Plonowski A, Halmos G
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70146, USA.
Cancer Res. 1998 Sep 15;58(18):4132-7.
Receptors for somatostatin (SST) that are found on prostate cancers might be used for targeting of chemotherapeutic agents. Thus, doxorubicin derivative 2-pyrrolinodoxorubicin (AN-201) can be linked to SST analogue RC-121 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2) to form targeted cytotoxic SST analogue AN-238. In this study, we evaluated the effects of AN-238 on the growth of SST receptor (SSTR)-positive androgen-independent Dunning R-3327-AT-1 prostate cancers in Copenhagen rats. The dose range and tumor growth-inhibitory effects of AN-238 and AN-201 were investigated in preliminary experiments. Administration of cytotoxic radical AN-201 at single i.v. doses of 110, 125, and 150 nmol/kg resulted in 0, 77.7, and 100% mortality, respectively, within 6-10 days. Four weeks after the injection of 110 nmol/kg AN-201, mean tumor volume was reduced by 35.1 % (P < 0.05), as compared with controls. In contrast, a single i.v. injection of analogue AN-238 at a dose of 300 nmol/kg was nontoxic and remarkably potent in inhibiting the growth of Dunning AT-1 tumors, resulting in a 85.9% (P < 0.01) reduction in tumor volume after 4 weeks. Treatment with AN-238 extended the survival time of tumor-bearing rats from 52.0+/-3.75 to 91.8+/-3.70 days, corresponding to a 76.5% (P < 0.01) increase. In a comprehensive experiment, we compared the effects of radical AN-201 at 115 nmol/kg, analogue AN-238 at 115 and 300 nmol/kg, carrier SST analogue RC-121 at 300 nmol/kg, and a mixture of AN-201 and RC-121 at doses of 300 nmol/kg administered i.v. Administration of AN-201 at 115 nmol/kg led to 90.0% mortality in 12 days, but animals treated with 115 nmol/kg of AN-238 showed no signs of toxicity, their tumor volume was reduced by 40.0% (P < 0.05), and their tumor weight was reduced by 42.8% (P < 0.01) after 4 weeks, as compared with controls. The dose of 300 nmol/kg of AN-238 was also nontoxic and diminished tumor volume by 80.9% (P < 0.01) and tumor weight by 82.0% (P < 0.01). No reduction in tumor growth or toxic effects was observed with carrier RC-121, but after the injection of unconjugated mixture of AN-201 and RC-121 at doses of 300 nmol/kg, all rats died within 4 days. Specific high-affinity receptors for SST were found on Dunning R-3327-AT-1 tumor membranes by radioligand binding assay and were identified by reverse transcription-PCR as SSTR2. Our study indicates that cytotoxic SST analogue AN-238 can be targeted to SSTRs on tumors and produces a powerful inhibition of the growth of Dunning-AT-1 rat prostate cancer at doses that are nontoxic, whereas its cytotoxic component, 2-pyrrolinodoxorubicin, is toxic and ineffective.
在前列腺癌中发现的生长抑素（SST）受体可用于靶向化疗药物。因此，阿霉素衍生物2-吡咯啉阿霉素（AN-201）可与SST类似物RC-121（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-NH2）连接，形成靶向细胞毒性SST类似物AN-238。在本研究中，我们评估了AN-238对哥本哈根大鼠中SST受体（SSTR）阳性雄激素非依赖性邓宁R-3327-AT-1前列腺癌生长的影响。在初步实验中研究了AN-238和AN-201的剂量范围及肿瘤生长抑制作用。以110、125和150 nmol/kg的单次静脉注射剂量给予细胞毒性自由基AN-201，分别在6 - 10天内导致0%、77.7%和100%的死亡率。注射110 nmol/kg AN-201四周后，与对照组相比，平均肿瘤体积减少了35.1%（P < 0.05）。相比之下，以300 nmol/kg的剂量单次静脉注射类似物AN-238无毒，且在抑制邓宁AT-1肿瘤生长方面非常有效，四周后肿瘤体积减少了85.9%（P < 0.01）。用AN-238治疗使荷瘤大鼠的生存时间从52.0±3.75天延长至91.8±3.70天，相应增加了76.5%（P < 0.01）。在一项综合实验中，我们比较了115 nmol/kg的自由基AN-201、115和300 nmol/kg的类似物AN-238、300 nmol/kg的载体SST类似物RC-121以及静脉注射剂量为300 nmol/kg的AN-201和RC-121混合物的效果。以115 nmol/kg的剂量给予AN-201在12天内导致90.0%的死亡率，但用115 nmol/kg的AN-238治疗的动物没有毒性迹象，四周后与对照组相比，其肿瘤体积减少了40.0%（P < 0.05），肿瘤重量减少了42.8%（P < 0.01）。300 nmol/kg剂量的AN-238也无毒，肿瘤体积减少了80.9%（P < 0.01），肿瘤重量减少了82.0%（P < 0.01）。载体RC-121未观察到肿瘤生长减少或毒性作用，但注射剂量为300 nmol/kg的AN-201和RC-121未结合混合物后，所有大鼠在4天内死亡。通过放射性配体结合试验在邓宁R-3327-AT-1肿瘤膜上发现了SST的特异性高亲和力受体，并通过逆转录 - PCR鉴定为SSTR2。我们的研究表明，细胞毒性SST类似物AN-238可靶向肿瘤上的SSTRs，在无毒剂量下对邓宁 - AT-1大鼠前列腺癌的生长产生强大抑制作用，而其细胞毒性成分2-吡咯啉阿霉素有毒且无效。
