Kiaris H, Schally A V, Nagy A, Sun B, Szepeshazi K, Halmos G
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70112, USA.
Clin Cancer Res. 2000 Feb;6(2):709-17.
Receptors for somatostatin (SST) found on brain tumors could be used for targeting of chemotherapeutic agents. This study was conducted to investigate the effects of targeted cytotoxic SST analogue AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201), a potent derivative of doxorubicin (DOX) linked to somatostatin analogue RC-121, on the growth of SST receptor-positive U-87 MG human glioblastomas. Nude mice bearing U-87 MG xenografts received i.v. saline or equimolar doses of AN-238 or AN-201 (150 nmol/kg). Experiments also included groups that were administered RC-121 prior to the injection of AN-238, and groups injected with AN-162, a cytotoxic SST analogue similar to AN-238 but containing DOX instead of AN-201. Tumor volume, weight, and burden were determined. The effect of AN-238 and AN-201 on the survival time of nude mice bearing orthotopically implanted U-87 MG tumors was also evaluated. The binding of AN-238 to U-87 MG tumors was determined by radioreceptor assay and SST receptor (SSTR) subtype by reverse transcription-PCR. Nineteen days after a single administration of AN-238 the growth of U-87 MG tumors in nude mice was significantly inhibited (P = 0.00168), whereas two injections of AN-238 produced the regression of tumors (P = 0.0046). AN-201 was toxic and ineffective at the same dose. The antitumor effect on AN-238 could be blocked by pretreatment of the tumor-bearing mice with RC-121. The mean survival time of nude mice inoculated orthotopically with U-87 MG cells into the brain was significantly prolonged by treatment with AN-238 (P = 0.0099). AN-162 failed to inhibit significantly the growth of U-87 MG xenografts. High affinity binding sites for SST and mRNA for SST-2 receptor subtype were detected in U-87 MG tumors. Cytotoxic SST analogue AN-238 can be targeted to SST receptors on U-87 MG human glioblastomas to produce powerful inhibition of growth.
在脑肿瘤上发现的生长抑素（SST）受体可用于靶向化疗药物。本研究旨在调查靶向细胞毒性SST类似物AN - 238对SST受体阳性的U - 87 MG人胶质母细胞瘤生长的影响，AN - 238由2 - 吡咯啉阿霉素（AN - 201）组成，它是阿霉素（DOX）的一种强效衍生物，与生长抑素类似物RC - 121相连。携带U - 87 MG异种移植物的裸鼠接受静脉注射生理盐水或等摩尔剂量的AN - 238或AN - 201（150 nmol/kg）。实验还包括在注射AN - 238之前给予RC - 121的组，以及注射AN - 162的组，AN - 162是一种类似于AN - 238的细胞毒性SST类似物，但含有DOX而非AN - 201。测定肿瘤体积、重量和负荷。还评估了AN - 238和AN - 201对原位植入U - 87 MG肿瘤的裸鼠存活时间的影响。通过放射受体测定法测定AN - 238与U - 87 MG肿瘤的结合，并通过逆转录 - PCR测定SST受体（SSTR）亚型。单次给予AN - 238 19天后，裸鼠体内U - 87 MG肿瘤的生长受到显著抑制（P = 0.00168），而两次注射AN - 238可使肿瘤消退（P = 0.0046）。相同剂量下，AN - 201有毒且无效。用RC - 121预处理荷瘤小鼠可阻断AN - 238的抗肿瘤作用。用AN - 238治疗可显著延长原位接种U - 87 MG细胞至脑内的裸鼠的平均存活时间（P = 0.0099）。AN - 162未能显著抑制U - 87 MG异种移植物的生长。在U - 87 MG肿瘤中检测到SST的高亲和力结合位点和SST - 2受体亚型的mRNA。细胞毒性SST类似物AN - 238可靶向U - 87 MG人胶质母细胞瘤上的SST受体，从而强力抑制其生长。
