Keller Gunhild, Schally Andrew V, Nagy Attila, Baker Benjamin, Halmos Gabor, Engel Jörg B
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70112, USA.
Int J Oncol. 2006 Jun;28(6):1507-13.
Malignant melanomas are characterized by a high intrinsic resistance to chemotherapy. Multiple drug resistance (MDR) can be mediated by transport proteins such as MDR-1, multidrug resistance-associated protein (MRP) or lung resistance protein (LRP). The cytotoxic analogue of somatostatin AN-238 consisting of 2-pyrrolinodoxorubicin (AN-201) linked to a somatostatin analogue RC-121 binds to receptors for somatostatin and is targeted to tumors expressing these receptors. We evaluated the expression of somatostatin receptors on human malignant melanoma tumor lines MRI-H255 and MRI-H187 and examined the effects of the targeted analogue AN-238 and its cytotoxic radical AN-201 on growth of these tumors in nude mice. We also studied the effects of AN-238 and AN-201 on the expression of MDR-1, MRP-1 and LRP by real-time PCR. AN-238 inhibited the growth of MRI-H255 and MRI-H187 tumors while AN-201 was ineffective. Blockade of somatostatin receptors by somatostatin analogue RC-121 abolished the effects of AN-238. Targeted therapy with AN-238 did not produce an induction of mRNA of MDR-1, MRP-1 or LRP. Our findings show that targeted chemotherapy with cytotoxic somatostatin analogue AN-238 inhibits the growth of malignant melanomas. AN-238 could provide a novel treatment approach for advanced malignant melanomas.
恶性黑色素瘤的特点是对化疗具有高度的内在抗性。多药耐药性（MDR）可由诸如MDR-1、多药耐药相关蛋白（MRP）或肺耐药蛋白（LRP）等转运蛋白介导。生长抑素类似物AN-238的细胞毒性类似物由与生长抑素类似物RC-121相连的2-吡咯啉阿霉素（AN-201）组成，它与生长抑素受体结合，并靶向表达这些受体的肿瘤。我们评估了生长抑素受体在人恶性黑色素瘤肿瘤细胞系MRI-H255和MRI-H187上的表达，并研究了靶向类似物AN-238及其细胞毒性基团AN-201对这些肿瘤在裸鼠体内生长的影响。我们还通过实时PCR研究了AN-238和AN-201对MDR-1、MRP-1和LRP表达的影响。AN-238抑制了MRI-H255和MRI-H187肿瘤的生长，而AN-201则无效。生长抑素类似物RC-121对生长抑素受体的阻断消除了AN-238的作用。用AN-238进行靶向治疗并未诱导MDR-1、MRP-1或LRP的mRNA表达。我们的研究结果表明，用细胞毒性生长抑素类似物AN-238进行靶向化疗可抑制恶性黑色素瘤的生长。AN-238可为晚期恶性黑色素瘤提供一种新的治疗方法。
