Effective therapy of experimental human malignant melanomas with a targeted cytotoxic somatostatin analogue without induction of multi-drug resistance proteins

Abstract

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.