Endocrine Abstracts

Medical treatment of adrenocortical carcinoma (ACC) is limited to common cytotoxic agents, which are usually given in combination with mitotane. Recently we have developed a novel therapeutic approach by coupling a monoclonal IGF1 receptor blocking antibody (1H7) to sterically stabilized liposomal doxorubicin (SSLD). 1H7 coupled liposomes showed in vitro high and significant cellular association and furthermore internalization in various human tumor cell lines as well as in vivo superior anti-tumor efficacy against neuroendocrine tumors of the gastroenteropancreatic system. Flow cytometry and fluorescence microscopy demonstrated high internalization of 1H7 coupled liposomes (50.13±2.2) also for the adrenocortical tumor cell line NCIh295, but surprisingly an even higher uptake of plain liposomes (84.57±0.82; P=0.0001). This extraordinary uptake phenomenon was independent on liposomal cholesterol content (cholesterol free preparation, 82.92±1.63; P=0.11) and was not exclusively dependent on caveolae- (66.47±2.2) and clathrin-mediated endocytosis (57.27±1.9) since specific inhibitors were only partially able to inhibit the investigated effect. We evaluated the therapeutic efficacy of liposomal preparations in an in vivo model for ACCs. A significant reduction in tumor size (cm) was detectable 32 days after a single treatment of NCIh295 tumor-bearing mice with SSLD-1H7 (0.89±0.15; P=0.006) and diminished for SSLD (1.01±0.19; P=0.04) compared with untreated controls (1.5±0) while no significant effects were seen for treatments with free 1H7 (1.38±0.11; P=0.36) LD (1.2±0.3; P=0.36), unspecific SSLD-IgG (1.45±0.5; P=0.36) or SSLD + free 1H7 (1.29±0.17; P=0.25). Thus, SSLD-1H7 could represent a promising approach for the treatment of ACCs in the future. Moreover, a combination of mitotane plus encapsulated cytostatic agents instead of the free drugs could also represent an interesting novel treatment option.