title: Liposomal doxorubicin-based treatment in a preclinical model of adrenocortical carcinoma.
abstract: Adrenocortical carcinoma (ACC) is a rare endocrine tumor entity with poor prognosis. Medical treatment is limited to common cytotoxic agents, which are associated with low treatment responses. Thus, lack of therapeutic efficacy demands innovative treatment options for patients with advanced ACC. Recently, we have developed and characterized anti-IGF1 receptor (IGF1-R) immunoliposomes (SSLD-1H7) for the treatment of neuroendocrine tumors of the gastroenteropancreatic system. As previous results indicated putative applicability also for other IGF1-R-overexpressing tumor entities, we initiated testing of liposomal preparations in in vitro and in vivo models of ACC. Adrenocortical NCIh295 cells were used for in vitro association studies with different liposomal formulations. Thereby, flow cytometry revealed high cellular association and internalization of anti-IGF1-R immunoliposomes (soy phosphatidylcholine (SPC)/cholesterol (Chol)-polyethyleneglycol (PEG)-1H7, 50.1±2.2%). Moreover, internalization of pegylated liposomes (SPC/Chol-PEG, 57.1±2.4%) and an even higher uptake of plain liposomes (84.6±0.8%; P<0.0001) were detectable in adrenocortical tumor cells. In vivo, liposomal treatments were investigated on NCIh295 tumor xenografts in pharmacokinetic and therapeutic experiments. A significant reduction in tumor size was detectable in NCIh295 tumor-bearing mice after a single treatment with SSLD-1H7 (0.89±0.15 cm; P=0.006) and a diminished efficacy for SSLD-PEG+ (1.01±0.19 cm; P=0.04) in comparison with untreated controls (1.5±0.0 cm). Thus, anti-IGF1-R immunoliposomes have been successfully tested in vitro and in vivo in a preclinical model for ACCs and could, therefore, represent a promising therapeutic approach for this tumor entity. Moreover, a combination of mitotane plus liposomally encapsulated cytostatic agents instead of free drugs could also be an interesting novel treatment option for ACC in the future.
authors.affiliation: Endocrine Research Unit, Medizinische Klinik and Poliklinik IV, Ludwig-Maximilians-University, Ziemssenstraße 1, D-80336 Munich, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Hantel
authors.forename: Felicitas
authors.initials: F
authors.lastname: Lewrick
authors.forename: Martin
authors.initials: M
authors.lastname: Reincke
authors.forename: Regine
authors.initials: R
authors.lastname: Süss
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy*; D018268:Adrenocortical Carcinoma / Q000188:drug therapy*; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D000911:Antibodies, Monoclonal; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D017526:Receptor, IGF Type 1 / Q000276:immunology
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D008081:Liposomes; D004317:Doxorubicin; D017526:Receptor, IGF Type 1