Investigation of a novel liposomal chemotherapy protocol in three preclinical models for adrenocortical carcinoma in vivo

Recently, we demonstrated for adrenocortical carcinoma (ACC) promising antitumoral effects for LEDP-M (etoposide, liposomal doxorubicin, liposomal cisplatin, mitotane) a novel liposomal variant of the classical EDP-M protocol (etoposide, doxorubicin, cisplatin, mitotane). However, clinical translation of novel therapeutic regimens remains challenging due to high tumor heterogeneity. Thus, to obtain preclinical results with more clinically predictive power we investigated for the first time LEDP-M comparatively in three different xenograft models for ACC in vivo. Moreover, we included liposomal etoposide resulting in a novel treatment scheme called L(l)EDP-M. After one therapeutic cycle NCI-H295R, SW-13 and SJ-ACC3 tumors were excised and immunohistochemically [cells/high power fields (HPF)] analysed regarding total number of tumor cells [Ki67 positive and negative/HPF] and apoptosis [TUNEL positive cells/HPF]. In previous experiments on NCI-H295R xenografts we detected a significant reduction in overall tumor cell count for LEDP-M which was in the current study not reached by L(l)EDP-M. In contrast, regarding apoptosis L(l)EDP-M (p < 0.01) led to a further improvement of therapeutic effects already detected for LEDP-M (p < 0.05 vs. controls). In SW-13 xenografts, the number of tumor cells decreased in all treatment schemes with highest therapeutic efficacy of the liposomal variants (EDP-M: 20.5 ± 1.6 p < 0.01; LEDP-M: 17.2 ± 1.3 p < 0.001; L(l)EDP-M: 14.7 ± 0.9 p < 0.001) vs. controls (28.9 ± 2.2). In addition, most distinctive necrosis was detectable for L(l)EDP-M followed by LEDP-M, EDP-M and controls. In SJ-ACC3 xenografts a decrease in tumor cell number was found after EDP-M treatment only (30.3 ± 1.2 vs. controls 35.9 ± 1.3, p < 0.05). In summary, liposomal regimens represent for adult, but not for pediatric ACC, promising treatment options for clinical translation. However, our results also show that tumor heterogeneity should be taken into account in preclinical studies.