Investigation of novel chemotherapeutic combinations in a tumor model of adrenocortical carcinoma

Medical treatment of adrenocortical carcinoma (ACC) is limited to common cytotoxic agents, which are usually given in combination with mitotane (M). Recently, we investigated in combination with M the effects of two different chemotherapies on human NCIh295 cells in vitro: 1. The classical EDP (etoposide, doxorubicin, cisplatin) and 2. a novel paclitaxel containing scheme PDP (paclitaxel, doxorubicin, cisplatin) indicating superiority of PDP-M over EDP-M regarding reduction of cell viability (% of 100% basal; EDP-M: 69.7 ± 0.9%, PDP-M: 40.7 ± 1.7%; p = 0.001), induction of apoptosis (EDP-M: 473.3 ± 11.7%, PDP-M: 629 ± 16%; p = 0.001) and inhibition of proliferation (EDP-M: 105.3 ± 9.4%, PDP-M: 14.5 ± 4.4%; p = 0.0009). In a next step, we performed short-term therapeutic experiments with EDP-M and PDP-M on NCIh295 xenografts in mice. Since we found evidence for an extraordinary uptake phenomenon of liposomes by ACC cells we furthermore included together with M liposomal variants of the treatment schemes called LEDP-M (etoposide, liposomal doxorubicin, liposomal cisplatin) and LPDP-M (nab-paclitaxel, liposomal doxorubicin, liposomal cisplatin). EDP-M treatment resulted in leucopenia and did not induce a significant loss of tumor cells (% of basal; 83.9 ± 10.1) while PDP-M (83.6 ± 1.9%, p = 0.003), LEDP-M (72.5 ± 1.9%, p = 0.003) and LPDP-M (61.2 ± 3.5%, p = 0.0002) resulted overall in a significant reduction in the number of tumor cells compared with controls (100%). LEDP-M (150.3 ± 8.3%, p = 0.004) and LPDP-M (146.7 ± 13.7%, p = 0.02) induced furthermore apoptosis. Only minor grades of leucopenia [leukocytes G/l; controls: 6.1 ± 1.3] were detected following LPDP-M treatment (3.2 ± 0.2) compared with EDP-M (1.9 ± 0.2; p = 0.003). Moreover, in a consecutive long-term study we were able to confirm therapeutic superiority of LEDP-M versus EDP-M regarding tumor regression over time. In summary PDP-M, LPDP-M and specially LEDP-M could represent novel treatment options compared with classical EDP-M scheme.