Liposomal polychemotherapy improves adrenocortical carcinoma treatment in a preclinical rodent model

Abstract

Owing to high relapse rates and early metastatic spread, prognosis in adrenocortical carcinoma (ACC) patients remains poor, highlighting the importance of developing new treatment alternatives for them. Recently, polychemotherapy regimens including etoposide, doxorubicin, and cisplatin together with mitotane (EDP-M) have been defined as the standard treatment for late-stage disease patients. Nevertheless, the administration of conventional cytostatic drugs is associated with severe and dose-limiting side effects. In an attempt to optimize existing clinical treatment regimens, in this study, we investigated the therapeutic efficacy of EDP-M in comparison with that of a paclitaxel-modified scheme (paclitaxel, doxorubicin, cisplatin plus mitotane (PDP-M)) in preclinical in vitro and in vivo models. In addition, based on an extraordinary uptake phenomenon of liposomes in ACC cells, we further evaluated liposomal variants of these protocols (etoposide, liposomal doxorubicin, liposomal cisplatin plus mitotane (LEDP-M) and nab-paclitaxel, liposomal doxorubicin, liposomal cisplatin plus mitotane (LPDP-M)). In vitro, PDP-M was more potent in the induction of apoptosis and inhibition of cell viability as well as cell proliferation than EDP-M. Following the administration of a single therapeutic cycle, we further demonstrated that LEDP-M and LPDP-M exerted significant antitumoral effects in vivo, which were not as evident upon EDP-M and PDP-M treatments. These results were confirmed in a long-term experiment, in which the highest and sustained antitumoral effects were observed for LEDP-M. In summary, liposomal cytostatic substances could represent a promising option that deserves testing in appropriate clinical protocols for the treatment of ACC patients.

Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation

“…Previous studies with clone 1 had revealed significant differences between controls and LEDPM-treated tumors. Moreover, we detected significantly reduced tumor sizes in LEDP-M-treated tumors in comparison with EDP-M-treated tumors following the second therapeutic cycle as depicted by stars (Figure 1K, [13]). Analogous chemotherapeutic treatments on xenografts obtained from clone 2 did not reveal any significant reduction in tumor sizes upon EDP-M or LEDP-M treatment (Figure 1L).…”

“…Before implantation of these 2 × 2 mm measuring tumor pieces appropriate samples of SJ-ACC3 tumors were transferred from liquid nitrogen to a 37°C water bath and tumor tissue was rinsed several times in medium 199 (Gibco Invitrogen, Darmstadt, Germany) supplemented with 1% penicillin/streptomycin. Therapeutic experiments were performed as previously described [13]. …”

Targeting the multidrug transporter Patched potentiates chemotherapy efficiency on adrenocortical carcinoma in vitro and in vivo

“…All experiments were carried out following protocols approved by the Regierung von Oberbayern and in accordance with the German guidelines for animal studies. H295R xenografts were induced as described before . For short‐term experiments, tumor‐bearing mice ( n = 4–5) were treated with one therapeutic cycle which consisted of either liposomal doxorubicin (lipdxr) (6 mg/kg body weight, intravenously on Days 4 and 10), P375 (2 mg/kg body weight, intraperitoneally on Days 1–11) or a combination of lipdxr and P375 (P375: 2 mg/kg body weight intraperitoneally on Days 1–11 plus lipdxr 6 mg/kg body weight intravenously on Days 4 and 10).…”

EJE PRIZE 2014: Current and evolving treatment options in adrenocortical carcinoma: where do we stand and where do we want to go?

“…In a very recent approach, the group from Felix Beuschlein provided evidence that nanotechnologically modified cytotoxic drugs, especially liposomal doxorubicin and liposomal cisplatin, were more effective in a mouse xenograft model for ACCs than the plain drugs (62).…”