Preclinical progress and first translational steps for a liposomal chemotherapy protocol against adrenocortical carcinoma

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   Figure 1

   Schematic illustration of the preclinical treatment schemes EDP-M, LEDP-M and L(l)EDP-M adapted from the clinical EDP-M protocol exemplified for one therapeutic cycle.
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   Figure 2

   Immunohistochemical and histological analysis of SW-13 (A, B and E) and SJ-ACC3 (C and D) xenografts derived from the short-term therapeutic experiment with quantification of Ki67-positive, Ki67-negative (A and C) and TUNEL-positive cells (B and D). Necrosis was analyzed semi-quantitatively using four categories ranked in ascending order from 0 (no necrosis) until 3 (extensive necrosis) for each SW-13 tumor, respectively (E). Representative pictures from Ki67 (F–I) and H&E staining (J–M) are presented for NaCl (F and J), EDP-M (G and K), LEDP-M (H and L) and L(l)EDP-M (I and M)-treated SW-13 tumors. Statistical significance vs controls is denoted as stars (*P < 0.05; **P < 0.01; ***P < 0.001).
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   Figure 3

   Effects on tumor size of SW-13 (A) and SJ-ACC3 (B) xenografts after two therapeutic cycles with the different treatment modalities. Statistical comparisons were performed using a one-way ANOVA followed by Bonferroni’s Multiple Comparison Test (compare all groups). Stars (*P < 0.05; **P < 0.01; ***P < 0.001) denote significant differences compared with controls, comparisons to other treatment groups were not significant (P > 0.05). SW-13 tumor-bearing mice that received up to four therapeutic cycles of NaCl, EDP-M, LEDP-M or L(l)EDP-M treatment were killed after achieving pre-defined endpoints. Regarding the achievement of study termination, the comparison of all treatment groups resulted in significant differences using a log-rank (Mantel-Cox) analysis. Significant differences are illustrated in (C) in comparison to L(l)EDP-M. Individual reasons for study termination are furthermore depicted in (D).
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   Figure 4

   Pathological examination of HE-stained kidneys and hearts from the different treatment groups: control (NaCl), EDP-M, LEDP-M and L(l)EDP-M. Black arrows indicate vacuole formation and single-cell necrosis in hearts affected by EDP-M treatment.
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   Figure 5

   Quantitative real-time PCR analysis of intratumoral and circulating miR 483-5p (A) and miR-210 (B) of control (NaCl) and LEDP-M-treated SW-13 and SJ-ACC3 tumor-bearing mice. For analysis of changes upon therapeutic treatment in individual animals, the ratio of intratumoral to circulating miR level was calculated after normalization to controls. A value of 1 indicates unchanged equal levels in tumor and plasma. A value of >1 reveals an elevated expression of intratumoral miR, whereas a ratio of <1 indicates elevated expression of circulating miR. Stars denote significant differences (*P < 0.05).

• © 2016 Society for Endocrinology