Figure 4. Roc has 50% oral bioavailability and potently suppresses the growth of orthotopic MPNST xenografts.

(A) Plasma concentration-time profiles of Roc were obtained by PK analysis according to Methods. The mean concentration of Roc with standard deviation (SD) in mouse plasma for each time point after IV, IP, and PO administration was plotted. For each dosing route, two independent studies were performed. (B) Shown are representative BL images of ST8814-Luc MPNST-bearing mice prior to (PreTx) and 4 weeks (wks) after treatment with Roc at 4mg/kg by IP, 1.2mg/kg by PO, or HPβCD vehicle every other day. (C) The relative tumor-emitted BL signals were denoted as % of total flux after treatment relative to the total flux prior to treatment designated as one (100%). The data are shown as mean ± SD. For each treatment group, at least 7 mice completed the full treatment schedule. Note that tumor bioluminescence from vehicle-treated mice rapidly increased by an average of ~17,000-fold over four weeks. However, tumor bioluminescence from the Roc IP group grow only by ~3-fold and from the Roc PO group increased ~470-fold on average. (D) H&E staining show that while vehicle-treated xenografts contained large vesicular nuclei with prominent nucleoli and mitotic activity, tumors treated with Roc by IP had pleomorphic nuclei and many enlarged tumor cells had abundant foamy cytoplasm resembling histiocytoid degenerative changes along with scattered apoptosis (top panels). Degenerative tumor cells were also present in tumors treated with orally-delivered Roc. Tumor necrosis with necrotic debris separating mostly degenerative tumor cells with viable vasculature was also observed. Immunostaining revealed abundant phospho-histone H3 (pH3)-labeled cells in Roc-treated tumors compared to vehicle-treated tumors (middle panels). Increased numbers of cleaved caspase-3 (CC3)-positive cells were detected in Roc-treated tumors (bottom panels).