Abstract 3377: Bevacizumab-improved distribution of paclitaxel in ovarian cancer xenografts potentiates antitumor efficacy

Abstract

Abstract Angiogenesis inhibitors have shown antitumor efficacy when combined with chemotherapy. It has been proposed that this potentiation is related to better drug delivery to the tumor due to improved vessel functionality. This work combined classical pharmacokinetics and imaging analysis to study the delivery and distribution of paclitaxel after bevacizumab in ovarian cancer. The study was conducted on ovarian cancer models (A2780-1A9 and IGROV-1) xenografted orthotopically under the bursa of the nude mouse ovary. Mice bearing tumors in the ovary, treated with bevacizumab (150μg/mouse) and 24 hours later with paclitaxel (60mg/kg), were sacrificed and tumor excised for analysis, or monitored for anti-tumor activity. Paclitaxel spatial distribution after bevacizumab was analyzed by MALDI-Mass Spectrometry Imaging (MALDI-MSI) on frozen tumor slices, and compared with adjacent histochemical images stained for CD31 (vessel analysis) and Ki-67 (proliferation/necrosis); total paclitaxel in tumor homogenates, liver and plasma was evaluated by high-performance liquid chromatography (HPLC). Tumor growth of A2780-1A9 and IGROV-1, carrying the firefly luciferase gene luc2, was monitored by Bioluminescence imaging (BLI) and survival recorded. Bevacizumab decreased tumor vessel number/size compared to vehicle treated mice, but potentiated the antitumor activity of paclitaxel in both models. MALDI-MSI showed that after bevacizumab, paclitaxel was more homogenously distributed and mainly in actively proliferating areas of the tumor where vessels were uniformly diffused, despite paclitaxel concentration did not increase after antiangiogenic drug. No changes in paclitaxel systemic exposure was found in normal tissue. These findings suggest that a more uniform distribution of paclitaxel in the tumor of the mouse ovary is responsible for the better antitumor activity of the combination. A.D. and I.F.N. are the recipients of a fellowship from the Italian Foundation for Cancer Research (FIRC). Citation Format: Marta Cesca, Lavinia Morosi, Alexander Berndt, Ilaria Fuso Nerini, Alessandra Decio, Massimo Zucchetti, Raffaella Giavazzi. Bevacizumab-improved distribution of paclitaxel in ovarian cancer xenografts potentiates antitumor efficacy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3377.