Establishment of a Mouse Ovarian Cancer and Peritoneal Metastasis Model to Study Intraperitoneal Chemotherapy

• Published in: Cancers 2020-12, Vol.12 (12), p.3818
• Main Authors: Rezniczek, Günther A, Buggisch, Jonathan, Sobilo, Julien, Launay, Alexandre, Lerondel, Stéphanie, Le Pape, Alain, Ouaissi, Mehdi, Göhler, Daniel, Senkal, Metin, Giger-Pabst, Urs, Tempfer, Clemens B
• Format: Article
• Language: English
• Subjects: Aerosols; Antitumor agents; Bioluminescence; Body weight; Cancer therapies; Cell proliferation; Chemotherapy; Doxorubicin; Drug dosages; Medical prognosis; Metastases; Metastasis; Ovarian cancer; Peritoneum; Single photon emission computed tomography; Surgery; Trachea; Tumors; Xenografts
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers12123818

Intraperitoneal chemotherapy (IPC) is a locoregional treatment option in patients with peritoneal metastases (PM). Here, we present an ovarian cancer (OC)-derived PM mouse model for the study of different forms of IPC. Xenograft cell proliferation (luciferase-transfected OVCAR3 and SKOV3 clones) and growth kinetics were assessed using PET scan, bioluminescence imaging (BLI), and histological tumor analysis. Liquid IPC was achieved by intraperitoneal injection with/without capnoperitoneum (6-7 mmHg). Pressurized intraperitoneal aerosol chemotherapy (PIPAC) was mimicked using an intratracheal drug aerosol administration system (micro-nozzle), which, as demonstrated by ex vivo granulometric analysis using laser diffraction spectrometry, produced a polydisperse, bimodal aerosol with a volume-weighted median diameter of (26.49 ± 2.76) µm. Distribution of Tc-99m-labeled doxorubicin in mice was characterized using SPECT and was dependent on the delivery mode and most homogeneous when the micro-nozzle was used. A total of 2 mg doxorubicin per kg body weight was determined to be the optimally effective and tolerable dose to achieve at least 50% tumor reduction. Repeated PIPAC (four times at seven-day-intervals) with doxorubicin in SKOV3-luc tumor-bearing mice resulted in halted tumor proliferation and tumor load reduced after the second round of PIPAC versus controls and the number of tumor nodules was significantly reduced (27.7 ± 9.5 vs. 57.3 ± 9.5; = 0.0003). Thus, we established the first mouse model of OC PM for the study of IPC using a human xenograft with SKOV3 cells and an experimental IPC setup with a miniaturized nozzle. Repeated IPC was feasible and demonstrated time-dependent anti-tumor activity.