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

Abstract

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; p = 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.

Mouse Models of Peritoneal Carcinomatosis to Develop Clinical Applications

“…These mice are unable to generate an immune response against human cells and tumor engraftment is thus promoted in the peritoneal cavity. The xenografted PCa models have been studied using colon cancer (HCT-116, LS174T, HT29, SW480, SW620, LoVo, RKO, Caco-2, KM12, MDST8, HUTU80) [57][58][59][60][61], pancreatic cancer (Panc-1, TCC-Pan2, BxPC3, AsPC-1) [62][63][64], gastric cancer (60As6, HSC-44PE, HSC-58, MKN45-P) [56][57][58][59][60][61][62][63][64][65][66][67][68][69], and ovarian cancer (OVCAR3, OVCAR4, OVCAR5, OVCAR8, CAOV3, OVSAHO, OV2944-HM-1, SKOV-3) [59,[70][71][72] cell lines. These models have been used to attain proofs of concept and explore treatments that determine in vivo tumor cell cytotoxicity of drugs, such as chemotherapeutic agents.…”

Development of a rat capnoperitoneum phantom to study drug aerosol deposition in the context of anticancer research on peritoneal carcinomatosis

“…With regard to anticancer research on peritoneal carcinomatosis, rodent cancer models 13 – 15 were designed recently to study beside the efficacy of pressurized intraperitoneal chemotherapy (PIPAC) 1 also the suitability of different drugs and pharmacokinetic effects. In two studies 6 , 13 , the conventional PIPAC technology for humans was used, while in Rezniczek et al 15 a more species-appropriate procedure for drug aerosolization and supply was designed. But mindless of conventional PIPAC or alternative procedures, there are a lot of knowledge gaps concerning drug aerosol supply, drug aerosol propagation and particle deposition.…”

“…To prevent such large wound dimensions, more suitable approaches for performing PIPAC in rodents are required in parallel to the cancer models. Modified PIPAC approaches for rodents were designed for example in parallel to a mouse ovarian cancer model (OVCAR3 and SKOV3) 15 .…”

Establishment of a new valid animal model for the evaluation of hyperthermic intraperitoneal chemotherapy (HIPEC) in pediatric rhabdomyosarcoma

“…MRI scans confirmed the tumor growth and showed the performance of HIPEC in vivo for the first time. Besides our animal model, there are only few recent comparable HIPEC mouse models but using non‐pediatric tumor entities like adult ovarian cancer or performing HIPEC as pressurized aerosol 9,10 . Especially pressurized intraperitoneal chemotherapy (PIPAC) has not been applied in children.…”