Cytotoxic effect of different treatment parameters in pressurized intraperitoneal aerosol chemotherapy (PIPAC) on the in vitro proliferation of human colonic cancer cells.
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has been recently reported as a new approach for intraperitoneal chemotherapy (IPC). By means of a patented micropump, the liquid chemotherapy is delivered into the peritoneal cavity as an aerosol which is supposed to achieve "gas-like" distribution. However, recent data report that the fraction of the submicron aerosol (gas-like) is less than 3 vol% of the total amount of aerosolized chemotherapy. Until today, possible modifications of treatment parameters during PIPAC with the aim of improving therapeutic outcomes have not been studied yet. This study aims to establish an in vitro PIPAC model to explore the cytotoxic effect of the submicron aerosol fraction and to investigate the impact of different application parameters on the cytotoxic effect of PIPAC on human colonic cancer cells.



An in vitro model using HCT8 colon adenocarcinoma wild-type cells (HCT8WT) and multi-chemotherapy refractory subline (HCT8RT) was established. Different experimental parameters such as pressure, drug dosage, time exposure, and system temperature were monitored in order to search for the conditions with a higher impact on cell toxicity. Cell proliferation was determined by means of colorimetric MTT assay 48 h following PIPAC exposures.



Standard operational parameters applied for PIPAC therapy depicted a cytotoxic effect of the submicron aerosol fraction generated by the PIPAC micropump. We also observed that increasing pressure significantly enhanced tumor cell toxicity in both wild-type and chemotherapy-resistant cells. A maximum of cytotoxicity was observed at 15 mmHg. Pressure >15 mmHg did not show additional cytotoxic effect on cells. Increased oxaliplatin dosage resulted in progressively higher cell toxicity as expected. However, in resistant cells, a significant effect was only found at higher drug concentrations. Neither an extension of exposure time nor an increase in temperature of the aerosolized chemotherapy solution added an improvement in cytotoxicity.



In this in vitro PIPAC model, the gas-like PIPAC aerosol fraction showed a cytotoxic effect which was enhanced by higher intra-abdominal pressure with a maximum at 15 mmHg. Similar findings were observed for drug dose escalation. A phase I dose escalation study is currently performed at our institution. However, increasing the intra-abdominal pressure might be a first and simple way to enhance the cytotoxic effect of PIPAC therapy which needs further clinical investigations.
Department of General Surgery and Therapy Center for Peritonealcarcinomatosis, St. Mary's Hospital Herne, Ruhr University of Bochum, Hölkeskampring 40, 44625, Herne, Germany.|Basic Research Laboratory Department of Surgery, St. Mary's Hospital Herne, Ruhr University of Bochum, Herne, Germany.
Veria
V
Khosrawipour
Department of Hematology and Medical Oncology, St. Mary's Hospital Herne, Ruhr University Bochum, Herne, Germany.
David
D
Diaz-Carballo
Department of Hematology and Medical Oncology, St. Mary's Hospital Herne, Ruhr University Bochum, Herne, Germany.
Ali-Haydar
AH
Acikelli
Department of General Surgery and Therapy Center for Peritonealcarcinomatosis, St. Mary's Hospital Herne, Ruhr University of Bochum, Hölkeskampring 40, 44625, Herne, Germany. tanja.khosrawipour@rub.de.|Basic Research Laboratory Department of Surgery, St. Mary's Hospital Herne, Ruhr University of Bochum, Herne, Germany. tanja.khosrawipour@rub.de.
Tanja
T
Khosrawipour
Basic Research Laboratory Department of Surgery, St. Mary's Hospital Herne, Ruhr University of Bochum, Herne, Germany.
Thomas Albert
TA
Falkenstein
Department of General Surgery and Therapy Center for Peritonealcarcinomatosis, St. Mary's Hospital Herne, Ruhr University of Bochum, Hölkeskampring 40, 44625, Herne, Germany.|Basic Research Laboratory Department of Surgery, St. Mary's Hospital Herne, Ruhr University of Bochum, Herne, Germany.
Dan
D
Wu
Department of General Surgery and Therapy Center for Peritonealcarcinomatosis, St. Mary's Hospital Herne, Ruhr University of Bochum, Hölkeskampring 40, 44625, Herne, Germany.
Jürgen
J
Zieren
Department of General Surgery and Therapy Center for Peritonealcarcinomatosis, St. Mary's Hospital Herne, Ruhr University of Bochum, Hölkeskampring 40, 44625, Herne, Germany.|Basic Research Laboratory Department of Surgery, St. Mary's Hospital Herne, Ruhr University of Bochum, Herne, Germany.
Urs
U
Giger-Pabst
D000336:Aerosols; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000077150:Oxaliplatin; D010537:Peritoneum / Q000187:drug effects*; D011312:Pressure; D014407:Tumor Cells, Cultured
D000336:Aerosols; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin
Cytotoxicity; Human colonic cancer cells; In vitro model; Oxaliplatin dose escalation; PIPAC; Pressure