Hypoxic single-pass isolated hepatic perfusion of hypotonic Cisplatin: safety study in the pig.
BACKGROUND
Isolated hepatic perfusion (IHP) of chemotherapy has been proposed to deliver high doses of drug while avoiding systemic toxicity. Hypotonic cisplatin has a high in vitro activity on human colon cancer cells. We studied the safety of a 30-min hypoxic single-pass IHP with hypotonic cisplatin.


METHODS
A preliminary in vitro assay was performed to compare the cytotoxicity of cisplatin and oxaliplatin, in either a normotonic or hypotonic medium. Cisplatin in hypotonic medium was then chosen for the in vivo IHP. Eleven pigs underwent 30 min of IHP with 0, 50, 75, or 100 mg/L of cisplatin in a hypotonic solution under total vascular exclusion of the liver. Clinical and biological parameters were recorded for 30 days, and liver histology was performed at necropsy. The cytotoxic activity of the effluent against resistant human colon cancer cells was tested in vitro.


RESULTS
No hepatic failure was recorded after IHP with cisplatin, but limited foci of necrosis were found at necropsy in animals receiving 75 or 100 mg/L of cisplatin. No clinical, biological, macroscopic, or microscopic toxicity was observed after IHP with 50 mg/L of hypotonic cisplatin. The liver effluent showed high in vitro cytotoxic activity against colon cancer cells.


CONCLUSIONS
A hypoxic single-pass isolated liver perfusion with hypotonic cisplatin is feasible and safe. Effluent from the liver is highly cytotoxic on cancer cells. A clinical study with 50 mg/L of hypotonic cisplatin is warranted in patients with unresectable liver metastases from colon cancer.
INSERM UMR 866, School of Medicine, University of Burgundy, Burgundy, France. pablo.ortega-deballon@chu-dijon.fr
Pablo
P
Ortega-Deballon
Olivier
O
Facy
David
D
Consolo
Guy
G
Magnin
Hervé
H
Tixier
Michel
M
Simonet
Patrick
P
Rat
Bruno
B
Chauffert
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D010478:Chemotherapy, Cancer, Regional Perfusion; D002945:Cisplatin / Q000008:administration & dosage*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007038:Hypotonic Solutions; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000601:surgery; D034421:Sus scrofa; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007038:Hypotonic Solutions; D002945:Cisplatin