High intra-abdominal pressure enhances the penetration and antitumor effect of intraperitoneal cisplatin on experimental peritoneal carcinomatosis.
OBJECTIVE
To investigate the role of increased intra-abdominal pressure (IAP) on the intratumoral accumulation and the antitumor effect of intraperitoneal cisplatin in rats with advanced peritoneal carcinomatosis. To evaluate the tolerance of IAP in pigs, as it is a large animal with a body size equivalent to humans.


BACKGROUND
To investigate if an active convection, driven by a positive IAP, increases cisplatin penetration and antitumor effectiveness in a model of advanced peritoneal carcinomatosis in rats.


METHODS
BDIX rats with macroscopic peritoneal tumors received cisplatin administered as intravenous injection (IV), conventional intraperitoneal injection (IP), or sustained intraperitoneal injection of cisplatin given in a large volume of solvent for maintaining IAP for 1 hour. Platinum tissue concentration was measured by atomic absorption spectroscopy (AAS), and platinum distribution into the tumor nodules was assessed by the particular-induced x-ray emission (PIXE) method. The antitumor effect was assessed in a survival experiment. The hemodynamic, local, and systemic tolerance of IAP, with or without cisplatin, was evaluated in Large White pigs.


RESULTS
The maximum tolerated IAP was 22 mm Hg for 1 hour in nonventilated rats. IAP, in comparison with IV or conventional IP injections, resulted in the increased concentration and depth of diffusion of platinum into diaphragm and peritoneal tumor nodules. Consequently, IAP treatment induced an extended survival of rats treated at an advanced stage of carcinomatosis. In 7 50- to 70-kg ventilated pigs, a 40-mm Hg IAP was well tolerated when maintained stable for 2 hours. Renal failure occurred in pigs receiving a total dose of 200 and 400 mg of cisplatin with IAP, but a dose of 100 mg was well tolerated.


CONCLUSIONS
Intraperitoneal chemotherapy with increased IAP, in comparison with conventional IP or IV chemotherapy, improved the tumor accumulation and the antitumor effect of cisplatin in rats bearing advanced peritoneal carcinomatosis. In preclinical conditions, the tolerance of sustained IAP was manageable in ventilated pigs.
Esquis
Philippe
P
INSERM unit 517, Faculty of Medicine, Dijon, France. esquisp@yahoo.fr
Consolo
David
D
Magnin
Guy
G
Pointaire
Philippe
P
Moretto
Philippe
P
Ynsa
Maria Dolores
MD
Beltramo
Jean-Luc
JL
Drogoul
Carole
C
Simonet
Michel
M
Benoit
Laurent
L
Rat
Patrick
P
Chauffert
Bruno
B
D000005:Abdomen / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002277:Carcinoma / Q000401:mortality / Q000473:pathology*; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D007263:Infusions, Parenteral; D007274:Injections, Intraperitoneal; D008297:Male; D010534:Peritoneal Neoplasms / Q000401:mortality / Q000473:pathology*; D011312:Pressure; D051381:Rats; D011919:Rats, Inbred Strains; D013054:Spectrophotometry, Atomic; D015996:Survival Rate; D013552:Swine
D000970:Antineoplastic Agents; D002945:Cisplatin