Pre-clinical study of the epinephrine-cisplatin association for the treatment of intraperitoneal carcinomatosis.
We have previously shown that intraperitoneal (i.p.) epinephrine enhances tumour penetration and anti-cancer activity of i.p.-administered cisplatin in rats with peritoneal carcinomatosis. Here, we show a direct correlation between the i.p. epinephrine concentration and cisplatin accumulation in rat peritoneal tumour nodules up to a concentration of 5 mg/l. This concentration leads to a maximal 3.7-fold increase of tumour platinum content and a maximal vasoconstriction of the peritoneal and tumour superficial microcirculation when registered by a laser doppler probe. Further, epinephrine half-life was 20.8+/-3.6 min in the peritoneal cavity of two laparotomized pigs. In these animals, epinephrine plasma concentration, heart rate and systolic blood pressure were dependent on the intraperitoneal dose of epinephrine, and life-threatening signs were not observed in either animal. In conclusion, a 5 mg/l concentration of epinephrine could be safely maintained in peritoneal fluid by regular replacement. This concentration is sufficient to maintain a constant vasoconstriction of the peritoneal and tumoral microvascular bed, and enhance the slow diffusion of cisplatin into peritoneal tumour nodules in the course of per-operative intraperitoneal chemotherapy.
Faculty of Medicine, Unité INSERM 517, Dijon, France.
P
P
Favoulet
G
G
Magnin
J C
JC
Guilland
J L
JL
Beltramo
L
L
Osmak
L
L
Benoit
P
P
Rat
S
S
Douvier
C
C
Duvillard
B
B
Chauffert
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001201:Ascites / Q000378:metabolism; D002277:Carcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D004837:Epinephrine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D007274:Injections, Intraperitoneal; D017078:Laser-Doppler Flowmetry; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D010534:Peritoneal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D010537:Peritoneum / Q000098:blood supply; D051381:Rats; D011919:Rats, Inbred Strains; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D014662:Vasoconstrictor Agents; D002945:Cisplatin; D004837:Epinephrine