Recombinant interleukin-2 treatment decreases P-glycoprotein activity and paclitaxel metabolism in mice.
Recombinant rIL-2 was reported to be able to decrease P-glycoprotein (P-gp) expression in cultured cells from human colon carcinoma. P-gp is considered an important factor in the control of Taxol efflux from tumor cells. Based on the premise that Taxol pharmacokinetic parameters could be modified as a result of diminished P-gp expression induced by recombinant interleukin (rIL)-2 and that this might elicit an interaction between the two drugs, we evaluated the pharmacokinetics of a novel strategy combining i.p. immunotherapy with rIL-2 and a cytotoxic agent, Taxol. Mice were allocated to two groups treated with rIL-2 (15 microg x 2/day from day 1 to 4) then Taxol (10 mg/kg i.p. day 5) or Taxol (10 mg/kg i.p.) alone (control group). The Taxol + rIL-2 combination provoked the development of ascites, presumably due to the presence of Cremophor EL in the Taxol preparation. Paclitaxel was measured in plasma and ascites by HPLC with UV detection. Paclitaxel pharmacokinetics were strongly modified by rIL-2 pretreatment. Compared to that observed in control mice, the apparent volume of distribution increased dramatically (Vd/F = 18.2 versus 4.1 l/kg) and the apparent plasma clearance decreased (Cl/F = 1.12 versus 1.66 l/h/kg). P-gp expression was determined in the liver, lung, intestine, brain and kidney in the two groups by immunodetection with the C219 anti-P-gp monoclonal antibody. A significant decrease in P-gp expression was observed in the intestine and in the brain in the rIL-2-pretreated mice as compared to controls. To study the functionality of P-gp, we compared digoxin (a model P-gp substrate) pharmacokinetics before and after pretreatment with rIL-2 (10 microg x 2/day from day 1 to 4), after a single 1 microg oral dose of digoxin used to quantify P-gp activity. Results showed a decrease in oral digoxin clearance after rIL-2 pretreatment indicating modified P-gp activity. We conclude that rIL-2 pretreatment is able to decrease P-gp activity and paclitaxel metabolism in vivo. This is the first study to demonstrate a decrease in P-gp activity and expression in organs such as the brain in vivo. A novel strategy combining immunotherapy with rIL-2 and a cytotoxic agent could potentially improve clinical results, particularly in brain cancer.
Bonhomme-Faivre
Laurence
L
Service de Pharmacologie, Hôpital Paul Brousse, 94800 Villejuif, France. laurence.bonhomme-faivre@pbr.ap-hop-paris.fr
Pelloquin
Anne
A
Tardivel
Sylviane
S
Urien
Saik
S
Mathieu
Marie-Christine
MC
Castagne
Vincent
V
Lacour
Bernard
B
Farinotti
Robert
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D015153:Blotting, Western; D004077:Digoxin / Q000493:pharmacokinetics; D015536:Down-Regulation; D006801:Humans; D007167:Immunotherapy; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D017239:Paclitaxel / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D007376:Interleukin-2; D011994:Recombinant Proteins; D004077:Digoxin; D017239:Paclitaxel