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Recombinant interleukin-2 treatment decreases P-glycoprotein activity and paclitaxel metabolism in mice
Laurence Bonhomme-Faivre1, Anne Pelloquin, Sylviane Tardivel
1Service de Pharmacologie, Hôpital Paul Brousse, 94800 Villejuif, France. laurence.bonhomme-faivre@pbr.ap-hop-paris.fr
Abstract:
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.
Insights
Recombinant interleukin-2 (rIL-2) pretreatment decreases P-glycoprotein (P-gp) activity and expression in vivo. This combination therapy may enhance paclitaxel (Taxol) efficacy, particularly for brain cancers.
Area of Science:
- Pharmacology and Drug Interactions
- Cancer Immunotherapy
- Molecular Biology
Background:
- P-glycoprotein (P-gp) mediates drug efflux, impacting chemotherapy efficacy.
- Recombinant interleukin-2 (rIL-2) has shown potential to reduce P-gp expression in vitro.
- Taxol (paclitaxel) is a key chemotherapeutic agent whose efflux is P-gp dependent.
Purpose of the Study:
- To evaluate the pharmacokinetic interaction between rIL-2 and Taxol.
- To investigate the effect of rIL-2 pretreatment on P-gp expression and activity in vivo.
- To explore a novel combination therapy strategy for cancer treatment.
Main Methods:
- Mice were treated with rIL-2 followed by Taxol, or Taxol alone.
- Paclitaxel pharmacokinetics were analyzed using HPLC.
- P-gp expression was assessed via immunodetection; P-gp activity was evaluated using digoxin pharmacokinetics.
Main Results:
- rIL-2 pretreatment significantly altered paclitaxel pharmacokinetics, increasing volume of distribution and decreasing plasma clearance.
- A significant decrease in P-gp expression was observed in the intestine and brain of rIL-2 pretreated mice.
- rIL-2 pretreatment reduced oral digoxin clearance, indicating decreased P-gp activity in vivo.
Conclusions:
- rIL-2 pretreatment effectively reduces P-gp activity and expression in vivo, including in the brain.
- This study demonstrates the first in vivo evidence of rIL-2 modulating P-gp activity.
- Combining rIL-2 immunotherapy with cytotoxic agents like Taxol presents a promising strategy to improve cancer treatment outcomes, especially for brain tumors.