title: Ritonavir inhibits intratumoral docetaxel metabolism and enhances docetaxel antitumor activity in an immunocompetent mouse breast cancer model.
abstract: Docetaxel (Taxotere(®)) is currently used intravenously as an anticancer agent and is primarily metabolized by Cytochrome P450 3A (CYP3A). The HIV protease inhibitor ritonavir, a strong CYP3A4 inhibitor, decreased first-pass metabolism of orally administered docetaxel. Anticancer effects of ritonavir itself have also been described. We here aimed to test whether ritonavir co-administration could decrease intratumoral metabolism of intravenously administered docetaxel and thus increase the antitumor activity of docetaxel in an orthotopic, immunocompetent mouse model for breast cancer. Spontaneously arising K14cre;Brca1(F/F) ;p53(F/F) mouse mammary tumors were orthotopically implanted in syngeneic mice lacking Cyp3a (Cyp3a(-/-)) to limit ritonavir effects on systemic docetaxel clearance. Over 3 weeks, docetaxel (20 mg/kg) was administered intravenously once weekly, with or without ritonavir (12.5 mg/kg) administered orally for 5 days per week. Untreated mice were used as control for tumor growth. Ritonavir treatment alone did not significantly affect the median time of survival (14 vs. 10 days). Median time of survival in docetaxel-treated mice was 54 days. Ritonavir co-treatment significantly increased this to 66 days, and substantially reduced relative average tumor size, without altering tumor histology. Concentrations of the major docetaxel metabolite M2 in tumor tissue were reduced by ritonavir co-administration, whereas tumor RNA expression of Cyp3a was unaltered. In this breast cancer model, we observed no direct antitumor effect of ritonavir alone, but we found enhanced efficacy of docetaxel treatment when combined with ritonavir. Our data, therefore, suggest that decreased docetaxel metabolism inside the tumor as a result of Cyp3a inhibition contributes to increased antitumor activity.
authors: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Jeroen J M A
authors: JJ
authors: Hendrikx
authors: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Jurjen S
authors: JS
authors: Lagas
authors: Department of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Ji-Ying
authors: JY
authors: Song
authors: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Hilde
authors: H
authors: Rosing
authors: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Jan H M
authors: JH
authors: Schellens
authors: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Jos H
authors: JH
authors: Beijnen
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Sven
authors: S
authors: Rottenberg
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Alfred H
authors: AH
authors: Schinkel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D007121:Immunocompetence; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D019438:Ritonavir / Q000494:pharmacology*; D043823:Taxoids / Q000378:metabolism / Q000494:pharmacology*; D008565:Membrane Proteins
chemical_list: D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000077143:Docetaxel; D017320:HIV Protease Inhibitors; D019438:Ritonavir; D043823:Taxoids; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins
keywords: Cyp3a inhibition; antitumor activity; breast cancer; docetaxel; ritonavir