Ritonavir inhibits intratumoral docetaxel metabolism and enhances docetaxel antitumor activity in an immunocompetent mouse breast cancer model

Hendrikx, Jeroen J M A; Lagas, Jurjen S; Song, Ji-Ying; Rosing, Hilde; Schellens, Jan H M; Beijnen, Jos H; Rottenberg, Sven; Schinkel, Alfred H (2016). Ritonavir inhibits intratumoral docetaxel metabolism and enhances docetaxel antitumor activity in an immunocompetent mouse breast cancer model. International journal of cancer, 138(3), pp. 758-769. Wiley-Blackwell 10.1002/ijc.29812

[img] Text
ijc29812.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (723kB) | Request a copy

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Rottenberg, Sven

Subjects:

600 Technology > 630 Agriculture

ISSN:

0020-7136

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Barbara Gautschi-Steffen

Date Deposited:

15 Feb 2016 12:02

Last Modified:

18 Feb 2016 00:38

Publisher DOI:

10.1002/ijc.29812

PubMed ID:

26297509

Uncontrolled Keywords:

Cyp3a inhibition; antitumor activity; breast cancer; docetaxel; ritonavir

BORIS DOI:

10.7892/boris.75554

URI:

https://boris.unibe.ch/id/eprint/75554

Actions (login required)

Edit item Edit item
Provide Feedback