Abstract 4241: Preclinical studies of brain/brain tumor disposition and antitumor efficacy of the aromatase inhibitor letrozole
Authors: Dave Nimita , Desai Pankaj B. , Gudelsky Gary A. , LaSance Kathleen , Chow Lionel M.L. , Qi Xiaoyang 
Published: May 2015

In this study, we investigated the potential role of aromatase (CYP19) as a target for the treatment of CNS malignancies, as well as brain disposition and anti-tumor efficacy of letrozole, an aromatase inhibitor, in Sprague Dawley rats.

Cytotoxicity and aromatase activity of letrozole against human glioma cell lines were measured using MTT assay and Enzyme Immunoassay respectively. For brain and brain tumor PK of letrozole, rats with and without orthotopic implantation of C6 glioma received letrozole (4 - 12 mg/kg; i.v. andor oral). Dual probe intracerebral microdialysis was performed to determine the unbound extracellular fluid (ECF) letrozole concentrations. Serial ECF and blood samples were simultaneously collected over 8 hrs. µPET/CT imaging was performed using 18F FDG to evaluate changes in active tumor volumes pre- and post-treatment of letrozole. Brain tissues were collected at the end of the experiment for histological evaluations.

All glioma cell lines included in this study expressed CYP19 and letrozole exerted marked cytotoxicity against these cells ( IC50s 0.1 - 3.5 μM). The relative brain distribution coefficients, measured as the ratio of the observed AUC in ECF and AUC of unbound letrozole in plasma (AUCecf/AUCp,ub) ranged from 0.31 - 0.98. Furthermore, the tumoral ECF levels of letrozole was 1.5 - 2 fold higher relative to tumor-free region of the brain, resulting in tumoral ECF Cmax values that were 10 and 35-fold higher than the observed IC50 value of 0.1 µM against C6 gliomas cells in culture. µPET/CT imaging showed a marked reduction of active tumor volume (75-90%) after 8-10 days of letrozole treatment (N=7). Oral administration of letrozole showed similar brain disposition and efficacy of letrozole. Immunohistochemical analysis of aromatase demonstrated selectivelymarkedly higher aromatase expression in tumoral regions of the brain as well asand a clear considerable reduction in aromatase expression in letrozole the treated rats relative to the treatment group as compared to the control group. Thus, employing multifaceted and cutting edge in vitro and in vivo methods, we conclude: a) aromatase is abundantly expressed in glioma cell lines examined, b) letrozole exerts marked cytotoxicity in these cells presumably due to aromatase inhibition, c) letrozole has selectively higher accumulation in tumoral region of the brain and d) In vivo µPET/CT studies show marked efficacy of letrozole on C6 glioma in a preclinical rat model.

Note: This abstract was not presented at the meeting.

Citation Format: Nimita Dave, Pankaj B. Desai, Gary A. Gudelsky, Kathleen LaSance, Lionel M.L. Chow, Xiaoyang Qi. Preclinical studies of brain/brain tumor disposition and antitumor efficacy of the aromatase inhibitor letrozole. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4241. doi:10.1158/1538-7445.AM2014-4241