Abstract 3249: Long-term Calcitriol Therapy alters Prostate Tumor Vascularity in TRAMP mice
Authors: Seshadri Mukund , Guess Alex , Foster Barbara 
Published: February 2011

Abstract
Calcitriol (1,25 dihydroxycholecalciferol), the active metabolite of vitamin D exhibits potent antitumor activity against a variety of murine tumors and human tumor xenografts. We have previously demonstrated that early administration of calcitriol to transgenic adenocarcinoma of the mouse prostate (TRAMP) mice has a chemopreventive effect as measured by decreased prostate weight, lower tumor grade (high to low), decreased proliferation and increase in E-cadherin expression. However, the mechanisms that contribute to the observed tumor control are poorly understood. Recent studies by others and us have demonstrated significant inhibition of endothelial proliferation and angiogenesis following calcitriol treatment. The overall goal of this study was to examine the effects of calcitriol treatment on tumor vascular function in the TRAMP model. To achieve this goal, non-invasive magnetic resonance imaging (MRI) was used for morphologic and functional assessment of prostate cancer in TRAMP mice. T2-weighted MRI was initially performed on TRAMP mice at different times (6-26 weeks) to visualize changes in prostate tumor growth in vivo. To study the effects of calcitriol on tumor vascular function in the prostate, T1-weighted contrast-enhanced MRI was performed in calcitriol-treated and saline-treated TRAMP mice. TRAMP mice received calcitriol (20µg/kg i.p. x 3/week, MWF) from 4 weeks of age until time of palpable tumor. Control TRAMP mice received equal volume of saline during this period. At 16 weeks of age, T1-weighted contrast-enhanced MRI was carried out using the intravascular contrast agent, albumin-GdDTPA. T1-relaxation rates (R1=1/T1) of the prostate were measured before and after contrast agent administration in calcitriol-treated and saline-treated mice (n=5 per group). The change in R1 (ΔR1) of prostate tissues were normalized to murine muscle tissue of individual mice to account for potential differences in contrast agent administration. Linear regression analysis of normalized contrast agent concentration (ΔR1tumor/muscle) was performed to estimate relative vascular volume and permeability. No significant differences in prostate volume or vascular permeability were observed between calcitriol-treated mice and saline-treated controls. However, at 16 weeks of age, calcitriol-treated animals showed a marked reduction in relative vascular volume (y-intercept; P&lt;0.0001) compared to control animals. R1-maps calculated on a pixel-by-pixel basis allowed for visualization of prostate vascular response to calcitriol treatment. Our results demonstrate the usefulness of MRI in monitoring prostate tumor growth in vivo and demonstrate, for the first time, functional vascular changes following calcitriol therapy in TRAMP mice. These vascular changes detected using contrast-enhanced MRI indicate an anti-angiogenic effect of calcitriol in the TRAMP model.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3249.