Anti‐angiogenic therapy affects the relationship between tumor vascular structure and function: A correlation study between micro–computed tomography angiography and dynamic contrast enhanced MRI

2区 · 医学

Article

作者: Mælandsmo, Gunhild Mari ; Moestue, Siver Andreas ; Kim, Eugene ; Kim, Jana ; Johansen, Berit

PurposeTo compare the effects of two anti‐angiogenic drugs, bevacizumab and a cytosolic phospholipase A2‐α inhibitor (AVX235), on the relationship between vascular structure and dynamic contrast enhanced (DCE)‐MRI measurements in a patient‐derived breast cancer xenograft model.MethodsMice bearing MAS98.12 tumors were randomized into three groups: bevacizumab‐treated (n = 9), AVX235‐treated (n = 9), and control (n = 8). DCE‐MRI was performed pre‐ and post‐treatment. Median initial area under the concentration‐time curve (IAUC60) and volume transfer constant (Ktrans) were computed for each tumor. Tumors were excised for ex vivo micro‐CT (computed tomography) angiography, from which the vascular surface area (VSA) and fractional blood volume (FBV) were computed. Spearman correlation coefficients (ρ) were computed to evaluate the associations between the DCE‐MRI and micro‐CT parameters.ResultsWith the groups pooled, IAUC60 and Ktrans correlated significantly with VSA (ρ = 0.475 and 0.527; P = 0.019 and 0.008). There were no significant correlations within the control group. There were various significant correlations within the treatment groups, but the correlations in the bevacizumab group were of opposite sign, for example, Ktrans versus FBV: AVX235, ρ = 0.800 (P = 0.014); bevacizumab, ρ = –0.786 (P = 0.023).ConclusionDCE‐MRI measurements can highly depend on vascular structure. The relationship between vascular structure and function changed markedly after anti‐angiogenic treatment. Magn Reson Med 78:1513–1522, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

2016-12-01·BMC Cancer2区 · 医学

Anti-vascular effects of the cytosolic phospholipase A2 inhibitor AVX235 in a patient-derived basal-like breast cancer model

2区 · 医学

ArticleOA

作者: Vettukattil, Riyas ; Mælandsmo, Gunhild Mari ; Feuerherm, Astrid Jullumstrø ; Kim, Eugene ; Moestue, Siver Andreas ; Cebulla, Jana ; Helgesen, Heidi ; Johansen, Berit ; Engebråten, Olav ; Tunset, Hanna Maja

BACKGROUNDGroup IVA cytosolic phospholipase A2 (cPLA2α) plays an important role in tumorigenesis and angiogenesis. It is overexpressed in basal-like breast cancer (BLBC), which is aggressive and usually triple-negative, making it unresponsive to current targeted therapies. Here, we evaluated the anti-angiogenic effects of a specific cPLA2α inhibitor, AVX235, in a patient-derived triple-negative BLBC model.METHODSMice bearing orthotopic xenografts received i.p. injections of AVX235 or DMSO vehicle daily for 1 week and then every other day for up to 19 days. Six treated and six control mice were terminated after 2 days of treatment, and the tumors excised for high resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS) and prostaglandin E2 (PGE2) enzyme immunoassay (EIA) analysis. A 1-week imaging study was performed on a separate cohort of mice. Longitudinal dynamic contrast enhanced (DCE)-MRI was performed before, after 4 days, and after 1 week of treatment. The mice were then perfused with a radiopaque vascular casting agent, and the tumors excised for micro-CT angiography. Subsequently, tumors were sectioned and stained with lectin and for Ki67 or α-smooth muscle actin to quantify endothelial cell proliferation and vessel maturity, respectively. Partial least squares discriminant analysis was performed on the multivariate HR MAS MRS data, and non-parametric univariate analyses using Mann-Whitney U tests (α = 0.05) were performed on all other data.RESULTSGlycerophosphocholine and PGE2 levels, measured by HR MAS MRS and EIA, respectively, were lower in treated tumors after 2 days of treatment. These molecular changes are expected downstream effects of cPLA2α inhibition and were followed by significant tumor growth inhibition after 8 days of treatment. DCE-MRI revealed that AVX235 treatment caused a decrease in tumor perfusion. Concordantly, micro-CT angiography showed that vessel volume fraction, density, and caliber were reduced in treated tumors. Moreover, histology showed decreased endothelial cell proliferation and fewer immature vessels in treated tumors.CONCLUSIONSThese results demonstrate that cPLA2α inhibition with AVX235 resulted in decreased vascularization and perfusion and subsequent inhibition of tumor growth. Thus, cPLA2α inhibition may be a potential new therapeutic option for triple-negative basal-like breast cancer.

100 项与 AVX-235 相关的药物交易

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