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Assessment of multiparametric MRI in a human glioma model to monitor cytotoxic and anti-angiogenic drug effects.

ABSTRACT: Early imaging or blood biomarkers of tumor response is needed to customize anti-tumor therapy on an individual basis. This study evaluates the sensitivity and relevance of five potential MRI biomarkers. Sixty nude rats were implanted with human glioma cells (U-87 MG) and randomized into three groups: one group received an anti-angiogenic treatment (Sorafenib), a second a cytotoxic drug [1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU (Carmustine)] and a third no treatment. The tumor volume, apparent diffusion coefficient (ADC) of water, blood volume fraction (BVf), microvessel diameter (vessel size index, VSI) and vessel wall integrity (contrast enhancement, CE) were monitored before and during treatment. Sorafenib reduced tumor CE as early as 1 day after treatment onset. By 4 days after treatment onset, tumor BVf was reduced and tumor VSI was increased. By 14 days after treatment onset, ADC was increased and the tumor growth rate was reduced. With BCNU, ADC was increased and the tumor growth rate was reduced 14 days after treatment onset. Thus, the estimated MRI parameters were sensitive to treatment at different times after treatment onset and in a treatment-dependent manner. This study suggests that multiparametric MR monitoring could allow the assessment of new anti-tumor drugs and the optimization of combined therapies.

SUBMITTER: Lemasson B

PROVIDER: S-EPMC3351072 | biostudies-other | 2011 Jun

REPOSITORIES: biostudies-other

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Project description:BACKGROUND: Anti-angiogenic therapy in certain cancers has been associated with improved control of tumor growth and metastasis. Development of anti-angiogenic agents has, however, been saddled with higher attrition rate due to suboptimal efficacy, narrow therapeutic windows, or development of organ-specific toxicities. The aim of this study was to evaluate the translational ability of the zebrafish efficacy-toxicity model to stratify anti-angiogenic agents based on efficacy, therapeutic windows, and off-target effects to streamline the compound selection process in anti-angiogenic discovery. METHODS: The embryonic model of zebrafish was employed for studying angiogenesis and toxicity. The zebrafish were treated with anti-angiogenic compounds to evaluate their effects on angiogenesis and zebrafish-toxicity parameters. Angiogenesis was measured by scoring the development of subintestinal vessels. Toxicity was evaluated by calculating the median lethal concentration, the lowest observed effect concentration, and gross morphological changes. Results of efficacy and toxicity were used to predict the therapeutic window. RESULTS: In alignment with the clinical outcomes, the zebrafish assays demonstrated that vascular endothelial growth factor receptor (VEGFR) inhibitors are the most potent anti-angiogenic agents, followed by multikinase inhibitors and inhibitors of endothelial cell proliferation. The toxicity assays reported cardiac phenotype in zebrafish treated with VEGFR inhibitors and multikinase inhibitors with VEGFR activity suggestive of cardiotoxic potential of these compounds. Several other pathological features were reported for multikinase inhibitors suggestive of off-target effects. The predicted therapeutic window was translational with the clinical trial outcomes of the anti-angiogenic agents. The zebrafish efficacy-toxicity approach could stratify anti-angiogenic agents based on the mechanism of action and delineate chemical structure-driven biological activity of anti-angiogenic compounds. CONCLUSION: The zebrafish efficacy-toxicity approach can be used as a predictive model for translational anti-angiogenic drug discovery to streamline compound selection, resulting in safer and efficacious anti-angiogenic agents entering the clinics.

Project description:Aims: To evaluate the utility of fasudil in a rat model of contrast-associated acute kidney injury (CA-AKI) and explore its underlying mechanism through multiparametric renal magnetic resonance imaging (mpMRI). Methods: Experimental rats (n = 72) were grouped as follows: controls (n = 24), CA-AKI (n = 24), or CA-AKI + Fasudil (n = 24). All animals underwent two mpMRI studies (arterial spin labeling, T1 and T2 mapping) at baseline and post iopromide/fasudil injection (Days 1, 3, 7, and 13 respectively). Relative change in renal blood flow (ΔRBF), T1 (ΔT1) and T2 (ΔT2) values were assessed at specified time points. Serum levels of cystatin C (CysC) and interleukin-1β (IL-1β), and urinary neutrophil gelatinase-associated lipocalin (NGAL) concentrations were tested as laboratory biomarkers, in addition to examining renal histology and expression levels of various proteins (Rho-kinase [ROCK], α-smooth muscle actin [α-SMA]), hypoxia-inducible factor-1α (HIF-1α), and transforming growth factor-β1 (TGF-β1) that regulate renal fibrosis and hypoxia. Results: Compared with the control group, serum levels of CysC and IL-1β, and urinary NGAL concentrations were clearly increased from Day 1 to Day 13 in the CA-AKI group (all p < 0.05). There were significant reductions in ΔT2 values on Days 1 and 3, and ΔT1 reductions were significantly more pronounced at all time points (Days 1-13) in the CA-AKI + Fasudil group (vs. CA-AKI) (all p < 0.05). Fasudil treatment lowered expression levels of ROCK-1, and p-MYPT1/MYPT1 proteins induced by iopromide, decreasing TGF-β1 expression and suppressing both extracellular matrix accumulation and α-SMA expression relative to untreated status (all p < 0.05). Fasudil also enhanced PHD2 transcription and inhibition of HIF-1α expression after CA-AKI. Conclusions: In the context of CA-AKI, fasudil appears to reduce renal hypoxia, fibrosis, and dysfunction by activating (Rho/ROCK) or inhibiting (TGF-β1, HIF-1α) certain signaling pathways and reducing α-SMA expression. Multiparametric MRI may be a viable noninvasive tool for monitoring CA-AKI pathophysiology during fasudil therapy.

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Assessment of multiparametric MRI in a human glioma model to monitor cytotoxic and anti-angiogenic drug effects.

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