The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function.

BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) mediates the transcriptional response to hypoxic stress, promoting tumour progression and survival. This study investigated the acute effects of the small-molecule HIF-pathway inhibitor NSC-134754. METHODS: Human PC-3LN5 prostate cancer cells were treated with NSC-134754 for 24 h in hypoxia. Orthotopic prostate tumour-bearing mice were treated with a single dose of NSC-134754 for 6, 24 or 48 h. Treatment response was measured using magnetic resonance spectroscopy and imaging. Ex-vivo histological validation of imaging findings was also sought. RESULTS: In vitro, NSC-134754 significantly reduced lactate production and glucose uptake (P<0.05), while significantly increasing intracellular glucose (P<0.01) and glutamine uptake/metabolism (P<0.05). Increased glutamine metabolism was independent of c-Myc, a factor also downregulated by NSC-134754. In vivo, a significantly higher tumour apparent diffusion coefficient was determined 24 h post-treatment (P<0.05), with significantly higher tumour necrosis after 48 h (P<0.05). NSC-134754-treated tumours revealed lower expression of HIF-1α and glucose transporter-1, at 6 and 24 h respectively, while a transient increase in tumour hypoxia was observed after 24 h. Vessel perfusion/flow and vascular endothelial growth factor levels were unchanged with treatment. CONCLUSION: NSC-134754 induces metabolic alterations in vitro and early anti-tumour activity in vivo, independent of changes in vascular function. Our data support the further evaluation of NSC-134754 as an anti-cancer agent

26.1 MOTOR SUBTYPES AND PREDICTION OF COURSE IN PSYCHOSIS RISK YOUTH

The aim of this study was to use the combined carbogen-ultrasmall superparamagnetic iron oxide (CUSPIO) magnetic resonance imaging (MRI) method, which uses spatial correlations in independent susceptibility imaging biomarkers, to investigate and compare the impact of tumor size and anatomical site on vascular structure and function in vivo. Mice bearing either subcutaneous or orthotopic PC3 LN3 prostate tumors were imaged at 7 T, using a multi-gradient echo sequence to quantify R2, before and during carbogen (95% O2/5% CO2) breathing, and subsequently following intravenous administration of USPIO particles. Carbogen and USPIO-induced changes in R2 were used to inform on hemodynamic vasculature and fractional blood volume (%), respectively. The CUSPIO imaging data were also segmented to identify and assess five categories of R2 response. Small and large subcutaneous and orthotopic tumor cohorts all exhibited significantly (P < 0.05) different median baseline R2, ΔR2carbogen, and fractional blood volume. CUSPIO imaging showed that small subcutaneous tumors predominantly exhibited a negative ΔR2carbogen followed by a positive ΔR2USPIO, consistent with a well perfused tumor vasculature. Large subcutaneous tumors exhibited a small positive ΔR2carbogen and relatively low fractional blood volume, suggesting less functional vasculature. Orthotopic tumors revealed a large, positive ΔR2carbogen, consistent with vascular steal, and which may indicate that vascular function is more dependent on site of implantation than tumor size. Regions exhibiting significant ΔR2carbogen, but no significant ΔR2USPIO, suggesting transient vascular shutdown over the experimental timecourse, were apparent in all 3 cohorts. CUSPIO imaging can inform on efficient drug delivery via functional vasculature in vivo, and on appropriate tumor model selection for pre-clinical therapy trials

Acute tumour response to a bispecific Ang-2-VEGF-A antibody: insights from multiparametric MRI and gene expression profiling.

Background To assess antivascular effects, and evaluate clinically translatable magnetic resonance imaging (MRI) biomarkers of tumour response in vivo, following treatment with vanucizumab, a bispecific human antibody against angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A).Methods Colo205 colon cancer xenografts were imaged before and 5 days after treatment with a single 10 mg kg(-1) dose of either vanucizumab, bevacizumab (anti-human VEGF-A), LC06 (anti-murine/human Ang-2) or omalizumab (anti-human IgE control). Volumetric response was assessed using T2-weighted MRI, and diffusion-weighted, dynamic contrast-enhanced (DCE) and susceptibility contrast MRI used to quantify tumour water diffusivity (apparent diffusion coefficient (ADC), × 10(6) mm(2) s(-1)), vascular perfusion/permeability (K(trans), min(-1)) and fractional blood volume (fBV, %) respectively. Pathological correlates were sought, and preliminary gene expression profiling performed.Results Treatment with vanucizumab, bevacizumab or LC06 induced a significant (P<0.01) cytolentic response compared with control. There was no significant change in tumour ADC in any treatment group. Uptake of Gd-DTPA was restricted to the tumour periphery in all post-treatment groups. A significant reduction in tumour K(trans) (P<0.05) and fBV (P<0.01) was determined 5 days after treatment with vanucizumab only. This was associated with a significant (P<0.05) reduction in Hoechst 33342 uptake compared with control. Gene expression profiling identified 20 human genes exclusively regulated by vanucizumab, 6 of which are known to be involved in vasculogenesis and angiogenesis.Conclusions Vanucizumab is a promising antitumour and antiangiogenic treatment, whose antivascular activity can be monitored using DCE and susceptibility contrast MRI. Differential gene expression in vanucizumab-treated tumours is regulated by the combined effect of Ang-2 and VEGF-A inhibition

Evaluating Imaging Biomarkers of Acquired Resistance to Targeted EGFR Therapy in Xenograft Models of Human Head and Neck Squamous Cell Carcinoma.

Background: Overexpression of EGFR is a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). Patients with HNSCC who respond to EGFR-targeted tyrosine kinase inhibitors (TKIs) eventually develop acquired resistance. Strategies to identify HNSCC patients likely to benefit from EGFR-targeted therapies, together with biomarkers of treatment response, would have clinical value. Methods: Functional MRI and 18F-FDG PET were used to visualize and quantify imaging biomarkers associated with drug response within size-matched EGFR TKI-resistant CAL 27 (CALR) and sensitive (CALS) HNSCC xenografts in vivo, and pathological correlates sought. Results: Intrinsic susceptibility, oxygen-enhanced and dynamic contrast-enhanced MRI revealed significantly slower baseline R2∗ , lower hyperoxia-induced ΔR2∗ and volume transfer constant Ktrans in the CALR tumors which were associated with significantly lower Hoechst 33342 uptake and greater pimonidazole-adduct formation. There was no difference in oxygen-induced ΔR1 or water diffusivity between the CALR and CALS xenografts. PET revealed significantly higher relative uptake of 18F-FDG in the CALR cohort, which was associated with significantly greater Glut-1 expression. Conclusions: CALR xenografts established from HNSCC cells resistant to EGFR TKIs are more hypoxic, poorly perfused and glycolytic than sensitive CALS tumors. MRI combined with PET can be used to non-invasively assess HNSCC response/resistance to EGFR inhibition

Direct medical costs of adverse events in Dutch hospitals

Background: Various international studies have shown that a substantial number of patients suffer from injuries or even die as a result of care delivered in hospitals. The occurrence of injuries among patients caused by health care management in Dutch hospitals has never been studied systematically. Therefore, an epidemiological study was initiated to determine the incidence, type and impact of adverse events among discharged and deceased patients in Dutch hospitals. Methods/Design: Three stage retrospective patient record review study in 21 hospitals of 8400 patient records of discharged or deceased patients in 2004. The records were reviewed by trained nurses and physicians between August 2005 and October 2006. In addition to the determination of presence, the degree of preventability, and causes of adverse events, also location, timing, classification, and most responsible specialty of the adverse events were measured. Moreover, patient and admission characteristics and the quality of the patient records were recorded. Discussion: In this paper we report on the design of the retrospective patient record study on the occurrence of adverse events in Dutch hospitals. Attention is paid to the strengths and limitations of the study design. Furthermore, alterations made in the original research protocol in comparison with former international studies are described in detail.

Noninvasive Imaging of Cycling Hypoxia in Head and Neck Cancer Using Intrinsic Susceptibility MRI.

Purpose: To evaluate intrinsic susceptibility (IS) MRI for the identification of cycling hypoxia, and the assessment of its extent and spatial distribution, in head and neck squamous cell carcinoma (HNSCC) xenografts and patients.Experimental Design: Quantitation of the transverse relaxation rate, R2*, which is sensitive to paramagnetic deoxyhemoglobin, using serial IS-MRI acquisitions, was used to monitor temporal oscillations in levels of paramagnetic deoxyhemoglobin in human CALR xenografts and patients with HNSCC at 3T. Autocovariance and power spectrum analysis of variations in R2* was performed for each imaged voxel, to assess statistical significance and frequencies of cycling changes in tumor blood oxygenation. Pathologic correlates with tumor perfusion (Hoechst 33342), hypoxia (pimonidazole), and vascular density (CD31) were sought in the xenografts, and dynamic contrast-enhanced (DCE) MRI was used to assess patient tumor vascularization. The prevalence of fluctuations within patient tumors, DCE parameters, and treatment outcome were reported.Results: Spontaneous R2* fluctuations with a median periodicity of 15 minutes were detected in both xenografts and patient tumors. Spatially, these fluctuations were predominantly associated with regions of heterogeneous perfusion and hypoxia in the CALR xenografts. In patients, R2* fluctuations spatially correlated with regions of lymph nodes with low Ktrans values, typically in the vicinity of necrotic cores.Conclusions: IS-MRI can be used to monitor variations in levels of paramagnetic deoxyhemoglobin, associated with cycling hypoxia. The presence of such fluctuations may be linked with impaired tumor vasculature, the presence of which may impact treatment outcome. Clin Cancer Res; 23(15); 4233-41. ©2017 AACR

Evaluation of novel combined carbogen USPIO (CUSPIO) imaging biomarkers in assessing the antiangiogenic effects of cediranib (AZD2171) in rat C6 gliomas

The recently described combined carbogen USPIO (CUSPIO) magnetic resonance imaging (MRI) method uses spatial correlations in independent imaging biomarkers to assess specific components of tumor vascular structure and function. Our study aimed to evaluate CUSPIO biomarkers for the assessment of tumor response to antiangiogenic therapy. CUSPIO imaging was performed in subcutaneous rat C6 gliomas before and 2 days after treatment with the potent VEGF-signaling inhibitor cediranib (n = 12), or vehicle (n = 12). Histological validation of Hoechst 33342 uptake (perfusion), smooth muscle actin staining (maturation), pimonidazole adduct formation (hypoxia) and necrosis were sought. Following treatment, there was a significant decrease in fractional blood volume (-43%, p &lt; 0.01) and a significant increase in hemodynamic vascular functionality (treatment alteredδ R 2* carbogen from 1.2 to -0.2 s -1, p &lt; 0.05). CUSPIO imaging revealed an overall significant decrease in plasma perfusion (-27%, p &lt; 0.05) following cediranib treatment, that was associated with selective effects on immature blood vessels. The CUSPIO responses were associated with a significant 15% reduction in Hoechst 33342 uptake (p &lt; 0.05), but no significant difference in vascular maturation or necrosis. Additionally, treatment with cediranib resulted in a significant 40% increase in tumor hypoxia (p &lt; 0.05). The CUSPIO imaging method provides novel and more specific biomarkers of tumor vessel maturity and vascular hemodynamics, and their response to VEGF-signaling inhibition, compared to current MR imaging biomarkers utilized in the clinic. Such biomarkers may prove effective in longitudinally monitoring tumor vascular remodeling and/or evasive resistance in response to antiangiogenic therapy. © 2011 UICC

Renal Drug Transporters and Drug Interactions.

Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers