Tumor Concentrations Research Articles

Quantitative Imaging Parameters of Contrast-Enhanced Micro-Computed Tomography Correlate with Angiogenesis and Necrosis in a Subcutaneous C6 Glioma Model.

Simple SummaryContrast-enhanced (CE) X-ray imaging techniques have been used to assess angiogenesis in patients and animal models of cancer in order to overcome the limitations of histological quantification of angiogenesis, such as spatial and temporal heterogeneity of tumors. Some studies have compared the quantitative imaging parameters obtained with static and dynamic CE X-ray imaging techniques, but their association with histological biomarkers of angiogenesis has never been directly compared. This study aimed to provide such a comparison in a suitable animal model for the study of angiogenesis, namely, the subcutaneous C6 glioma model. We found an agreement among the quantitative imaging parameters obtained with these techniques, and we also found an association between a set of them with angiogenesis and necrosis descriptors. This set of quantitative imaging parameters demonstrated a high potential to describe angiogenesis and could be used to assess treatment response in further studies with this animal model.The aim of this work was to systematically obtain quantitative imaging parameters with static and dynamic contrast-enhanced (CE) X-ray imaging techniques and to evaluate their correlation with histological biomarkers of angiogenesis in a subcutaneous C6 glioma model. Enhancement (E), iodine concentration (CI), and relative blood volume (rBV) were quantified from single- and dual-energy (SE and DE, respectively) micro-computed tomography (micro-CT) images, while rBV and volume transfer constant (Ktrans) were quantified from dynamic contrast-enhanced (DCE) planar images. CI and rBV allowed a better discernment of tumor regions from muscle than E in SE and DE images, while no significant differences were found for rBV and Ktrans in DCE images. An agreement was found in rBV for muscle quantified with the different imaging protocols, and in CI and E quantified with SE and DE protocols. Significant strong correlations (Pearson r > 0.7, p < 0.05) were found between a set of imaging parameters in SE images and histological biomarkers: E and CI in tumor periphery were associated with microvessel density (MVD) and necrosis, E and CI in the complete tumor with MVD, and rBV in the tumor periphery with MVD. In conclusion, quantitative imaging parameters obtained in SE micro-CT images could be used to characterize angiogenesis and necrosis in the subcutaneous C6 glioma model.

Tumor, skin, and plasma concentrations of protein kinase inhibitors (PKIs) in patients with advanced cancer.

11087 Background: PKIs are selective for target receptors at low concentrations, but they act promiscuously at higher concentrations (PMID 18183025). This lack of selectivity may be relevant for their antitumor activity and for the development of PKI treatment selection tools. To obtain more insight in their clinical mechanism of action, we designed a pilot study to determine PKI tumor, skin and plasma concentrations in patients (pts) after 2 weeks of treatment. Results are related to cell line sensitivity data. Methods: Prior to standard palliative systemic treatment, pts were allocated to standard-dose PKI treatment (N=5 per PKI) for 10-14 days. Plasma, tumor and skin biopsies were collected within 24 hours of last dose. Sample PKI concentrations were determined by liquid chromatography – tandem mass spectrometry (LC-MS/MS); tissue concentrations in pg/mg were converted to molarity for comparison with preclinical sensitivity data (PMID 21980135). Concentrations of sunitinib (SUN), sorafenib (SOR), erlotinib (ERL), dasatinib (DAS) and everolimus (EVE) that inhibit 50% of cell proliferation (IC50) were determined by MTT assay in 1 RCC (786-O) and 8 CRC cell lines (HCT 116, HT-29, RKO, SW480, SW1398, DLD-1, COLO 205, CaCo-2). Results: Since August 2011 samples were obtained from 27 pts; 5 received SUN, 4 SOR, 4 ERL, 5 DAS and 5 EVE. After 12 ± 1 days of treatment, median tumor concentration (TC) was 9.0 µM (2.3-50.0) (range) for SUN, 8.5 µM (3.7-22.0) for SOR, 5.3 µM (0.9-10.8) for ERL and 2.1 µM (0.2-64.0) for DAS. EVE was measurable in 2 of 5 tumors: 3.5 µM (3.4-3.6). On average, PKI skin concentrations were 2.4-fold lower than TCs. SOR and ERL plasma concentrations (PCs) were in the range of TCs while SUN and DAS PCs were at least 14-fold lower than in tumors. Mean IC50 of the cell line panel was 1.3 µM (0.8-1.4) for SUN, 2.2 µM (1.4-3) for SOR, 8.2 µM (4-11.5) for ERL, 0.06 µM (0.02-1.8) for DAS and 1.2 µM (0.05-11) for EVE. Conclusions: PKI tumor concentrations may vary considerably from plasma concentrations, but are in the IC50 range of cancer cells in vitro. These results are indicative for the inhibitory concentrations of PKIs in patient tumors and should be considered for the development of individualized treatment strategies. Clinical trial information: NCT01636908.