Littérature scientifique sur le sujet « Fluoroazomycin arabinoside (18F-FAZA) »

Hypoxic areas are typically resistant to treatment. However, the fluorine-18-fluoroazomycin-arabinoside (FAZA) and fluorine 18 misonidazole (FMISO) tracers have never been compared in non small cell lung cancer (NSCLC). This study compares the capability of 18F-FAZA PET/CT with that of 18F-FMISO PET/CT for detecting hypoxic tumour regions in early and locally advanced NSCLC patients. We prospectively evaluated patients who underwent preoperative PET scans before surgery for localised NSCLC (i.e., fluorodeoxyglucose (FDG)-PET, FMISO-PET, and FAZA-PET). The PET data of the three tracers were compared with each other and then compared to immunohistochemical analysis (GLUT-1, CAIX, LDH-5, and HIF1-Alpha) after tumour resection. Overall, 19 patients with a mean age of 68.2 ± 8 years were included. There were 18 lesions with significant uptake (i.e., SUVmax >1.4) for the F-MISO and 17 for FAZA. The mean SUVmax was 3 (±1.4) with a mean volume of 25.8 cc (±25.8) for FMISO and 2.2 (±0.7) with a mean volume of 13.06 cc (±13.76) for FAZA. The SUVmax of F-MISO was greater than that of FAZA (p = 0.0003). The SUVmax of F-MISO shows a good correlation with that of FAZA at 0.86 (0.66–0.94). Immunohistochemical results are not correlated to hypoxia PET regardless of the staining. The two tracers show a good correlation with hypoxia, with FMISO being superior to FAZA. FMISO, therefore, remains the reference tracer for defining hypoxic volumes.

Tumors lack a well-regulated vascular supply of O2 and often fail to balance O2 supply and demand. Net O2 tension within many tumors may not only depend on O2 delivery but also depend strongly on O2 demand. Thus, tumor O2 consumption rates may influence tumor hypoxia up to true anoxia. Recent reports have shown that many human tumors in vivo depend primarily on oxidative phosphorylation (OxPhos), not glycolysis, for energy generation, providing a driver for consumptive hypoxia and an exploitable vulnerability. In this regard, IACS-010759 is a novel high affinity inhibitor of OxPhos targeting mitochondrial complex-I that has recently completed a Phase-I clinical trial in leukemia. However, in solid tumors, the effective translation of OxPhos inhibitors requires methods to monitor pharmacodynamics in vivo. Herein, 18F-fluoroazomycin arabinoside ([18F]FAZA), a 2-nitroimidazole-based hypoxia PET imaging agent, was combined with a rigorous test-retest imaging method for non-invasive quantification of the reversal of consumptive hypoxia in vivo as a mechanism-specific pharmacodynamic (PD) biomarker of target engagement for IACS-010759. Neither cell death nor loss of perfusion could account for the IACS-010759-induced decrease in [18F]FAZA retention. Notably, in an OxPhos-reliant melanoma tumor, a titration curve using [18F]FAZA PET retention in vivo yielded an IC50 for IACS-010759 (1.4 mg/kg) equivalent to analysis ex vivo. Pilot [18F]FAZA PET scans of a patient with grade IV glioblastoma yielded highly reproducible, high-contrast images of hypoxia in vivo as validated by CA-IX and GLUT-1 IHC ex vivo. Thus, [18F]FAZA PET imaging provided direct evidence for the presence of consumptive hypoxia in vivo, the capacity for targeted reversal of consumptive hypoxia through the inhibition of OxPhos, and a highly-coupled mechanism-specific PD biomarker ready for translation.

4049 Background: We previously demonstrated correlation between hypoxia and aggressive tumor biology in orthotopic, patient-derived pancreatic xenografts (Chang et al. Cancer Res 2011). With the development of hypoxia-directed therapies, there is a need to understand the range and relevance of hypoxia in PDAC patients. We therefore launched two complementary clinical trials using 2-nitroimidazole-based hypoxia probes. Methods: PIMO-PANC involves pre-operative administration of pimonidazole to patients (pts) undergoing PDAC resection. Hypoxic percent (HP) of tumors is determined by semi-automated image analysis (on Aperio’s Genie) of multiple histological sections stained for pimonidazole by immunohistochemistry (IHC). FAZA-PANC uses the positron emission tomography (PET) tracer fluoroazomycin arabinoside (18F-FAZA) to evaluate hypoxia by functional imaging. 2 hours post-injection of (5.2 MBq/kg) 18F-FAZA, static scans are acquired followed by computed tomography for anatomic registration. Skeletal muscle is a non-hypoxic reference tissue to define standardized uptake values (SUV), tumor to muscle uptake ratios (T/M’s) and a threshold for hypoxia. Results: PIMO-PANC has enrolled 29 pts and FAZA-PANC 16. IHC analysis of the first 10 pt tumors demonstrates considerable intra- and inter-tumoral heterogeneity of hypoxia (HP: 1 to 26% across pt tumors); minimal hypoxia (< 5%) was observed in 3 pts. 18F-FAZA-PET in the first 11 pts demonstrates SUVmax from 1.02 to 1.83, median T/M's from 0.84 to 1.31. A threshold of 1.27 SUVmax defines HP of 0 to 60% with minimal hypoxia (<10%) in 5 pts. Conclusions: There is significant heterogeneity of hypoxia across the spectrum of clinical PDAC (local to metastatic disease) using the 2-nitroimidazole hypoxia probes pimonidazole and 18F-FAZA. Given the intra-tumoral heterogeneity of hypoxia by histopathology, functional imaging is the preferred method to assess hypoxia in PDAC patients. Importantly, both methods identified a group of PDAC tumors with low levels of hypoxia. This is relevant to the on-going development of hypoxia-targeting strategies. Accrual to PIMO-PANC is on-going and will address the prognostic relevance of hypoxia in PDAC. Clinical trial information: NCT01542177 and NCT01248637.

Abstract Purpose We evaluated the kinetics of the hypoxia PET radiotracers, [18F]fluoromisonidazole ([18F]FMISO) and [18F]fluoroazomycin-arabinoside ([18F]FAZA), for tumor hypoxia detection and to assess the correlation of hypoxic kinetic parameters with static imaging measures in canine spontaneous tumors. Methods Sixteen dogs with spontaneous tumors underwent a 150-min dynamic PET scan using either [18F]FMISO or [18F]FAZA. The maximum tumor-to-muscle ratio (TMRmax) > 1.4 on the last image frame was used as the standard threshold to determine tumor hypoxia. The tumor time-activity curves were analyzed using irreversible and reversible two-tissue compartment models and graphical methods. TMRmax was compared with radiotracer trapping rate (k3), influx rate (Ki), and distribution volume (VT). Results Tumor hypoxia was detected in 7/8 tumors in the [18F]FMISO group and 4/8 tumors in the [18F]FAZA group. All hypoxic tumors were detected at > 120 min with [18F]FMISO and at > 60 min with [18F]FAZA. [18F]FAZA showed better fit with the reversible model. TMRmax was strongly correlated with the irreversible parameters (k3 and Ki) for [18F]FMISO at > 90 min and with the reversible parameter (VT) for [18F]FAZA at > 120 min. Conclusions Our results showed that [18F]FAZA provided a promising alternative radiotracer to [18F]FMISO with detecting the presence of tumor hypoxia at an earlier time (60 min), consistent with its favorable faster kinetics. The strong correlation between TMRmax over the 90–150 min and 120–150 min timeframes with [18F]FMISO and [18F]FAZA, respectively, with kinetic parameters associated with tumor hypoxia for each radiotracer, suggests that a static scan measurement (TMRmax) is a good alternative to quantify tumor hypoxia.

2009 - 2010
The present Ph.D. project was divided into different work parts, in a way that helps to understand and define the goals of this project. In particular: I) Design, synthesis and evaluation of antiviral activity of Arbidol analogs. II) Evaluation of mechanism of Arbidol anti-influenza action. III) Synthesis and characterization of a P.E.T. radiotracer for tumor hypoxia: 1- (5- [18F] Fluoro-5-deoxy-α-D-arabinofuranosyl) -2-nitroimidazole or 18F-FAZA. The initial research activity concerned the design and synthesis of indole derivatives using as a lead compound Arbidol (ARB), a compound that exerts immunomodulatory, antioxidant, antiviral and antimetastatic effects1. ARB is a Russian-made potent broad-spectrum antiviral with demonstrated activity against a number of DNA and RNA viruses, enveloped and non-enveloped viruses, and pH-dependent and pH-independent viruses. It exhibits antiviral activity against a number of viruses including influenza A (H1N1, H2N2 and H3N2), B and C viruses, respiratory syncytial virus (RSV), adenovirus type 7, coxsackie B3 virus, parainfluenza type 5 and rhinovirus type 14, avian coronavirus, infectious bronchitis virus and Marek disease virus, hepatitis B virus and hepatitis C virus. The wide spectrum of ARB’s activity suggests that ARB targets common critical step(s) in virus – cell interaction. Several studies have shown that the affinity of ARB for lipid membranes could account for its antiviral actions, together with a differential level of interaction with key motifs in glycoproteins of different viruses. Its antiviral activity toward viruses is due probably to a direct effect of ARB on virus-cell membrane interactions where ARB intercalates into membranes and induces membrane alterations. This leads to excessive stabilization of cell membranes, which become resistant to virus fusion and in some cases (HCV) to virus replication2-4. The known biological properties of Arbidol led us to focus on its derivatives as potential antiviral agents. In order to maintain antiviral activity we preserved the groups responsible of Arbidol interaction with membranes (indole ring, S-phenyl group, ester group and amino group) eliminating those that were not considered pharmacophores (hydroxy and bromo groups at the 5- and 6-positions of the indole ring). Moreover we introduced different substituents at the 2- and 5-position of the indole ring to investigate the influence of these variations on antiviral activity. The synthesis of Arbidol derivatives has been established through the validation of two synthetic schemes. Then, to evaluate anti-HCV and anti-HSV activity of synthesized compounds, biological assays were made. ARB derivatives showed antiviral activity comparable and, in some cases, even better than those of lead Arbidol, on both systems. In particular, it was shown that synthesized compounds are fusion inhibitors on both viruses and also non-selective inhibitors of HCV replication. The second part of the present research project concerned the study of mechanism of Arbidol anti-influenza action. There are experimental evidences that ARB does not affect viral neuraminidase (NA, a surface protein of influenza virus) activity. It affects early post-adsorption stages of virus replication with possible involvement of the second surface viral protein, the haemagglutinin (HA). Arbidol could act increasing influenza virus HA stability and preventing low pH induced HA transition to its fusogenic state, thus blocking infection at the viral fusion stage5. To support this hypothesis, the interaction of Arbidol with the N-terminal hydrophobic fusion domain of haemagglutinin (HA) was evaluated. Therefore, the peptide host-guest (P20H6) was synthesized using techniques of Solid Phase Peptide Synthesis (SPPS) and Circular dichroism studies were made6.From these studies we demonstrated that Arbidol interacts with the haemagglutinin fusion domain at pH 5 and 7, through changes in the secondary structure of peptide. At the end of present Ph.D. project, I spent six months at the University of Aberdeen where I worked to the synthesis of a PET (Positron Emission Tomography) radiotracer for tumour hypoxia: the [18F]1-α-D-(5-Fluoro-5-deoxyarabinofuranosyl)-2-nitroimidazole, known as 18F-FAZA. 18F-FAZA is currently the gold standard for PET Imaging of diseases characterized by hypoxia (solid tumours, ischemia, stroke)7, but it is not routinely used and synthesized in Scotland. The work done is an important starting point for the introduction of 18F-FAZA in Scotland with the aim of using it in clinical imaging and research. In particular, following a detailed bibliography research on this compound and its synthesis, that is not fully reported, and a subsequent optimization of the synthetic scheme used, the 18F-FAZA precursor was obtained: 1-α-D-[5’-O-Toluenesulfonyl-2’,3’-Di-Oacetylarabinofuranosyl]-2-nitroimidazole (DAcTs-AZA). [edited by author]
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