18f-faza and Disease-Models--Animal

Glioblastoma (GB) is the most common primary malignant brain tumor. Standard medical treatment consists of a maximal safe surgical resection, subsequently radiation therapy (RT) and chemotherapy with temozolomide (TMZ). An accurate definition of the tumor volume is of utmost importance for guiding RT. In this project we investigated the feasibility and treatment response of subvolume boosting to a PET-defined tumor part.. F98 GB cells inoculated in the rat brain were imaged using T2- and contrast-enhanced T1-weighted (T1w) MRI. A dose of 20 Gy (5 × 5 mm. When comparing the dose volume histograms, a significant difference was found exclusively between the D. In this study we showed the feasibility of PET guided subvolume boosting of F98 glioblastoma in rats. No evidence was found for a beneficial effect regarding tumor response. However, improvements for dose targeting in rodents and studies investigating new targeted drugs for GB treatment are mandatory.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Disease Models, Animal; Feasibility Studies; Female; Glioblastoma; Nitroimidazoles; Positron-Emission Tomography; Radiopharmaceuticals; Radiotherapy Dosage; Radiotherapy, Image-Guided; Rats, Inbred F344; Treatment Outcome; Tumor Burden; Tyrosine

Pharmacokinetic (PK) data are generally derived from blood samples withdrawn serially over a defined period after dosing. In small animals, blood sampling after dosing presents technical difficulties, particularly when short time intervals and frequent sampling are required. Positron emission tomography (PET) is a non-invasive functional imaging technique that can provide semi-quantitative temporal data for defined volume regions of interest (vROI), to support kinetic analyses in blood and other tissues. The application of preclinical small-animal PET to determine and compare PK parameters for [18F]FDG and [18F]FAZA, radiopharmaceuticals used clinically for assessing glucose metabolism and hypoxic fractions, respectively, in the same mammary EMT6 tumor-bearing mouse model, is reported here.. Two study groups were used: normal BALB/c mice under isoflurane anesthesia were intravenously injected with either [18F]FDG or [18F]FAZA. For the first group, blood-sampling by tail artery puncture was used to collect blood samples which were then analyzed with Radio-microTLC. Dynamic PET experiments were performed with the second group of mice and analyzed for blood input function and tumor uptake utilizing a modified two compartment kinetic model. Heart and inferior vena cava vROIs were sampled to obtain image-derived data. PK parameters were calculated from blood samples and image-derived data. Time-activity curves (TACs) were also generated over regions of liver, kidney and urinary bladder to depict clearance profiles for each radiotracer.. PK values generated by classical blood sampling and PET image-derived analysis were comparable to each other for both radiotracers. Heart vROI data were suitable for analysis of [18F]FAZA kinetics, but metabolic uptake of radioactivity mandated the use of inferior vena cava vROIs for [18F]FDG analysis. While clearance (CL) and blood half-life (t½) were similar for both [18F]FDG and [18F]FAZA for both sampling methods, volume of distribution yielded larger differences, indicative of limitations such as partial volume effects within quantitative image-derived data. [18F]FDG underwent faster blood clearance and had a shorter blood half-life than [18F]FAZA. Kinetic analysis of tumor uptake from PET image data showed higher uptake and longer tumor tissue retention of [18F]FDG, indicative of the tumor's glucose metabolism rate, versus lower tumor uptake and retention of [18F]FAZA. While [18F]FAZA possesses a somewhat greater hepatobiliary clearance , [18F]FDG clears faster through the renal system which results in faster radioactivity accumulation in the urinary bladder.. The present study provides a working example of the applicability of functional PET imaging as a suitable tool to determine PK parameters in small animals. The comparative analysis in the current study demonstrates that it is feasible to use [18F]FDG PET and [18F]FAZA PET in the same model to analyze their blood PK parameters, and to estimate kinetic parameters for these tracers in tumor. This non-invasive imaging-based determination of tissue kinetic parameters facilitates translation from pre-clinical to clinical phases of drug development. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Topics: Animals; Breast Neoplasms; Disaccharides; Disease Models, Animal; Female; Kinetics; Mice; Mice, Inbred BALB C; Nitroimidazoles; Positron-Emission Tomography; Tissue Distribution

1-α-D-(5-Deoxy-5-[18F]fluoroarabinofuranosyl)-2-nitroimidazole([18F] FAZA) is a PET radiotracer that demonstrates excellent potential in imaging regional hypoxia, and is clinically used in diagnosing a wide range of solid tumors in cancer patients. [18F]FAZA, however, is radiofluorinated in only moderate recovered radiochemical yield (rRCY, ~12%). It is postulated that the relative stability of the C1' β-anomeric bond at C5' will make 1-β-D-(5-fluoro-5-deoxyarabinofuranosyl)-2-nitroimidazole (β-FAZA), the β-conformer of FAZA, an attractive candidate for clinical hypoxia imaging.. The principle goals were to synthesize β-FAZA and β-Ac2TsAZA, the radiofluorination precursor, to establish the radiofluorination chemistry leading to β-[18F]FAZA, and to investigate the biodistribution of β-[18F]FAZA in an animal tumor-bearing model using PET imaging.. The appropriately-protected furanose sugar was coupled with 2-nitroimidazole to afford 1-β-D-(2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (β-Ac2AZA). Fluorination of β-Ac2AZA with DAST, followed by alkaline hydrolysis, afforded β-FAZA (21%). The radiolabeling synthon, 1-β-D-(5-O-toluenesulfonyl-2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (β-Ac2TsAZA), on radiofluorination using the 18F/K222 complex under various reaction conditions, followed by base-catalyzed deacetylation, afforded β-[18F]FAZA. β-[18F]FAZA was radiochemically stable for at least 8 h when stored in aqueous ethanol (8%) at 22 °C. A preliminary PET imaging-based biodistribution study of β-[18F]FAZA was performed in A431 tumor-bearing nude mice.. β-FAZA and β-Ac2TsAZA were synthesized in satisfactory yield. Radiochemistry of [18F]FAZA was established. PET images showed strong uptake in hypoxic regions of the tumor.. The synthesis of β-FAZA and β-[18F]FAZA are reported. Radiofluorination of β-Ac2TsAZA and the deprotection of β-Ac2[18F]FAZA were facile, but led to a more complex mixture of radiofluorinated by-products than observed with the corresponding precursor of α-[18F]FAZA. PET images were indicative of hypoxia-selective accumulation of β-[18F]FAZA in tumor.

Topics: Animals; Cell Line, Tumor; Disease Models, Animal; Fluorine Radioisotopes; Male; Mice; Mice, Nude; Neoplasms; Nitroimidazoles; Positron-Emission Tomography; Radiochemistry; Radiopharmaceuticals; Tissue Distribution; Tumor Hypoxia

To assess the predictive value of hypoxia imaging by (18)F-FAZA PET in identifying tumors that may benefit from radiotherapy combined with nimorazole, a hypoxic radiosensitizer.. Rats of two tumor models (Rhabdomyosarcoma and 9L-glioma) were divided into two treated groups: radiotherapy (RT) alone or RT plus nimorazole. (18)F-FAZA PET images were obtained to evaluate tumor hypoxia before the treatment. Treatment outcome was assessed through the tumor growth time assay, defined as the time required for tumor to grow to 1.5 times its size before irradiation.. For rhabdomyosarcomas, the benefit of adding nimorazole to RT was not significant when considering all tumors. When stratifying into more and less hypoxic tumors according to the median (18)F-FAZA T/B ratio, we found that the combined treatment significantly improved the response of the "more hypoxic" subgroup, while there was no significant difference in the tumor growth time between the two treatment modalities for the "less hypoxic" subgroup. For 9L-gliomas, a clear benefit was demonstrated for the group receiving RT+nimorazole. However, the individual responses within the RT+nimorazole group were highly variable and independent of the (18)F-FAZA uptake.. (18)F-FAZA PET may be useful to guide hypoxia-directed RT using nimorazole as radiosensitizer. It identified a subgroup of more hypoxic tumors (displaying T/B ratio>2.72) that would benefit from this combined treatment. Nevertheless, the predictive power was limited to rhabdomyosarcomas and ineffective for 9L-gliomas.

Topics: Animals; Cell Hypoxia; Chemoradiotherapy; Disease Models, Animal; Fluorine Radioisotopes; Glioma; Male; Nimorazole; Nitroimidazoles; Positron-Emission Tomography; Radiopharmaceuticals; Random Allocation; Rats; Rats, Inbred F344; Rhabdomyosarcoma

Hypoxia-driven intervention (oxygen manipulation or dose escalation) could overcome radiation resistance linked to tumor hypoxia. Here, we evaluated the value of hypoxia imaging using (18)F-FAZA PET to predict the outcome and guide hypoxia-driven interventions.. Two hypoxic rat tumor models were used: rhabdomyosarcoma and 9L-glioma. For the irradiated groups, the animals were divided into two subgroups: breathing either room air or carbogen. (18)F-FAZA PET images were obtained just before the irradiation to monitor the hypoxic level of each tumor. Absolute pO2 were also measured using EPR oximetry. Dose escalation was used in Rhabdomyosarcomas.. For 9L-gliomas, a significant correlation between (18)F-FAZA T/B ratio and tumor growth delay was found; additionally, carbogen breathing dramatically improved the tumor response to irradiation. On the contrary, Rhabdomyosarcomas were less responsive to hyperoxic challenge. For that model, an increase in growth delay was observed using dose escalation, but not when combining irradiation with carbogen.. (18)F-FAZA uptake may be prognostic of outcome following radiotherapy and could assess the response of tumor to carbogen breathing. (18)F-FAZA PET may help to guide the hypoxia-driven intervention with irradiation: carbogen breathing in responsive tumors or dose escalation in tumors non-responsive to carbogen.

Topics: Animals; Carbon Dioxide; Cell Hypoxia; Diagnostic Imaging; Disease Models, Animal; Glioma; Male; Nitroimidazoles; Oximetry; Oxygen; Partial Pressure; Positron-Emission Tomography; Prognosis; Radiotherapy Planning, Computer-Assisted; Random Allocation; Rats; Rats, Inbred F344; Rhabdomyosarcoma

The prognosis of malignant gliomas remains largely unsatisfactory for the intrinsic characteristics of the pathology and for the delayed diagnosis. Multimodal imaging based on PET and MRI may assess the dynamics of disease onset and progression allowing the validation of preclinical models of glioblastoma multiforme (GBM). The aim of this study was the characterization of a syngeneic rat model of GBM using combined in vivo imaging and immunohistochemistry.. Four groups of Fischer rats were implanted in a subcortical region with increasing concentration of rat glioma F98 cells and weekly monitored with Gd-MR, [(18)F]FDG- and [(18)F]FAZA-PET starting one week after surgery. Different targets were evaluated on post mortem brain specimens using immunohistochemistry: VEGF, GFAP, HIF-1α, Ki-67 and nestin.. Imaging results indicated that tumor onset but not progression was related to the number of F98 cells. Hypoxic regions identified with [(18)F]FAZA and high-glucose metabolism regions recognized with [(18)F]FDG were located respectively in the core and in external areas of the tumor, with partial overlap and remodeling during disease progression. Histological and immunohistochemical analysis confirmed PET/MRI results and revealed that our model resumes biological characteristics of human GBM. IHC and PET studies showed that necrotic regions, defined on the basis of [(18)F]FDG uptake reduction, may include hypoxic clusters of vital tumor tissue identified with [(18)F]FAZA. This last information is particularly relevant for the identification of the target volume during image-guided radiotherapy.. In conclusion, the combined use of PET and MRI allows in vivo monitoring of the biological modification of F98 lesions during tumor progression.

Topics: Animals; Cell Differentiation; Cell Line, Tumor; Disease Models, Animal; Fluorodeoxyglucose F18; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Nitroimidazoles; Positron-Emission Tomography; Rats; Survival Analysis

Tumor hypoxia is a known cause of resistance to radiotherapy. The aim of this study was to investigate the prognostic value of hypoxia measured by (18)F-fluoroazomycin arabinoside ((18)F-FAZA) PET or the Eppendorf oxygen electrode in a pre-clinical tumor model.. Pretreatment (18)F-FAZA PET scans and blood sampling was conducted in 92 Female CDF1 mice with subcutaneous C3H mammary carcinomas grown in the right foot. Similarly, oxygenation status of 80 equivalent tumors was assessed using an invasive oxygen sensitive electrode. Tumors were then irradiated with a single dose of 55 Gy and local tumor control up to 90 days after the treatment was determined.. A significant difference in local tumor control between "more hypoxic" or "less hypoxic" groups separated either by a median (18)F-FAZA PET determined tumor-to-blood ratio (P=0.007; hazard ratio, HR=0.21 [95% CI: 0.06-0.74]), or the fraction of oxygen partial pressure (pO(2)) values ≤2.5 mmHg (P=0.018; HR=0.31 [95% CI: 0.11-0.87]), was found. Both assays showed that the more hypoxic tumors had significantly lower tumor control.. (18)F-FAZA PET analysis showed that pre treatment tumor hypoxia was prognostic of radiation response. Similar results were obtained when oxygenation status was assessed by the Eppendorf pO(2) Histograph. The results of this study support the role of (18)F-FAZA as a non-invasive prognostic marker for tumor hypoxia.

Topics: Animals; Cell Hypoxia; Disease Models, Animal; Electrodes; Female; Fluorine Radioisotopes; Mammary Neoplasms, Experimental; Mice; Nitroimidazoles; Positron-Emission Tomography; Prognosis; Radiation Tolerance

PET allows non-invasive mapping of tumor hypoxia, but the combination of low resolution, slow tracer adduct-formation and slow clearance of unbound tracer remains problematic. Using a murine tumor with a hypoxic fraction within the clinical range and a tracer post-injection sampling time that results in clinically obtainable tumor-to-reference tissue activity ratios, we have analyzed to what extent inherent limitations actually compromise the validity of PET-generated hypoxia maps.. Mice bearing SCCVII tumors were injected with the PET hypoxia-marker fluoroazomycin arabinoside (FAZA), and the immunologically detectable hypoxia marker, pimonidazole. Tumors and reference tissue (muscle, blood) were harvested 0.5, 2 and 4h after FAZA administration. Tumors were analyzed for global (well counter) and regional (autoradiography) tracer distribution and compared to pimonidazole as visualized using immunofluorescence microscopy.. Hypoxic fraction as measured by pimonidazole staining ranged from 0.09 to 0.32. FAZA tumor to reference tissue ratios were close to unity 0.5h post-injection but reached values of 2 and 6 when tracer distribution time was prolonged to 2 and 4h, respectively. A fine-scale pixel-by-pixel comparison of autoradiograms and immunofluorescence images revealed a clear spatial link between FAZA and pimonidazole-adduct signal intensities at 2h and later. Furthermore, when using a pixel size that mimics the resolution in PET, an excellent correlation between pixel FAZA mean intensity and density of hypoxic cells was observed already at 2h post-injection.. Despite inherent weaknesses, PET-hypoxia imaging is able to generate quantitative tumor maps that accurately reflect the underlying microscopic reality (i.e., hypoxic cell density) in an animal model with a clinical realistic image contrast.

Topics: Animals; Carcinoma, Squamous Cell; Cell Count; Cell Hypoxia; Disease Models, Animal; Female; Hypoxia; Mice; Mice, Inbred C3H; Nitroimidazoles; Oxygen; Positron-Emission Tomography; Radiopharmaceuticals; Random Allocation; Sensitivity and Specificity; Tissue Distribution

The study was performed to compare the (18)F-labeled nitroimidazole compound fluoroazomycin arabinoside ((18)F-FAZA) with the standard hypoxia tracer fluoromisonidazole ((18)F-FMISO) in detection of tumor tissue hypoxia and to verify the oxygenation dependency of (18)F-FAZA uptake.. Biodistribution of (18)F-FAZA was studied at various time points in EMT6 tumor-bearing BALB/c mice and in AR42J and A431 tumor-bearing nude mice and compared with that of (18)F-FMISO. The presence of tumor tissue hypoxia was verified in 5 EMT6 and 5 AR42J tumors using an oxygen-sensing needle electrode system. To evaluate the oxygenation dependency of (18)F-FAZA uptake, using the Munich prototype animal PET scanner, 2 serial PET scans were performed in 13 A431 tumor-bearing nude mice breathing pure oxygen or room air on 1 d and then selecting the other oxygen breathing condition on the following day. In addition, digital autoradiography was performed with EMT6 tumor-bearing (18)F-FAZA-dosed, nude mice breathing either room air (n = 8) or carbogen (n = 9).. Tissue partial pressure of oxygen (Po(2)) electrode measurements revealed that tumor hypoxia was present under room air breathing in EMT6 (tissue Po(2) = 2.9 +/- 2.6) and AR42J tumors (tissue Po(2) = 0.4 +/- 0.2), which was significantly lower compared with that of reference tissue (tissue Po(2) = 25.8 +/- 6.7 and tissue Po(2) = 29.0 +/- 3.0 [mean +/- SD], respectively; P < 0.01). In all tumor models, (18)F-FAZA displayed significantly higher tumor-to-muscle and tumor-to-blood ratios compared with (18)F-FMISO, indicating a faster clearance of (18)F-FAZA from normal tissues. In AR42J tumors, (18)F-FAZA tumor-to-normal ratios were found to increase over time. Serial animal (18)F-FAZA PET studies showed that the tumor-to-background ratio was significantly higher in animals breathing room air compared with that of animals breathing pure oxygen (7.3 +/- 2.3 vs. 4.2 +/- 1.2, respectively; P < 0.001). Similarly, autoradiography showed significantly higher tumor-to-muscle ratios in mice breathing room air compared with those of animals breathing carbogen (5.3 +/- 0.8 vs. 2.2 +/- 0.8; respectively; P < 0.02).. (18)F-FAZA shows superior biokinetics and is, thus, a promising PET tracer for the visualization of tumor hypoxia. This study also verified a hypoxia-specific uptake mechanism for (18)F-FAZA in murine tumor models.

Topics: Animals; Cell Hypoxia; Disease Models, Animal; Female; Metabolic Clearance Rate; Mice; Mice, Inbred BALB C; Mice, Nude; Misonidazole; Neoplasms; Nitroimidazoles; Organ Specificity; Oxidation-Reduction; Oxygen; Radionuclide Imaging; Radiopharmaceuticals; Tissue Distribution