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Henry AM, Wilkinson C, Wylie JP, et al., 2004, Trans-perineal implantation of radio-opaque treatment verification markers into the prostate: an assessment of procedure related morbidity, patient acceptability and accuracy, Radiother Oncol, Vol: 73, Pages: 57-59
On-line imaging of prostate markers can be used to compensate for errors in radiation delivery. This study assessed the patient acceptability and morbidity associated with the trans-perineal route of implantation. A minority experienced acute pain or bleeding. Placement was accurate in all but one subject. An operator related learning curve exists. Although this is an invasive procedure most patients found it acceptable. Implementation for routine clinical practice is feasible.
Hutchison GJ, Valentine HR, Loncaster JA, et al., 2004, Hypoxia-inducible factor 1alpha expression as an intrinsic marker of hypoxia: correlation with tumor oxygen, pimonidazole measurements, and outcome in locally advanced carcinoma of the cervix, Clin Cancer Res, Vol: 10, Pages: 8405-8412
PURPOSE: Hypoxia-inducible factor (HIF)-1alpha expression was studied retrospectively in locally advanced carcinoma of the cervix in relation to other methods for measuring/assessing tumor hypoxia and outcome after radiotherapy. EXPERIMENTAL DESIGN: HIF-1alpha expression was examined in formalin-fixed tumor biopsies using a semiquantitative scoring system and correlated with measurements of hypoxia obtained using oxygen electrodes, pimonidazole staining, and carbonic anhydrase 9. RESULTS: High HIF-1alpha expression showed a weak correlation with low pO2 (r = -0.26; P = 0.030; n = 72). Weak significant correlations were found between HIF-1alpha and pimonidazole staining (r = 0.34; P = 0.040; n = 36) and carbonic anhydrase IX (r = 0.27; P = 0.001; n = 160). There was no relationship with surviving fraction at 2 Gy. The relationship between HIF-1alpha expression and radiotherapy outcome was examined in 99 patients. HIF-1alpha expression did not correlate with disease stage, grade, tumor size, and patient age. HIF-1alpha alone was not a significant prognostic factor for disease-free survival, metastasis-free survival, or local recurrence-free survival. High HIF-1alpha expression tended to be associated with poor outcome in small tumors but good outcome in large tumors, with statistically significant interactions between HIF-1alpha and tumor size for survival (P = 0.046) and local control (P = 0.009). CONCLUSIONS: In this study, HIF-1alpha had no prognostic significance in locally advanced carcinoma of the cervix. The possible switch in large tumors for an association between high HIF-1alpha expression and good outcome might relate to tumor size-related changes in the balance of genes up-regulated by HIF-1alpha. Whereas angiogenesis-promoting genes might be preferentially up-regulated in small tumors, proapoptotic genes might be induced in large tumors. This hypothesis needs testing in future work.
Jones B, Price P, 2004, Proton therapy: expanding clinical indications, Clin Oncol (R Coll Radiol), Vol: 16, Pages: 324-325
Khoo VS, Saunders MP, Gowda R, et al., 2004, Anal canal cancer and chemoradiation treatment in two patients with systemic lupus erythematosus treated by chronic therapeutic immunosuppression, Clin Oncol (R Coll Radiol), Vol: 16, Pages: 1-5
Two case reports of anal cancer developing during chronic therapeutic immunosuppression for systemic lupus erythematosus (SLE) and their cancer management are presented. The complex issues of delivery of curative chemoradiation treatment for anal cancer in the context of co-existing autoimmune connective tissue disease (AICD) are discussed. These two cases show that combined chemotherapy and radiation regimens are possible in patients with SLE. However, frequent, careful assessment with judicious and prompt management of haematological and other complications during treatment is important.
Madhusudan S, Deplanque G, Braybrooke JP, et al., 2004, Antiangiogenic therapy for von Hippel-Lindau disease, JAMA, Vol: 291, Pages: 943-944
Wells P, West C, Jones T, et al., 2004, Measuring tumor pharmacodynamic response using PET proliferation probes: the case for 2-[(11)C]-thymidine, Biochim Biophys Acta, Vol: 1705, Pages: 91-102
[(18)F]-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) is becoming accepted as a diagnostic tool for cancer, but the potential uses of PET in oncology extend beyond the imaging of glucose metabolism. The development of a PET proliferation probe would be a useful pharmacodynamic tool. [(11)C]-thymidine PET has been assessed in man as a specific measure of tumor proliferation. Uptake of [(11)C]-thymidine is related to DNA synthesis and, in human tumors, correlates with proliferation. When compared with (18)F-FDG, it has been shown to be a more sensitive discriminator of early clinical tumor response. 2-[(11)C]-thymidine PET scanning of patients enrolled in early phase clinical trials is feasible and should support future drug development. Although recent research is moving away from the validation of thymidine towards thymidine analogues radiolabeled with (18)F, the better specificity of thymidine for DNA should be the rationale for its continued development and application as a PET probe. This review describes the historical development, application and current research status of [(11)C]-thymidine PET, and aims to highlight the need for its continuing development as a marker of tumor proliferation.
West CM, Jones T, Price P, 2004, The potential of positron-emission tomography to study anticancer-drug resistance, Nat Rev Cancer, Vol: 4, Pages: 457-469
Positron-emission tomography (PET) is a powerful tool for imaging and quantifying cellular and molecular processes in humans. It has enormous potential to increase our understanding of the pathophysiology of human tumours and to support the development of anticancer drugs. The ability of PET to image mechanisms of anticancer-drug resistance in vivo should be exploited in proof-of-concept studies at early stages of drug development.
West CM, Price P, 2004, Combretastatin A4 phosphate, Anticancer Drugs, Vol: 15, Pages: 179-187
Combretastatin A4 phosphate (CA4P) is a water-soluble prodrug of combretastatin A4 (CA4). The vascular targeting agent CA4 is a microtubule depolymerizing agent. The mechanism of action of the drug is thought to involve the binding of CA4 to tubulin leading to cytoskeletal and then morphological changes in endothelial cells. These changes increase vascular permeability and disrupt tumor blood flow. In experimental tumors, anti-vascular effects are seen within minutes of drug administration and rapidly lead to extensive ischemic necrosis in areas that are often resistant to conventional anti-cancer treatments. Following single-dose administration a viable tumor rim typically remains from which tumor regrowth occurs. When given in combination with therapies targeted at the proliferating viable rim, enhanced tumor responses are seen and in some cases cures. Results from the first clinical trials have shown that CA4P monotherapy is safe and reduces tumor blood flow. There has been some promising demonstration of efficacy. CA4P in combination with cisplatin is also safe. Functional imaging studies have been used to aid the selection of doses for phase II trials. Both dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and positron emission tomography can measure the anti-vascular effects of CA4P in humans. This review describes the background to the development of CA4P, its proposed mechanism of action, the results from the first clinical trials with CA4P and the role of imaging techniques in its clinical development.
West CML, Jones T, Price P, 2004, Positron Emission Tomography (PET) and anticancer drug development, Discovery Medicine, Vol: 4, Pages: 303-306
Gupta N, Price P, 2004, Imaging in Oncology, Imaging in Oncology, Editors: Husband, Reznek, Publisher: Taylor and Francis
Barthel H, Aboagye E, Price P, 2003, Correspondence re:: H.!Barthel <i>et al.</i>, 3′-deoxy-3′-[<SUP>18</SUP>F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy <i>in vivo</i> with positron emission tomography.: Cancer Res., <i>63</i>: 3791-3798,2003.: Reply, CANCER RESEARCH, Vol: 63, Pages: 8560-8560, ISSN: 0008-5472
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Wells P, Aboagye E, Gunn RN, et al., 2003, 2-[11C]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337, J Natl Cancer Inst, Vol: 95, Pages: 675-682
BACKGROUND: Some anticancer drugs inhibit thymidylate synthase (TS), a key enzyme for thymidine nucleotide biosynthesis. Cells can compensate for depleted thymidine levels by taking up extracellular thymidine via a salvage pathway. We investigated the use of 2-[11C]thymidine positron emission tomography (PET) to measure thymidine salvage kinetics in vivo in humans. METHODS: Five patients with advanced gastrointestinal cancer were PET scanned both before and 1 hour after oral administration of the TS inhibitor AG337 (THYMITAQ [nolatrexed]); seven control patients were scanned twice but not treated with AG337. Thymidine salvage kinetics were measured in vivo using 2-[11C]thymidine PET and spectral analysis to obtain the standardized uptake values (SUV), the area under the time-activity curve (AUC), and the fractional retention of thymidine (FRT). Changes in PET parameters between scans in the AG337-treated and control groups were compared using the Mann-Whitney U test. The relationship between AG337 exposure and AG337-induced changes in tumor FRT and in plasma deoxyuridine levels (a conventional pharmacodynamic systemic measure of TS inhibition) was examined using Spearman's regression analysis. Statistical tests were two-sided. RESULTS: The between-scan change in FRT in patients treated with AG337 (38% increase, 95% confidence interval [CI] = 8% to 68%) was higher than that in control patients (3% increase, 95% CI = -11% to 17%) (P =.028). The level of AG337-induced increase in both 2-[11C]thymidine FRT and plasma deoxyuridine levels was statistically significantly correlated with AG337 exposure (r = 1.00, P =.01 for both). CONCLUSIONS: AG337 administration was associated with increased tumor tracer retention that was consistent with tumor cell uptake of exogenous 2-[11C]thymidine as a result of TS inhibition. 2-[11C]Thymidine PET can be used to measure thymidine salvage kinetics directly in the tissue of interest.
Leach MO, Brindle KM, Evelhoch JL, et al., 2003, Assessment of antiangiogenic and antivascular therapeutics using MRI: recommendations for appropriate methodology for clinical trials, Br J Radiol, Vol: 76 Suppl 1, Pages: S87-S91
Rustin GJ, Galbraith SM, Anderson H, et al., 2003, Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results, J Clin Oncol, Vol: 21, Pages: 2815-2822
PURPOSE: A phase I trial was performed with combretastatin A4 phosphate (CA4P), a novel tubulin-binding agent that has been shown to rapidly reduce blood flow in animal tumors. PATIENTS AND METHODS: The drug was delivered by a 10-minute weekly infusion for 3 weeks followed by a week gap, with intrapatient dose escalation. Dose escalation was accomplished by doubling until grade 2 toxicity was seen. The starting dose was 5 mg/m2. RESULTS: Thirty-four patients received 167 infusions. CA4P was rapidly converted to the active combretastatin A4 (CA4), which was further metabolized to the glucuronide. CA4 area under the curve (AUC) increased from 0.169 at 5 mg/m2 to 3.29 micromol * h/L at 114 mg/m2. The mean CA4 AUC in eight patients at 68 mg/m2 was 2.33 micromol * h/L compared with 5.8 micromol * h/L at 25 mg/kg (the lowest effective dose) in the mouse. The only toxicity that possibly was related to the drug dose up to 40 mg/m2 was tumor pain. Dose-limiting toxicity was reversible ataxia at 114 mg/m2, vasovagal syncope and motor neuropathy at 88 mg/m2, and fatal ischemia in previously irradiated bowel at 52 mg/m2. Other drug-related grade 2 or higher toxicities seen in more than one patient were pain, lymphopenia, fatigue, anemia, diarrhea, hypertension, hypotension, vomiting, visual disturbance, and dyspnea. One patient at 68 mg/m2 had improvement in liver metastases of adrenocortical carcinoma. CONCLUSION: CA4P was well tolerated in 14 of 16 patients at 52 or 68 mg/m2; these are doses at which tumor blood flow reduction has been recorded.
Propper DJ, De Bono J, Saleem A, et al., 2003, Use of Positron Emission Tomography in Pharmacokinetic Studies to Investigate Therapeutic Advantage in a Phase I Study of 120-Hour Intravenous Infusion XR5000, J Clin Oncol, Vol: 21, Pages: 203-210
Purpose: XR5000 (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) is a topoisomerase I and II inhibitor. Because the cytotoxicity of XR5000 increases markedly with prolonged exposure, we performed a phase I study of weekly XR5000 by 120-hour continuous infusion over 3 weeks. Patients and Methods: Twenty-four patients with advanced solid cancer were treated at seven dose levels (700 to 4,060 mg/m(2)/120 hrs) for a total of 67 cycles. Three patients underwent positron emission tomography (PET) studies at the maximum-tolerated dose (MTD) to evaluate normal tissue and tumor carbon-11 radiolabeled XR5000 ([(11)C]XR5000) pharmacokinetics. Results: The dose-limiting toxicity was National Cancer Institute Common Toxicity Criteria (version 1) grade 4 chest and abdominal pain affecting the single patient receiving 4,060 mg/m(2)/120 hours, and the MTD was 3,010 mg/m(2)/120 hours. Other grade 3-4 toxicities, affecting single patients at the MTD, were myelosuppression (grade 4), raised bilirubin, vomiting, and somnolence (all grade 3). There was one partial response (adenocarcinoma of unknown primary); the remainder had progressive disease. [(11)C]XR5000 distributed well into the three tumors studied by PET. Tumor uptake (maximum concentration or area under the concentration versus time curve [AUC]) was less than in normal tissue in which the tumors were located. Tumor exposure (AUC; mean +/- SD in m(2)/mL/sec) increased when [(11)C]XR5000 was administered during an infusion of XR5000 (0.403 +/- 0.1), compared with [(11)C]XR5000 given alone (0.292 +/- 0.1; P <.05), indicating that tumor drug exposure was not saturated. Conclusion: The recommended dose for XR5000 in phase II studies is 3,010 mg/m(2)/120 hours. PET studies with (11)C-labeled drug were feasible and demonstrated in vivo distribution into tumors. Saturation of tumor exposure was not reached at the MTD.
Saleem A, Brown GD, Brady F, et al., 2003, Metabolic Activation of Temozolomide Measured in Vivo Using Positron Emission Tomography, Cancer Res, Vol: 63, Pages: 2409-2415
The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic activation of temozolomide. The secondary aims were to evaluate the tumor, normal tissue, and plasma pharmacokinetics of temozolomide in vivo, and to determine whether such pharmacokinetics resulted in tumor targeting. [(11)C]temozolomide kinetics were studied in men using positron emission tomography (PET). It has been postulated that temozolomide undergoes decarboxylation and ring opening in the 3-4 position to produce the highly reactive methyldiazonium ion that alkylates DNA. To investigate this, a dual radiolabeling strategy, with [(11)C]temozolomide separately radiolabelled in the 3-N-methyl and 4-carbonyl positions, was used. We hypothesized that (11)C in the C-4 position of [4-(11)C-carbonyl]temozolomide would be converted to [(11)C]CO(2) if the postulated mechanism of metabolic conversion was true resulting in lower [(11)C]temozolomide tumor exposure. Paired studies were performed with both forms of [(11)C]temozolomide in 6 patients with gliomas. Another PET scan with (11)C-radiolabelled bicarbonate was performed and used to account for the metabolites of temozolomide using a data-led analytical approach. Plasma was analyzed for [(11)C]temozolomide and [(11)C]metabolites throughout the scan duration. Exhaled air was also sampled throughout the scan for [(11)C]CO(2). The percentage ring opening of temozolomide over 90 min was also calculated to evaluate whether there was a differential in metabolic breakdown among plasma, normal tissue, and tumor. There was rapid systemic clearance of both radiolabelled forms of [(11)C]temozolomide over 90 min (0.2 liter/min/m(2)), with [(11)C]CO(2) being the primary elimination product. Plasma [(11)C]CO(2) was present in all of the studies with [4-(11)C-carbonyl]temozolomide and in half the studies with [3-N-(11)C-methyl]temozolomide. The mean contributions to total plasma activity by [(11)C]CO(2) at 10 and 90 min were 12% and 28%
Collingridge DR, Glaser M, Osman S, et al., 2003, In vitro selectivity, in vivo biodistribution and tumour uptake of annexin V radiolabelled with a positron emitting radioisotope, Br J Cancer, Vol: 89, Pages: 1327-1333
The availability of a noninvasive method to detect and quantify apoptosis in tumours will enable tumour response to several cancer therapies to be assessed. We have synthesised two radiotracers, annexin V and the N-succinimidyl-3-iodobenzoic acid (SIB) derivative of annexin V, labelled with radio-iodine ((124)I and (125)I) and provided proof of the concept by assessing specific binding and biodistribution of these probes to apoptotic cells and tumours. We have also assessed the tumour uptake of [(124)I]annexin V in a mouse model of apoptosis. RIF-1 cells induced to undergo apoptosis in vitro showed a drug concentration-dependent increased binding of [(125)I]annexin V and [(125)I]SIB-annexin V. In the same model system, there was an increase in terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL)-positive cells and a decrease in clonogenic survival. Radiotracer binding was completely inhibited by preincubation with unlabelled annexin V. In RIF-1 tumour-bearing mice, rapid distribution of [(125)I]SIB-annexin V-derived radioactivity to kidneys was observed and the radiotracer accumulated in urine. The binding of [(125)I]SIB-annexin V to RIF-1 tumours increased by 2.3-fold at 48 h after a single intraperitoneal injection of 5-fluorouracil (165 mg kg(-1) body weight), compared to a 4.4-fold increase in TUNEL-positive cells measured by immunostaining. Positron emission tomography images with both radiotracers demonstrated intense localisation in the kidneys and bladder. Unlike [(124)I]SIB-annexin V, [(124)I]annexin V also showed localisation in the thyroid region presumably due to deiodination of the radiolabel. [(124)I]SIB-annexin V is an attractive candidate for in vivo imaging of apoptosis by PET.British Journal of Cancer (2003) 89, 1327-1333. doi:10.1038/sj.bjc.6601262 www.bjcancer.com
Laking GR, Price PM, 2003, Positron emission tomographic imaging of angiogenesis and vascular function, Br J Radiol, Vol: 76 Suppl 1, Pages: S50-S59
Surrogate markers of clinical outcome are important in anticancer drug research, since clinical criteria of response develop only slowly and may be confounded by other processes than drug effect. The need for surrogate outcome markers is especially great with newer agents that may act by tumour stabilization as opposed to shrinkage. Neoplastic angiogenesis is associated with a number of detectable changes at molecular and microcirculatory levels. Therefore, direct study of angiogenic molecular biology and tumour circulation before during and after treatment may offer useful surrogate markers for vascular-targeted therapies. The main advantage of radiotracer imaging with positron emission tomography (PET) is its functional specificity. This article will review two main areas: (a) the methodology behind PET imaging of tumour blood supply with (15)O-oxygen labelled compounds; and (b) newer tracers in development as markers of angiogenetic biology.
Anderson HL, Yap JT, Miller MP, et al., 2003, Assessment of pharmacodynamic vascular response in a phase I trial of combretastatin A4 phosphate, J Clin Oncol, Vol: 21, Pages: 2823-2830
PURPOSE: Clinical evaluation of novel agents that target tumor blood vessels requires pharmacodynamic end points that measure vascular damage. Positron emission tomography (PET) was used to measure the effects of the vascular targeting agent combretastatin A4 phosphate (CA4P) on tumor and normal tissue perfusion and blood volume. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled onto part of a phase I, accelerated-titration, dose-escalation study. The effects of 5 to 114 mg/m2 CA4P on tumor, spleen, and kidney were investigated. Tissue perfusion was measured using oxygen-15 (15O)-labeled water and blood volume was measured using 15O-labeled carbon monoxide (C15O). Scans were performed immediately before, and 30 minutes and 24 hours after the first infusion of each dose level of CA4P. All statistical tests were two sided. RESULTS: PET data were obtained for 13 patients with intrapatient dose escalation. Significant dose-dependent reductions were seen in tumor perfusion 30 minutes after CA4P administration (mean change, -49% at >or= 52 mg/m2; P =.0010). Significant reductions were also seen in tumor blood volume (mean change, -15% at >or= 52 mg/m2; P =.0070). Although by 24 hours there was tumor vascular recovery, for doses >or= 52 mg/m2 the reduction in perfusion remained significant (P =.013). Thirty minutes after CA4P administration borderline significant changes were seen in spleen perfusion (mean change, -35%; P =.018), spleen blood volume (mean change, -18%; P =.022), kidney perfusion (mean change, -6%; P =.026), and kidney blood volume (mean change, -6%; P =.014). No significant changes were seen at 24 hours in spleen or kidney. CONCLUSION: CA4P produces rapid changes in the vasculature of human tumors that can be assessed using PET measurements of tumor perfusion.
Price P, 2003, Molecular Imaging in Oncology, Clin Advan in Hematol and Oncol, Vol: 1, Pages: 343-344
Hutchinson OC, Collingridge DR, Barthel H, et al., 2003, Pharmacodynamics of radiolabelled anticancer drugs for positron emission tomography, Curr Pharm Des, Vol: 9, Pages: 931-944
Positron Emission Tomography (PET) offers an exciting opportunity to monitor key pathways involved in malignant transformation due to the ability to radiolabel and image the behaviour of biological probes. In this review, we will describe how PET can use various radiolabelled compounds to monitor various targets including ligand-receptor interactions using 16alpha-[(18)F]fluoro-17beta-oestradiol (FES) pathways involved in metabolism with [(18)F]fluorodeoxy-glucose ([(18)F]FDG), (11)C-methyl-choline for signal transduction, cell cycle and proliferation with 2-[(11)C]thymidine, cell death using [(124)I]annexin V, [(124)C]colchicine for drug resistance and angiogenesis using [(124)I]anti-VEGF.
Barthel H, Cleij MC, Collingridge DR, et al., 2003, 3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography, Cancer Res, Vol: 63, Pages: 3791-3798
3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) has been proposed as a new marker for imaging tumor proliferation by positron emission tomography (PET). The uptake of [(18)F]FLT is regulated by cytosolic S-phase-specific thymidine kinase 1 (TK1). In this article, we have investigated the use of [(18)F]FLT to monitor the response of tumors to antiproliferative treatment in vivo. C3H/Hej mice bearing the radiation-induced fibrosarcoma 1 tumor were treated with 5-fluorouracil (5-FU; 165 mg/kg i.p.). Changes in tumor volume and biodistribution of [(18)F]FLT and 2-[(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) were measured in three groups of mice (n = 8-12/group): (a) untreated controls; (b) 24 h after 5-FU; and (c) 48 h after 5-FU. In addition, dynamic [(18)F]FLT-PET imaging was performed on a small animal scanner for 60 min. The metabolism of [(18)F]FLT in tumor, plasma, liver, and urine was determined chromatographically. Proliferation was determined by staining histological sections for proliferating cell nuclear antigen (PCNA). Tumor levels of TK1 protein and cofactor (ATP) were determined by Western blotting and bioluminescence, respectively. Tumor [(18)F]FLT uptake decreased after 5-FU treatment (47.8 +/- 7.0 and 27.1 +/- 3.7% for groups b and c, respectively, compared with group a; P < 0.001). The drug-induced reduction in tumor [(18)F]FLT uptake was significantly more pronounced than that of [(18)F]FDG. The PET image data confirmed lower tumor [(18)F]FLT retention in group c compared with group a, despite a trend toward higher radiotracer delivery for group c. Other than phosphorylation in tumors, [(18)F]FLT was found to be metabolically stable in vivo. The decrease in tumor [(18)F]FLT uptake correlated with the PCNA-labeling index (r = 0.71, P = 0.031) and tumor volume changes after 5-FU treatment (r = 0.58, P = 0.001). In this model system, the decrease in [(18)F]FLT uptake could be explained by changes in catalytic activity but not translation of TK1 protei
Glaser M, Collingridge DR, Aboagye EO, et al., 2003, Iodine-124 labelled Annexin-V as a potential radiotracer to study apoptosis using positron emission tomography, Appl Radiat Isot, Vol: 58, Pages: 55-62
Annexin-V is a calcium-dependent protein that binds with high affinity to phosphaditylserine exposed during apoptosis. The aim of this study was to radiolabel annexin-V with iodine-124 for use as a potential probe of apoptosis by positron emission tomography. Annexin-V was radioiodinated directly using the cyclotron-produced positron emitter iodine-124 by the chloramine-T (CAT) method and indirectly by the pre-labelled reagent N-succinimidyl 3-[124I]iodobenzoate ([124I]m-SIB). Some reaction parameters of the CAT method such as reaction time and pH were optimised to give radiochemical yields of 22.3+/-2.6%(n=3, gel-filtration). After incubation with [124I]m-SIB, radiolabelled annexin-V was obtained in 14% and 25% yield by FPLC and gel-filtration, respectively. The radiochemical purities from direct and indirect labelling were 97.7+/-1.0%(n=3) and 96.7+/-2.1%(n=3), respectively. The new radiotracers could be stored for up to four days without significant de-iodination. The biological activity of radiolabelled annexin-V was tested in control and camptothecin-treated (i.e. apoptotic) human leukaemic HL60 cells. A significantly higher (21%) binding in treated cells was observed with [125I]m-SIB-annexin-V. The binding of [125I]m-SIB labelled annexin-V to camptothecin treated cells was blocked (68%) by a 100-fold excess of unlabelled annexin-V.ABBREVIATIONS: Fast protein liquid chromatography (FPLC), Instant thin layer chromatography (ITLC), Sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE), 3-iodobenzoate (m-IBA), N-succinimidyl 3-(trimethylstannyl)benzoate (m-MeATE)
Price P, 2003, Pat Price discusses the potential of molecular imaging for drug development. Interview by Joanna Owens, Drug Discov Today, Vol: 8, Pages: 196-198
Wells P, Jones T, Price P, 2003, Assessment of inter- and intrapatient variability in C15O2 positron emission tomography measurements of blood flow in patients with intra-abdominal cancers, Clin Cancer Res, Vol: 9, Pages: 6350-6356
PURPOSE: The aim of the study was to evaluate the inter- and intrapatient variability of positron emission tomography (PET) measurements of perfusion in advanced solid cancers. EXPERIMENTAL DESIGN: Thirty-seven patients with predominantly intra-abdominal tumors underwent PET imaging using inhaled C15O2. Repeat data were obtained by scanning five patients twice, 1 week apart, with no intervening therapy. Regional flow and the volume of distribution (V(d)) were measured from dynamic images by use of a one-compartment model. Inter- and intrapatient variability were measured as the coefficient of variability (CV). Data were also obtained for regions of interest in normal liver, spleen, and kidney. RESULTS: The mean (+/-SD) regional flow in the tumors was 0.46 +/- 0.19 ml(blood)/min/ml(tissue), and the mean V(d) was 0.74 +/- 0.15 ml(blood)/ml(tissue). Variability in tumor flow was greater between (n = 37; CV = 41%) than within (n = 5; CV = 11%) patients. Variability in tumor V(d) was greater between (CV = 21%) than within (CV = 6%) patients. There was a good correlation between the repeat tumor data for both regional flow (rho = 0.82; P = 0.023) and V(d) (rho = 0.89; P = 0.007). Normal tissue variability was also greater between than within patients. In all cases, no statistically significant differences were seen between repeat measurements in the same patient. CONCLUSIONS: Dynamic C15O2 PET measurements of regional flow are reproducible in patients with predominantly intra-abdominal malignancies and may be useful for the pharmacodynamic evaluation of novel antivascular and antiangiogenic cancer therapeutic agents.
Price P, Errington RD, Jones B, 2003, Report on the U.K. meeting September 2001 to discuss the clinical and scientific case for a high-energy proton therapy facility in the U.K, Clin Oncol (R Coll Radiol), Vol: 15, Pages: S1-S9
Aboagye EO, Price PM, 2003, Use of positron emission tomography in anticancer drug development, Invest New Drugs, Vol: 21, Pages: 169-181
Positron emission tomography (PET) is increasingly being used in anticancer drug development. The technique is applicable to studies of drug delivery, and where specific probes are available, to provide pharmacodynamic readouts noninvasively in patients. Mathematical modeling of the imaging data enhances the quality of information that is obtained from such studies. This section provides a review of the PET methodologies that have been used for the development of new cancer therapies. Other than imaging of radiolabeled drugs, PET modeling has found extensive application in studies with 2-[11C]thymidine, [18F]fluorodeoxyglucose, H2(15)O, C15O, and receptor ligands.
Laking GR, Price PM, 2003, On the development of rational standards for nuclear response evaluation, Q J Nucl Med, Vol: 47, Pages: 3-7
AIM: Small variations in test protocols can disproportionately affect the sensitivity and specificity of response evaluation in nuclear medicine. Although use of standardised methods can remedy this, standards must be shown to add value. We think a concept of "societal efficacy" is the benchmark criterion for value of medical interventions. This paper gives an overview of literature on nuclear response evaluation, and promotes a decision-analytic approach to the synthesis of standards. METHODS: A Medline search using the OVID database, 1966-January 2002. Reports were organised in relation to mode of treatment and timing of follow-up evaluation. Protocols of multimodality treatment were classified according to the treatment with the greatest tissue-inflammatory potential. The database will be made available on-line at the Website of the European Organisation for the Research and Treatment of Cancer (EORTC) Functional Imaging Group (http://www.eortc.be). RESULTS: Two hundred and twelve reports could be classified as primary studies in humans. 125 were formal "before-and-after" studies of response to anticancer therapy. More than 60 reported the use of serial positron emission tomography (PET) with fluorodeoxyglucose (FDG). CONCLUSION: Descriptive reports of the accuracy and applications of new diagnostic technologies need to be linked to an expectation of improved research or clinical outcomes. To manage the large volume of information will require a trans-disciplinary perspective and use of advanced decision-analytic METHODS: At stake is the possibility of an "industrial" upscaling of one of nuclear oncology' strongest applications.
Price P, Saleem A, Aboagye E, 2003, PET in development and use of anticancer drugs, Positron Emission Tomography Basic Science and Clinical Practice, Editors: Valk, Bailey, Townsend, Maisey, London, Publisher: Springer-Verlag
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