Publications
472 results found
McParland BJ, Miller MP, Spinks TJ, et al., 2008, The Biodistribution and Radiation Dosimetry of the Arg-Gly-Asp Peptide <SUP>18</SUP>F-AH111585 in Healthy Volunteers, JOURNAL OF NUCLEAR MEDICINE, Vol: 49, Pages: 1664-1667, ISSN: 0161-5505
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- Citations: 67
Leyton J, Smith G, Lees M, et al., 2008, Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901, MOLECULAR CANCER THERAPEUTICS, Vol: 7, Pages: 3112-3121, ISSN: 1535-7163
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- Citations: 37
Kenny LM, Coombes RC, Oulie I, et al., 2008, Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand <SUP>18</SUP>F-AH111585 in breast cancer patients, JOURNAL OF NUCLEAR MEDICINE, Vol: 49, Pages: 879-886, ISSN: 0161-5505
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- Citations: 264
Pillai RG, Forster M, Perumal M, et al., 2008, Imaging pharmacodynamics of the α-folate receptor-targeted thymidylate synthase inhibitor BGC 945, CANCER RESEARCH, Vol: 68, Pages: 3827-3834, ISSN: 0008-5472
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- Citations: 34
Aboagye EO, 2008, Design and Development of Probes for In vivo Molecular and Functional Imaging of Cancer and Cancer Therapies by Positron Emission Tomography (PET), Modern Biopharmaceuticals: Design, Development and Optimization, Pages: 1243-1270, ISBN: 9783527311842
Molecular imaging with positron emission tomography (PET) is now evolving as a unique non-invasive method for studying tumor and normal tissue biochemistry, physiology, and pharmacology. In oncology, a range of drugs can be radiolabeled for pharmacokinetic studies including "microdosing" of human subjects prior to Phase I trials. Gene delivery can be assessed by incorporating a reporter gene that is detectable by PET within the vector of interest. This chapter also reviews progress made in the PET imaging field in the design of pharmacodynamic markers including assays of cell surface receptor status, angiogenesis, apoptosis, proliferation, glucose metabolism, and hypoxia. Such probes are potentially useful in patient management and for drug development. PET is particularly attractive for the development of cancer-targeted therapies where assessment of plasma drug levels or assays of the target protein in peripheral blood cells are less specific than direct assessment of the tumor or tumor material. The recent introduction of dedicated small-animal scanners has helped bridge in vitro science with in vivo clinical studies for the efficient development of modern biopharmaceuticals. © 2005 WILEY-VCH Verlag GmbH & Co. KGaA.
Saleem A, Aboagye EO, Matthews JC, et al., 2008, Plasma pharmacokinetic evaluation of cytotoxic agents radiolabelled with positron emitting radioisotopes, Cancer Chemother Pharmacol, Vol: 61, Pages: 865-873
PURPOSE: This study aimed to evaluate the utility of plasma pharmacokinetic analyses of anti-cancer agents from data obtained during positron emission tomography (PET) oncology studies of radiolabelled anti-cancer agents. PATIENTS AND METHODS: Thirteen patients were administered fluorine-18 radiolabelled 5-FU ([(18)F]5-FU) admixed with 5-FU, corresponding to a total 5-FU dose of 380-407 mg/m(2) (eight patients) and 1 mg/m(2) (five patients). Nine patients received 2.2-19.2 mug/m(2) of carbon-11 radiolabelled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide ([(11)C]DACA) at 1/1,000th of phase I dose, as part of phase 0 microdosing study. Radioactivity of parent drug obtained from arterial blood samples, the injected activity of the radiolabelled drug, and the total dose of injected drug were used to obtain plasma drug concentrations. Plasma pharmacokinetic parameters were estimated using model-dependent and model-independent methods. RESULTS: 5-FU plasma concentrations at therapeutic doses were above the Km and a single compartment kinetic model was best used to fit the kinetics, with a mean half-life of 8.6 min. Clearance and volumes of distribution (V (d)) obtained using both model-dependent and model-independent methods were similar. Mean (SE) clearance was 1,421(144), ml min(-1) and 1,319 (119) ml min(-1) and the mean (SE) V (d) was 17.3 (1.8) l and 16.3 (1.9) l by the model-independent method and model-dependent methods, respectively. In contrast, with 1 mg/m(2), plasma concentrations of 5-FU were less than the Km and a two-compartment model was used to best fit the kinetics, with the mean 5-FU half-life of 6.5 min. The mean (SE) clearances obtained by the model-independent method and model-dependent methods were 3,089 (314) ml min(-1) and 2,225 (200) ml min(-1), respectively and the mean (SE) V (d) were 27.9 (7.0) l and 2.3 (0.4) l, by the model independent and dependent methods, respectively. Extrapolation of AUC(0-Clast) to AUC(0-infinity) was less than 3% in
Chan F, Sun C, Perumal M, et al., 2007, Mechanism of action of the Aurora kinase inhibitor CCT129202 and <i>in vivo</i> quantification of biological activity, MOLECULAR CANCER THERAPEUTICS, Vol: 6, Pages: 3147-3157, ISSN: 1535-7163
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- Citations: 63
Chan F, Sun C, Perumal M, et al., 2007, Characterization of CCT129202, a novel Aurora kinase inhibitor and in vivo quantification of biological activity, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 3413S-3413S, ISSN: 1535-7163
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- Citations: 1
Leyton J, Aboagye EO, 2007, PET Tracers as biomarkers in oncology drug development, MOLECULAR CANCER THERAPEUTICS, Vol: 6, Pages: 3627S-3628S, ISSN: 1535-7163
Kenny L, Coombes RC, Vigushin DM, et al., 2007, Imaging early changes in proliferation at 1 week post chemotherapy:: a pilot study in breast cancer patients with 3′-deoxy-3′-[<SUP>18</SUP>F]fluorothymidine positron emission tomography, EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, Vol: 34, Pages: 1339-1347, ISSN: 1619-7070
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- Citations: 216
Kenny LM, Aboagye E, Cohen PS, et al., 2007, Imaging of angiogenesis in metastatic breast cancer by positron emission tomography (PET) using [18F]AH11585, an [18F]- labeled alphaVbeta3 (αvβ3) peptide, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Aboagye EO, 2006, Imaging in drug development., Clin Adv Hematol Oncol, Vol: 4, Pages: 902-904, ISSN: 1543-0790
Leyton J, Lockley M, Aerts JL, et al., 2006, Quantifying the activity of adenoviral E1A CR2 deletion mutants using <i>Renilla</i> luciferase bioluminescence and 3′-deoxy-3′-[<SUP>18</SUP>F] fluorothymidine positron emission tomography imaging., CANCER RESEARCH, Vol: 66, Pages: 9178-9185, ISSN: 0008-5472
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- Citations: 22
Perumal M, Pillai RG, Barthel H, et al., 2006, Redistribution of nucleoside transporters to the cell membrane provides a novel approach for imaging thymidylate synthase inhibition by positron emission tomography, CANCER RESEARCH, Vol: 66, Pages: 8558-8564, ISSN: 0008-5472
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- Citations: 88
Leyton J, Alao JP, Da Costa M, et al., 2006, <i>In vivo</i> biological activity of the histone deacetylase inhibitor LA0824 is detectable with 3′-deoxy-3′-[<SUP>18</SUP>F]fluorothymidine positron emission tomography, CANCER RESEARCH, Vol: 66, Pages: 7621-7629, ISSN: 0008-5472
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- Citations: 59
Kenny LM, Coombes RC, Al-Nahhas A, et al., 2006, A feasibility study of [<SUP>11</SUP>C]choline for the molecular imaging of human breast cancer <i>in vivo</i> using positron emission tomography (PET)., 42nd Annual Meeting of the American-Society-of-Clinical-Oncology, Publisher: AMER SOC CLINICAL ONCOLOGY, Pages: 31S-31S, ISSN: 0732-183X
Baird SK, Lockley M, Leyton J, et al., 2006, E1A CR2 deletion mutant adenoviral vectors in ovarian cancer: combination with apoptosis inducers and monitoring with [18F] FLT-PET imaging, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Workman P, Aboagye EO, Chung YL, et al., 2006, Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies, J Natl Cancer Inst, Vol: 98, Pages: 580-598
Clinical trials of new cancer drugs should ideally include measurements of parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints that can be linked to measures of clinical effect. Appropriate PK/PD biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule; aid decision-making, such as whether to continue or close a drug development project; and may explain or predict clinical outcomes. In addition, measurement of PK/PD biomarkers can minimize uncertainty associated with predicting drug safety and efficacy, reduce the high levels of drug attrition during development, accelerate drug approval, and decrease the overall costs of drug development. However, there are many challenges in the development and implementation of biomarkers that probably explain their disappointingly low implementation in phase I trials. The Pharmacodynamic/Pharmacokinetic Technologies Advisory committee of Cancer Research UK has found that submissions for phase I trials of new cancer drugs in the United Kingdom often lack detailed information about PK and/or PD endpoints, which leads to suboptimal information being obtained in those trials or to delays in starting the trials while PK/PD methods are developed and validated. Minimally invasive PK/PD technologies have logistic and ethical advantages over more invasive technologies. Here we review these technologies, emphasizing magnetic resonance spectroscopy and positron emission tomography, which provide detailed functional and metabolic information. Assays that measure effects of drugs on important biologic pathways and processes are likely to be more cost-effective than those that measure specific molecular targets. Development, validation, and implementation of minimally invasive PK/PD methods are encouraged.
Kenny LM, Aboagye EO, Al-Nahhas A, et al., 2006, [<SUP>11</SUP>C]choline-PET in human breast cancer:: utility, reproducibility and effect of receptor tyrosine kinase inhibition by trastuzumab., 29th Annual San Antonio Breast Cancer Symposium, Publisher: SPRINGER, Pages: S212-S212, ISSN: 0167-6806
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- Citations: 1
Gupta N, Saleem A, Kotz B, et al., 2006, Carbogen and nicotinamide increase blood flow and 5-fluorouracil delivery but not 5-fluorouracil retention in colorectal cancer metastases in patients, Clin Cancer Res, Vol: 12, Pages: 3115-3123
PURPOSE: To examine whether carbogen and nicotinamide increases 5-fluorouracil (5-FU) delivery to colorectal cancer metastases. EXPERIMENTAL DESIGN: Six patients were scanned using positron emission tomography. Two scans were done to coincide with the start of separate chemotherapy cycles. At the second positron emission tomography session, 60 mg/kg nicotinamide was given orally 2 to 3 hours before 10-minute carbogen inhalation. In the middle of carbogen treatment, [15O]H2O (to measure regional tissue perfusion) and then [18F]5-FU (to measure 5-FU tissue pharmacokinetics) were administered. RESULTS: Regions of interest were drawn in 12 liver metastases, 6 spleens, 6 livers, and 12 kidneys. Nicotinamide and carbogen administration increased mean blood pO2 from 93 mm Hg (95% confidence interval, 79-198) to 278 mm Hg (95% confidence interval, 241-316; P = 0.031). Regional perfusion (mL(blood)/min/mL(tissue)) increased in metastases (mean change = 52%, range -32% to +261%, P = 0.024), but decreased in kidney (mean change = -42%, range -82% to -11%, P = 0.0005) and liver (mean change = -34%, range -43% to -26%, P = 0.031). 5-FU uptake at 3.75 minutes (m(2)/mL) increased in tumor (mean change = 40%, range -39% to +196%, P = 0.06) and decreased in kidney (mean change = -25%, range -71% to 12%, P = 0.043). 5-FU delivery measured as K1 increased in tumor (mean change = 74%, range -23% to +293%, P = 0.0039). No differences were seen in [18F]5-FU tumor exposure (net area under curve) and retention. CONCLUSION: Nicotinamide and carbogen administration can increase 5-FU delivery to colorectal cancer liver metastases. Despite an increase in perfusion and 5-FU delivery, the effects were not directly related and did not increase 5-FU retention or tissue exposure.
Yau K, Price P, Pillai RG, et al., 2006, Elevation of radiolabelled thymidine uptake in RIF-1 fibrosarcoma and HT29 colon adenocarcinoma cells after treatment with thymidylate synthase inhibitors, Eur J Nucl Med Mol Imaging, Vol: 33, Pages: 981-987, ISSN: 1619-7070
PURPOSE: We recently showed an increase in tumour uptake of 2-[(11)C]thymidine in patients with gastrointestinal malignancies after thymidylate synthase (TS) inhibition. To understand the phenomenon in more detail, we investigated whether TS inhibition by different TS inhibitors leads to a dose- and time-dependent change in the uptake of radiolabelled thymidine, and whether radiotracer uptake is related to changes in cell viability resulting from treatment. METHODS: RIF-1 and HT29 cells were treated with the TS inhibitors 5-fluorouracil (5-FU) and AG337 (nolatrexed dihydrochloride), as well as cisplatin as control. The cell viability and net accumulation of [(3)H]thymidine after a 1-h pulse was determined at different times after drug treatment. RESULTS: In both cell lines, [(3)H]thymidine uptake increased after a 2-h treatment with 5-FU, in a dose- and time-dependent manner. [(3)H]thymidine uptake decreased at 24 and 48 h post treatment. AG337 also produced a similar effect. In contrast to the TS inhibitors, cisplatin decreased [(3)H]thymidine uptake in RIF-1 and HT29 cells at all time points. Cell viability was compromised only after 24 h. CONCLUSION: Using two types of TS inhibitor, we have shown an increase in [(3)H]thymidine uptake, in a dose-dependent manner, a few hours after TS inhibition when the cell viability was not compromised. This effect was not seen with a non-TS inhibitor. These findings suggest that 2-[(11)C]thymidine positron emission tomography can be used to study TS inhibition in vivo at early time points when cell viability is not compromised and may therefore be helpful in the development of new TS inhibitors and in differentiating between patients with tumours sensitive to TS inhibitors and those unlikely to respond.
Kenny LM, Vigushin DM, Al-Nahhas A, et al., 2005, Quantification of cellular proliferation in tumor and normal tissues of patients with breast cancer by [<SUP>18</SUP>F]fluorothymidine-positron emission tomography imaging:: Evaluation of analytical methods., CANCER RESEARCH, Vol: 65, Pages: 10104-10112, ISSN: 0008-5472
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- Citations: 159
Kenny LM, Vigushin DM, Coombes RC, et al., 2005, Early assessment of response to treatment in breast cancer by [<SUP>18</SUP>F]fluorathymidine-positron emission tomography., 41st Annual Meeting of the American-Society-of-Clinical-Oncology, Publisher: AMER SOC CLINICAL ONCOLOGY, Pages: 155S-155S, ISSN: 0732-183X
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- Citations: 1
Leyton J, Latigo JR, Perumal M, et al., 2005, Early detection of tumor response to chemotherapy by 3′-deoxy-3′-[<SUP>18</SUP> F]fluorothymidine positron emission tomography:: The effect of cisplatin on a fibrosarcoma tumor model <i>in vivo</i>, CANCER RESEARCH, Vol: 65, Pages: 4202-4210, ISSN: 0008-5472
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- Citations: 139
Buluwela L, Pike J, Mazhar D, et al., 2005, Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-α and the transcriptional repressor PLZF (vol 12, pg 452, 2005), GENE THERAPY, Vol: 12, Pages: 862-862, ISSN: 0969-7128
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- Citations: 1
Buluwela L, Pike J, Mazhar D, et al., 2005, Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-α and the transcriptional repressor PLZF (vol 12, pg 452, 2005), GENE THERAPY, Vol: 12, Pages: 552-552, ISSN: 0969-7128
Buluwela L, Pike J, Mazhar D, et al., 2005, Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-α and the transcriptional repressor PLZF, GENE THERAPY, Vol: 12, Pages: 452-460, ISSN: 0969-7128
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- Citations: 15
Aboagye EO, Price PM, Padhani AR, 2005, Imaging of Pharmacodynamic End Points in Clinical Trials, Novel Anticancer Agents: Strategies for Discovery and Clinical Testing, Pages: 299-XX, ISBN: 9780120885619
This chapter describes the application of noninvasive imaging methods positron emission tomography (PET) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for the pharmacodynamic evaluation of existing and new cancer therapeutics. PET methodology is being developed to enable evaluation of pathophysiology and pharmacodynamics in oncology. The high sensitivity and specificity of PET assays allow the mechanism of drug action to be assessed in patients. DCE-MRI is one of a number of MRI techniques that evaluates tumors with respect to their state of angiogenesis. There are a number of requirements that need to be met before DCE-MRI techniques can become mainstream diagnostic tools. Requirements include agreed protocols for data acquisition, analysis, and presentation methods. Appropriate imaging processing and visualization tools are needed to achieve this. The image acquisition techniques that are able to sample the whole tumor volume are also needed, particularly if the technique is to be extended to organs with significant physiological motion. It is suggested that macromolecular contrast enhanced MRI may become the preferred choice for these evaluations.
Yatham LN, Liddle PF, Lam RW, et al., 2005, A positron emission tomography study of the effects of treatment with valproate on brain 5-HT2A receptors in acute mania., Bipolar Disord, Vol: 7 Suppl 5, Pages: 53-57, ISSN: 1398-5647
OBJECTIVE: To examine the effects of treatment with valproate on brain 5-HT2A receptors in acute manic patients using positron emission tomography (PET) and [18F]-setoperone. METHODS: Patients with DSM-IV bipolar I disorder-manic episode were recruited. Patients were drug free or drug naïve at the time of baseline PET scan. All patients were treated with valproate and one patient received lithium in addition to valproate for 3-5 weeks following which they had a post-treatment PET scan. The effect of treatment on brain 5-HT2A receptor binding was determined using statistical parametric mapping (SPM) and region of interest (ROI) analyses. Of the 12 manic patients recruited, seven patients had both baseline and post-treatment PET scans. RESULTS: All seven patients improved with treatment and were in remission at the time of the second PET scan. Both SPM and ROI analyses showed that treatment with mood stabilizers had no significant effect on brain 5-HT2A receptor binding in manic patients. CONCLUSION: This study suggests that changes in brain 5-HT2A receptors are not involved in the antimanic effects of mood stabilizers however, we cannot exclude the possibility of 5-HT2A receptor involvement in down-stream signaling pathways.
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