Publications
310 results found
Anderson H, Yap JT, Wells P, et al., 2003, Measurement of renal tumour and normal tissue perfusion using positron emission tomography in a phase II clinical trial of razoxane, Br J Cancer, Vol: 89, Pages: 262-267
Measurement of tumour and normal tissue perfusion in vivo in cancer patients will aid the clinical development of antiangiogenic and antivascular agents. We investigated the potential antiangiogenic effects of the drug razoxane by measuring the changes in parameters estimated from H(2)(15)O and C(15)O positron emission tomography (PET) to indicate alterations in vascular physiology. The study comprised 12 patients with primary or metastatic renal tumours >3 cm in diameter enrolled in a Phase II clinical trial of oral razoxane. Perfusion, fractional volume of distribution of water (VD) and blood volume (BV) were measured in tumour and normal tissue before and 4-8 weeks after treatment with 125 mg twice-daily razoxane. Renal tumour perfusion was variable but lower than normal tissue: mean 0.87 ml min(-1) ml(-1) (range 0.33-1.67) compared to renal parenchyma: mean 1.65 ml min(-1) ml(-1) (range 1.16-2.88). In eight patients, where parallel measurements were made during the same scan session, renal tumour perfusion was significantly lower than in normal kidney (P=0.0027). There was no statistically significant relationship between pretreatment perfusion and tumour size (r=0.32, n=13). In six patients scanned before and after razoxane administration, there was no statistically significant change in tumour perfusion: mean perfusion pretreatment was 0.81 ml min(-1) ml(-1) (range 0.46-1.26) and perfusion post-treatment was 0.72 ml min(-1) ml(-1) (range 0.51-1.15, P=0.15). Tumour VD and BV did not change significantly following treatment: mean pretreatment VD=0.66 (range 0.50-0.87), post-treatment VD=0.71 (range 0.63-0.82, P=0.22); pretreatment BV=0.18 ml ml(-1) (range 0.10-0.25), post-treatment BV=0.167 ml ml(-1) (range 0.091-0.24, P=0.55). Tumour perfusion, VD and BV did not change significantly with tumour progression. This study has shown that H(2)(15)O and C(15)O PET provide useful in vivo physiological measurements, that even highly angiogenic renal cancers have poor
James RD, Botwood N, Vernon CC, et al., 2003, Raltitrexed plus radiotherapy for the treatment of unresectable/recurrent rectal cancer: a phase I study, Ann Oncol, Vol: 14, Pages: 570-573
BACKGROUND: Current consensus is that a combination of radiotherapy and chemotherapy may provide the optimal treatment for patients with unresectable rectal cancer. Raltitrexed has proven efficacy in the treatment of advanced colorectal cancer and has an acceptable toxicity profile. The aim of this phase I study was to determine the recommended dose of raltitrexed in combination with radiotherapy in patients with unresectable/recurrent rectal cancer. PATIENTS AND METHODS: Patients were treated with radiotherapy (25 fractions at 2.0 Gy per fraction) five times per week for 5 weeks. Raltitrexed was administered on days 1 and 22 at 2.0, 2.6 and 3.0 mg/m(2). RESULTS: A total of 20 patients were entered into the study. Dose-limiting toxicities were recorded in three of 20 patients following the first dose of raltitrexed; one patient at 2.6 mg/m(2) (grade 3 diarrhoea, grade 3 neutropenia and grade 2 pyrexia) and two patients at 3.0 mg/m(2) (one grade 3 neutropenia and one grade 4 diarrhoea). The most common non-haematological and haematological treatment-related adverse events were diarrhoea (11 of 20, two grade 3, one grade 4) and leukopenia (eight of 20, one grade 3, one grade 4), respectively. CONCLUSIONS: The recommended dose of raltitrexed in combination with radiotherapy for future studies is 2.6 mg/m(2).
Khoo V, Price P, 2003, Preoperative radiotherapy for rectal cancer: current status and residual issues., Colonews, Vol: 11, Pages: 1-5
Levene S, Scott G, Price P, et al., 2003, Does the occurrence of certain rare cancers indicate an inherited cancer susceptibility?, Fam Cancer, Vol: 2, Pages: 15-25
We sought to determine whether rare cancers indicate an increased risk of inherited cancer susceptibility. We ascertained 77 individuals with rare cancers which occur with increased relative risk in carriers of germline BRCA1/BRCA2 (fallopian, young-onset pancreatic) or HNPCC (biliary, small intestinal, urothelial, gallbladder, young-onset pancreatic) mutations. Individuals with two primary neoplasms (7), or with a first- or two second-degree relatives with breast/ovarian cancer were tested for BRCA1/BRCA2 mutations (18); those with two primary HNPCC cancers or one first degree relative with an HNPCC-related cancer were tested for mutations in MLH1/MSH2 (19). Of these 77 individuals with cancer (19 fallopian, 8 gallbladder, 17 biliary, 17 pancreatic, 11 urothelial, 5 small intestinal), 39 (50.6%) had at least one first degree relative with cancer (excluding lung and skin); two conformed to Bethesda HNPCC criteria. No definitely pathogenic germline MLH1 and MSH2 mutations were found in 19 individuals, although 2 MSH2 variants were detected. A family history of breast/ovarian, HNPCC or colon cancer in a first degree relative was found in 40% of fallopian, 20% of biliary, 35% of pancreatic, 27% of urothelial and 20% of small bowel cancer patients. A BRCA1 frameshift mutation was detected in a woman with fallopian (54 y) and breast (39 y) cancers, and a BRCA2 nonsense mutation in a woman with biliary (48 y) and breast (45 y) cancers. This study supports the premise that the occurrence of rare (especially double primary) cancers does indicate an increased cancer susceptibility, although the numbers of cases ascertained were too small to draw firm conclusions.
Aboagye EO, Salaam A, Gupta N, et al., 2002, What new pharmacokinetic information can molecular imaging provide us, 14th EORTC/NCI/AACR Symposium on Molecular Targets and Cancer Therapeutics, Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: S12-S12, ISSN: 0959-8049
Yau K, Price P, Aboagye EO, 2002, Detection of thymidylate synthase (TS) inhibition, BRITISH JOURNAL OF CANCER, Vol: 86, Pages: S110-S110, ISSN: 0007-0920
Liu D, Hutchinson OC, Osman S, et al., 2002, Use of radiolabelled choline as a pharmacodynamic marker for the signal transduction inhibitor geldanamycin, Br J Cancer, Vol: 87, Pages: 783-789
There is an urgent need to develop non-invasive pharmacodynamic endpoints for the evaluation of new molecular therapeutics that inhibit signal transduction. We hypothesised that, when labelled appropriately, changes in choline kinetics could be used to assess geldanamycin pharmacodynamics, which involves inhibition of the HSP90 molecular chaperone-->Raf1-->Mitogenic Extracellular Kinase-->Extracellular Signal-Regulated Kinase 1 and 2 signal transduction pathway. Towards identifying a potential pharmacodynamic marker response, we have studied radiolabelled choline metabolism in HT29 human colon carcinoma cells following treatment with geldanamycin. We studied the effects of geldanamycin, on net cellular accumulation of (methyl-(14)C)choline and (methyl-(14)C)phosphocholine production. In parallel experiments, the effects of geldanamycin on extracellular signal-regulated kinase 1 and 2 phosphorylation and cell viability were also assessed. Additional validation studies were carried out with the mitogenic extracellular kinase inhibitor U0126 as a positive control; a cyclin-dependent kinase-2 inhibitor roscovitine and the phosphatidylinositol 3-kinase inhibitor LY294002 as negative controls. Hemicholinium-3, an inhibitor of choline transport and choline kinase activity was included as an additional control. In exponentially growing HT29 cells, geldanamycin inhibited extracellular signal-regulated kinase 1 and 2 phosphorylation in a concentration- and time-dependent manner. These changes were associated with a reduction in (methyl-(14)C)choline uptake, (methyl-(14)C) phosphocholine production and cell viability. Brief exposure to U0126, suppressed phosphocholine production to the same extent as Hemicholinium-3. In contrast to geldanamycin and U0126, which act upstream of extracellular signal-regulated kinase 1 and 2, roscovitine and LY294002 failed to suppress phosphocholine production. Our results suggest that when labelled with carbon-11 isotope, (methyl-(11)C
Collingridge DR, Carroll VA, Glaser M, et al., 2002, The development of [(124)I]iodinated-VG76e: a novel tracer for imaging vascular endothelial growth factor in vivo using positron emission tomography, Cancer Res, Vol: 62, Pages: 5912-5919
The development of anticancer therapies that target the angiogenic process is an area of major growth in oncology. A method of noninvasively measuring tumor vascular endothelial growth factor (VEGF) in vivo could provide important efficacy information for VEGF-dependent antiangiogenic agents and the role of VEGF in cancer biology. We have developed a novel radiotracer for use with positron emission tomography (PET) that enables noninvasive imaging of VEGF. This radiotracer comprises an IgG1 monoclonal antibody, known as VG76e, that binds to human VEGF, labeled with a positron-emitting radionuclide, iodine-124 ([(124)I]-SHPP-VG76e). Three radiolabeling strategies were evaluated to synthesize the radiotracer with optimal radiochemical yield, purity, and immunoreactivity. To evaluate the pharmacokinetics and VEGF-specific localization of [(124)I]-SHPP-VG76e, two subclones of the HT1080 human fibrosarcoma selected on the basis of differing VEGF production (26.6 and 1/3C, the former producing 2-4-fold more in vitro) were established in culture and grown as solid tumor xenografts in immune-deficient mice. A single i.v. injection of the radiotracer into tumor-bearing mice revealed a time dependent and specific localization of [(125)I]-SHPP-VG76e to the tumor tissue. Three validation studies established the VEGF specificity and potential for use of [(124)I]-SHPP-VG76e in vivo: (a) uptake of [(125)I]-SHPP-VG76e was 1.8-fold higher in HT1080-26.6 compared with HT1080-1/3C tumors (P < 0.05); (b) uptake of [(125)I]-SHPP-VG76e in HT1080-26.6 tumors was specifically blocked by prior administration of excess unlabeled VG76e (P < 0.05); and (c) tumor uptake of the IgG1, [(125)I]-SHPP-CIP5, which has a similar molecular weight as [(125)I]-SHPP-VG76e but does not recognize VEGF, was the same for both HT1080-26.6 and HT1080-1/3C (P > 0.05). Other than tumor localization, [(125)I]-SHPP-VG76e was present in urine and blood and to a lesser extent in heart, lungs, liver, kidney
Quaia E, Blomley MJ, Patel S, et al., 2002, Initial observations on the effect of irradiation on the liver-specific uptake of Levovist, Eur J Radiol, Vol: 41, Pages: 192-199
The aim of this pilot study was to see if the biodistribution of the microbubble Levovist (SHU 508 A; Schering AG, Berlin) during its liver specific phase is altered by radiotherapy. The mechanism of this liver-specific phase of this agent remains poorly understood. One way of investigating this is to see what effect radiotherapy has on liver uptake, as both Kupffer cell function and vascular endothelial integrity are selectively damaged by irradiation. The regional liver specific uptake of Levovist was evaluated in eight patients undergoing radiotherapy to the hepatic area. Ultrasound (US) sweeps were made 4 min after Levovist injection using the phase inversion mode (PIM) which is specific for microbubbles. Differences between irradiated and non-irradiated areas were observed in 2/8 subjects completing the study. Both subjective and objective evaluations in these subjects showed a significantly reduced grey scale unit in non-irradiated versus irradiated liver regions (average values 99 vs. 89, P < 0.0045 and 75 vs. 62, P < 0.0001). These findings are somewhat inconclusive, but given the difficulty in defining areas of irradiated and non-irradiated liver, because multiple radiotherapy portals were used in all patients, tentatively suggests a radiotherapy induced effect in at least some patients. The two likely mechanisms would be damage to the Kupffer cells and or the vascular endothelium, although the relative contribution of these is unclear.
Laking GR, Price PM, 2002, Clinical value of positron emission tomography, AJR Am J Roentgenol, Vol: 178
Laking G R, & Price P M, 2002, Clinical impact of F-18-FDG PET in thyroid carcinoma patients with elevated thyroglobulin levels and negative I-131 scanning results after therapy, Journal of Nuclear Medicine, Vol: 43, Pages: 1728-1729
Gupta N, Price PM, Aboagye EO, 2002, PET for in vivo pharmacokinetic and pharmacodynamic measurements, Eur J Cancer, Vol: 38, Pages: 2094-2107
Positron emission tomography (PET) scanning is evolving as a unique tool for drug development in oncology for improving both the efficacy of established treatment and in evaluating novel anticancer agents. As a non-invasive functional imaging modality, PET has an unrivalled sensitivity when monitoring the pharmacokinetics and pharmacodynamics of drugs and biochemicals when radiolabelled with short living positron-emitting radioisotopes. This is of particular relevance in assessing newer molecular-targeted therapy where conventional evaluation criteria (maximum tolerated dose and tumour shrinkage for example) may be inappropriate. PET has already been applied to a wide number of drugs to demonstrate activity in vivo from standard chemotherapy such as 5-fluorouracil (5-FU) [J Clin Oncol 17 (1999) 1580], to novel molecular agents such as those involved in tumour angiogenesis [Br J Cancer 83 (2000) P6] and antivascular therapy [Proc Annu Meet Am Soc Clin Oncol 19 (2000) 179a]. This review will evaluate the achievements of PET in the drug development process, an approach that promises to facilitate the rapid translation of scientific research into current clinical practice.
Laking GR, Price PM, 2002, FDG-PET for response assessment: answers in search of questions, Ann Oncol, Vol: 13, Pages: 345-347
Barthel H, Cleji MC, Collingridge DR, et al., 2002, In vivo evaluation of F-18-FLT for monitoring drug-induced modulation of tumor proliferation with positron emission tomography, Journal of Nuclear Medicine, Vol: 43
Laking GR, Price PM, Sculpher MJ, 2002, Assessment of the technology for functional imaging in cancer, Eur J Cancer, Vol: 38, Pages: 2194-2199
Functional imaging can address hitherto irresolvable questions about cancer biology in both research and practice. In the clinic, by combining features of systemic and local disease markers into reference standards for the diagnosis of new disease entities functional imaging has the potential to literally redefine illness. Clinical assessments can be conducted at two levels: establishment of new reference standards, and evaluation of successor technologies that will substitute for a reference standard in practice. A union of functional imaging with anatomical criteria of disease has shown great promise in the management of numerous cancers. More work is required to use functional imaging to develop 'functional' approaches to diagnosis and therapy. Many methodologies exist for the acquisition of primary data on imaging technology efficacy. A form of economic cost-effectiveness modelling called iterative decision analysis can be used to set research and service priorities. Cancer clinicians need to take an increased role in functional imaging research, as they have primary expertise in the development and use of treatments modifying cell and tissue function.
Aboagye EO, Luthra SK, Brady F, et al., 2002, Cancer Research UK procedures in manufacture and toxicology of radiotracers intended for pre-phase I positron emission tomography studies in cancer patients, Br J Cancer, Vol: 86, Pages: 1052-1056
Radiolabelled compounds formulated for injection (radiopharmaceuticals), are increasingly being employed in drug development studies. These can be used in tracer amounts for either pharmacokinetic or pharmacodynamic studies. Such radiotracer studies can also be carried out early in man, even prior to conventional Phase I clinical testing. The aim of this document is to describe procedures for production and safety testing of oncology radiotracers developed for imaging by positron emission tomography in cancer patients. We propose strategies for overcoming the inability to produce compounds in sufficient quantities via the radiosynthetic routes for full chemical characterisation and toxicology testing including (i) independent confirmation as far as possible that the stable compound associated with the radiopharmaceutical is identical to the non-labelled compound, (ii) animal toxicity studies with > or = 10 times (typically 100 times) the intended tracer dose in humans scaled by body surface area, and (iii) patient monitoring during the radiotracer positron emission tomography clinical trial.
Glaser M, Carrol VA, Collingridge DR, et al., 2002, Preparation of the iodine-124 derivative of the Bolton-Hunter reagent ([124I]I-SHPP) and its use for labelling a VEGF antibody as a potential PET tracer., J Label Cmpds Radiopharm, Vol: 45, Pages: 1077-1090
Corrie P, Mayer A, Shaw J, et al., 2002, Phase II study to evaluate combining gemcitabine with flutamide in advanced pancreatic cancer patients, Br J Cancer, Vol: 87, Pages: 716-719
A phase II study was undertaken to determine the safety of combining flutamide with gemcitabine, with response rate being the primary end point. Twenty-seven patients with histologically proven, previously untreated, unresectable pancreatic adenocarcinoma received gemcitabine, 1 g m(-2) intravenously on days 1, 8 and 15 of a 28 day cycle, and flutamide 250 mg given orally three times daily. Treatment was halted if there was unacceptable toxicity, or evidence of disease progression. Toxicity was documented every cycle. Tumour assessment was undertaken after cycles 2 and 4, and thereafter at least every additional four cycles. One hundred and seventeen cycles of treatment were administered, median four cycles per patient (range 1-18). Gemcitabine combined with flutamide was well tolerated, with most toxicities being recorded as grade 1 or 2 and only nine treatment cycles associated with grade 3 toxicity. The most frequent toxicity was myelosuppression. One case of transient jaundice was recorded. The commonest symptomatic toxicity was nausea and vomiting. The response rate was 15% (four partial responses), median survival 6 months and 22% of patients were alive at 1 year. These results suggest antitumour activity of the combination therapy to be equivalent to single agent gemcitabine. doi:10.1038/sj.bjc.6600523 www.bjcancer.comCopyright 2002 Cancer Research UK
Wells P, Gunn RN, Alison M, et al., 2002, Assessment of proliferation in vivo using 2-[(11)C]thymidine positron emission tomography in advanced intra-abdominal malignancies, Cancer Res, Vol: 62, Pages: 5698-5702
The purpose of this study was to determine the relationship between 2-[(11)C]thymidine positron emission tomography (PET) in vivo-derived parameters and the ex vivo Ki-67 index of proliferation in human tumors. The study comprised 17 treatment-naive patients with advanced intra-abdominal malignancies. Tumor thymidine kinetics were measured using 2-[(11)C]thymidine PET. Tissue data were analyzed to give the standardized uptake value, the area under the time activity curve, and the fractional retention of thymidine (FRT) obtained by kinetic modeling. For the latter, the contribution of labeled metabolites was accounted for by measuring thymidine metabolites in arterial plasma. To examine the influence of tumor blood flow on the thymidine PET data, a perfusion scan using inhaled [(15)O]CO(2) was carried out in a subset of 11 patients. Biopsies were stained with a MIB1 antibody to obtain a Ki-67 index, and correlations with the PET-derived parameters were investigated. There was no relationship between tumor blood flow and the thymidine PET data, showing that the retention of 2-[(11)C]thymidine in tumors was independent of tumor perfusion. There was no correlation between the Ki-67 index and either standard uptake value or area under the curve. There was a correlation between the Ki-67 index and FRT (r = 0.58; P = 0.01). The correlation between the Ki-67 index and FRT in this dataset was not influenced by the interval between biopsy and imaging (0.1-126 weeks), the origin of the biopsy for Ki-67 staining (primary tumor or metastasis), or whether the biopsy was from an imaged or a nonimaged tumor. This is the first report in human tumors showing that 2-[(11)C]thymidine PET-derived parameters correlate with the level of tumor proliferation measured using Ki-67 immunohistochemistry. The study shows that the in vivo measurement of 2-[(11)C]thymidine in tumors using PET can provide a surrogate marker of proliferation and supports the potential use of the technique in the ear
Brown GD, Luthra SK, Brock CS, et al., 2002, Antitumor Imidazotetrazines. 40. Radiosyntheses of [4-11C-Carbonyl]- and [3-N-11C-Methyl]-8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one (Temozolomide) for Positron Emission Tomography (PET) Studies, J Med Chem, Vol: 45, Pages: 5448-5457
8-Carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide, 1) is an anticancer prodrug. As part of investigations to probe its postulated mode of action using PET we have developed two rapid radiosynthetic routes for the preparation of temozolomide labeled with the short-lived positron emitter, carbon-11 (t(1/2) = 20.4 min). Reaction of 5-diazoimidazole-4-carboxamide (7) with the novel labeling agent [(11)C-methyl]methyl isocyanate (8) gave [3-N-(11)C-methyl]temozolomide (9) in 14-20% radiochemical yield from [(11)C-methyl]methyl isocyanate (8) (decay corrected). The position of radiolabeling in the 3-N-methyl group was confirmed by [(11/13)C]colabeling and subsequent carbon-13 NMR spectroscopy. Similarly, the reaction of 5-diazoimidazole-4-carboxamide (7) with [(11)C-carbonyl]methyl isocyanate (10) gave [4-(11)C-carbonyl]temozolomide (11) in 10-15% radiochemical yield from [(11)C-carbonyl]methyl isocyanate (10) (decay corrected). Apyrogenic samples of [3-N-(11)C-methyl]temozolomide (9) and [4-(11)C-carbonyl]temozolomide (11), with good chemical and radiochemical purities, have been prepared and used in human PET studies.
Aboagye E, Saleem A, Price P, 2002, Tumour imaging applications in the testing of new drugs, Anticancer drug development, Editors: Kerr, Baguley, San Diego, Publisher: Academic Press, Pages: 353-369, ISBN: 9780120726516
Anderson H, Price P, 2002, Clinical measurement of blood flow in tumours using positron emission tomography: a review, Nucl Med Commun, Vol: 23, Pages: 131-138
In oncology drug development there is an increasing need for the in vivo physiological measurement of changes in tumour blood flow in response to therapy. Positron Emission Tomography (PET) is being increasingly used in oncology patients to measure blood flow. Here we review the clinical use of PET to measure vascular parameters in man.
Brunner N, Double J, Fichtner I, et al., 2002, The EORTC Laboratory Research Division. European Organisation for Research and Treatment of Cancer, Eur J Cancer, Vol: 38 Suppl 4, Pages: S14-S18
The Laboratory Research Division (LRD) of the EORTC currently consists of five Groups with expertise that includes pre-clinical drug development, all aspects of cancer pharmacology, clinically-relevant receptor and biomarker studies, functional imaging and contemporary pathology. The LRD provides a Europewide resource for cancer clinical trials with particular expertise in the evolving field of translational research. In the development of therapies designed to exploit the molecular and cellular pathology of cancer, it is essential that translational research is included at all stages and the EORTC, through the LRD, has access to such expertise. In addition to providing support for drug development and clinical trials, the LRD represents a unique forum for the development of contemporary translational research expertise, the establishment of quality standards and the education of young laboratory and clinical scientists embarking on careers in oncology.
Khoo VS, Price P, 2002, Unresolved issues in the management of locally advanced non-metastatic pancreas cancer, Clin Oncol, Vol: 14, Pages: 303-307
Laking GR, Price PM, 2002, Clinical impact of (18)F-FDG PET in thyroid carcinoma patients with elevated thyroglobulin levels and negative (131)I scanning results after therapy, J Nucl Med, Vol: 43, Pages: 1728-1729
Price P, Jones T, 2002, Molecular imaging: what picture does it paint for future oncology?, Drug Discov Today, Vol: 7, Pages: 741-743
Hutchinson OC, Liu D, Osman S, et al., 2001, Use of <SUP>14</SUP>C methyl choline to monitor inhibition of the extracellular signal-regulated kinase cascade:: A novel approach towards imaging of signal-transduction inhibition, BRITISH JOURNAL OF CANCER, Vol: 85, Pages: 89-89, ISSN: 0007-0920
Aboagye EO, Padhani AR, Price PM, 2001, Imaging of pharmacodynamic endpoints in clinical trials, Strategies for Discovery and Clinical Testing of Novel Anticancer Agents, Editors: Adjei, Buolamwini, Publisher: Elsevier Science
Price P, 2001, Cholangiocarcinoma and the role of radiation and chemotherapy, Hepatogastroenterology, Vol: 48, Pages: 51-52
Cholangiocarcinoma is a rare tumor. Many cases are localized while metastatic disease within the liver and abdomen do occur. There is as yet no standard therapy for advanced bile duct tumors. Radiotherapy and chemotherapy are not curative modalities in this condition but are being assessed adjuvantly following surgery, and as palliative treatment in an attempt to either extend progression-free and overall survival or to palliate symptoms. Advances may be made by: (i) The combined use of radiation and chemotherapy, (ii) High dose conformal radiotherapy, (iii) Novel chemotherapeutic agents. Patients should be given the opportunity to participate in clinical trials.
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