Publications
310 results found
Price P, 2001, PET as a potential tool for imaging molecular mechanisms of oncology in man, Trends Mol Med, Vol: 7, Pages: 442-446
During the past ten years, positron emission tomography (PET) has been increasingly developed for imaging and quantifying molecular mechanisms in oncology. The technique uses radionuclides to label molecules, which can then be imaged in man. The inherent sensitivity and specificity of PET is unrivalled because it can image molecular interactions and pathways, providing quantitative kinetic information down to the subpicomolar level. This technology has the potential to answer a large number of important clinical questions in translational research in oncology. However, the challenges in the methodology are substantial. Molecular imaging has the potential to assist in the optimization of molecular-based targeted therapies in cancer and to investigate the function of the genome.
Stewart D, Price P, 2001, 'Indolent' plasmacytoma, Australas Radiol, Vol: 45, Pages: 531-533
A patient presented with lethargy, nausea and diarrhoea and had a 10-year history of neurological symptoms in his legs. He was found to have renal failure. Investigations demonstrated a longstanding plasmacytoma of the sacrum and progression to myeloma. Such an indolent course for plasmacytoma is rare. A review of the clinical case and management of solid plasmacytomas is presented.
Laking G, Price P, 2001, 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) and the staging of early lung cancer, Thorax, Vol: 56 Suppl 2, Pages: ii38-ii44
Laking G, Price P, 2001, Radicalism in treatment of lung cancer, Lancet, Vol: 358
Osman S, Rowlinson-Busza G, Luthra SK, et al., 2001, Comparative biodistribution and metabolism of carbon-11-labeled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide and DNA-intercalating analogues, Cancer Res, Vol: 61, Pages: 2935-2944
The tricyclic carboxamide N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is a DNA-intercalating agent capable of inhibiting both topoisomerases I and II and is currently in Phase II clinical trial. Many related analogues have been developed, but despite their potent in vitro cytotoxicities, they exhibit poor extravascular distribution. As part of an ongoing drug development program to obtain related "minimal intercalators" with lower DNA association constants, we have compared the biodistribution and metabolite profiles of the prototype compound, DACA, with three analogues to aid rational drug selection. All of these compounds share a common structural feature, N-dimethyl side chain, which was radiolabeled with the positron-emitting radioisotope, carbon-11. This strategy was selected because it allows promising candidates emerging from preclinical studies in animals to be evaluated rapidly in humans using positron emission tomography (PET). The acridine DACA, the phenazine SN 23490, the pyridoquinoline SN 23719, and the dibenzodioxin SN 23935 were found to be cytotoxic in in vitro assays with an IC50 of 1.4-1.8 microM, 0.4-0.6 microM, 1.3-1.6 microM, and 24-36 microM, respectively, in HT29, U87MG, and A375M cell lines. Ex vivo biodistribution studies with carbon-11 radiolabeled compounds in mice bearing human tumor xenografts showed rapid clearance of 11C-radioactivity (parent drug and metabolites) from blood and the major organs. Rapid hepatobiliary clearance and renal excretion were also observed. There was low [<5% of injected dose/gram (%ID/g)] and variable uptake of 11C-radioactivity in three tumor types for all of the compounds. Tumor (U87MG) to blood 11C-radioactivity for [11C]DACA, [11C](9-methoxyphenazine-1-carboxamide (SN 23490), [11C]2-(4-pyridyl)quinoline-8-carboxamide (SN 23719), and [11C]dibenzo[1,4]dioxin-1-carboxamide (SN 23935) at 30 min were 2.9 +/- 1.1, 2.3 +/- 0.6, 2.6 +/- 0.6, and 0.7 +/- 0.2, respectively. For SN 23719, th
Aboagye EO, Price PM, Jones T, 2001, In vivo pharmacokinetics and pharmacodynamics in drug development using positron-emission tomography, Drug Discov Today, Vol: 6, Pages: 293-302
Positron-emission tomography (PET) is a sensitive technique that can be used to measure drug pharmacokinetics and pharmacodynamics non-invasively in target tissues of patients. Here we focus on the application of this technology to address some of the bottlenecks in drug development, including: elucidation of pathophysiology, evaluation of pharmacokinetics, proof of principle of mechanism, and assessment of efficacy and/or response to therapy.
Harvey CJ, Blomley MJ, Dawson P, et al., 2001, Functional CT imaging of the acute hyperemic response to radiation therapy of the prostate gland: early experience, J Comput Assist Tomogr, Vol: 25, Pages: 43-49
PURPOSE: Functional CT can measure perfusion and permeability. We hypothesized that acute changes could be measured in these indexes following radiation therapy (RT) to the prostate gland. METHOD: Twenty-two patients with prostatic cancer were studied before and 1-2 and 6-12 weeks after RT. A single section through the prostate was repeatedly scanned after contrast medium bolus injection. Contrast agent clearance per unit volume (alpha/V) and fractional vascular volume (fvv) were calculated using Patlak graphical analysis. Perfusion was calculated as the ratio between maximal rate of tissue enhancement and peak arterial enhancement. RESULTS: Significant increases in all indexes occurred after RT. Mean perfusion rose from 0.122 to 0.263 ml/min/ml at 1-2 weeks, mean alpha/V increased from 0.0012 to 0.0016 ml/min/ml at 1-2 weeks, and mean fvv increased from 13.7 to 21% at 1-2 weeks. All three indexes remained elevated at 6-12 weeks after the start of RT. CONCLUSION: Functional CT demonstrated an acute hyperemic response following RT to the prostate gland.
Aboagye EO, Saleem A, Cunningham VJ, et al., 2001, Extraction of 5-fluorouracil by tumor and liver: a noninvasive positron emission tomography study of patients with gastrointestinal cancer, Cancer Res, Vol: 61, Pages: 4937-4941
Tumor and normal tissue pharmacokinetics of 5-Fluorouracil (5-FU) in patients can be determined with positron emission tomography scanning. However, the data obtained are of limited value because of the inability to distinguish catabolites (inactive species) from parent 5-FU and anabolites (cytotoxic species). In this paper, we have blocked 5-FU catabolism in one arm of a paired study with eniluracil, an inactivator of dihydropyrimidine dehydrogenase, enabling catabolite correction and calculation of tissue pharmacokinetic parameters to be achieved. Using this novel approach, we report for the first time that the net clearance of 5-[(18)F]FU from plasma into tumors (liver metastases and pancreatic tumor) of patients is low (K(I) = 0.0033 +/- 0.0005 ml plasma/ml tissue/min). In contrast, the initial (up to 10 min) clearance through catabolism in liver was high (K(I) = 0.7313 +/- 0.092 ml plasma/ml tissue/min). In the absence of eniluracil, catabolites in tumors accounted for 83% of total tumor exposure (range, 66-91%), whereas catabolites in liver accounted for 96% of total liver exposure (range, 94-98%). This study provides definitive evidence that the cytotoxicity of 5-FU in patients with gastrointestinal cancer could be compromised by its intrinsically low uptake by tumors, as well as decreased systemic availability through hepatic catabolism.
Brady F, Luthra SK, Brown GD, et al., 2001, Radiolabelled tracers and anticancer drugs for assessment of therapeutic efficacy using PET, Curr Pharm Des, Vol: 7, Pages: 1863-1892
Positron Emission Tomography (PET) has the potential to improve efficacy of established and novel cancer therapies and to assist more rapid and rational progression of promising novel therapies into the clinic. This is due to PET's unrivalled sensitivity and ability to monitor the pharmacokinetics and pharmacodynamics of drugs and biochemicals radiolabelled with short -lived positron emitting radioisotopes. PET is a multidisciplinary science which employs chemists, biologists, mathematical modellers, pharmacologists as well as clinicians. Clinical research questions in oncology determine the methodological challenges faced by these other disciplines. Within this context we focus on the developments of the radiolabelled compounds that have underpinned the clinical work in oncology for monitoring tumour and normal tissue pharmacokinetics, assessment of tumour response, cell proliferation, gene expression, hypoxia, multidrug resistance and status of receptors on tumours.
Saleem A, Harte RJ, Matthews JC, et al., 2001, Pharmacokinetic evaluation of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in patients by positron emission tomography, J Clin Oncol, Vol: 19, Pages: 1421-1429
PURPOSE: To evaluate tumor, normal tissue, and plasma pharmacokinetics of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA). The study aimed to determine the pharmacokinetics of carbon-11-labeled DACA ([11C]DACA) and evaluate the effect of pharmacologic doses of DACA on radiotracer kinetics. PATIENTS AND METHODS: [11C]DACA (at 1/1,000 phase I starting dose) was administered to 24 patients with advanced cancer (pre-phase I) or during a phase I trial of DACA in five patients. Positron emission tomography (PET) was performed to assess pharmacokinetics and tumor blood flow. Plasma samples were analyzed for metabolite profile of [11C]DACA. RESULTS: There was rapid systemic clearance of [11C]DACA over 60 minutes (1.57 and 1.46 L x min(-1) x m(-2) in pre-phase I and phase I studies, respectively) with the production of several radiolabeled plasma metabolites. Tumor, brain, myocardium, vertebra, spleen, liver, lung, and kidneys showed appreciable uptake of 11C radioactivity. The area under the time-versus-radioactivity curves (AUC) showed the highest variability in tumors. Of interest to potential toxicity, maximum radiotracer concentrations (Cmax) in brain and vertebra were low (0.67 and 0.54 m(2) x mL(-1), respectively) compared with other tissues. A moderate but significant correlation was observed for tumor blood flow with AUC (r = 0.76; P =.02) and standardized uptake value (SUV) at 55 minutes (r = 0.79; P =.01). A decrease in myocardial AUC ( P =.03) and splenic and myocardial SUV ( P =.01 and.004, respectively) was seen in phase I studies. Significantly higher AUC, SUV, and Cmax were observed in tumors in phase I studies. CONCLUSION: The distribution of [11C]DACA and its radiolabeled metabolites was observed in a variety of tumors and normal tissues. In the presence of unlabeled DACA, pharmacokinetics were altered in myocardium, spleen, and tumors. These data have implications for predicting activity and toxicity of DACA and support the use of PET early in drug
Brown G, Osman S, Wilson H, et al., 2001, Metabolism of [11-C-methyl]choline in tumour bearing mice and synthesis and isolation of its catabolite [11-C-methyl]betaine., J Label Cmpds Radiopharm, Vol: 44, Pages: 107-109, ISSN: 0362-4803
Kahnum N, Luthra S, Zhao Y, et al., 2001, Carbon-11 labelling of a half mustard prodrug by reductive alkylation using [11-C]acetaldehyde. A potential tracer for evaluation of ADEPT or GDEPT using PET., J Label Cmpds Radiopharm, Vol: 44, Pages: 319-321
Anderson H, Price P, Blomley M, et al., 2001, Measuring changes in human tumour vasculature in response to therapy using functional imaging techniques, Br J Cancer, Vol: 85, Pages: 1085-1093
Antiangiogenic and antivascular agents provide new approaches to treating tumours. These may avoid many of the problems experienced with current approaches such as inherent and acquired resistance to treatment. Tumours do not grow beyond 1-2 mm(3) in size without the development of new vessels (Folkman, 1971). Such neo-vascularization (angiogenesis) allows tumour cells to increase their nutrient supply, survive and proliferate despite the new vessels often having structural and functional differences compared to normal tissue vasculature. Treatments targeted at tumour vasculature have produced impressive results in animal models (Lindsay et al, 1996; Watson et al, 1996; O'Reilly, 1997; Horsman et al, 1998). These therapies are now entering clinical trials. However, the successful introduction of these therapies into clinical practice will require the development of reliable ways to assess angiogenesis and its modification or inhibition in vivo. Here we discuss some of the emerging imaging techniques that may be useful.
Brown GD, Henderson D, Steel C, et al., 2001, Two routes to [11C-carbonyl]organo-isocyanates utilizing [11C]phosgene ([11C]organo-isocyanates from [11C]phosgene), Nucl Med Biol, Vol: 28, Pages: 991-998
Two generic radiosynthetic routes for the preparation of [11C-carbonyl]isocyanates have been developed. Reaction of N-organo-sulfinylamines; RNSO, (R = Me, Et, allyl, cyclohexyl and phenyl) with [11C]phosgene gave the corresponding [11C-carbonyl]isocyanates in good radiochemical yield (53-68%) from [11C]phosgene (decay corrected) in ca 16 min from EOB. Alternatively, the reaction of [11C]phosgene with N,N'-organo-ureas; (RNH)(2)CO, (R = Me, Et, Pr and phenyl) also gave the corresponding [11C-carbonyl]isocyanates in moderate radiochemical yield (9-37%) from [11C]phosgene (decay corrected) in ca 16 min from EOB. For identification, the [11C-carbonyl]organo-isocyanates were derivatized with 1-(2-methoxyphenyl)piperazine in situ to [11C-carbonyl]carboxamides and the position of radiolabelling in the carbonyl group confirmed by [11/13C]co-labeling and subsequent carbon-13 NMR spectroscopy.
Price P, Saleem A, Aboagye E, 2001, PET for oncology research and development, Positron Emission Tomography: Principles and Practice, Editors: Bailey, Townsend, Valk, Maisey, London, Publisher: Springer-Verlag
Carroll VA, Glaser M, Aboagye E, et al., 2000, Imaging vascular endothelial growth factor <i>in vitro</i> with positron emission tomography, Publisher: CHURCHILL LIVINGSTONE, Pages: 30-30, ISSN: 0007-0920
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Brock CS, Young H, O'Reilly SM, et al., 2000, Early evaluation of tumour metabolic response using [18F]fluorodeoxyglucose and positron emission tomography: a pilot study following the phase II chemotherapy schedule for temozolomide in recurrent high-grade gliomas, Br J Cancer, Vol: 82, Pages: 608-615
Quantitation of metabolic changes in tumours may provide an objective measure of clinical and subclinical response to anticancer therapy. This pilot study assesses the value of quantitation of metabolic rate of glucose (MRGlu) measured in mmol min(-1) ml(-1) to assess early subclinical response to therapy in a relatively non-responsive tumour. Nine patients receiving the CRC Phase II study schedule of temozolomide were assessed with [18F]fluorodeoxyglucose ([18F]FDG) dynamic positron emission tomography (PET) scans prior to and 14 days after treatment with temozolomide given as 750-1000 mg m(-2) over 5 days every 28 days. Tumour MRGlu was calculated and compared with objective response at 8 weeks. Pretreatment MRGlu was higher in responders than non-responders. The responding patient group had a greater than 25% reduction in MRGlu in regions of high focal tumour uptake (HFU). Whole tumour changes in MRGlu did not correlate with response. Percentage change in HFU standardized uptake value (SUV) did discriminate the responding from the non-responding patients, but not as well as with MRGlu. Large differences also occurred in the normal brain SUV following treatment. Thus, MRGlu appeared to be a more sensitive discriminator of response than the simplified static SUV analysis. Changes in MRGlu may reflect the degree of cell kill following chemotherapy and so may provide an objective, quantitative subclinical measure of response to therapy.
Gunn RN, Yap JT, Wells P, et al., 2000, A general method to correct PET data for tissue metabolites using a dual-scan approach, J Nucl Med, Vol: 41, Pages: 706-711
This article presents and analyses a general method of correcting for the presence of radiolabeled metabolites from a parent radiotracer in tissue during PET scanning. The method is based on a dual-scan approach, i.e., parent scan together with an independent supplementary scan in which the radiolabeled metabolite of interest itself is administered. The method corrects for the presence of systemically derived radiolabeled metabolite delivered to the tissues of interest through the blood. METHODS: Data from the supplementary scan are analyzed to obtain the tissue impulse response function for the metabolite. The time course of the radiolabeled metabolite in plasma in the parent scan is convolved with its tissue impulse response function to derive a correction term. This is not a simple subtraction technique but 1 that takes account of the different time-activity curves of the radiolabeled metabolite in the 2 scans. RESULTS: The method, its implications, and its limitations are discussed with respect to [11C]thymidine and its principal metabolite 11CO2. CONCLUSION: The general method, based on a dual-scan approach, can be used to correct for radiolabeled metabolites in tissues of interest during PET scanning. The correction accounts for radiolabeled metabolites that are derived systemically and delivered to the tissues of interest through the blood.
Saleem A, Aboagye EO, Price PM, 2000, In vivo monitoring of drugs using radiotracer techniques, Adv Drug Deliv Rev, Vol: 41, Pages: 21-39
There is an increasing realization of the role of non-invasive monitoring of drug pharmacology. In this review, we discuss the role of positron emission tomography in such monitoring of tumour and normal tissue drug pharmacokinetics as well as assessment of tumour response, drug-receptor interactions and mechanisms of drug action and resistance. These studies represent a multidisciplinary research effort involving radiochemists, imaging scientists, clinicians, pharmacologists and mathematical modellers. This review evaluates achievements in the field from assessment of commonly used therapeutic agents such as 5-fluorouracil to target specific molecules such as markers for gene expression. It is envisaged that application of this technology will facilitate rational drug design and rapid translation of new ideas to the bedside.
Botwood N, James R, Vernon C, et al., 2000, Raltitrexed ('Tomudex') and radiotherapy can be combined as postoperative treatment for rectal cancer, Ann Oncol, Vol: 11, Pages: 1023-1028
BACKGROUND: The optimal adjuvant therapy for operable rectal cancer is likely to be a combination of radiotherapy and chemotherapy. Raltitrexed ('Tomudex') is a specific thymidylate synthase inhibitor with a convenient administration schedule, acceptable and manageable toxicity, radiosensitising properties, and proven efficacy in the treatment of advanced colorectal cancer. It may, therefore, offer advantages compared with standard 5-FU chemotherapy regimens used in colorectal cancer. The aim of this phase I, dose-escalation study was to determine the recommended dose of raltitrexed for use with postoperative pelvic radiotherapy in patients with rectal cancer. PATIENTS AND METHODS: Patients with resected Dukes' stage B or C rectal cancer were treated with a combination of raltitrexed and radiotherapy (50.4 Gy at 1.8 Gy per fraction over five to six weeks). At least three patients were treated at each of three escalating raltitrexed dose levels (2.0, 2.6 and 3.0 mg/m2) once every three weeks. Toxicity was assessed by the recording of WHO adverse events and biochemistry and haematology determinations. RESULTS: A total of 22 patients entered the study, 17 of whom had Dukes' stage C disease. All three patients entered at a dose level of 3.0 mg/m2 experienced dose-limiting toxicity (DLT) (2 patients had grade 3 leucopenia and 1 patient had grade 2 leucopenia and grade 3 diarrhoea); however, only 2 of 1 patients entered at a dose level of 2.6 mg/m2 experienced DLT (1 patient had grade 4 neutropenia and 1 patient died probably due to aspiration pneumonia unrelated to treatment). The most common haematological toxic events were leucopenia (8 patients) and anaemia (6 patients). Only four haematological or biochemical toxic events were of grade 3 or 4. Other common toxicities were diarrhoea and nausea, which occurred in 15 and 9 patients, respectively. CONCLUSIONS: This study demonstrates that raltitrexed can be combined with postoperative radiotherapy for treatment of patien
Cleator SJ, Price P, 2000, Management problems in oncology, Pages: 3-10
Man has evolved sophisticated defence mechanisms over millions of years to combat insertion of foreign DNA into his cells. However, gene therapy carries huge potential for the treatment of cancer. The challenge is therefore to translate our scientific knowledge into a clinical reality.
Price P, 2000, Positron emission tomography (PET) in diagnostic oncology: is it a necessary tool today?, Eur J Cancer, Vol: 36, Pages: 691-693
Price P, 2000, Changes in 18F-FDG uptake measured by PET as a pharmacodynamic end-point in anticancer therapy. How far have we got?, Br J Cancer, Vol: 83, Pages: 281-283
Price P, 2000, Monitoring response to treatment in the development of anticancer drugs using PET, Nucl Med Biol, Vol: 27
Saleem A, Yap J, Osman S, et al., 2000, Modulation of fluorouracil tissue pharmacokinetics by eniluracil: in-vivo imaging of drug action, Lancet, Vol: 355, Pages: 2125-2131
BACKGROUND: Fluorouracil is widely used for chemotherapy of gastrointestinal cancer, but response rates are poor. Eniluracil is being developed as an inactivator of dihydropyrimidine dehydrogenase, the enzyme that brings about first-pass degradation of fluorouracil. We studied the mechanism of action of eniluracil by measuring with positron emission tomography (PET) the effect of eniluracil on tumour and normal-tissue pharmacokinetics of fluorine-18-labelled fluorouracil. METHODS: Six patients with advanced gastrointestinal cancers were studied. PET scanning was done after injection of oxygen-15-labelled water to assess tissue blood flow, followed by 1 mg/m2 18F-fluorouracil. We compared the pharmacokinetics of 18F-fluorouracil when the patients had not received eniluracil, during a 4-day course of oral eniluracil, and during a 28-day course of oral fluorouracil plus eniluracil. FINDINGS: In eniluracil-naive patients, 18F-fluorouracil localised more strongly (mean 0.0234% [SE 0.0019] of injected activity per mL tissue at 11 min) in liver than in tumours (0.0032% [0.0004]). There was substantial inhibition, after eniluracil administration, of radiotracer uptake and retention in normal liver (mean area under the time versus radioactivity curve 0.927 [SE 0.086] vs 1.857 [0.169] m2 mL(-1) s) and kidneys (1.096 [0.048] vs 5.043 [0.915] m2 mL(-1) s). There was also an increase in plasma uracil and unmetabolised 18F-fluorouracil and an increase in the radiotracer half-life in tumours (2.3 h to >4.0 h). INTERPRETATION: Two events strongly suggested increased exposure of 18F-fluorouracil and its anabolites in the tumours, consistent with the inactivation of dihydropyrimidine dehydrogenase: a selective decrease in radiotracer exposure in normal liver and kidneys compared with tumours; and an increase in radiotracer half-life in tumours.
Anderson H, Price P, 2000, What does positron emission tomography offer oncology?, Eur J Cancer, Vol: 36, Pages: 2028-2035
The origins of positron emission tomography (PET) date back 70 years. Since the 1970s, however, its use has increased exponentially in the fields of neurology, cardiology and oncology. [18F]-Fluorodeoxyglucose (FDG) whole-body scanning is by far the most widely utilised and recognised application of PET in oncology. However, PET is a very versatile and powerful imaging modality capable of helping bridge the gap between the laboratory and the clinic. This article reviews the history and current applications of PET in oncology and then explores some of the newer applications and potential future uses of this versatile technology particularly in the area of cancer research.
Keogan MT, McDermott VG, Price SK, et al., 1999, The role of imaging in the diagnosis and management of biliary complications after liver transplantation, AJR. American journal of roentgenology, Vol: 173, Pages: 215-219, ISSN: 0361-803X
Harte RJ, Matthews JC, O'Reilly SM, et al., 1999, Tumor, normal tissue, and plasma pharmacokinetic studies of fluorouracil biomodulation with N-phosphonacetyl-L-aspartate, folinic acid, and interferon alfa, J Clin Oncol, Vol: 17, Pages: 1580-1588
PURPOSE: To evaluate the effect of N-phosphonacetyl-L-aspartate (PALA), folinic acid (FA), and interferon alfa (IFN-alpha) biomodulation on plasma fluorouracil (5FU) pharmacokinetics and tumor and liver radioactivity uptake and retention after [18F]-fluorouracil (5-[18F]-FU) administration. PATIENTS AND METHODS: Twenty-one paired pharmacokinetic studies were completed on patients with colorectal, gastric, and hepatocellular cancer, utilizing positron emission tomography (PET), which allowed the acquisition of tumor, normal tissue, and plasma pharmacokinetic data and tumor blood flow (TBF) measurements. The first PET study was completed when the patient was biomodulator-naive and was repeated on day 8 after the patient had been treated with either PALA, FA, or IFN-alpha in recognized schedules. RESULTS: TBF was an important determinant of tumor radioactivity uptake (r = .90; P < .001) and retention (r = .96; P < .001), for which radioactivity represents a composite signal of 5-[18F]-FU and [18F]-labeled metabolites and catabolites. After treatment with PALA, TBF decreased (four of four patients; P = .043), as did tumor radioactivity exposure (five of five patients; P = .0437), with no change in plasma 5FU clearance. With FA treatment, there were no differences observed in whole-body metabolism, plasma 5FU clearance, or tumor and liver pharmacokinetics. IFN-alpha had measurable effects on TBF and 5-[18F]-FU metabolism but had no apparent affect on liver blood flow. CONCLUSION: The administration of PALA and IFN-alpha produced measurable changes in plasma, tumor, and liver pharmacokinetics after 5-[18F]-FU administration. No changes were observed after FA administration. In vivo effects may negate the anticipated therapeutic advantage of 5FU biomodulation with some agents.
Young H, Brock CS, Wells P, et al., 1999, Monitoring response to treatment in the development of anti-cancer drugs using positron emission tomography (PET)., Drug Information Journal, Vol: 33, Pages: 237-244
James R, Price P, Valentini V, 1999, Raltitrexed (TomudexTM) concomitant with radiotherapy as adjuvant treatment for patients with rectal cancer: preliminary results of phase I studies, Eur J Cancer, Vol: 35 Suppl 1, Pages: S19-S22
Radiotherapy, either alone or in combination with chemotherapy, may reduce local recurrence of rectal cancer following surgery and improve survival of patients with operable and advanced/recurrent/inoperable disease. Chemotherapy with 5-fluorouracil in combination with radiotherapy has been used both before and after surgery; however, the optimum schedule is unclear. In addition, alternative chemotherapy with raltitrexed (Tomudex) may be more convenient and better tolerated. The preliminary results of three phase I dose-finding studies are described, combining escalating doses of raltitrexed with radiotherapy as pre- or postoperative treatment for operable rectal cancer or as treatment for advanced/inoperable/recurrent rectal cancer. The recommended dose of raltitrexed when combined with adjuvant radiotherapy is likely to be 2.6 mg/m2. This is a small dose reduction compared with the dose of raltitrexed for the treatment of advanced colorectal cancer (3.0 mg/m2); however, toxicity appears to be lower using the pre-operative approach. Neo-adjuvant therapy with raltitrexed plus radiotherapy also demonstrated clinical activity in the pre-operative study, which showed that 22% of patients achieved a complete response and 56% a partial response. Once the recommended dose has been defined in each setting, large-scale studies will be undertaken as appropriate.
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