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Biomedical subjects

S J Mather

Publications and source records attributed to S J Mather.

At least 19 recordsLinked to original sources
PubMed2005

(99m)Tc-rituximab radiolabelled by photo-activation: a new non-Hodgkin's lymphoma imaging agent.

PURPOSE: Rituximab was the first chimeric monoclonal antibody to be approved for treatment of indolent B-cell non-Hodgkin's lymphoma (NHL). It is directed against the CD20 antigen, which is expressed by 95% of B-cell NHLs. The aim of this study was to explore the possibility of radiolabelling rituximab with (99m)Tc for use as an imaging agent in NHL for early detection, staging, remission assessment, monitoring for metastatic spread and tumour recurrence, and assessment of CD20 expression prior to (radio)immunotherapy. METHODS: Rituximab was purified from Mabthera solution (Roche), photo-activated at 302 nm by UV irradiation and radiolabelled with (99m)Tc. The effectiveness of the labelling method was evaluated by determination of the number of free thiol groups per photoreduced antibody, radiochemical purity and in vitro stability of (99m)Tc-rituximab. RESULTS: On average, 4.4 free thiol groups per photoreduced antibody were determined. Radiolabelling yields greater than 95% were routinely observed after storage of the photo-activated antibody at -80 degrees C for 195 days. The direct binding assay showed preserved ability of (99m)Tc-rituximab to bind to CD20, with an average immunoreactive fraction of 93.3%. The internalisation rate was proven to be low, with only 5.3% of bound (99m)Tc-rituximab being internalised over 4 h at 37 degrees C. CONCLUSION: Our results demonstrate that (99m)Tc-rituximab of high radiochemical purity and with preserved binding affinity for the antigen can be prepared by photoreduction and that the method shows good reproducibility. (99m)Tc-rituximab will be further explored as an imaging agent applicable in NHL for the purposes mentioned above.

Antibodies, Monoclonal↗
PubMed2004

Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin's lymphoma.

PURPOSE: An open-label phase II study was conducted at two centers to establish the efficacy and safety of tositumomab and iodine I 131 tositumomab at first or second recurrence of indolent or transformed indolent B-cell lymphoma. PATIENTS AND METHODS: A single dosimetric dose was followed at 7 to 14 days by the patient-specific administered radioactivity required to deliver a total body dose of 0.75 Gy (reduced to 0.65 Gy for patients with platelets counts of 100 to 149 x 10(9)/L). Forty of 41 patients received both infusions. RESULTS: Thirty-one of 41 patients (76%) responded, with 20 patients (49%) achieving either a complete (CR) or unconfirmed complete remission [CR(u)] and 11 patients (27%) achieving a partial remission. Response rates were similar in both indolent (76%) and transformed disease (71%). The overall median duration of remission was 1.3 years. The median duration of remission has not yet been reached for those patients who achieved a CR or CR(u). Eleven patients continue in CR or CR(u) between 2.6+ and 5.2+ years after therapy. Therapy was well tolerated; hematologic toxicity was the principal adverse event. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia were observed in 5%, 45%, and 32% of patients, respectively. Secondary myelodysplasia has occurred in one patient. Four patients developed human antimouse antibodies after therapy. Five of 38 assessable patients have developed an elevated thyroid-stimulating hormone; treatment with thyroxine has been initiated in one patient. CONCLUSION: High overall and CR rates were observed after a single dose of tositumomab and iodine I 131 tositumomab in this patient group. Toxicity was modest and easily managed.

Adult↗
PubMed2004

Radiolabelling of glycosylated MFE-23::CPG2 fusion protein (MFECP1) with 99mTc for quantitation of tumour antibody-enzyme localisation in antibody-directed enzyme pro-drug therapy (ADEPT).

MFECP1 is a glycosylated recombinant fusion protein composed of MFE-23, a high-affinity anti-carcinoembryonic antigen (CEA) single chain Fv (scFv), fused to the enzyme carboxypeptidase G2 (CPG2), and has been constructed for use in antibody-directed enzyme pro-drug therapy (ADEPT). Radiolabelling of glycosylated MFECP1 with technetium-99m was developed for the purpose of determining tumour localisation of MFECP1 in a phase I ADEPT clinical study. The method used was 99mTc-carbonyl [99mTc(H2O)3(CO)3]+ (abbreviated to TcCO) mediated labelling of 99mTc to the hexahistidine (His) tag of MFECP1. MFECP1 fusion protein was labelled with TcCO under a variety of conditions, and this was shown to be a relatively simple and robust method. Tissue biodistribution was assessed in a CEA-expressing LS174T (human colon carcinoma) nude mouse xenograft model. Tissues were taken at 1, 4 and 6 h for assessment of distribution of radioactivity and for measurement of CPG2 enzyme levels. The amount of radioactivity retained by the tumour proved to be an accurate estimation of actual measured enzyme activity, indicating that this radiolabelling method does not appear to damage the antibody-antigen binding or the enzyme activity of MFECP1. However, correlation between CPG2 enzyme activity and measured radioactivity in liver, spleen and kidney was poor, indicating retention of radioactivity in non-tumour sites but loss of enzyme activity. The high retention of technetium radioisotope in normal tissues may limit the clinical applicability of this radiolabelling method for MFECP1; however, these results suggest that this technique does have applicability for measuring the biodistribution of His-tagged recombinant proteins.

Adenocarcinoma↗
PubMed2002

Axillary node status in breast cancer patients prior to surgery by imaging with Tc-99m humanised anti-PEM monoclonal antibody, hHMFG1.

In early breast cancer axillary nodes are usually impalpable and over 50% of such patients may have an axillary clearance when no nodes are involved. This work identifies axillary node status by imaging with a Tc-99m radiolabelled anti-Polymorphic Epithelial Mucin, humanised monoclonal antibody (human milk fat globule 1), prior to surgery in 30 patients. Change detection analysis of image data with probability mapping is undertaken. A specificity of 93% and positive predictive value of 92% (both 100% if a second cancer in the axilla with negative nodes is considered) were found. A strategy for combining negative imaging with the sentinel node procedure is presented.

Adult↗
PubMed2002

Optimization of the small-scale synthesis of DOTA-Tyr3 -octreotide.

The clinical potential of 111In and 90Y labelled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid conjugated Tyr3-octreotide (DOTA-TOC) have been reported in a number of publications, and Phase II clinical trials of 90Y-DOTA-TOC are currently in progress. However, to date, only a summary of the large-scale preparation of these radiopharmaceuticals has been published. This publication aims to describe our experience of the small-scale synthesis of DOTA-TOC in the hope that this will assist others in the preparation of this and other similar radioconjugates. DOTA in the form of the tri-t-butyl ester was coupled to the Lys5 (BOC) protected Tyr3-octreotide in N,N-dimethylformamide or N-methyl-2-pyrolidinone, in a three-step reaction involving conjugation, using O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and diisopropylethyamine (DIPEA) as coupling reagents, deprotection with trifluoroacetic acid and HPLC purification of the conjugates. The product was obtained in final yields of 60+/-5%. The purified product was characterized by mass spectroscopy, showing a molecular weight of 1421.55+/-0.08. In somatostatin receptor binding assays, the unlabelled DOTA-TOC showed an effective displacement of 99mTc labelled HYNIC-TOC (where HYNIC is hydrazinonicotinamide) (IC50=0.31+/-0.07 nm), confirming the retention of receptor-binding affinity. The conjugate could be efficiently labelled with 111In by addition of 111InCl3 and ammonium acetate buffer pH5 and heating (95 degrees C, 20 min).

Animals↗
PubMed2002

The influence of chelator on the pharmacokinetics of 99mTc-labelled peptides.

Because of the ideal properties of technetium-99m for imaging, more methods have been developed for labelling peptides and other biomolecules with this radionuclide that any other. While few detailed comparative studies have been performed, it has become apparent that the use of different labelling procedures can exert a profound effect on the pattern of biodistribution after intravenous administration of the radiotracer. The most significant influence of the labelling method is on the rate and route of excretion of the radionuclide. While some procedures tend to direct excretion towards the hepatobiliary route, others tend to favour renal clearance. Although the factors which exert this influence are still not fully understood, it is clear that the charge, lipophilicity and stability of the technetium-peptide complexes play major roles. A greater understanding of these factors will allow the development of improved radiotracers which demonstrate improved targeting potential as a result of lower uptake and consequent radiation dose by normal tissues.

Biomarkers, Tumor↗
PubMed2001

Antibody targeting studies in a transgenic murine model of spontaneous colorectal tumors.

Monoclonal antibodies (mAbs) have been used to treat malignancies in humans with varying degrees of success. Progress has been hindered by the lack of suitable animal models, which would ideally consist of immunocompetent animals that are tolerant to tumor-associated antigens. Suitable models would allow the study and optimization of anti-tumor immunotherapy. We describe a murine model for the study of immunotherapy in colorectal cancers. Carcinoembryonic antigen (CEA) is a cell-surface glycoprotein that is expressed on normal human intestinal epithelium and that is overexpressed in intestinal tumors. Mice that are transgenic for the human CEA gene (CEA.Tg) were crossed with multiple intestinal neoplasia (MIN) mice. MIN mice carry a germline APC mutation and are prone to the development of intestinal adenomas. The offspring from the MIN x CEA.Tg cross developed intestinal adenomas that were shown by immunohistochemistry to overexpress CEA. Pharmacokinetic studies by using (125)I-labeled anti-CEA mAb PR1A3 showed rapid localization of antibody to tissues expressing CEA, especially the gastrointestinal tract. Macroscopic and microscopic radioautographic analysis of the gastrointestinal tracts from MIN/CEA.Tg mice indicated that PR1A3 targeted and was retained in tumors at levels higher than in areas of normal gut. These results demonstrate the utility of the MIN/CEA.Tg mouse as a model for the study of anti-CEA immunotherapy and, furthermore, demonstrate the efficiency of tumor localization by PR1A3.

Animals↗
PubMed2001

General aspects of the cellular response to low- and high-LET radiation.

Radiobiological studies have shown for some time that the effects of ionising radiation on cells are mainly explained by modification of the DNA. Numerous studies over the past 50 years have accumulated clear evidence of the cause-effect relationship between damage to DNA and the cytotoxic and mutagenic effects of ionising radiation. However, the path from irradiation of the cells to the induction of biological effects comprises several complex steps. The first step involves interactions between the radiation and the cellular environment. These consist of physical and chemical reactions which produce ions, excited molecules and radical species. Excitations and ionisations are complete in about 10(-15) s, and are followed by a chemical thermal equilibrium of the species produced within 10(-12) s. These species then diffuse from their site of production and provoke alterations to a variety of cellular components. This damage is detected by cellular surveillance systems, which in turn activate signalling cascades, gene transcription and enzyme recruitment, which participate in the cellular response. In most cases, cell cycle arrest occurs, allowing, according to the biological relevance of the DNA damage, either a process of DNA repair or programmed cell death (apoptosis). The accuracy of the DNA repair which is performed depends on the complexity of the DNA lesion and on the DNA repair machinery fidelity itself. Improper DNA repair can lead to mutation, chromosome aberration, genetic instability, oncogenic transformation and, ultimately, cell death.

Animals↗
PubMed2001

Fasting regimens for regional ophthalmic anaesthesia. A survey of members of the British Ophthalmic Anaesthesia Society.

Members of the British Ophthalmic Anaesthesia Society were surveyed using a postal questionnaire. The response rate was 72.3%. Respondents were asked about starvation before regional anaesthesia for cataract surgery, the use of sedation in these patients, monitoring and if oxygen supplementation was given. The results show that most patients are not starved before this type of regional anaesthesia, and that the majority of patients receive no supplementary sedation or intravenous analgesia. Over 70% of patients received oxygen supplementation.

Anesthesia, Conduction↗
PubMed2001

Hybridization and cell uptake studies with radiolabelled antisense oligonucleotides.

BACKGROUND: Radiolabelled antisense oligonucleotides have been proposed as radiopharmaceuticals for imaging changes in the level of gene expression in vivo. This paper describes a study of the uptake of radiolabelled oligonucleotides in cell lines expressing different levels of the target mRNA. METHODS: A 15-mer phosphorodiester deoxyoligonucleotide antisense to c-myc was labelled with 99mTc and 32P. Hybridization and stability studies were performed in vitro. Cell uptake studies were carried out in a c-myc expressing transformed rat embryonic fibroblast cell-line, TGR-1, and a knock-out cell line HO15.19 which does not express c-myc. RESULTS: The oligonucleotides were efficiently labelled with both radionuclides and retained their ability to hybridize with their complementary mRNA when extracted from cell lines. The radiolabelled oligonucleotides were stable for a few hours in human serum. No statistically significant difference was found between the uptake of radioactivity by the two cell lines. CONCLUSIONS: Although able to bind efficiently to their target in cell-free systems, radiolabelled oligonucleotides may be prevented from performing effectively as radiopharmaceutical vectors by the barriers imposed by cell membranes and/or intracellular metabolism.

Animals↗
PubMed2000

99mTc-EDDA/HYNIC-TOC: a new 99mTc-labelled radiopharmaceutical for imaging somatostatin receptor-positive tumours; first clinical results and intra-patient comparison with 111In-labelled octreotide derivatives.

[111In-diethylene triamine penta-acetic acid-D-Phe1]-octreotide (DTPA-octreotide) scintigraphy has gained widespread acceptance as a diagnostic clinical procedure in oncology for imaging somatostatin receptor-positive tumours. However, indium-111 as a radiolabel has several drawbacks, including limited availability, suboptimal gamma energy and high radiation burden to the patient. We have recently reported on the preclinical development of 99mTc-EDDA/HYNIC-TOC, a new octreotide derivative which showed promising results both in vitro and in vivo. We now report our initial clinical experiences with this new radiopharmaceutical in ten oncological patients. The clinical diagnoses were: carcinoid syndrome (n=5), thyroid cancer (n=3), pancreatic cancer (n=1) and pituitary tumour (n=1). The biodistribution and kinetics of 99mTc-EDDA/HYNIC-TOC were compared with those of 111In-DTPA-octreotide in six cases, and with those of 111In-DOTA-TOC in five cases. With the new tracer tumours were imaged within 15 min after injection and showed the highest target/non-target ratios 4 h after injection. Tumour uptake persisted up to 20 h p.i. The rate of blood clearance was similar to that of 111In-DTPA-octreotide but faster than that of 111In-DOTA-TOC, while urinary excretion was lower compared with the 111In derivatives. Semi-quantitative region of interest analysis showed that 99mTc-EDDA/HYNIC-TOC produced higher tumour/organ (target/non-target) ratios than the 111In derivatives, especially in relation to heart and muscle. Significantly more lesions could be detected in 99mTc images. We conclude that 99mTcEDDA/HYNIC-TOC shows better imaging properties for the identification of somatostatin receptor-positive tumour sites than currently available 111In-labelled octreotide derivatives.

Adult↗
PubMed2000

Periodontal pocket clearance by gamma scintigraphy in human volunteers.

BACKGROUND: With the interest in the delivery of drugs to the periodontal pocket has come an increased need to determine the loss of formulations from the site of application. In this respect, gamma scintigraphy has been used to measure formulation clearance in mucosal sites such as the oesophagus, nose and eyes by assessing the persistence of an incorporated radiolabel. However, the technique has not been used to follow clearance from the periodontal pocket. AIMS: The aim of this study was therefore to assess the potential of gamma scintigraphy to follow the loss of 2 contrasting formulations. 10% chitosan gel and normal saline. METHOD: Technitium-99m was used as the radionuclide and was incorporated into the formulations on the day of use. 9 subjects contributed up to 2 pockets for each formulation with probing depths > or = 5 mm. RESULTS: The results demonstrated that gamma scintigraphy was able to follow the loss of the radiolabel despite the small volumes of formulation placed in situ. The mean (SD) times (min) for the original counts to decline to 10%, 50% and 90% of the original values were: T10: chitosan 74.5 (59.0), saline 40.3 (21.1), T50: chitosan 41.5 (34.1) saline 20.8 (11.7) and T90: chitosan 8.5 (10.8), saline 1.4 (3.7) respectively. Clearance times of the 2 formulations were significantly different from each other (p<0.05). CONCLUSION: In conclusion, gamma scintigraphy is a sensitive method for assessing clearance from the periodontal pocket, and further studies are merited to optimise the use of the technique.

Adult↗
PubMed2000

Imaging with prostate-specific membrane antigen (PSMA) in prostate cancer.

Radioimmunoscintigraphy using a radio-labelled antibody to prostate-specific membrane antigen (PSMA) has growing applications as a means of tissue-specific imaging based on functional characteristics and complements traditional staging investigations. Clinical applications in men with carcinoma of the prostate are being refined, and this study reports outcomes with this technique in our practice. Prostatic immunoscintigraphy scans were performed with In-111 CYT 356 in 49 men with carcinoma of the prostate, obtaining sequential images in two and three dimensions at 10 min, 24 and 48 h. Of the 49 men, 36 had clinically localized cancer, 10 had recurrent disease after radical radiotherapy or radical prostatectomy and three had rising PSA after primary endocrine treatment. Scan findings are discussed in the context of clinical management. Of the 36 men with clinically localized cancer, seven had increased uptake in regional and distant lymph nodes. Of these seven, three were treated with hormone manipulation, two by radical prostatectomy and two by radical radiotherapy. Among 10 patients who had recurrence after radical treatment of the primary tumour, scans showed local recurrence alone in four, and six had regional or distant metastases. Three patients treated with primary hormone manipulation had scans for rising PSA, and of these one had a positive regional node and two had distant soft tissue and bone metastases. In conclusion, prostatic radio-immunoscintigraphy scans highlight tissues involved by prostate cancer, including the prostate, lymph nodes, soft tissues and bone metastases as well as pelvic recurrence. Results may contribute to the clinical management of individual patients, although histological confirmation may be appropriate when considering alternative treatment. Prostate Cancer and Prostatic Diseases (2000) 3, 47-52

Journal Article↗