Journal of nuclear biology and medicine (Turin, Italy : 1991)最新文献

The aim of the present study was to evaluate whether the different methodologies used for human polyclonal immunoglobulin (HIG) preparation can affect the radiochemical purity of 99mTc-HIG and its binding affinity to infection sites. Three intravenous immunoglobulin preparations, beta-propiolactone treated, hydrochloric acid/pepsin treated, and an unmodified HIG molecule were studied. The HIG preparations were analysed by size-esclusion HPLC. The UV chromatogram profiles obtained showed some percentage of polymeric and dimeric fractions in all of them. The three HIG studied were directly radiolabelled via 2-mercaptoethanol reduction. Lyophilized kits containing 1 mg of HIG and a small amount of MDP(Sn) solution were prepared and then radiolabelled by adding pertechnetate-99m. The radiolabelled products, evaluated by ITLC, showed high radiochemical purity and in vitro stability. Biodistribution studies were performed in mice with an infection in the right thigh induced by the im administration of a single isolate of S. aureus, in order to compare the ability of 99mTc-HIG to detect an infectious focus. This study suggests that any damage during immunoglobulin treatment can influence the in vivo behaviour of 99mTc-HIG.

The monoclonal antibody (MoAb) 174H.64 (Truscint SQ, Biomira Inc.) is a murine-derived MoAb reacting with an extracellular surface component of the cytoskeletal matrix ectopically expressed on squamous-cell carcinoma cell-surface membranes. A chimeric form of this MoAb has also been produced by genetically modifying the Fc portion of the MoAb by the insertion of a human Fc fragment. During this process the isotype was altered from an IgG1 (murine) to an IgG3 (chimeric). Pilot and phase I/II clinical trials of the murine and chimeric 99mTc-labelled 174H.64 MoAbs have been undertaken at selected European and North American sites. As part of this evaluation serum, urine and image data were collected at specific time intervals and used to obtain a kinetic model to describe the in vivo distribution of the MoAbs. A two-compartment model of the form: C(t) = C1 e-lambda 1t + Cz e-lambda zt was found to best describe the serum distribution of radioactivity of both the murine and chimeric MoAbs. The initial distribution half-lives were 2.9 +/- 0.7 hours and 2.7 +/- 0.2 hours, and the terminal elimination half-lives were 17.6 +/- 3.8 hours and 22.5 +/- 1.3 hours for the murine and chimeric MoAbs, respectively. No significant difference was found between the kinetic model parameters of two MoAbs at the 95% level. Assuming a similar clinical efficacy, these MoAbs could then be used interchangeably, with the chimeric MoAb offering potential advantages in reducing HAMA response.

The clinical use of anthracyclines, such as doxorubicin (DXR), is hampered by tumour development of multidrug resistance (MDR). The drug efflux associated with MDR could be characterised in vivo using Positron Emission Tomography (PET) in conjunction with a suitable radiolabelled drug. We are investigating DXR labelled with the positron emitter 57Ni as a potential analogue of the parent drug. Essential to this work is the production of a high purity radionuclide in a suitable chemical form for the preparation of radiolabelled DXR. To optimise production parameters, excitation functions (reaction cross section as a function of beam energy) for proton induced reactions in cobalt were measured up to 60 MeV. The excitation function for the 59Co(p,3n)57Ni reaction shows a maximum cross section of 13.8 +/- 1.5 mb at 38 MeV. The optimum energy range for production of 57Ni was found to be 41-->26 MeV resulting in an experimental thick target yield of 17.8 MBq/muAh. The level of the 56Ni impurity is only 0.21% at the end of bombardment. A radiochemical procedure, based on cation-exchange chromatography, has been developed for the separation of radionickel from the cobalt target and other radiochemical and chemical impurities. The 57Ni activity was eluted, using 2M HCl, from a Dowex-50Wx8(H+) column, in a 95% radiochemical yield. Optimum labelling of DXR has been investigated in terms of pH, reaction time and temperature, achieving radiochemical yields > 94%. DXR labelled with 57Ni therefore shows promise as a radiotracer for pharmacokinetic studies using PET.

Dynamic cardiomyoplasty improves ventricular function by increasing pump function and by limiting cardiac dilatation. The aim of this study was to assess long-term myocardial performance by radionuclide ventriculography on dilated cardiomyopathy patients subjected to cardiomyoplasty. Thirteen survivors were included. Radionuclide ventriculography was performed one week before surgery and one year later. Five patients were also studied two years following surgery. The left ventricular ejection fraction (LVEF), end-diastolic volume (EDV) and ventricular amplitude ratio (VAR) to assess mitral regurgitation were measured. Every case after one year showed a non-significant increase in LVEF. However, the decrease in EDV and in VAR was significant (p < 0.01). No significant difference in these values was found after two years. We conclude that the effects of cardiomyoplasty--reduction of cardiac dilatation, wall stress and mitral regurgitation--are more evident during the first year after surgery. Thereafter, a certain stabilization is observed.

In the radioimmunotherapy of malignancies the uptake of monoclonal antibodies (MoAb) is commonly low in tumors compared with normal tissue. Several methods have been suggested to increase the tumor-to-normal tissue (T/N) ratio. In this study we have investigated the biodistribution of different amounts of 125I-L6-biotin MoAb in combination with a preload of unlabeled L6 MoAb. Nude rats were injected with 50 micrograms or 250 micrograms of unlabeled L6 24 hours prior to the injection of 10 micrograms, 50 micrograms or 250 micrograms of 125I-L6, antipancarcinoma MoAb. Dissections were performed 24 hours after the injection of radiolabeled MoAb. The maximal enhancement of tumor uptake with simultaneously decreased uptake in normal tissues was with 250 micrograms of 125I-L6 preceded by a preload of 50 micrograms unlabeled L6. Mean T/N ratios were improved by a factor of 2.9 for bone marrow, 3.4 for liver, 3.7 for lungs and 2.3 for kidneys as compared with the corresponding controls. This study demonstrated that preinjection of optimal amounts of unlabeled L6 MoAb may increase the uptake of 125I-L6 by tumor and improve the T/N ratios. Based on present data, preloading with unlabeled MoAb should be considered in future clinical studies with immunoconjugates to improve the radioimmunotargeting of tumors. It is essential to titrate an appropriate amount of the preload, thus avoiding possible tumor antigen saturation of unlabeled MoAbs but simultaneously decreasing the uptake of subsequently injected radiolabeled MoAb in normal tissues.

Radiolabelled amino acids combined with Positron Emission Tomography (PET) may be useful for delineation of the extent of viable tumour and may also provide a rapid and sensitive indicator of response to therapy. Promising early clinical reports led us to investigate the potential use of the amino acid analogue L-3-iodo-alpha-methyl tyrosine (IMT), which may be radioiodinated with isotopes suitable for PET or conventional single photon imaging. We have studied the biodistribution and kinetics of [125I]IMT using two transplantable tumour systems in hooded rats, and have compared the findings with those using the natural amino acid L-tyrosine (TYR) radiolabelled with tritium. Similar levels of IMT and TYR uptake were found in HSN and OES.HR1 tumours during tumour growth. Following arrest of OES.HR1 tumour growth by oestrogen ablation, reduced IMT and TYR uptake was found to be closely matched by a fall in tumour blood flow. Unlike IMT, a substantial proportion of TYR uptake in tumours was found to be protein incorporated, even following tumour growth arrest. Quantitative autoradiography revealed sharp delineation of tumour boundary using either radiotracer. We conclude that IMT and TYR kinetics are strongly influenced by blood flow and diffusion, and that tumour growth status may not be closely associated with amino acid uptake.

Oxamniquine (OXY), a tetrahydroquinoline derivative, is used as an antischistosomal drug and generally has been labeled with carbon-14 and tritium. We decided instead to label it with technetium-99 (99mTc). In order to determine the optimal conditions, different concentrations of this drug were incubated with various stannous chloride solutions. We then added 99mTc, and chromatography was performed using 0.9% NaCl solution, acetone and 1.2N HCl as the mobile phase. Using a solution of 1.0 mg/mL stannous chloride and 0.5 mg/mL oxamniquine, over 94% of the radioactivity bound to oxamniquine (99mTc-OXY). In the biodistribution study, 99mTc-OXY was administered in mice intramuscularly, orally and intravenously. When the intramuscular route was used, the main uptake (after 30 minutes) of the labeled drug was in the kidneys, liver and intestines; after 240 minutes the labeled drug was still found in the liver and kidneys, but at increased levels in the intestines. It was also present in the faeces. When the oral route was employed, labeled OXY was mainly found in the stomach after 30 minutes, but there was a decrease after 240 minutes. During this period radioactivity increased in the intestines. When the intravenous route was employed the labeled OXY was found in the liver and spleen. The radioactivity decreased with time in these organs. Using infected animals, radioactivity was found in isolated worms.

This pharmacokinetic study was performed in order to assess the potential usefulness of the murine monoclonal antibody (MoAb) AR-3-IgG1 as an immunoscintigraphy agent for pancreatic cancer. This MoAb, which defines a mucin-like antigen (CAR-3) expressed by a large fraction of pancreatic cancers, shows in fact favourable in vivo localizing properties in the experimental animal model of human tumor xenograft. 131I-AR-3-IgG1 was injected i.v. into 5 patients with suspected pancreatic cancer. Whole-body maps and spot views of the abdominal area were recorded with a computerized gamma-camera, and specific regions of interest drawn over the liver and spleen helped to define the kinetics of activity in these organs. Blood samples taken from 0.1-144 hours post-injection and daily urine collections over the same interval served to define the kinetics of plama distribution and removal of activity from the body. Different multicompartmental models were tested to fit the experimental data, assuming as the starting hypothesis that there was to be significant nonspecific tracer accumulation in the liver, spleen and bone marrow, as already observed for the majority of radioiodinated murine MoAbs injected into humans. Surgery confirmed pancreatic cancer in 3 out of the 5 patients (chronic pancreatitis and periampullary cancer in one each); in all these 3 patients immunostaining with the MoAb AR-3 demonstrated the presence of the CAR-3 antigen (with a cytoplasmic and endoluminal/secretory pattern of distribution). Nonspecific radioactivity accumulation in the liver, spleen and bone marrow was extremely low, linked essentially to the blood pool effect of circulating activity in these organs.(ABSTRACT TRUNCATED AT 250 WORDS)

A case of a patient with small cell lung cancer and right submandibular node enlargement due to granulomatous lymphadenitis is presented. Diagnostic procedures included: biopsy of the cervical node, transmission computed tomography of the chest, bronchoscopic examination and biopsy of the pulmonary lesion. The patient underwent 111In-octreotide scintigraphy (whole body and single photon emission tomography) which revealed both lesions. We conclude that granulomatous lesions are to be considered as a possible cause of false positive results, when octreotide scintigraphy is used to evaluate distant metastases in patients with known cancer.

In 28 blood samples from 21 patients undergoing 131I treatment after surgical thyroidectomy for cancer, the micronucleus (MN) frequency observed in peripheral blood lymphocytes (MN-test on binucleated cells) had a weighted mean of 0.044 +/- 0.006 (SEM), which was significantly different (p < 0.001) from that observed in 93 healthy individuals (0.025 +/- 0.001). The MN frequency (F(MN)) of the patients correlated fairly well (R = 0.736) with the modified activity (Amod) calculated by the following equation: [formula: see text] where Ai is the 131I activity on a determined day, e the logarithm base, di the number of days that have passed between the determined day and the day when the blood was drawn, and k is a day coefficient, defined in this context as the "daily attenuation factor". The use of the value of 0.0003 for k allowed the following equation to be obtained: F(MN) = 7.9 x 10(-5) (+/- 1.4 x 10(-5)).Amod + 0.014 (R = 0.736) The MN frequency was used to estimate, by our DOSIME program, the dose (Gy) received at the individual level in the 131I treatment. In these subjects the calculated dose was well correlated with Amod by the relationship: DBio = 0.0009 (+/- 0.0002).Amod + 0.0675 (R = 0.755) 3-aminobenzamide (3AB), an inhibitor of the poly(ADP-ribose)polymerase enzyme involved in DNA repair, induced and increase in X-ray cytogenetic damage (MN yields), evaluated at the individual level using the 3AB-index (I-3AB). The index was obtained from the MN-yield count after x-irradiation with (MN + 3AB) and without (MN - 3AB) 3AB, using the following formula: I = 1-(MN - 3AB/MN + 3AB).(ABSTRACT TRUNCATED AT 250 WORDS)