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PubMed1992

Samarium-153-EDTMP: pharmacokinetic, toxicity and pain response using an escalating dose schedule in treatment of metastatic bone cancer.

Samarium-153 emits medium-energy beta particles and an imageable gamma photon with a physical half-life of 46.3 hr. When chelated to ethylenediaminetetramethylenephosphonic acid (EDTMP), it is remarkably stable in vitro and in vivo. In this study, we administered escalating amounts of 153Sm-EDTMP, from 0.1 to 1.0 mCi/kg (3.7-37 MBq/kg), to 22 patients with painful metastatic bone cancer. A complete concordance was found when the scintigrams of 153Sm-EDTMP were compared qualitatively to 99mTc-HDP bone images. Moreover, the skeletal uptake of the 153Sm-EDTMP related to the number of metastatic sites (r = 0.65; p = 0.001) showed an inverse proportion to the plasma radioactivity at 30 min following injection (r = -0.79; p = 0.0001) and was unaffected by the administered (mCi/kg), (r = 0.33; p = 0.13). Myelotoxicity was observed in 10 of the 29 treatment courses and leukopenia occurred in two. Thrombocytopenia occurred in patients who had low pretreatment platelet counts, albeit within the normal range (p = 0.001), most suffered from prostate cancer (p = 0.007) and retained a higher percentage of the 153Sm-EDTMP in their skeleton (p = 0.057). In four patients an exacerbation of the pre-existing pain ("flare reaction") was recorded. Pain palliation occurred in 65% of the treated patients (mean: 3.8 mo, range: 1-11 mo). Retreatment in first time responder patients was quite effective. Our preliminary results indicate that 153Sm-EDTMP is a promising radiotherapeutic agent for palliative treatment of metastatic bone cancer pain, and further study is necessary to ascertain its optimal dose, efficacy and toxicity.

Adult↗
PubMed1992

A quantitative autoradiographic study of the heterogeneous activity distribution of different indium-111-labeled radiopharmaceuticals in rat tissues.

In light of the increased interest in small scale dosimetry, this paper presents a quantitative autoradiographic method for evaluation of heterogeneous activity distribution in tissues. This was studied in rat tissues after administration of 111In-chloride, -oxine, -tropolone, 111In-labeled homologous blood cells and 111In-anti-CEA-F(ab')2, using quantitative whole-body autoradiography. Quantification was performed utilizing an image analyzing system designed for whole-body autoradiographs. Very heterogeneous activity distribution was found in several tissues including the liver, spleen, kidneys, bone marrow, lymph nodes and testes. Notable was the high 111In uptake in organs characterized as rapidly proliferating, and known to have numerous transferrin receptors. In the gastrointestinal tract, all activity was associated with the intestinal walls. The heterogeneous tissue distribution shown in this investigation accentuates the necessity for performing detailed studies of the tissue distribution of radiopharmaceuticals. This is especially important for the radiation dosimetry of radionuclides emitting beta-particles or low energy electrons. We suggest whole-body autoradiography as an excellent implement to determine local activity concentrations in organs and tissues necessary for accurate absorbed dose calculations.

Animals↗
PubMed2004

Health physics aspects of neutron activated components in a linear accelerator.

The purpose of this study was to investigate the residual radioactivity in the therapy accessories of a medical x ray linear accelerator. The residual radioactivity mainly originated from nuclear activation reactions by neutrons, which are present as a contamination radiation in the x-ray beam. The radiation used in this study was the 25 MV x-ray beam produced by a CGR Saturne III linear accelerator. The five treatment aids include four wedges of various angles and one cerrobend block. The decrease in dose rates with time was followed for 60 min for each of the five treatment aids immediately after 999 monitor units of irradiation. The integral doses from the surface of each of four activated therapy accessories following three different radiation doses were measured by using thermoluminescent dosimeters (CaF2). In the TLD measurement, polyethylene filters were used to differentiate beta or beta particles from the mixed decay radiation. A high-purity germanium detection system was utilized to collect and to analyze the gamma spectra from the activated therapy accessories. The residual radioisotopes found in the 15 degree wedge and 30 degree wedge included V, Cr, Cr, Mn, Fe, Co, and Ni. In the 45 degree and 60 degree wedges, the radionuclides identified were Co, Ni, Cu, and W. The principal nuclides identified in the irradiated cerrobend block were In, Sn, Cd, Pb. The corresponding nuclear reactions from which the residual radionuclides produced were confirmed by consulting the current literature.

Equipment Contamination↗
PubMedDate not supplied

Depleted uranium: an overview of its properties and health effects.

There has been much debate about the use of depleted uranium in the Gulf War and its health effects on United States and European war veterans. However, studies on the impact of this radioactive substance on the residents of the surrounding Gulf region are far from adequate. Depleted uranium introduces large quantities of radioactive material that is hazardous to biological organisms, continues to decay for millennia and is able to travel tens of kilometres in air. If depleted uranium were used in the Gulf War, its impact on the health of people in the area would have been considerable. This review of depleted uranium--its origin, properties, uses and effects on the human environment and health--aims to trigger further research on this subject.

Alpha Particles↗
PubMedDate not supplied

[The lethal and mutagenic action of 3H incorporated into the 2' position of the deoxyribose in the DNA of the extracellular phage lambda].

The lethal and mutagenic effects of 3H decay in 2' position of deoxyribose residues in DNA of extracellular lambda phage were studied, [2'-3H]-deoxyadenosine (3H-dA) or [2'-3H]-thymidine (3H-dT) being used as labelled DNA precursors. As estimated by the efficiency of the lethal and mutagenic actions of 3H decay in position 2' was significantly lower than that of the decay in the incorporated 3H-pyrimidines. The genetic effects of 3H decay in 2' position may be attributed to the radiation effect of beta-particles on DNA. In UV-irradiated E. coli cells, with the induced SOS repair, the mutagenic effect of 3H-dA in phage lambda is significantly higher than that of 3H-dT. This is perhaps related to the formation in DNA of AP-sites, resulting from 3H-decay in 2' position, and to the predominant incorporation of adenosine residues opposite to AP-sites during SOS repair.

Bacteriophage lambda↗
PubMed2005

Bone-seeking radionuclides for therapy.

Systemic therapy using bone-seeking radiopharmaceuticals has clear advantages for the treatment of multisite metastatic pain. Evidence supporting the use of beta-particle, electron, and alpha-particle-emitting radiopharmaceuticals is reviewed here. Appropriate patient selection relies on correlating clinical symptoms with focal abnormalities on conventional bone scintigraphy. Time to symptom relief and response duration vary with the physical half-life and dose rate of the radionuclide used, offering the opportunity to tailor radiopharmaceutical choice to individual patient circumstances. Toxicity is limited to temporary myelosuppression, governed by the administered activity and underlying bone marrow reserve. Optimal responses are achieved in patients with a modest skeletal tumor burden, suggesting that targeted therapy should be considered early in the management of bone metastases. The development of reliable dosimetric models will facilitate patient-specific prescribing to deliver enhanced symptom response within acceptable toxicity limits. It is likely that targeted therapy will be most effective in the context of multimodality tumor management. Further research is required to examine the potential of radionuclides in combination with external-beam irradiation, bisphosphonates, or chemotherapy. This approach might allow targeted therapy to progress beyond symptom palliation to early intervention for survival gain.

Animals↗
PubMed2005

Prediction of myelotoxicity based on bone marrow radiation-absorbed dose: radioimmunotherapy studies using 90Y- and 177Lu-labeled J591 antibodies specific for prostate-specific membrane antigen.

UNLABELLED: In radioimmunotherapy, myelotoxicity due to bone marrow radiation-absorbed dose is the predominant factor and frequently is the dose-limiting factor that determines the maximum tolerated dose (MTD). With (90)Y- and (131)I-labeled monoclonal antibodies, it has been reported that myelotoxicity cannot be predicted on the basis of the amount of radioactive dose administered or the bone marrow radiation-absorbed dose (BMrad), estimated using blood radioactivity concentration. As part of a phase I dose-escalation study in patients with prostate cancer with (90)Y-DOTA-J591 (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) ((90)Y-J591) and (177)Lu-DOTA-J591 ((177)Lu-J591), we evaluated the potential value of several factors in predicting myelotoxicity. METHODS: Seven groups of patients (n = 28) received 370-2,775 MBq/m(2) (10-75 mCi/m(2)) of (177)Lu-J591 and 5 groups of patients (n = 27) received 185-740 MBq (5-20 mCi/m(2)) of (90)Y-J591. Pharmacokinetics and imaging studies were performed for 1-2 wk after (177)Lu treatment, whereas patients receiving (90)Y had these studies performed with (111)In-DOTA-J591 ((111)In-J591) as a surrogate. The BMrad was estimated based on blood radioactivity concentration. Myelotoxicity consisting of thrombocytopenia or neutropenia was graded 1-4 based on criteria of the National Cancer Institute. RESULTS: Blood pharmacokinetics are similar for both tracers. The radiation dose (mGy/MBq) to the bone marrow was 3 times higher with (90)Y (0.91 +/- 0.43) compared with that with (177)Lu (0.32 +/- 0.10). The MTD was 647.5 MBq/m(2) with (90)Y-J591 and 2,590 MBq/m(2) with (177)Lu-J591. The percentage of patients with myelotoxicity (grade 3-4) increased with increasing doses of (90)Y (r = 0.91) or (177)Lu (r = 0.92). There was a better correlation between the radioactive dose administered and the BMrad with (177)Lu (r = 0.91) compared with that with (90)Y (r = 0.75). In addition, with (177)Lu, the fractional decrease in platelets (FDP) correlates well with both the radioactive dose administered (r = 0.88) and the BMrad (r = 0.86). In contrast, with (90)Y, there was poor correlation between the FDP and the radioactive dose administered (r = 0.20) or the BMrad (r = 0.26). Similar results were also observed with white blood cell toxicity. CONCLUSION: In patients with prostate cancer, myelotoxicity after treatment with (177)Lu-J591 can be predicted on the basis of the amount of radioactive dose administered or the BMrad. The lack of correlation between myelotoxicity and (90)Y-J591 BMrad may be due to several factors. (90)Y-J591 may be less stable in vivo and, as a result, higher amounts of free (90)Y may be localized in the bone. In addition, the cross-fire effect of high-energy beta(-)-particles within the bone and the marrow may deliver radiation dose nonuniformly within the marrow.

Aged↗
PubMed1992

[Somatostatin analog (octreotide) in clinical use: current and potential indications].

The long-acting somatostatin analogue octreotide is a synthetic cyclic peptide consisting of 8 amino acids. Depending on the organ, it acts either as a hormone or as a neurotransmitter. The effect on various physiological functions in the brain and the gastrointestinal tract is mainly inhibitory. Due to its inhibitory actions, the possibility of intravenous and subcutaneous administration and the lack of serious side-effects, octreotide offers a broad spectrum of possible indications. Today octreotide is recommended in acromegaly patients and for the treatment of hormone dependent symptoms in patients with gastroenteropancreatic tumours. New indications are enterocutaneous and pancreatic fistulas and the prevention of complications in major pancreatic surgery. In patients with dumping and short-bowel syndrome, octreotide may be helpful until dietary regimens are established. In Aids patients with severe diarrhea, octreotide can be used to stabilize patients with severe dehydration and malnutrition. The clinical effectiveness on upper GI-bleeding due to gastric ulcer and oesophageal varices is still controversial. Future studies must prove whether octreotide may be helpful in treating diabetic retino- and nephropathy because of the possibility of suppressing growth hormone and IGF-I. The antiproliferative effect of octreotide also allows its use in patients with somatostatin-receptor-positive, non-endocrine solid tumors (e.g. brain, breast and small-cell lung cancer). A promising area is the scintigraphic visualization of somatostatin-receptor-positive tumors with a radio-labelled octreotide analogue and the possible target irradiation of these tumors by beta-particle emitting isotopes attached to such analogues.

Acromegaly↗
PubMed2005

Ibritumomab: new drug. Interesting concept, disappointing in practice.

(1) First-line standard chemotherapy for follicular non-Hodgkin's lymphoma is based on alkylating agents. For patients who relapse, rituximab, a monoclonal antibody targeting CD20 receptors on tumour cells, induces remissions lasting at least 9 months in about 50% of cases. However, the infusions are often poorly tolerated and reactions can be severe. (2) Ibritumomab is a monoclonal antibody similar to rituximab. It is not in itself cytotoxic. Yttrium-90-radiolabeled ibritumomab has been licensed in the EU since 2004 for local tumour radiotherapy, administered shortly after rituximab therapy. It is approved as a third-line treatment for follicular lymphoma, after rituximab failure. (3) The only available comparative trial, lasting 4 years, involved 143 patients who were treated either with rituximab followed by radiolabeled ibritumomab, or with rituximab alone. The sequential treatment yielded more tumour responses but the time to lymphoma progression and clinical outcomes did not differ between the two treatment groups. (4) In a non comparative trial about half the patients in whom rituximab had failed responded to rituximab + radiolabeled ibritumomab, but lymphoma progression occurred after a median of only 7 months. (5) Patients who receive sequential therapy with rituximab + ibritumomab are exposed to the adverse effects of rituximab plus supplementary gastrointestinal, respiratory, haematological and infectious risks, mainly due to persistent myelosuppression. (6) The radiation hazard for the patient (irradiation of healthy organs) and for the environment appears to be limited, because of the short reach of beta particle emission (5 mm) and the short half-life of yttrium 90 (2.7 days). (7) Yttrium 90 radiolabeling requires special equipment and specialised personnel working in an approved centre, which can restrict access to treatment. (8) Radiolabeled ibritumomab appears to have a negative risk-benefit balance, and should only be used in clinical trials.

Antibodies, Monoclonal↗
PubMed1990

Future medical prospects for Sandostatin.

Because of its widespread distribution within the nervous system and the gastro-enteropancreatic (GEP) system and its diverse physiological inhibitory actions on various gastrointestinal functions, including endocrine and exocrine secretion, motility, liver and splanchnic blood flow and absorption, native somatostatin has been viewed as a possible therapy for many diseases. However, its short duration of action and consequent limited clinical usefulness have been overcome with the availability of Sandostatin, a long-acting, synthetic octapeptide analogue of the naturally occurring hormone. Sandostatin represents a significant advance in the treatment of GH and TSH secreting pituitary tumours and GEP endocrine tumours (carcinoid tumour, VIPoma, glucagonoma, insulinoma, and gastrinoma). Preclinical in vitro and animal studies have shown the antineoplastic activity of the compound. Moreover, because of a possible direct effect on somatostatin receptor-positive endocrine tumour cells and indirect effect whereby Sandostatin lowers GH, IGF-1 and numerous gastrointestinal peptides, Sandostatin may prove useful as an adjunctive therapy in cancer patients. In vivo labelling of somatostatin receptor-positive tumours with radiolabelled somatostatin analogues now allows localisation of such tumours and their metastases. Moreover, targeted irradiation of these tumours by beta particle emitting isotopes attached to such somatostatin analogues may become possible. The use of Sandostatin in acute oesophageal variceal bleeding, pancreatic pseudocysts, gastrointestinal and pancreatic external fistulae, short bowel syndrome, dumping syndrome and AIDS-related refractory hypersecretory diarrhea has provided encouraging results. Preliminary reports indicate efficacy of Sandostatin in psoriasis, autonomic neuropathy (postprandial and orthostatic hypotension) and its ability to reduce height velocity in tall adolescents. The ultimate role of Sandostatin as a therapeutic agent in these disorders is being explored in prospective clinical trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1991

Current status of bioassay procedures to detect and quantify previous exposures to radioactive materials. Bioassay Procedures Working Group.

This report was prepared by a working group established by the Oak Ridge Associated Universities (ORAU) for the purpose of assessing the current capabilities of bioassay methods that can be used to determine the occurrence and magnitude of a previous internal deposition of one or more radionuclides. The first five sections discuss general features of the use of in-vitro bioassay samples to achieve this purpose. The remainder of the report is focused on the possible use of urine bioassay procedures to detect and quantify internal depositions of radionuclides that may have occurred in United States occupation troops in Hiroshima or Nagasaki, Japan, prior to 1 July 1946, or to personnel who participated in atmospheric nuclear weapons tests conducted between 1945 and 1962. Theoretical calculations were made to estimate the quantities of various radionuclides produced in a 20-kiloton (kt) nuclear detonation that might still be present in measurable quantities in people today if they were exposed 25 to 40 y ago. Two radionuclides that emerged as good choices for this type of bioassay analysis were 90Sr, which emits beta particles, and 239,240Pu, which emits alpha particles. The current status and future prospects of chemical procedures for analyzing in-vitro urine bioassay samples for these two radionuclides were examined to determine the minimum amounts that could be detected with current methods and how much one might expect the sensitivity of detection to improve in the near future. Most routine 239,240Pu bioassay analyses involve detection by alpha spectrometry. The current minimum detectable amount (MDA) is about 0.74 mBq L-1 (20 fCi L-1), but this could be lowered to 74 muBq L-1 (2 fCi L-1). An MDA of 0.74 mBq L-1 (20 fCi L-1) is adequate for routine bioassay analyses but is too high to detect most uptakes of 239,240Pu that may have occurred 25 to 40 y ago. Methods under development that are or can be much more sensitive and have lower MDAs than alpha spectrometry for 239Pu are fission track analysis and mass spectrometry. Currently, the fission track analysis method has an MDA of about 19 muBq L-1), and this may eventually be lowered to 1.9 muBq L-1 (0.005 fCi L-1). The current MDA for 239Pu by mass spectrometry is about 7.4 mBq L-1 (200 fCi L-1), but the potential exists that it could be lowered to a value of about 0.37 muBq L-1 (0.01 fCi L-1).(ABSTRACT TRUNCATED AT 400 WORDS)

Feces↗
PubMed1990

Tumor, red marrow, and organ dosimetry for 131I-labeled anti-carcinoembryonic antigen monoclonal antibody.

Tumor-, red marrow-, and organ-absorbed doses were calculated for patients receiving 131I-labeled monoclonal antibodies against carcinoembryonic antigen for either diagnosis or therapy. Ten patients with confirmed liver tumors who received doses ranging from 10.79 to 200 mCi were evaluated. Urine and blood samples were taken in order to determine total body and red marrow activity, respectively. Anterior and posterior gamma camera images were obtained at multiple times postinjection in order to quantitate activity uptake using the conjugate view counting method for the following organs and regions: lungs, liver, spleen, kidneys, and the liver tumors. In addition, sacral regions of interest were drawn to generate red marrow-absorbed dose estimates for comparison to those obtained by blood sampling. Tumor volumes were obtained from volumetric analysis of the patient's computed tomographic study and tumor S values were obtained by assuming uniform distribution of the 131I-labeled monoclonal antibody in spherical tumor regions considering all emitted electrons, beta-particles, and photons. The following mean absorbed doses in rads/mCi injected were obtained: lungs, 2.3 +/- 1.6 (SD); liver, 1.4 +/- 0.7; spleen, 2.6 +/- 1.4; kidneys, 3.1 +/- 1.5; total body, 0.7 +/- 0.5; red marrow from blood sampling, 2.9 +/- 1.9; red marrow from sacral scintigraphy, 1.7 +/- 1.2; and liver tumors, 69.3 +/- 92.5. Tumor volumes ranged from 1 to 216 g and the percentage of uptake/g of monoclonal antibody into these tumors ranged from 0.0006 to 1.040. There was a statistically significant difference between the two techniques for estimation of red marrow dose (P less than 0.01). This methodology, permits calculation of tumor, red marrow, and organ dosimetry using planar gamma camera imaging.

Antibodies, Monoclonal↗
PubMed1990

Hybribox: a device for processing numbers of radioactively labeled hybridization filters with a minimum of personal exposure.

The device described permits the rapid and efficient processing of large numbers of filter hybridizations while virtually eliminating exposure to radioactive emission from the labeled probe. The filters are annealed and washed without being transferred from the holder. Throughout the process, the Plexiglas composition of the device absorbs the beta particles and exposure to the hands and arms is essentially zero. Since the hybridization solution can be reused several times, the cost involved approximates that of the conventional methods for hybridization.

Cloning, Molecular↗
PubMed1988

[Signs of developmental dysplasia and function of the genetic apparatus of children and adolescents].

Using scanning cytospectrophotometry and radiometry of beta-particles of 3H-thymidine incorporated into DNA the authors studied chromatin in interphase nuclei of lymphocytes in children and adolescents with Down's syndrome, childhood cerebral paralysis, and undifferentiated oligophrenia, as well as in healthy subjects. The findings obtained are compared with the results of cytogenetic examination of metaphase chromosomes and the number of stigmas of dysembryogenesis. Aberrations of metaphase chromosomes were found in 4.4% of patients with childhood cerebral paralysis and oligophrenia while the pattern of changes in interphase chromatin corresponding to the chromosomal imbalance was detected in 36% of these individuals. In all cases they had from 15 to 30 stigmas of dysembryogenesis.

Adolescent↗
PubMed1988

Copper-67-labeled monoclonal antibody Lym-1, a potential radiopharmaceutical for cancer therapy: labeling and biodistribution in RAJI tumored mice.

Copper-67 (67Cu) is one of the most promising radiometals for radioimmunotherapy because of its 61.5 hr physical half-life, abundant beta particles, and gamma emissions suitable for imaging. However, 67Cu is readily transferred from the usual chelates of EDTA or DTPA to albumen. We developed a new macrocycle (6-p-nitrobenzyl-TETA) to chelate copper. Bifunctional chelating agent p-bromoacetamidobenzyl-TETA was conjugated to Lym-1, a monoclonal antibody against human B cell lymphoma, without significantly altering its immunoreactivity. This conjugate was stably labeled with 67Cu under conditions chosen to optimize the yield of a high specific activity radiopharmaceutical. The biodistribution in RAJI tumor bearing mice demonstrated significant tumor uptake (14.7% ID per gram) and extended residence time (120 hr) in contrast to normal organs. After 24 hr, radioactivity was continuously cleared from all tissues except the tumor. This study suggests 67Cu labeled Lym-1 to be a promising radiopharmaceutical for potential use for radioimmunotherapy of B cell lymphoma.

Animals↗
PubMed1986

[Factors affecting 3H-thymidine incorporation into cells synthesizing DNA].

Potential sources of errors in 3H-thymidine use in cell proliferation studies are reviewed. Many factors affect the uptake of this agent into newly synthesized DNA: predominance of denovo and salvage pathways of thymidilate biosynthesis, activity of certain enzymes, size of thymidilate and TTP endogenous pools, differences in 3H-thymidine utilization rate during S-period, its catabolism in cell and tissue culture systems, degradation by bacteria, its reutilization in vivo and in vitro, effects of the isotope activity, of the exposition time of autoradiographs and of the beta-particles absorbance in the specimen. Practical recommendations are given to avoid these errors.

Animals↗