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PubMed1972

Biological damage from intranuclear tritium: DNA strand breaks and their repair.

Isotopic decay in tritiated thymidine in the DNA of frozen (-196 degrees C) Chinese hamster cells causes breaks in DNA strands to accumulate at a rate of 2.1 breaks per decay. After DNA is thawed the tritium-induced breaks repair rapidly with a half-time of 15 minutes at 37 degrees C. In comparison to breakage by x-rays, the efficiency of DNA strand breakage by tritium is equivalent to 0.48 rad per decay. This dose per decay is close to that predicted by simple dosimetric considerations (0.38 rad per decay) for irradiation by the beta particles from tritium.

Animals↗
PubMed1990

Re-186(Sn) HEDP for treatment of painful osseous metastases: initial clinical experience in 20 patients with hormone-resistant prostate cancer.

Rhenium-186(tin) hydroxyethylidene diphosphonate (HEDP) is a new radiopharmaceutical that localizes in areas of osseous metastases in a manner similar to that of standard bone-scanning agents. It also emits beta particles with sufficient energy to be therapeutically useful. A single intravenous injection of about 33 mCi (1,221 MBq) was given to each of 20 elderly patients with advanced skeletal metastases from hormonally resistant prostate cancer. Prompt, significant relief of pain occurred 80% of the time with no significant side effects and only minimal, transient marrow toxicity. Re-186(Sn) HEDP appears to be a useful new agent for the palliation of painful osseous metastases in prostate cancer.

Adenocarcinoma↗
PubMed2005

Assessment of low linear energy transfer radiation-induced bystander mutagenesis in a three-dimensional culture model.

A three-dimensional cell culture model composed of human-hamster hybrid (A(L)) and Chinese hamster ovary (CHO) cells in multicellular clusters was used to investigate low linear energy transfer (LET) radiation-induced bystander genotoxicity. CHO cells were mixed with A(L) cells in a 1:5 ratio and briefly centrifuged to produce a spheroid of 4 x 10(6) cells. CHO cells were labeled with tritiated thymidine ([3H]dTTP) for 12 hours and subsequently incubated with A(L) cells for 24 hours at 11 degrees C. The short-range beta-particles emitted by [3H]dTTP result in self-irradiation of labeled CHO cells; thus, biological effects on neighboring A(L) cells can be attributed to the bystander response. Nonlabeled bystander A(L) cells were isolated from among labeled CHO cells by using a magnetic separation technique. Treatment of CHO cells with 100 microCi [3H]dTTP resulted in a 14-fold increase in bystander mutation incidence among neighboring A(L) cells compared with controls. Multiplex PCR analysis revealed the types of mutants to be significantly different from those of spontaneous origin. The free radical scavenger DMSO or the gap junction inhibitor Lindane within the clusters significantly reduced the mutation incidence. The use of A(L) cells that are dominant negative for connexin 43 and lack gap junction formation produced a complete attenuation of the bystander mutagenic response. These data provide evidence that low LET radiation can induce bystander mutagenesis in a three-dimensional model and that reactive oxygen species and intercellular communication may have a modulating role. The results of this study will address the relevant issues of actual target size and radiation quality and are likely to have a significant effect on our current understanding of radiation risk assessment.

Animals↗
PubMed2005

In vitro cytotoxicity of carcinoma cells with 111In-labeled antibodies to HER-2.

Antibodies conjugated to radionuclides emitting low-energy electrons, which include Auger electrons and some conversion electrons, were recently shown to efficiently kill cells bearing a high density of the antigen recognized. The primary purpose of this study was to determine if such killing could be obtained with anti-HER-2 antibodies conjugated to (111)In, using the chelator benzyl-diethylenetriaminepentaacetic acid, or (125)I. Target cells were the breast carcinoma SK-BR-3 and the ovarian carcinoma SK-OV-3.ip1. In preliminary experiments, antibody accumulation and catabolism during a 2- to 3-day incubation with antibody was investigated. The level of antibody uptake, in terms of molecules per cell, was high enough such that killing seemed feasible. With an (125)I label, but not an (111)In label, increasing the antibody concentration past a certain point caused a decrease in total antibody accumulation, which might be attributed to effects of antibody binding. To test for cytotoxicity, cells were incubated for 2 days with the labeled antibody, then assayed for colony-forming units with a limiting dilution assay. SK-BR-3 cells were strongly killed ( approximately 3 logs) by antibody 21.1, and 100% kill was obtained by combining two noncompeting antibodies to HER-2 (21.1 and 4D5). SK-OV-3.ip.1 cells were more resistant to killing, but use of the two-antibody mixture produced a surviving fraction of approximately 0.002. (111)In-labeled antibodies to other high-density antigens, epithelial glycoprotein-1 and epithelial glycoprotein-2, also killed these target cells. In contrast, unlabeled antibodies or a nonreactive-labeled antibody produced much less cytotoxicity. The same experiment with an (131)I label (a beta-particle emitter) resulted in much greater levels of nonspecific cytotoxicity and essentially no specific cytotoxicity. This approach may be effective for therapy of micrometastases.

Antibodies↗
PubMed2007

Prospective evaluation of samarium-153-EDTMP radionuclide treatment for bone metastases in patients with hormone-refractory prostate cancer.

PURPOSE: Bone is a common site of metastatic disease and the most frequent site of metastatic spread in patients with prostate cancer. Most patients with bone metastases complain of bone pains. This pain may be alleviated or eliminated by administration of radiotherapy at the site of metastases. Currently, two forms of radiotherapy administration exist: external-beam irradiation or intravenous administration of bone-seeking therapeutic radiopharmacon such as samarium-153-ethylene-diamino-tetramethylene-phosphonate (EDTMP). This radiopharmacon produces beta-particles and concentrates in the areas of enhanced osteoblastic activity. The aim of this study was to assess the efficacy of (153)Sm-EDTMP therapy. MATERIALS AND METHODS: 32 men (aged 50-83, mean 70 years) with bone disseminated hormone-refractory prostate cancer and bone pain received (153)Sm-EDTMP. Mean applied dosage was 40 MBq/kg of the patient's body weight. Karnofsky performance status, pain score (numerical rating scale), analgesic score (WHO) and blood count were evaluated before, and 1 and 3 months after the treatment. RESULTS: Significant pain relief was observed in 44 and 38% of patients, mild relief in 31 and 34% and no effect in 25 and 28% of patients, 1 and 3 months after administration, respectively. Pain palliation was accompanied by an improvement in mobility and a decrease in necessary dosage of analgesics. Mild and transient bone marrow suppression was observed as a side effect of (153)Sm-EDTMP treatment. None of the patients showed hematological toxicity grade 4, and only 2 showed grade 3 (NCI CTC). The majority of the patients had hematological toxicity grade 1 or 2. CONCLUSION: After (153)Sm-EDTMP administration, bone pain palliation was observed in 72% of patients for 3 months. Hematological toxicity after (153)Sm-EDTMP treatment was mild and transient.

Aged↗
PubMed2001

Radioactive stents delay but do not prevent in-stent neointimal hyperplasia.

BACKGROUND: Restenosis after conventional stenting is almost exclusively caused by neointimal hyperplasia. Beta-particle-emitting radioactive stents decrease in-stent neointimal hyperplasia at 6-month follow-up. The purpose of this study was to evaluate the 1-year outcome of (32)P radioactive stents with an initial activity of 6 to 12 microCi using serial quantitative coronary angiography and volumetric ECG-gated 3D intravascular ultrasound (IVUS). METHODS AND RESULTS: Of 40 patients undergoing initial stent implantation, 26 were event-free after the 6-month follow-up period and 22 underwent repeat catheterization and IVUS at 1 year; they comprised half of the study population. Significant luminal deterioration was observed within the stents between 6 months and 1 year, as evidenced by a decrease in the angiographic minimum lumen diameter (-0.43+/-0.56 mm; P:=0.028) and in the mean lumen diameter in the stent (-0.55+/-0. 63 mm; P:=0.001); a significant increase in in-stent neointimal hyperplasia by IVUS (18.16+/-12.59 mm(3) at 6 months to 27.75+/-11. 99 mm(3) at 1 year; P:=0.001) was also observed. Target vessel revascularization was performed in 5 patients (23%). No patient experienced late occlusion, myocardial infarction, or death. By 1 year, 21 of the initial 40 patients (65%) remained event-free. CONCLUSIONS: Neointimal proliferation is delayed rather than prevented by radioactive stent implantation. Clinical outcome 1 year after the implantation of stents with an initial activity of 6 to 12 microCi is not favorable when compared with conventional stenting.

Adult↗
PubMed2001

Failure of a novel balloon-expandable gamma-emitting ((103)Pd) stent to prevent edge effects.

BACKGROUND: Balloon-expandable beta-particle-emitting ((32)P) stents inhibit within-stent neointimal hyperplasia but induce lumen narrowing beyond the stent margins, ie, the so-called "edge effects." METHODS AND RESULTS: We prospectively investigated the performance of novel stents impregnated with the gamma-emitting isotope (103)Pd, designed to reduce edge effects, in 24 rabbits. The stents had a length of 18 mm and were mounted on 20-mm-long delivery balloons for deployment. Angiograms were obtained immediately and 1 month after direct implantation of control and 1-, 2-, and 4-mCi (103)Pd stents into the iliac arteries without predilatation or postdilatation. Late lumen loss was measured with quantitative angiography. Neointimal hyperplasia and vascular remodeling were evaluated by histomorphometry. Late lumen loss was inhibited within (103)Pd stents (control 0.18 mm, 1 mCi 0.08 mm, 2 mCi 0.05 mm, and 4 mCi -0.03 mm, P<0.05 all activities versus control). Conversely, late lumen loss occurred at the edges of (103)Pd stents, correlating with areas of high balloon/artery ratios and vessel overstretch injury. Edge effects were primarily due to neointimal hyperplasia but were also caused by negative vessel remodeling at high stent activities. CONCLUSIONS: Edge effects after implantation of radioisotope stents can occur independently of the isotope chosen for stent impregnation.

Angiography↗
PubMedDate not supplied

Rhamnus cathartica (buckthorn) hepatocellular toxicity in mice.

The toxicity of the plant Rhamnus cathartica was assessed in mice after the plant was identified as a potential cause of an idiopathic neurologic disease in horses. Another member of the Rhamnaceae family, Karwinskia humboldtiana, is neurotoxic to mammals and birds and can induce hepatic degeneration and necrosis. To investigate the toxicity of R. cathartica, a 34-day feeding trial in mice was conducted using a complete rodent diet with 0, 5, or 25% added R. cathartica. No clinical signs or gross lesions were seen, and all major tissues were histologically normal except the liver. The livers of mice fed R. cathartica had marked hepatocellular swelling. Results from periodic acid-Schiff reaction staining and from electron microscopy confirmed that the swelling was due to deposits of monoparticulate glycogen (beta particles) in the cytoplasm. Glycogen deposition is an uncommon toxic change in cells. Apparently, compound(s) in R. cathartica directly or indirectly interfered with glycogen metabolism (either glycogenesis or glycogenolysis). Mechanistic and chronicity studies with R. cathartica are needed to investigate the pathophysiology of the glycogen disturbance and to determine if hepatic injury progresses and if other organs will be injured.

Animal Feed↗
PubMed1996

Nasopharyngeal brachytherapy for lymphoid hyperplasia: review of dosimetry.

Nasopharyngeal implants of radium sources were used in the 1940s and 1950s to treat children with otitis media and military personnel who had aerotitis media. Individuals received one or more treatments, typically for a total of 30 to 50 milligram-hours (mgh). Documentation of treatment parameters, including source strength and treatment times, allows estimation of organ doses in these patients. For example, for 40 mgh, radiation-absorbed doses to adjacent organs in an adult are estimated as follows: brain, 3; pituitary gland, 16; salivary glands, 8.5; and thyroid gland, 1.4 cGy. For a child 6 years of age, the doses for 40 mgh are: brain, 4; pituitary gland, 27; salivary glands, 11; and thyroid gland, 3.1 cGy. beta-Particles, in addition to gamma-rays, produce a high dose within a few millimeters of the source, but beyond 10 mm the dose is due to gamma-rays alone.

Brain↗
PubMed1996

Nasopharyngeal radium irradiation: fundamental considerations.

This article discusses the potential carcinogenic effects of radiation exposure from nasopharyngeal radium irradiation exposure and issues to consider when deciding whether to recommend screening for asymptomatic patients who have been treated by nasopharyngeal radium irradiation. The radiation exposure from the radium is primarily the result of gamma-rays, which are very penetrating. beta-Particles would affect only the tissues located within 1 cm of the eustachian tube orifice. On the basis of a quantitative risk assessment, the lifetime risk of brain cancer developing was estimated to be approximately 3 per 1000 persons, and the lifetime risk of a fatal cancer 5.6 per 1000 persons. When the medical benefits of screening asymptomatic patients are assessed, several factors, including the medical risks and benefits and cost-effectiveness of follow-up, should be considered.

Eustachian Tube↗
PubMed1991

Application of the linear-quadratic model with incomplete repair to radionuclide directed therapy.

The linear-quadratic (LQ) model for fractionated external beam therapy has been modified by previous authors to include the effects due to an exponentially decaying dose rate. However, the LQ model has now been extended to include a general time varying dose rate profile, and the equations can be readily evaluated if an exponential radiation damage repair process is assumed. These equations are applicable to radionuclide directed therapy, including brachytherapy. Kinetic uptake data obtained during radionuclide directed therapy may therefore be used to determine the radiobiological dosimetry of the target and non-target tissues. Also, preliminary tracer studies may be used to pre-plan the radionuclide directed therapy, provided that tracer and therapeutic amounts of the radionuclide carrier are identically processed by the tissues. It is also shown that continuous radionuclide therapy will induce less damage in late-responding tissues than 2 Gy/fraction external beam therapy if the ratio of the maximum dose rate and the sublethal damage repair half-life in the tissue is less than 1.0 Gy. Similar inequalities may be derived for beta-particle radionuclide directed therapy. For example, it can be shown that radionuclide directed therapy will induce less damage to slowly repopulating tissue than 2 Gy/fraction external beam therapy for the same total dose if the maximum percentage initial uptake in tissue is less than 0.046%/g or 0.23%/g for an injected activity of 50 mCi of 90Y or 131I, respectively.

Brachytherapy↗
PubMed2004

Antibody-based treatment of acute myeloid leukaemia.

Monoclonal antibodies have become an important treatment modality in cancer therapy. Genetically engineered chimaeric and humanised antibodies have demonstrated activity against a variety of tumours. Whereas the humanised anti-CD33 monoclonal antibody HuM195 has only modest activity against overt acute myeloid leukaemia (AML), it can eliminate minimal residual disease detectable by reverse transcription-polymerase chain reaction in acute promyelocytic leukaemia. High-dose radioimmunotherapy with beta-particle-emitting isotopes targeting CD33, CD45 and CD66 can potentially allow intensification of antileukaemic therapy before bone marrow transplantation. Conversely, alpha-particle immunotherapy with isotopes such as bismuth-213 or actinium-225 offers the possibility of selective tumour cell kill while sparing surrounding normal cells. Targeted chemotherapy with the anti-CD33-calicheamicin construct gemtuzumab ozogamicin has produced remissions as a single agent in patients with relapsed AML and appears promising when used in combination with standard chemotherapy in the treatment of newly diagnosed AML.

Acute Disease↗
PubMed2026

Whole genome and exome sequencing of pancreatic neuroendocrine tumour to investigate PRRT response.

Patients with pancreatic neuroendocrine tumours (PNETs) often have similar baseline clinical characteristics, including grade and molecular imaging phenotype, yet have highly variable responses to peptide receptor radionuclide therapy (PRRT). To identify genomic alterations and mutational patterns associated with PRRT treatment response and acquired somatic changes following PRRT exposure, whole genome or exome sequencing was applied to 40 PNET samples from 32 patients, including eight paired pre- or post-PRRT samples. The genomic profile of tumours reflected the known mutational landscape of PNET with MEN1 (34%), ATRX/DAXX (47%) alterations and a recurrent pattern of aneuploidy (38%) detected. A recurrent PSIP1::TBL1X fusion of unknown function was also identified in four tumours. The disease control rate following PRRT using RECIST1.1 and molecular imaging criteria was 88% (28/32). No mutational features were found to be statistically associated with progression-free survival. There was no significant increase in tumour mutational burden in the post-PRRT tumours, nor recurrent emergent mutational changes in cancer driver genes to explain progression to higher-grade disease, when observed. However, a small indel signature (ID8) previously associated with DNA damage repair by non-homologous end joining (NHEJ) was higher in PRRT-exposed compared with PRRT-naive samples (23.8 vs 4.8%, respectively; P < 0.001). Thus, comprehensive DNA analysis of pancreatic NETs did not identify biomarkers predictive of PRRT response nor evidence for high-level PRRT-induced genomic instability or hypermutation, yet mutation signature analysis supports NHEJ as being important for DNA repair and survival of neuroendocrine cells following exposure to beta-particle radiation.

Humans↗
PubMed2000

A new alpha-particle irradiator with absolute dosimetric determination.

A new experimental setup for uniform alpha-particle irradiation of cells in vitro is described. The alpha-particle irradiator is based on a radioactive (212)Pb/(212)Bi source. In the experimental setup proposed, cells are grown directly on a polylysine-coated track-etch material that forms the base of custom-made cell dishes. Alpha-particle irradiation is done through the base of the dish. Immediately prior to irradiation, the cell dish is scanned under a microscope, and images of cells with the corresponding coordinates are saved. After irradiation and after the biological end point under study has been determined, the cell dish is etched to develop alpha-particle tracks in the dish base. A microscope image series of alpha-particle track images is obtained by accurately revisiting every original (preirradiation) cell position in the track-etched dish. The number of alpha-particle traversals of each individual cell is scored by mapping images of alpha-particle tracks onto the images of cells recorded prior to irradiation. The uncertainty of the alpha-particle hit determination is 0.9 microm. The procedure described thus presents a method for radiobiological experiments with absolute, rather than statistical, cell dosimetry.

Air↗
PubMed2000

Induction and repair of DNA double-strand breaks under irradiation and microgravity.

The influence of microgravity on induction and repair of double-strand breaks was studied in the yeast mutant rad54-3, which is temperature-conditional for the repair of DNA double-strand breaks. The experiment was performed on the shuttle Atlantis flight STS-84. Cell samples were kept at 0-4 degrees C until they reached orbit, where they were transferred to 22 (permissive temperature for repair) and 37 degrees C (restrictive temperature). They were exposed to graded doses of beta particles from an in-built (63)Ni source during the repair period. After 152 h in microgravity, the radiation exposure was stopped, and the samples were returned to low-temperature conditions, where they remained until final evaluation in the home laboratory. The amount of double-strand breaks remaining was estimated from the differences in survival after plating and incubation at the restrictive temperature. The results show that there is no significant difference for both the induction and the repair of double-strand breaks between microgravity and terrestrial conditions.

DNA Damage↗
PubMed2000

Electron and photon spectra for three gadolinium-based cancer therapy approaches.

Some recent neutron capture therapy research has focused on using compounds containing the element gadolinium, which produces internal conversion and Auger cascade electrons. The low-energy, short-range Auger electrons are absorbed locally and increase cell killing dramatically as the gadolinium compounds are introduced into the cell nucleus and bind to the DNA. Detailed electron and photon spectra are needed for biophysical modeling and Monte Carlo calculations of damage to DNA. This paper presents calculated electron and photon spectra for three cases: thermal neutron absorption by (157)Gd, the beta-particle decay of (159)Gd, and the K-shell photoelectric event in gadolinium. The Monte Carlo sampling of atomic and nuclear transitions for each of the three cases was used to calculate a large number of representative decays. The sampled decays were used to determine average emissions and energy deposited in small spheres of tissue. The kinetic energy nuclear recoil from gamma-ray and electron emissions was calculated and found to be more than 10 eV for 26% of all (157)Gd neutron capture reactions.

Adult↗
PubMed2003

The nonuniformity of antibody distribution in the kidney and its influence on dosimetry.

The therapeutic efficacy of radiolabeled antibody fragments can be limited by nephrotoxicity, particularly when the kidney is the major route of extraction from the circulation. Conventional dose estimates in kidney assume uniform dose deposition, but we have shown increased antibody localization in the cortex after glomerular filtration. The purpose of this study was to measure the radioactivity in cortex relative to medulla for a range of antibodies and to assess the validity of the assumption of uniformity of dose deposition in the whole kidney and in the cortex for these antibodies with a range of radionuclides. Storage phosphor plate technology (radioluminography) was used to acquire images of the distributions of a range of antibodies of various sizes, labeled with 125I, in kidney sections. This allowed the calculation of the antibody concentration in the cortex relative to the medulla. Beta-particle point dose kernels were then used to generate the dose-rate distributions from 14C, 131I, 186Re, 32P and 90Y. The correlation between the actual dose-rate distribution and the corresponding distribution calculated assuming uniform antibody distribution throughout the kidney was used to test the validity of estimating dose by assuming uniformity in the kidney and in the cortex. There was a strong inverse relationship between the ratio of the radioactivity in the cortex relative to that in the medulla and the antibody size. The nonuniformity of dose deposition was greatest with the smallest antibody fragments but became more uniform as the range of the emissions from the radionuclide increased. Furthermore, there was a strong correlation between the actual dose-rate distribution and the distribution when assuming a uniform source in the kidney for intact antibodies along with medium- to long-range radionuclides, but there was no correlation for small antibody fragments with any radioisotope or for short-range radionuclides with any antibody. However, when the cortex was separated from the whole kidney, the correlation between the actual dose-rate distribution and the assumed dose-rate distribution, if the source was uniform, increased significantly. During radioimmunotherapy, the extent of nonuniformity of dose deposition in the kidney depends on the properties of the antibody and radionuclide. For dosimetry estimates, the cortex should be taken as a separate source region when the radiopharmaceutical is small enough to be filtered by the glomerulus.

Animals↗
PubMed2006

Development of an improved dose reconstruction system for the Techa River population affected by the operation of the Mayak Production Association.

The Techa River Dosimetry System (TRDS) has been developed to provide estimates of dose received by approximately 30,000 members of the Extended Techa River Cohort (ETRC). Members of the ETRC were exposed beginning in 1949 to significant levels of external and internal (mainly from (90)Sr) dose but at low to moderate dose rates. Members of this cohort are being studied in an effort to test the hypothesis that exposure at low to moderate dose rates has the same ability to produce stochastic health effects as exposure at high dose rates. The current version of the TRDS is known as TRDS-2000 and is the subject of this paper. The estimated doses from (90)Sr are supported strongly by approximately 30,000 measurements made with a tooth beta-particle counter, measurements of bones collected at autopsy, and approximately 38,000 measurements made with a special whole-body counter that detects the bremsstrahlung from (90)Y. The median doses to the red bone marrow and the bone surface are 0.21 and 0.37 Gy, respectively. The maximum doses to the red bone marrow and bone surface are 2.0 and 5.2 Gy, respectively. Distributions of dose to other organs are provided and are lower than the values given above. Directions for future work are discussed.

Body Burden↗