A comparison of thyroidal protection by stable iodine or perchlorate in the case of acute or prolonged radioiodine exposure.

In the case of a nuclear power plant accident, repetitive/prolonged radioiodine release may occur. Radioiodine accumulates in the thyroid and by irradiation enhances the risk of cancer. Large doses of non-radioactive iodine may protect the thyroid by inhibiting radioiodine uptake into the gland (iodine blockade). Protection is based on a competition at the active carrier site in the cellular membrane and the Wolff-Chaikoff effect, the latter being, however, only transient (24-48 h). Perchlorate may alternatively provide protection by a carrier competition mechanism only. Perchlorate has, however, a stronger affinity to the carrier than iodide. Based on an established biokinetic-dosimetric model developed to study iodine blockade, and after its extension to describe perchlorate pharmacokinetics and the inhibition of iodine transport through the carrier, we computed the protective efficacies that can be achieved by stable iodine or perchlorate in the case of an acute or prolonged radioiodine exposure. In the case of acute radioiodine exposure, perchlorate is less potent than stable iodine considering its ED50. A dose of 100 mg stable iodine has roughly the same protective efficacy as 1000 mg perchlorate. For prolonged exposures, single doses of protective agents, whether stable iodine or perchlorate, offer substantially lower protection than after acute radioiodine exposure, and thus repetitive administrations seem necessary. In case of prolonged exposure, the higher affinity of perchlorate for the carrier in combination with the fading Wolff-Chaikoff effect of iodine confers perchlorate a higher protective efficacy compared to stable iodine. Taking into account the frequency and seriousness of adverse effects, iodine and perchlorate at equieffective dosages seem to be alternatives in case of short-term acute radioiodine exposure, whereas preference should be given to perchlorate in view of its higher protective efficacy in the case of longer lasting radioiodine exposures.

Antioxidant effects of vitamin D on lacrimal glands against high dose radioiodine-associated damage in an animal model.

PURPOSE: To evaluate antioxidant effects of active vitamin D (calcitriol) against high-dose radioiodine (RAI) therapy-associated damage of lacrimal gland. MATERIALS AND METHODS: Wistar albino rats were used and divided into three groups randomly (n = 12/group). The first group was appointed as the negative control group and received no RAI or medication. The second group was appointed as the positive control group that only received 3 mCi/kg (111 MBq/kg) RAI via gastric gavage and the last group was the treatment group that received 3 mCi/kg RAI via same method and calcitriol (200 ng/kg/day) via intraperitoneal administration. Seven days after RAI administration, bilateral intraorbital (IG), extraorbital (EG) and Harderian (HG) glands were removed for the evaluations of histopathologic, tissue cytokine, total oxidant status (TOS) and total antioxidant status (TAS). RESULTS: RAI led to significant increase in tissue TOS, TNF-α, IL-6 levels and significant decrease in IL-10 and TAS levels (p < 0.05 for each). Addition of adjunctive calcitriol reversed all these parameters significantly (p < 0.05 for each).The following histopathologic parameters were seen more frequently in positive control group than the other groups: Abnormal lobular pattern, perivascular infiltration, periductal infiltration, lipofuscin-like accumulation, acinar atrophy, periductal and periacinar fibrosis in all lacrimal gland types (p < 0.05), acinar fibrosis in EG (p = 0.049), periductal fibrosis in EG and HG (p = 0.049 and 0.038, respectively), abnormal cell outlines in EG and HG (p = 0.020 and 0.011, respectively) and variation in cell size in the IG and the HG (p = 0.003 and 0.049 respectively). CONCLUSIONS: RAI caused significant oxidative stress and inflammation in lacrimal glands. Vitamin D demonstrated potent anti-inflammatory, antioxidant and radio-protective effects on lacrimal glands in histopathologic, tissue cytokine and oxidant/antioxidant level evaluations.

Protective Effect of Ginseng on Salivary Dysfunction Following Radioiodine Therapy in a Mouse Model.

BACKGROUND: Following radioiodine (RI) therapy, oxidative stress is a putative damage mechanism resulting in salivary gland (SG) dysfunction. Since ginseng is a known anti-oxidative herb, we examined the SG radioprotective effects of Korea red ginseng (KRG) in a mouse model, when administered prior to RI. METHODS: Four-week-old mice (n = 60) were divided into four groups: (1) normal control, (2) RI only treated (0.01 mCi/g, orally), (3) KRG administered (0.2 mg/g, intraperitoneal injection) 0.5 and 24 hours before RI, and (4) amifostine-treated group (0.2 mg/g, intraperitoneally) 0.5 hour before RI. The salivary lag times and flow rates were assessed, and sampled tissues were subjected to histologic examinations including hematoxylin and eosin and immunohistochemical staining. Apoptosis was examined by the terminal deoxynucleotidyl transferase biotin-dUDP nick end labeling (TUNEL) assay, and excretion changes in salivary 99mTc pertechnetate were evaluated by single-photon emission computed tomography. RESULTS: The body weight of the KRG group was similar to the control group. Salivary lag times and flow rates in the RI + KRG group were faster than in the RI only group. There was no significant intergroup difference in the SG weight. The RI + KRG group exhibited more mucin-containing parenchyma and less fibrotic tissues than the RI only group. Salivary epithelial (aquaporin 5) and myoepithelial (smooth muscle actin) cells of the RI + KRG group were protected from radiation damage. Low 8-OhdG (oxidative stress biomarker) and high superoxide dismutase 2 (reactive oxygen species scavenger) immunostaining reactivity was detected in the RI + KRG group when compared with the RI only group. Fewer apoptotic cells were observed in the RI + KRG or amifostine group compared to the RI only group in the TUNEL assay. The 99mTc pertechnetate excretion level recovered in the KRG group. CONCLUSION: Pretreatment with KRG before RI therapy is potentially beneficial in protecting against RI-induced salivary dysfunction.

Preparation and Characterization of Hyaluronic Acid-Polycaprolactone Copolymer Micelles for the Drug Delivery of Radioactive Iodine-131 Labeled Lipiodol.

Micelles, with the structure of amphiphilic molecules including a hydrophilic head and a hydrophobic tail, are recently developed as nanocarriers for the delivery of drugs with poor solubility. In addition, micelles have shown many advantages, such as enhanced permeation and retention (EPR) effects, prolonged circulation times, and increased endocytosis through surface modification. In this study, we measured the critical micelle concentrations, diameters, stability, and cytotoxicity and the cell uptake of micelles against hepatic cells with two kinds of hydrophilic materials: PEG-PCL and HA-g-PCL. We used 131I as a radioactive tracer to evaluate the stability, drug delivery, and cell uptake activity of the micelles. The results showed that HA-g-PCL micelles exhibited higher drug encapsulation efficiency and stability in aqueous solutions. In addition, the 131I-lipiodol loaded HA-g-PCL micelles had better affinity and higher cytotoxicity compared to HepG2 cells.

Excretion and toxicity evaluation of 131I-Sennoside A as a necrosis-avid agent.

1. Sennoside A (SA) is a newly identified necrosis-avid agent that shows capability for imaging diagnosis and tumor necrosis targeted radiotherapy. As a water-soluble compound, 131I-Sennoside A (131I-SA) might be excreted predominately through the kidneys with the possibility of nephrotoxicity. 2. To further verify excretion pathway and examine nephrotoxicity of 131I-SA, excretion and nephrotoxicity were appraised. The pharmacokinetics, hepatotoxicity and hematotoxicity of 131I-SA were also evaluated to accelerate its possible clinical translation. All these studies were conducted in mice with ethanol-induced muscular necrosis following a single intravenous administration of 131I-SA at 18.5 MBq/kg or 370 MBq/kg. 3. Excretion data revealed that 131I-SA was predominately (73.5% of the injected dose (% ID)) excreted via the kidneys with 69.5% ID detected in urine within 72 h post injection. Biodistribution study indicated that 131I-SA exhibited initial high distribution in the kidneys but subsequently a fast renal clearance, which was further confirmed by the results of autoradiography and single-photon emission computed tomography-computed tomography (SPECT-CT) imaging. The maximum necrotic to normal muscle ratio reached to 7.9-fold at 48 h post injection, which further verified the necrosis avidity of 131I-SA. Pharmacokinetic parameters showed that 131I-SA had fast blood clearance with an elimination half-life of 6.7 h. Various functional indexes were no significant difference (p > 0.05) between before administration and 1 d, 8 d, 16 d after administration. Histopathology showed no signs of tissue damage. 4. These data suggest 131I-SA is a safe and promising necrosis-avid agent applicable in imaging diagnosis and tumor necrosis targeted radiotherapy.

Radioprotective effect of montelukast sodium in rat lacrimal glands after radioiodine treatment.

PURPOSE: The aim of this study was to evaluate the morphological changes of rat lacrimal glands at the third month following radioiodine (RAI) treatment and the radioprotective effect of montelukast (ML) sodium against RAI-related lacrimal gland damage. METHODS: Fifty female Wistar Albino rats were divided into three groups. The control group (n=10) consisted of rats with no intervention. RAI group (n=20) consisted of rats treated with oral (131)I (111 MBq). The ML group (n=20) consisted of rats treated with intraperitoneal 10mg/kg/day ML sodium, starting three days before and continuing for one week after oral RAI administration. Intraorbital (IG), extraorbital (EG) and Harderian glands (HG) were removed bilaterally after three months. RESULTS: The existence of acinar atrophy, acinar fibrosis, abnormal cell lines, peripheral basophilia, cell size variation and decrease in amount of cytoplasm was significantly more common in the RAI-rat treated group than in the ML group, in each of the glands. The ML-treated group had less-frequent cell shape variation in EG (P=0.001) and HG (P=0.027), cell size variation in IG (P<0.001) and HG (P=0.01), ductal pathology in EG (P<0.001) and HG (P<0.001) and lipofuscin accumulation in EG (P=0.001) and in HG (P=0.01) than the RAI-treated group. CONCLUSIONS: RAI treatment seems to cause morphological damage to rat lacrimal glands, and ML sodium effectively protects against damage to lacrimal glands.

Cytotoxic and mutagenic effects of iodine-131 and radioprotection of acerola (Malpighia glabra L.) and beta-carotene in vitro.

The radioisotope iodine-131 [(131)I] can damage DNA. One way to prevent this is to increase the amount of antioxidants via dietary consumption. The goal of this study was to evaluate the radioprotective effect of fresh acerola pulp and synthetic beta-carotene in Rattus norvegicus hepatoma cells (HTC) in response to [(131)I] exposure in vitro. Cellular DNA damage was subsequently assessed using a cytokinesis block micronucleus assay. The mutagenic and cytotoxic activities of doses of [(131)I] (0.1, 0.5, 1, 5, and 10 µCi), acerola (0.025, 0.125, and 0.25 g acerola pulp/mL), and beta-carotene (0.2, 1, and 2 µM) were evaluated. Radioprotective tests were performed by simultaneous treatment with acerola (0.25 g/mL) plus [(131)I] (10 µCi) and beta-carotene (0.2 µM) plus [(131)I] (10 µCi). Acerola, beta-carotene, and low concentrations of [(131)I] did not induce micronucleus formation in HTC cells; in contrast, high concentrations of [(131)I] (10 µCi) were mutagenic and induced DNA damage. Moreover, neither acerola nor beta-carotene treatment was cytotoxic. However, acerola reduced the percentage of [(131)I]-induced damage, although beta-carotene did not show a similar effect. Thus, our results suggest that acerola diet supplementation may benefit patients who are exposed to [(131)I] during thyroid diagnostics and therapy.

Tumor response and toxicity with multiple infusions of high dose 131I-MIBG for refractory neuroblastoma.

BACKGROUND: (131)I Metaiodobenzylguanidine ((131)I-MIBG) is an effective targeted radiotherapeutic for neuroblastoma with response rates greater than 30% in refractory disease. Toxicity is mainly limited to myelosuppression. The aim of this study was to determine the response rate and hematologic toxicity of multiple infusions of (131)I-MIBG. PROCEDURE: Patients received two to four infusions of (131)I-MIBG at activity levels of 3-19 mCi/kg per infusion. Criteria for subsequent infusions were neutrophil recovery without stem cell support and lack of disease progression after the first infusion. RESULTS: Sixty-two infusions were administered to 28 patients, with 24 patients receiving two infusions, two patients receiving three infusions, and two patients receiving four infusions. All patients were heavily pre-treated, including 16 with prior myeloablative therapy. Eleven patients (39%) had overall disease response to multiple therapies, including eight patients with measurable responses to each of two or three infusions, and three with a partial response (PR) after the first infusion and stable disease after the second. The main toxicity was myelosuppression, with 78% and 82% of patients requiring platelet transfusion support after the first and second infusion, respectively, while only 50% had grade 4 neutropenia, usually transient. Thirteen patients did not recover platelet transfusion independence after their final MIBG infusion; stem cell support was given in ten patients. CONCLUSIONS: Multiple therapies with (131)I-MIBG achieved increasing responses, but hematologic toxicity, especially to platelets, was dose limiting. More effective therapy might be given using consecutive doses in rapid succession with early stem cell support.

Targeting of meta-iodobenzylguanidine to SK-N-SH human neuroblastoma xenografts: tissue distribution, metabolism and therapeutic efficacy.

The clinical results of [(131)I]meta-iodobenzylguanidine (MIBG)-targeted radiotherapy in neuroblastoma patients is highly variable. To assess the therapeutic potential of [(131)I]MIBG, we used the SK-N-SH human neuroblastoma, xenografted in nude mice. The model was first characterized for basic parameters of MIBG handling in the host species. This demonstrated the presence of both strain- and nu/nu mutation-related differences in [(131)I]MIBG biodistribution. Fecal and urinary clearance rates of [(131)I]MIBG in mice roughly resemble those in humans, but mice metabolize MIBG more extensively. In both species, enzymatic deiodination in vivo was not an important metabolic route. Therapy with increasing [(131)I]MIBG doses (25-92 MBq) given as single i.v. injections resulted in proportionally increasing specific growth delay values (tumor regrowth delay/doubling time) of 1 to 5. Using gamma-camera scintigraphy for non-invasive dosimetry, the corresponding calculated absorbed tumor radiation doses ranged from 2 to 11 Gy. We also compared the therapeutic effects of a single [(131)I]MIBG administration with those resulting from a more protracted exposure by fractionating the dose in 2 to 6 injections or with high dose rate external-beam irradiation. No therapeutic advantage of a fractionated schedule was observed, and 5.5 Gy delivered by low dose-rate [(131)I]MIBG endo-irradiation was equi-effective with 5.0 Gy X-rays. The SK-N-SH neuroblastoma xenograft model thus appears suitable to evaluate possible treatment improvements to reach full potential of MIBG radiotherapy.

Salivary gland protection by S-2-(3-aminopropylamino)-ethylphosphorothioic acid (amifostine) in high-dose radioiodine treatment: results obtained in a rabbit animal model and in a double-blind multi-arm trial.

Since differentiated thyroid cancer has an excellent prognosis, reduction of long-term side effects of high-dose radioiodine treatment (HD-RIT), i.e. salivary gland impairment is important. Thus, radioprotective effects of amifostine were studied. Salivary gland function was quantified by scintigraphy both in rabbits and patients. Fifteen rabbits were studied prior to and up to 6 months after HD-RIT applying 2 GBq 131I. Ten animals received 200 mg/kg amifostine prior to HD-RIT, and five served as controls. Animals were examined histopathologically. Fifty patients with differentiated thyroid cancer were evaluated prospectively prior to and 3 months after HD-RIT with either 3 or 6 GBq 131I in a double-blind, placebo-controlled study. Twenty-five patients were treated with 500 mg/m2 amifostine intravenously prior to HD-RIT, and 25 patients receiving physiological saline solution served as controls. Complete ablation of the thyroid was achieved in all rabbits four weeks after HD-RIT. In control rabbits 6 months after HD-RIT parenchymal function was reduced significantly (p < 0.0001) by 75.3 +/- 5.3% and 53.6 +/- 17.4% in parotid and submandibular glands, respectively. In contrast, in amifostine-treated rabbits parenchymal function was not significantly reduced. Histopathologically, marked lipomatosis was observed in control animals but was negligible in amifostine-treated animals. In control patients, salivary gland function was significantly (p < 0.001) reduced by 40.2 +/- 14.1% and 39.9 +/- 15.3% in parotid and submandibular glands, respectively, three months after HD-RIT, and 11 patients developed xerostomia. In 25 amifostine-treated patients, salivary gland function was not significantly reduced (p = 0.691), and xerostomia did not occur. Thus, parenchymal damage in salivary glands induced by high-dose radioiodine therapy can be reduced significantly by amifostine. This may improve quality of life of patients with differentiated thyroid cancer.

Vitamins as radioprotectors in vivo. II. Protection by vitamin A and soybean oil against radiation damage caused by internal radionuclides.

Tissue-incorporated radionuclides impart radiation energy over extended periods of time depending on their effective half-lives. The capacity of vitamin A dissolved in soybean oil to protect against the biological effects caused by internal radionuclides is investigated. The radiochemicals examined are DNA-binding 125IdU, cytoplasmically localized H125IPDM and the alpha-particle emitter 210Po citrate. As in our previous studies, spermatogenesis in mice is used as the experimental model and spermatogonial cell survival is the biological end point. Surprisingly, soybean oil itself provides substantial and equal protection against the Auger effect of 125IdU, which is comparable to a high-LET radiation effect, as well as the low-LET effects of H125IPDM, the dose modification factors (DMFs) being 3.6 +/- 0.9 (SEM) and 3.4 +/- 0.9, respectively. The protection afforded by the oil against the effects of 5.3 MeV alpha particles emitted by 210Po is also significant (DMF = 2.2 +/- 0.4). The presence of vitamin A in the oil further enhanced the radioprotection against the effect of 125IdU (DMF = 4.8 +/- 1.3) and H125IPDM (DMF = 5.1 +/- 0.6); however, no enhancement is provided against the effects of alpha particles. These interesting results with soybean oil and vitamin A, together with data on the subcellular distribution of the protectors, provide clues regarding the mechanistic aspects of the protection. In addition, the data for vitamin A reaffirm our earlier conclusion that the mechanism by which DNA-bound Auger emitters impart biological damage is primarily indirect in nature.

Suppression of 125I-uptake in mouse thyroid by seaweed feeding: possible preventative effect of dietary seaweed on internal radiation injury of the thyroid by radioactive iodine.

We conducted an animal experiment to determine how dietary seaweeds rich in iodine and dietary fibers suppress radioactive iodine uptake by the thyroid, using mice and four kinds of experimental diets, three with 1% or 2% powdered fronds of the kelp Laminaria religiosa and 2% powdered laver Porphyra yezoensis, and one with cellulose. Iodine content of a hot-water extract of the kelp was 0.530 +/- 0.001%, and its dietary fiber (DF) values were 52.8 +/- 1.2%. Iodine in an extract of the laver was 0.008 +/- 0.001%, and its DF values were 41.4% +/- 0.7%. A statistically significant reduction of 125I uptake by the thyroid, 3 hours after intragastric administration of the radionuclide at a dosage of 18.5 kBq or 185 kBq in 0.3 ml aqueous solution per mouse, was observed in mice previously fed the experimental diets containing 1% and 2% kelp during periods varying from 24 hours to 7 days. The degree of the suppression was observed to depend on the amount of iodine in the diet or in the injected sample, no matter whether organic or inorganic, judging from the results of an additional experiment. Thus, we conclude that previously fed iodine-rich material, especially dietary seaweeds rich in iodine and other minerals, vitamins, and beta-carotene, such as kelps or laver supplemented with inorganic iodine, may be effective in prevention of internal radiation injury of the thyroid.

Tumour development following internal exposures to radionuclides during the perinatal period.

Exposure to radiation from internally deposited radionuclides during the prenatal and/or neonatal periods bears a distinct oncogenic potential. The fundamental mechanisms of perinatal radionuclide carcinogenesis seem to be generally similar to those that pertain to external radiation exposures and other carcinogenic agents, but unique interactions may be superimposed. Specific dose-effect relationships differ among radionuclides; in many studies, there have been dose-related increases in the incidence of tumours or decreases in age at tumour appearance following prenatal or neonatal radiation exposure. Tumour incidences may be decreased, especially at high dose levels; these are usually attributable to cell death, inhibited development of target tissues or to endocrine malfunction. Age-related differences in predominant tumour types and/or sites of tumour development are often detected, and are explainable by the existence of nuclide-specific target organs or tissues, dosimetric factors and developmental considerations.