thiourea and Thyroid-Neoplasms

Topics: Adenoma; Animals; Dogs; Fluorenes; Humans; Iodine; Iodine Radioisotopes; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Radiation Effects; Radiotherapy; Rats; Sheep; Thiouracil; Thiourea; Thyroid Gland; Thyroid Neoplasms; Thyroidectomy; Transplantation, Homologous

Cancers and hepatoprotective prevention using traditional medicines have attracted increasing interest. The aim of our study was to characterize the putative protective effects of ethanol and chloroform extracts of Peganum harmala on thiourea-induced diseases in adult male rat. We seek to determine the effects of these plant extracts on body weight, thyroid and endocrine cancer parameters. In addition the putative hepatoprotective effect was checked by the determination of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the bilirubin level in the blood. Our data show that ethanol and chloroform extracts of Peganum harmala protected the animal against the carcinogenic effects induced by thiourea since neuron-specific enolase (NSE) and thyroglobulin (TG) levels were back to the normal range. In addition, the observed-hepatocytotoxicity after thiourea treatment was greatly reduced (AST and ALT activities were respectively 270 IU/l and 60 IU/l and in the same order of magnitude as in the untreated rats) as well as the bilirubin levels (6 micromol/l) especially for animals receiving the choroform preparation. Therefore we may suggest that extracts of Peganum harmala are efficient to reduce the toxicity induced by thiourea in male rat as far as the above parameters are concerned.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Bilirubin; Body Weight; Chloroform; Ethanol; Male; Multiple Endocrine Neoplasia; Peganum; Phosphopyruvate Hydratase; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Thiourea; Thyroglobulin; Thyroid Neoplasms; Time Factors

Five chemicals that are known to induce in rats thyroid follicular-cell adenomas and carcinomas were assayed for their ability to induce DNA damage and DNA repair synthesis in primary cultures of human thyroid cells. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measured by the same Comet assay, were obtained after a 20-h exposure to the following subtoxic concentrations of the five test compounds: methimazole from 2.5 to 10mM; nitrobenzene, potassium bromate, N,N'-diethylthiourea and ethylenethiourea from 1.25 to 5mM. Under the same experimental conditions, DNA repair synthesis, as evaluated by quantitative autoradiography, was present in potassium bromate-exposed thyroid cells from all the three donors and in those from two of three donors with either nitrobenzene or ethylenethiourea, but did not match the criteria for a positive response in thyroid cells from any of the donors with methimazole and N,N'-diethylthiourea. Consistently with their ability to induce thyroid tumors, all the five test compounds, administered p.o. in rats in a single dose corresponding to 1/2 LD50, induced a statistically significant degree of DNA fragmentation in the thyroid. These findings suggest that the five test compounds might be carcinogenic to thyroid in humans.

Topics: Adenocarcinoma, Follicular; Adenoma; Animals; Bromates; Carcinogens; Cells, Cultured; DNA Damage; DNA Fragmentation; DNA Repair; Ethylenethiourea; Humans; In Vitro Techniques; Kidney; Liver; Male; Methimazole; Nitrobenzenes; Rats; Rats, Sprague-Dawley; Thiourea; Thyroid Gland; Thyroid Neoplasms

Male Wistar rats were divided into two groups. Rats of group 1 were fed basal powdered diet containing 610 ppm 2,4- diaminoanisole sulfate (DAAS), 46 ppm 4,4'-thiodianiline (TDA) and 200 ppm N,N'-diethylthiourea (DETU) for 52 weeks (DTD treatment). Rats of group 2 were maintained on basal diet throughout the experiment as controls. At 52 weeks all surviving rats were sacrificed and subjected to an autopsy. Thyroid, lungs, stomach, liver, spleen, kidneys, testes and all gross lesions suspected of being a tumor were removed. After DTD treatment, the incidence of thyroid hyperplasia and papillary thyroid carcinoma was 59% (10/17) and 65% (11/17), respectively. Hepatocellular adenoma was induced in 2 of 17 rats (12%). Papillary thyroid carcinoma metastasis was found in the lung of 1 rat. No neoplastic tumors were found in kidney, spleen, stomach and testis tissue.

Topics: Adenoma, Liver Cell; Aniline Compounds; Animals; Carcinogens; Carcinoma, Papillary; Drug Synergism; Hyperplasia; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms, Experimental; Phenylenediamines; Rats; Rats, Inbred F344; Rats, Wistar; Species Specificity; Thiourea; Thyroid Gland; Thyroid Neoplasms

Topics: Animals; Anti-Infective Agents; Antifungal Agents; Antithyroid Agents; Carcinogens; Diuretics; Griseofulvin; Hair Dyes; Humans; Hypnotics and Sedatives; Pesticides; Pyrones; Spironolactone; Thiourea; Thyroid Neoplasms

In our previous investigation, which focused on two-stage carcinogenicity in the thyroid, rats were administered N-bis(2-hydroxypropyl)nitrosamine (DHPN), followed by thiourea (TU) over an experimental period of 19 weeks. Simultaneous treatment with a high level of vitamin A (VA) enhanced the induction of proliferative lesions that originated from the thyroidal follicular epithelium. To examine whether hormone synthesis in the thyroid could be inhibited by simultaneous treatment with a large amount of VA and TU, all of the rats were initially given a single subcutaneous injection of 2,800 mg DHPN/kg followed by a supply of 0% TU + 0% VA (DHPN only, control group), 0.2% TU in their drinking water (DHPN/TU group), 0.1% VA in their diet (DHPN/VA group), or 0.2% TU + 0.1% VA (DHPN/TU + VA group) during an experimental period of 4 weeks. Results obtained indicate that the iodine uptake and organification, namely iodination of tyrosine residue in thyroglobulin, of the thyroid, were significantly decreased in the DHPN/TU group compared to the DHPN control group. The variation in these values was attributable to the inhibitory effect of TU upon thyroid hormone synthesis. Results obtained from the DHPN/TU + VA and DHPN/TU groups were comparable. Therefore, the possibility that modification of hormone synthesis contributes to the enhancing effect of simultaneous treatment with a large amount of VA on thyroidal tumor induction by TU is considered to be very minimal.

Topics: Adenoma; Animals; Body Weight; Bromodeoxyuridine; Carcinogens; Drug Synergism; Hyperplasia; Iodine; Liver; Nitrosamines; Organ Size; Pituitary Gland; Rats; Rats, Inbred F344; Thiourea; Thyroid Gland; Thyroid Hormones; Thyroid Neoplasms; Vitamin A

Changes of TSH-producing cells in the pituitary and thyroid expression of the growth factors, transforming growth factor alpha (TGF alpha) and epidermal growth factor receptor (EGFR), as well as cyclin D1, were investigated immunohistochemically in order to clarify their contribution to the enhancing effects of excess vitamin A (VA) on thyroidal carcinogenesis induced by thiourea (TU). Male rats were allocated to 4 groups, control, TU, VA, and TU + VA, respectively, receiving no treatment, water containing 0.2% TU, diet containing 0.1% VA, and both for 10 or 19 weeks after a single s.c. injection of DHPN (2800 mg/kg) for initiation. Immunohistochemistry using antibodies against TSH demonstrated enlargement of TSH-producing cells in the TU + VA group as compared to the TU group, supporting our conclusion that enhanced TSH stimulation is mainly responsible for promoting the effects of excess VA. Since the expression of TGF alpha, EGFR, and cyclin D1 in thyroid proliferative lesions did not exhibit any differences between the TU and TU + VA groups in the present study, these factors are unlikely to participate in VA enhancement of carcinogenesis.

Topics: Animals; Cyclin D1; Drug Synergism; ErbB Receptors; Immunohistochemistry; Male; Pituitary Gland; Rats; Rats, Inbred F344; Thiourea; Thyroid Gland; Thyroid Neoplasms; Thyrotropin; Transforming Growth Factor alpha; Vitamin A

The mechanisms underlying enhanced cell proliferation in thyroid proliferative lesions of rats simultaneously treated with large amounts of vitamin A (VA) and thiourea (TU) were investigated. Male F344 animals were initiated with N-bis(2-hydroxypropyl)nitrosamine (2800 mg/kg body weight, single s.c. injection). Starting 1 week later, groups received water containing 0.2% TU (TU group), diet containing 0.1% VA (VA group), both 0.2% TU and 0.1% VA (TU + VA group) or tap water/basal diet without supplement (control group) for 10 weeks. The serum levels of triiodothyronine (T3) and thyroxine (T4) were decreased and the thyroid stimulating hormone (TSH) levels were elevated in the TU and TU + VA groups, with the degree of change being significantly greater in the combined treatment group. The induction of P450 isoenzymes by TU was not enhanced by VA supplementation, but uridine diphosphate glucuronosyltransferase (UDP-GT) activity in the liver was significantly increased in the TU + VA group compared to the TU group. Thyroid weights were increased in both the TU and TU + VA groups, this being more pronounced with VA supplementation. Thyroid follicular cell hyperplasias and neoplasias were induced to similar extents in both TU treated groups, but their cell proliferation appeared to be increased by the VA supplementation. The results of the present study suggest that enhanced cell proliferation is due to increased TSH stimulation, resulting from the decrease in serum T3/T4 levels brought about by induction of liver UDP-GT activity with the combined action of TU + VA as well as inhibition by TU of thyroid hormone synthesis in the thyroid.

Topics: Animals; Antithyroid Agents; Blotting, Western; Body Weight; Carcinogens; Cell Division; Glucuronosyltransferase; Isoenzymes; Liver; Male; Microsomes, Liver; Organ Size; Rats; Rats, Inbred F344; Thiourea; Thyroid Neoplasms; Triiodothyronine; Vitamin A

In order to examine modifying effects of simultaneous treatment with large amounts of vitamin A (VA) and thiourea (TU) on the thyroid tumorigenesis in rats, male F344 rats were initiated with N-bis(2-hydroxypropyl)nitrosamine (2800 mg/kg body weight, single s.c. injection), and starting 1 week later received diet containing 0.1% VA (VA group), drinking water containing 0.2% TU (TU group), 0.2% TU + 0.1% VA (TU + VA group) or tap water/basal diet (control group) for 19 weeks. Serum T3 and T4 in the TU and TU + VA groups were significantly decreased as compared to the control group, while serum TSH levels were remarkably increased. The ratios of T3 and T4 decrease and TSH increase in the TU + VA group were remarkably more pronounced than in the TU group. Thyroid neoplastic lesions were only induced in the TU and TU + VA groups. The multiplicity of intracapsular follicular cell proliferative foci in the TU + VA group was significantly increased as compared to the TU group value. Cell proliferation of hypertrophic and subcapsular follicular cells, as well as in hyperplasias, and neoplasias with adenomatous growth pattern was significantly higher in the combined treatment case than after TU alone. In the liver, centrilobular hypertrophy of hepatocytes was seen in the TU and TU + VA groups, this being especially marked in the latter group. In the combined group case the affected cells were strongly positive for GST-P antibody binding. The results of the present study suggest that cell proliferation of thyroid follicular cell proliferative lesions in rats is enhanced by strong TSH stimulation with simultaneous treatment of TU and large amounts of VA.

Topics: Adenoma; Animals; Body Weight; Carcinogens; Cell Division; Drug Synergism; Male; Nitrosamines; Rats; Rats, Inbred F344; Reference Values; Thiourea; Thyroid Gland; Thyroid Neoplasms; Thyrotropin; Thyroxine; Triiodothyronine; Vitamin A

To examine changes in serum TSH and determine whether the sustained excess is necessary for the development and/or progression of thyroid tumors, male F344 rats were administered drinking water containing thiourea (TU), at 0.1 or 0.05%, or sulfadimethoxine (SM), at 0.025 or 0.0125%, for one week in Experiment I. All of the treated animals showed decreased serum levels of T3 and T4 and an increased TSH. In Experiment II, male rats were given a s.c. injection of N-bis(2-hydroxypropyl) nitrosamine (DHPN:1500 mg/kg BW) and, starting one week later, received drinking water containing the same doses of TU or SM as in Experiment I for the following 20 weeks. Thyroid follicular proliferative lesions were induced in most rats treated with TU and SM. However, these treated animals did not demonstrate any consistent alterations in serum T3, T4 and TSH levels, except for the high dose TU group. The present studies thus suggest that thyroid tumors can grow even under conditions of fluctuating serum TSH levels during the progression phase, although TSH stimulation might be an absolute requirement in the early phase of tumor development.

Topics: Animals; Antithyroid Agents; Male; Nitrosamines; Rats; Rats, Inbred F344; Sulfadimethoxine; Thiourea; Thyroid Gland; Thyroid Neoplasms; Thyrotropin; Thyroxine; Triiodothyronine

Three thyroid carcinogens, 2,4-diaminoanisole sulfate (DAAS), N,N'-diethylthiourea (DETU) and 4,4'-thiodianiline (TDA), were simultaneously administered in the diet to male F344 rats at one-third the concentration of the reported TD50 levels (610, 200 and 46 p.p.m. respectively) for 52 weeks. The resultant incidence of thyroid adenocarcinomas in the combined treatment group (18/18: 100%) was significantly higher than those in each individual treatment group (DAAS, 0/21; DETU, 1/21; TDA, 2/20). Hepatocellular carcinomas (9/18, 50%) and lung adenomas (6/18, 33%) were also induced by the combined treatment, the incidences being higher than in the TDA group (3/20, 15% and 4/20, 20% respectively) to which these tumors were limited in the three groups treated with single chemicals. Thus, the results indicated that the three carcinogens exert apparent synergism in thyroid carcinogenesis when administered simultaneously.

Topics: Aniline Compounds; Animals; Drug Synergism; Male; Phenylenediamines; Rats; Rats, Inbred F344; Thiourea; Thyroid Neoplasms

As commonly depicted, in the thione form, thionamides (including thiourea and its derivatives) bear little resemblance to thyroid hormone. However, if placed in the thiol resonance form, these molecules are noted to structurally mimic the end of the tyrosine molecule (the precursor of thyroid hormone). Alternatively, tyrosine written in the -one configuration resembles the thionamides. This permits a better appreciation of why the thionamides may themselves be iodinated by thyroid peroxidase in some cases, and under other circumstances induce changes in the enzyme. The thiol resonant form can be written for naturally occurring goitrin, and for thiobarbituric acids with antithyroid activity. An hydroxyl resonant configuration can be drawn for the antithyroid compound 3-hydroxy-4-pyridone. Tetramethylthiourea is a thyroid carcinogen in rats. The compound can not be readily placed in the thiol resonant configuration; it also contains 2 methyl groups at both ends of the molecule. The hair dye 2,4-diaminoanisole sulfate induces thyroid neoplasms in rats. A similarity is pointed out both to tyrosine an to lower potency antithyroid aminobenzenes (described by Astwood and coworkers). Pyrazole, known to produce thyroid necrosis, is seen to have a distinct resemblance to the opposite end of several of these compounds.

Topics: Antithyroid Agents; Carcinogens; Chemical Phenomena; Chemistry; Pyridines; Structure-Activity Relationship; Thiobarbiturates; Thiones; Thiourea; Thyroid Hormones; Thyroid Neoplasms; Tyrosine

Topics: Animals; Blood Cell Count; Body Weight; Carcinogens; Female; Hemoglobinometry; Hyperplasia; Iodine; Iodine Radioisotopes; Male; Organ Size; Rats; Thiourea; Thyroid Gland; Thyroid Neoplasms; Time Factors

Topics: Animals; Female; Hyperthyroidism; Hypothalamus; Iodine Radioisotopes; Male; Mice; Mice, Inbred AKR; Skull Neoplasms; Thiourea; Thymectomy; Thyroid Gland; Thyroid Neoplasms; Thyroxine

Topics: Genetics, Medical; Goiter; Humans; Hyperthyroidism; Hypothyroidism; Japan; Nuclear Warfare; Phenylthiourea; Taste; Thiourea; Thyroid Neoplasms; Thyroiditis

Topics: Goiter; Neoplasms; Thiourea; Thyroid Gland; Thyroid Neoplasms

Topics: Animals; Goiter; Neoplasms; Rats; Thiourea; Thyroid Gland; Thyroid Neoplasms

Topics: Animals; Goiter; Rats; Thiourea; Thyroid Neoplasms