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PubMed1994

Pharmacokinetics in melanoma-bearing mice of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a candidate compound for boron neutron capture therapy.

Blood pharmacokinetics and tissue distribution of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a boron carrier with postulated melanin-seeking properties for boron neutron capture therapy, were determined in C57/BL mice with subcutaneous pigmented or non-pigmented B16 melanomas. Borocaptate sodium (BSH) was used as a boron compound without melanin-seeking properties in a comparative biodistribution study in the same animal tumour models. Administration of single doses showed that BPTU was retained better in the pigmented B16 tumour than in the non-pigmented variant. BPTU was found in large concentrations in kidney and liver. Brain boron was approximately 10-fold lower than tumour boron. On a molar basis, BPTU demonstrated higher affinity for B16 tumours than BSH. Owing to solubility limits, tumour boron concentrations in this mouse study were too low for effective application of BNCT. However, the high tumour-to-blood and tumour-to-normal tissues ratios indicate that, with appropriate formulation, BPTU could be a promising candidate for clinical BNCT.

Animals↗
PubMed1986

Accumulation of chlorpromazine and thiouracil by human melanoma cells in culture.

The uptake (total radioactivity in intact cells) and incorporation (radioactivity bound to acid-precipitable material) of 14C-chlorpromazine (CPZ) and 14C-thiouracil (TU) were studied using a library of 3 human fibroblast strains and 13 tumour cell lines. In contrast to previous studies using rodent melanomas in vivo, the melanoma lines, including lines with high tyrosinase and melanin contents, did not take up more CPZ and TU than non-melanoma cells (fibroblasts, HeLa cells). Incorporation of CPZ was also broadly similar in all cell types studied. TU was selectively incorporated into the melanoma line having a high tyrosinase and melanin content but not into lines with high tyrosinase activity and low melanin content. While supporting the possibility of selective therapy for heavily-pigmented melanomas using labelled TU derivatives, these results suggest that the action of potentially melanoma-affined compounds should be further evaluated in human cells. Unlabelled CPZ or TU was not selectively toxic to melanoma cells. Unexpectedly, methylation-sensitive tumour cells (Mer-phenotype) were highly resistant to TU, thus providing a new experimental tool for understanding the genesis of this phenotype in vivo.

Cell Line↗
PubMed1997

Upregulation of the angiogenic factors PlGF, VEGF and their receptors (Flt-1, Flk-1/KDR) by TSH in cultured thyrocytes and in the thyroid gland of thiouracil-fed rats suggest a TSH-dependent paracrine mechanism for goiter hypervascularization.

Placenta growth factor (PlGF) and vascular endothelial growth factor (VEGF) represent two closely related angiogenic growth factors active as homodimers or heterodimers. Since goiters of the thyroid gland are extremely hypervascular, we investigated the expression of PlGF, VEGF and their receptors, Flt-1 and Flk-1/KDR, in a small panel of human goiters from patients with Graves's disease, in an animal model of thyroid goitrogenesis and in in vitro cultured thyroid cells. Here we report that the mRNA expression of PlGF, VEGF and their receptors is markedly enhanced in biopsies of goiters resected from Graves's patients. In vivo studies demonstrated that in the thyroid gland of thiouracil-fed rats, increased mRNA and protein expression of PIGF, VEGF, Flt-1 and Flk-1/KDR occurred subsequent to the rise in the serum thyroid stimulating hormone (TSH) levels and in parallel with thyroid capillary proliferation. In vitro studies confirmed the existence of such TSH-dependent paracrine communication between thyroid epithelial cells and endothelium since the conditioned medium collected from TSH-stimulated thyrocytes acquired mitogenic activity for human umbilical vein endothelial (HUVE) cells. Altogether, these data suggest that PlGF and VEGF, released by thyrocytes in response to the chronic activation of the TSH receptor pathway, may act through a paracrine mechanism on thyroid endothelium.

Animals↗
PubMed2003

Synthesis and anti-HBV activity of thiouracils linked via S and N-1 to the 5-position of methyl beta-D-ribofuranoside.

Reverse nucleoside derivatives of 2-(methylsulfanyl)uracils 6a-d were prepared by treating of the sodium salt of 2-(methylsulfanyl)uracils (5a-d) with methyl 2,3-O-isopropylidene-5-O-p-toluenesulfonyl-beta-D-ribofuranoside (2). The alkylation of 2-thiouracils 4a-d with methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-D-ribofuranoside (3) afforded the corresponding S-ribofuranoside derivatives 8a-d. Deisopropylidenation of 6a-d and 8a-d afforded the corresponding deprotected derivatives 7a-d and 9a-d, respectively. The Anti-HBV activity of selected compounds was studied.

Animals↗
PubMed1996

Effects of transient prepubertal 6-N-propyl-2-thiouracil treatment on testis development and function in the domestic fowl.

It has been well established that thyroid hormones play an important role in regulating the onset of puberty and reproductive function in birds. In mammals it has been shown that transient hypothyroidism induced with the reversible goitrogen 6-N-propyl-2-thiouracil (PTU) can result in tremendous increases in testis size and sperm production and that the timing of hypothyroidism must correspond to the period of Sertoli cell proliferation. As the period of Sertoli cell proliferation is not precisely known in the fowl, an experiment was conducted to determine whether chicken testes have a similar window of sensitivity to PTU treatment. Broiler breeder male chicks (Peterson) were placed in floor pens at one day of age and reared according to the breeder's management guide for the entire 28-wk duration (controls) or up to the point of dietary treatment with PTU (0.1% w:w) for 6 wk that began at 2-wk intervals (2-8, 4-10, 6-12, 8-14, and 10-16 wk of age); after treatment, birds were returned to feed restriction and photostimulated at 20 wk of age. Birds were bled and killed, and testes were collected at 4-wk intervals. At 28 wk, one testis was fixed for histological examination and one was immediately placed in liquid N2 for sperm counts. Treatment with PTU from 6 to 12 wk of age resulted in a 96% increase in mean testis weight at 28 wk of age (treated 39.3 +/- 4.1 g per testis vs. control 20.0 +/- 1.6 g per testis). These testes exhibited normal morphology and increased relative sperm production. Treatment with PTU from either 8 to 14 or 10 to 16 wk of age resulted in approximately a 35% increase in testis mass at 28 wk of age relative to the control value (27.2 +/- 2.0 g and 27.7 +/- 3.6 g vs. 20.0 +/- 1.6 g per testis, respectively). However, both of these groups clearly demonstrated precocious puberty and abnormal spermatogenesis. These results suggest that appropriately timed PTU treatment may result in permanent increases in testis size and sperm production in the domestic fowl.

Animals↗
PubMed1985

Uptake of 123I-5-iodo-2-thiouracil, a possible radiopharmaceutical for noninvasive detection of ocular melanoma, in melanotic and amelanotic melanomas in hamsters.

The uptake of 123I-5-iodo-2-thiouracil in melanotic and amelanotic melanoma implanted in Syrian golden hamsters was studied. A selective accumulation was found in the tumours. Uptake of 123ITU in melanotic melanomas was 4 to 5 times the uptake in amelanotic ones. For both tumours high ratios of tumours versus non-tumour were found. The high accumulation of 123ITU in both kinds of tumours and the high tumour versus non-tumour ratios suggest that 123ITU may be a promising radiopharmaceutical for the detection of ocular melanoma.

Animals↗
PubMedDate not supplied

Uptake of [131I]thiouracil in tumours of patients with disseminated malignant melanoma. A pilot study.

Previous studies on mice carrying melanoma have shown that 5-iodo-2-thiouracil (ITU) is accumulated in the tumours due to its specific incorporation into melanin during its synthesis. ITU is also selectively localized in murine melanoma metastases and in cultured human melanoma cells. Progressive formation of melanin is, however, a prerequisite for the incorporation. Four patients with disseminated melanoma were injected intravenously with 39-62 MBq [131I]TU. Blood and urine samples were gradually collected, and 3-7 days postinjection tumours were biopsied and examined by impulse counting. The patients were scanned with a gamma camera over the total body daily for 3-4 days. The radioactivity was rapidly excreted. Poor melanin pigmentation of the tumours and low proliferation rate (possibly induced by chemotherapy) decreased the uptake of radioactivity by the tumors, and no imaging was possible. One of the patients, however, had clearly progressive disease with darkly pigmented metastases which contained considerably higher levels of radioactivity than the surrounding skin. Calculations indicated that a doubling of the radioiodine dose would probably make visualization of the tumours possible.

Bone Neoplasms↗
PubMed1990

Photosensitized damage to supercoiled plasmid DNA induced by 334-nm radiation in the presence of 2-thiouracil consists of alkali- and piperidine-labile sites as well as frank strand breaks.

A covalently closed, supercoiled plasmid was irradiated with 334-nm ultraviolet radiation in the presence of the naturally occurring photosensitizer 2-thiouracil (s2Ura). After irradiation, some DNA samples were treated to reveal labile sites. Agarose gel electrophoresis was then used to resolve the unrelaxed supercoils from the relaxed forms, and the DNA bands were quantitated by fluorescence scanning. Irradiation of the plasmid in the absence of s2Ura induced small numbers of frank DNA strand breaks (FSB), alkali-labile sites (ALS), and piperidine-labile sites (PLS). The induction of each of these lesions was enhanced 30 times when s2Ura was present during aerobic irradiation. Anoxia, as well as the hydroxyl radical scavengers acetate and formate, inhibited the formation of all three lesion types. The relative proportions of the three lesion types produced by several DNA damaging treatments were measured. Hydrogen peroxide, gamma-irradiation, and s2Ura photosensitization produced nearly identical damage proportions, with PLS: FSB ratios of 1.25:1, 0.78:1, and 0.84:1, respectively. Treatment with singlet oxygen [data from Blazek et al. (1989) Photochem. Photobiol. 48, 607-613] produced much different proportions, with a PLS:FSB ratio of 4.1:1. These results may indicate a role for hydroxyl radical in s2Ura-photosensitized DNA damage.

DNA Damage↗
PubMed1997

Induction of cell killing, mutation and umu gene expression by 6-mercaptopurine or 2-thiouracil with UVA irradiation.

When Escherichia coli cells were irradiated by UVA in the presence of 6-mercaptopurine (6-MP) or 2-thiouracil (S2Ura), two kinds of repair-deficient strains of recA- and uvrA- were killed more efficiently than the parental wild-type strain having normal repair capacities. In addition, these agents with UVA exposure greatly induced the incidence of mutations in the uvrA- strain as compared with the wild-type strain but not the recA- strain. Furthermore, the induction of expression of umuDC genes was investigated in two Salmonella typhimurium strains, TA1535 and TA1538, carrying a pSK1002 plasmid. In these systems, it is easy to measure beta-galactosidase activities for the induced activities of SOS responses. These agents with UVA exposure also induced expression of the umuDC genes. These results suggest that 6-MP and S2Ura with UVA induce DNA damage which is repairable by the excision repair mechanism.

Adenosine Triphosphatases↗
PubMed1977

Microbial formation of 4-thiouracil.

A soil organism identified as Streptomyces libani var. soldani was found to produce 4-thiouracil. The product was isolated in a yield of 150 mug/ml of filtered beer and characterized by C-13 magnetic resonance and high-resolution mass spectroscopy. The product has a broad antibacterial spectrum but low specific activity.

Bacillus subtilis↗
PubMed1967

Inactivation and heat stabilization of poliovirus by 2-thiouracil.

Treatment of poliovirus Type I with 10(-3)m 2-thiouracil (2-TU) resulted in the inactivation of greater than 90% of the virus infectivity and stabilization of approximately 50% of the residual virus to heat inactivation. These effects were due to a reaction with the protein moiety of the virus and could be blocked by pre-treatment of the virus with l-cystine or of the drug with cysteine. Both inactivation and stabilization occurred synchronously and reached equilibrium at the same time. Neither process was reversed by reducing agents. It is suggested that an oxidized form of 2-TU reacts with capsid sulfhydryl groups to form a product which is stable in either the inactive or heat-resistant form.

Animals↗
PubMed1979

Accumulation of radioiodine in thiouracil-hyperplastic thyroids of chicks.

Kinetics of accumulation of radioiodine was studied in thyroids of chickens before, during, and following ingestion of 0.25% thiouracil (TU). After a latent period of about 5 days, weight of the thyroid gland increased, reaching its maximum (42 mg/100 g body wt) after 21 days of TU ingestion; thyroid weight decreased immediately on withdrawal of TU but tended to plateau at a higher level than that of controls. One-way clearance increased by day 4 of ingestion of TU and reached its peak early during hyperplasia; it very quickly reverted to a control level on withdrawal of TU. Exit-rate constant increased markedly during early hyperplasia and decreased to a level less than normal after withdrawal of TU. Concentration of 127I decreased by a factor of 18 by 2 wk of feeding TU; it increased to practically a normal level by 1 wk after withdrawal of TU.

Animals↗
PubMed1989

The statistical analysis of a carcinogen mixture experiment. III. Carcinogens with different target systems, aflatoxin B1, N-butyl-N-(4-hydroxybutyl)nitrosamine, lead acetate, and thiouracil.

This paper describes factorial experiments designed to determine whether two carcinogens that lead to cancers in different organ systems act synergistically to produce cancers in Fischer 344 rats. Four carcinogens, aflatoxin B1 (AFLA), N-butyl-n-(4-hydroxybutyl)nitrosamine (NBBN), lead acetate (LA), and thiouracil (THIO) were studied in pairwise combinations. Each of the six possible pairs were studied by means of a 4 X 4 factorial experiment, each agent being fed at zero and at three non-zero doses. Methods of analysis designed explicitly for this study were derived to study interaction. These methods were supplemented by standard statistical methods appropriate for single agent studies. Neither synergism nor antagonism was demonstrated in these combined exposure studies. Findings for male and female animals were consistent.

Aflatoxin B1↗
PubMed1983

Capillary endothelial cell multiplication in adipose tissue pads on the thyroid during the feeding of thiouracil.

It has been reported that blood capillaries in adipose tissue pads on the upper and lower poles of the thyroid gland enlarge when Fischer rats are fed thiouracil (TU) in a low iodine diet. To test whether the enlargement is accompanied by proliferation of the endothelial cells, [3H]thymidine was injected into rats fed the TU-containing diet, and labeling of the endothelial cells was studied by autoradiography. Nuclear labeling of the capillary endothelial cells was observed in the mixed brown and white adipose tissue (BAT and WAT, respectively) pads on the thyroid. After a single pulse of [3H]thymidine, 10% of the nuclei were labeled at 10 days (the peak labeling), and labeling decreased thereafter. To test whether the adipose tissue was stimulated because of the poor nutritional quality of the low iodine diet, Purina Laboratory Chow (a nutritionally adequate diet) was tested and produced the same result. To test whether TU had a direct effect, 5 micrograms T4/100 g BW were given daily; there was then no response to the TU, suggesting that the effect was due to an elevated circulating concentration of TSH. The effect was generally restricted to the adipose tissue pads on the thyroid. There was no response in interscapular BAT, epididymal WAT, or sc WAT. However, there was a response in small clusters of adipocytes embedded in inguinal sc WAT. The results are consistent with the idea that the effects are directly or indirectly due to elevated circulating TSH levels.

Adipose Tissue↗
PubMed1984

Long-term effects of triiodothyronine and thiouracil on myocardial beta-adrenergic receptor numbers and cyclic AMP concentration in rats.

Long-term (35 days) effects of thyroid hormone on the number of myocardial beta-adrenergic receptors and the c-AMP concentration were studied in the rat. The ventricles from triiodothyronine-administered rats (T3 rats) showed an increase in the number of beta-receptors compared to controls (54.3 +/- 3.1 vs 39.3 +/- 1.8 fmole of [125I]-iodohydroxybenzylpindolol (IHYP) binding sites/mg protein p less than 0.001) on the 35th day. Conversely, the ventricles from thiouracil-administered rats (TU rats) showed a decrease in the number of beta-receptors compared to controls (31.4 +/- 1.6 vs. 38.4 +/- 2.6 fmole/mg protein, p less than 0.05). The equilibrium dissociation constants (Kd) for the interaction of receptors with IHYP did not differ significantly (0.10 to 0.15 nM). The myocardial concentration of cyclic AMP was not significantly different (T3 rats, 1.09 +/- 0.09 nM/g wet weight tissue; T3 controls, 1.12 +/- 0.07; TU rats, 1.13 +/- 0.07; TU controls, 1.16 +/- 0.12) on the 35th day. On serial effects of triiodothyronine from the first to the 35th day, the number of beta-receptors of T3 rats increased significantly on the 24th and the 35th day, but the c-AMP concentration was not significantly different from that in control rats. These results demonstrated that thyroid hormone affects the number of myocardial beta-receptors in rats, and suggested a different mechanism of action of thyroid hormone on the myocardium from that of catecholamines.

Animals↗
PubMed1998

Effects of thyroidectomy or thiouracil treatment on copulatory behavior in adult male rats.

Male copulatory behavior and the function of the hypothalamo-hypophysial-gonadal axis in hypothyroid male rats were investigated in the present study. Hypothyroidism was induced by thyroidectomy or thiouracil. In male copulatory behavior test, intromission latencies in hypothyroid rats were significantly longer than those in euthyroid rats and ejaculation frequencies were reduced in hypothyroid male rats compared to control rats without reduction of plasma concentrations of testosterone. These changes in copulatory behavior in hypothyroid male rats were restored to control levels by administration of T4 (5 micrograms/rat). Hypothyroidism decreased adrenal weights, and basal and peak concentrations of corticosterone during diurnal variation, whereas it increased peak concentrations of ACTH in adult male rats. These results indicate that hypothyroidism causes adrenal dysfunction directly and results in hypersecretion of ACTH. The adrenal disturbance observed in hypothyroid rats may affect male copulatory behavior.

Adrenal Glands↗
PubMed1996

Serum iodothyronine concentrations in intestinally decontaminated rats treated with a 5'-deiodinase type I inhibitor 6-anilino-2-thiouracil.

Enteric bacteria have been postulated to have a role in thyroid economy by promoting the hydrolysis of thyroid hormone conjugates of biliary origin, thus permitting the absorption and recycling of thyroxine (T4) and triiodothyronine (T3). An enterohepatic circulation of T3 might be more pronounced under conditions in which type I iodothyronine deiodinase activity (5'D-I) is inhibited, because this augments the accumulation of T3 sulfate conjugates in bile. This potential of increased gut reabsorption of T3 might explain, at least in part, the failure of serum T3 values to decrease appreciably when marked reductions in peripheral 5'D-I activity are induced by selenium deficiency or 6-anilino-2-thiouracil (ATU) administration. Thus, studies were performed to determine the effect of intestinal decontamination, in the absence and in the presence of 5'D-I inhibition, on plasma T4 and T3 concentrations. Groups of adult male rats received either enteric antibiotics or no antibiotics for 12 days and then, in half of the rats in each group, treatment for 10 days with ATU, a 5'D-I inhibitor that does not affect thyroid hormone synthesis. The activity of intestinal arylsulfatase and arylsulfotransferase, enzymes that catalyze hydrolysis of thyroid hormone conjugates, was reduced markedly by approximately 87% in rats that received antibiotics, regardless of whether or not they also received ATU. The ATU treatment markedly inhibited liver 5'D-I activity in antibiotic-treated as well as in non-antibiotic-treated rats (control = 399 +/- 32 U/mg protein (mean +/- SEM); ATU = 152 +/- 17: antibiotics = 351 +/- 29; antibiotics + ATU = 130 +/- 10; p < 0.01) and significantly increased plasma T4 and T3 sulfate (T4S, T3S) concentrations (control: T4S = 2.8 +/- 0.4 and T3S = 6.7 +/- 1.3 ng/dl; ATU: T4S = 6.2 +/- 1.4 and T3S = 10.6 +/- 2.1 ng/dl; antibiotics: T4S = 1.8 +/- 0.2 and T3S = 3.6 +/- 1.0 ng/dl; antibiotics + ATU: T4S = 6.8 +/- 0.7 and T3S = 9.7 +/- 1.8 ng/dl; p < 0.05). The ATU treatment was associated with a significant increase in plasma T4 and rT3 concentrations but did not affect plasma T3 concentrations, and intestinal decontamination did not alter these ATU-associated effects on circulating thyroid hormones. These results suggest that anaerobic enteric bacteria in the rat do not have an important role in recycling of thyroid hormones, either under normal conditions or in circumstances where 5'D-I activity is markedly reduced, and that increased gut absorption of T3 from T3S cannot explain the near-normal serum T3 values found when peripheral 5'D-I activity is markedly decreased.

Aniline Compounds↗
PubMed2002

Intra- and intermolecular electronic relaxation of the second excited singlet and the lowest excited triplet states of 1,3-dimethyl-4-thiouracil in solution.

Intramolecular processes of deactivation of 1,3-dimethyl-4-thiouracil (DMTU) from the second excited singlet (S2) (pi, pi*) and the lowest excited triplet (T1) (pi, pi*) states have been studied using perfluoro-1,3-dimethylcyclohexane (PFDMCH) as a solvent. The spectral and photophysical (PP) properties of DMTU in CCl4, hexane and water have also been described. For the first time, the fluorescence from S2 state DMTU has been observed. The picosecond lifetime of DMTU in the S2 state (tau(S2)) in PFDMCH has been proposed to be determined by a very fast intramolecular reversible process of hydrogen abstraction from the ortho methyl group by the thiocarbonyl group. The shortening of tau(S2) in CCl4 is interpreted to be caused by the intermolecular interactions between DMTU (S2) and the solvent. Results of the phosphorescence decay as a function of DMTU concentration were analyzed using the Stern-Volmer formalism, which enabled determination of the intrinsic lifetime of the T1 state (tau0(T1)) and rate constants of self-quenching (k(sq)). The lifetimes, tau0(T1), of DMTU in PFDMCH and CCl4 are much longer than the values hitherto obtained in more reactive solvents. The PP properties of DMTU both in the S2 and T1 states have been shown to be determined by the thiocarbonyl group.

Affinity Labels↗