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At least 19 recordsLinked to original sources
PubMed2002

Effect of the organotin compound triethyltin on Ca2+ handling in human prostate cancer cells.

The effects of triethyltin on Ca2+ mobilization in human PC3 prostate cancer cells have been explored. Triethyltin increased [Ca2+]i at concentrations larger than 3 microM with an EC50 of 30 microM. Within 5 min, the [Ca2+]i signal was composed of a gradual rise and a sustained phase. The [Ca2+]i signal was reduced by half by removing extracellular Ca2+. The triethyltin-induced [Ca2+]i increases were inhibited by 40% by 10 microM nifedipine, nimodipine and nicardipine, but were not affected by 10 microM of verapamil or diltiazem. In Ca2+-free medium, pretreatment with thapsigargin (1 microM), an endoplasmic reticulum Ca+ pump inhibitor, reduced 200 microM triethyltin-induced Ca+ increases by 50%. Pretreatment with U73122 (2 microM) to inhibit phospholipase C did not alter 200 microM triethyltin-induced [Ca2+]i increases. Incubation with triethyltin at a concentration that did not increase [Ca2+]i (1 microM) in Ca2+-containing medium for 3 min potentiated ATP (10 microM)- or bradykinin (1 microLM)-induced [Ca2+]i increases by 41 +/- 3% and 51 +/- 2%, respectively. Collectively, this study shows that the environmental toxicant triethyltin altered Ca2+ handling in PC3 prostate cancer cells in a concentration-dependent manner: at higher concentrations it increased basal [Ca2+]i; and at lower concentrations it potentiated agonists-induced [Ca2+]i increases.

Calcium↗
PubMed2001

Antiproliferative activity and interactions with cell-cycle related proteins of the organotin compound triethyltin(IV)lupinylsulfide hydrochloride.

Organotin compounds, particularly tri-organotin, have demonstrated cytotoxic properties against a number of tumor cell lines. On this basis, triethyltin(IV)lupinylsulfide hydrochloride (IST-FS 29), a quinolizidine derivative, was synthesized and developed as a potential antitumor agent. This tin-derived compound exhibited potent antiproliferative effects on three different human cancer cell lines: teratocarcinoma of the ovary (PA-1), colon carcinoma (HCT-8) and glioblastoma (A-172). Cytotoxic activity was assessed by MTT and cell count assays during time course experiments with cell recovery after compound withdrawal. Significant cell growth inhibition (up to 95% in HCT-8 after 72 h of exposure), which also persisted after drug-free medium change, was reported in all the cell lines by both assays. In addition, the cytocidal effects exerted by IST-FS 29 appeared more consistent with necrosis or delayed cell death, rather than apoptosis, as shown by morphologic observations under light microscope, DNA fragmentation analysis and flow cytometry. In the attempt to elucidate whether this compound might affect genes playing a role in G1/S phase transition, the expressions of p53, p21(WAF1), cyclin D1 and Rb, mainly involved in response to DNA-damaging stress, were analyzed by Western blot. Heterogeneous patterns of expression during exposure to IST-FS 29 were evidenced in the different cell lines suggesting that these cell-cycle-related genes are not likely the primary targets of this compound. Thus, the present data seem more indicative of a direct effect of IST-FS-29 on macromolecular synthesis and cellular homeostasis, as previously hypothesized for other organotin complexes.

Antineoplastic Agents↗
PubMed2002

Chemosensitivity of glioblastoma cells during treatment with the organo-tin compound triethyltin(IV)lupinylsulfide hydrochloride.

Malignant gliomas are the most common primary brain tumors in humans. However, poor response to conventional therapeutic approaches, including chemotherapy, leads invariably to disease recurrence and progression. The organo-tin derivative triethyltin(IV)lupinylsulfide hydrochloride (IST-FS 29) was identified and developed as potential antiproliferative agent in human cancer cell lines. However, for its peculiar chemical structure and good lipophilicity, this compound also appeared an eligible candidate for the treatment of gliobastoma cells. The present experiments were designed to explore the in vitro effects of IST-FS 29 on four human glioblastoma cell lines: A-172, DBTRG.05MG, U-87MG and CAS-1. The average IC50 values were obtained by MTT assay and ranged between 3 and 10 microM. Time-course assays with cell recovery after drug withdrawal, demonstrated marked cytotoxicity following exposure to IST-FS 29 for 8, 24 and 72 h. Cultures treated for 8 h were able to partially re-grow by 144 h; on the contrary, longer times of exposure did not allow surviving cells to recover from the damage and actively proliferate. Cell morphology of cultures exposed to IST-FS 29 was assessed by inverted light microscopy after 24 and 72 h and was more consistent with cell death by necrosis which included cell size reduction, vacuolation of cytoplasm, round dying cells. The present results and our previous data, in vitro and in vivo, indicate the relevant cytotoxic activity of this organo-tin compound and suggest that IST-FS 29 might be a promising novel agent to be developed for the treatment of malignant brain neoplasms.

Antineoplastic Agents↗
PubMed1984

Effect of triethyltin on autonomic and behavioral thermoregulation of mice.

The organotin compound, triethyltin (TET), produces toxic effects in a variety of physiological systems. Thermoregulatory control appears to be especially susceptible to TET toxicity, since TET administration has been shown to cause a pronounced hypothermia in rats. To further elucidate effects of TET on thermoregulation, we measured metabolic rate, evaporative water loss (EWL), body temperature, and preferred ambient temperature (Ta) of mice treated intraperitoneally with TET (bromide salt). At a Ta of 23 to 24 degrees C, TET (6 and 8 mg/kg) inhibited metabolic rate by 23 and 66%, respectively. TET resulted in hypothermia at Ta's of 20 and 30 degrees C but not 35 degrees C. TET had little effect on EWL. Mice given TET at doses of 4, 6, and 8 mg/kg selected a cooler Ta (ca. 25 degrees C) compared to controls (ca. 29 degrees C). Thus, the mice selected a Ta associated with a hypothermic body temperature. At a relatively cool Ta, mice treated with TET had a reduced rate of heat production and, consequently, were hypothermic. At a relatively warm Ta, TET had no effect on heat production and did not increase active heat dissipation (i.e., EWL), thus the mice remained normothermic. The behavioral data indicate that TET evokes a type of regulated hypothermia in mice.

Animals↗
PubMed1976

Toxicity and health effects of selected organotin compounds: a review.

The toxicity of selected tin compounds is reviewed. Over the years, a variety of uses has been found for organic and inorganic tin compounds, as fungicides, as stablizers in plastics, moluscicides, and miticides; they have also been suggested as insect chemosterilants and for other industrial uses. Many of these products are unpalatable when mixed into diets and have been suggested as rodent repellents. Inhaling tin as dust or fumes may cause a benign pneumoconiosis in exposed workers. The organotin compounds can be divided into alkyltin and aryltin compounds. The trimethyl and triethyltin compounds are well absorbed from the gastrointestinal tract and are the most toxic in this group. Triethyltin particularly produces status spongiosus of the white matter of the central nervous system. Most of the other alkyl and aryl tin compounds are poorly absorbed from the gastrointestinal tract, and are less toxic when given orally than when given parentally. Only one compound, tricyclohexyltin hydroxide, is now registered by the Environmental Protection Agency as a miticide. This product produces skin irritation in rabbits. Studies should be conducted to determine whether it causes contact dermatitis in humans.

Animals↗
PubMed2002

Antitumor activity of a new orally active organotin compound: a preliminary study in murine tumor models.

The toxicity and antitumor activity of the novel organotin compound triethyltin(IV)lupinylsulfide hydrochloride (IST-FS 29), administered by the oral route, have been evaluated against three transplantable murine tumor models: P388 lymphocytic leukemia, B16F10 melanoma and 3LL Lewis lung carcinoma. Mild and reversible signs of acute toxicity such as behavioral symptoms, weight loss and histological alterations were mainly reported at the highest single dose of 28 mg/kg. Conversely, lower concentrations of compound ranging from 7 to 21 mg/kg did not result in major toxic effects, even after repeated dosing. The antitumor activity studies showed that fractionation dosing, rather than single bolus administration, over 1 week, might prove more active and better tolerated by allowing the achievement of the highest therapeutic total dose of IST-FS 29 (42 mg/kg). Indeed, repeated administrations of IST-FS 29 resulted in marked significant improvement of antitumor activity against B16F10 (50% of tumor volume inhibition, p = 0.0003) and, to a greater extent, 3LL (90% of tumor volume inhibition, p = 0.0001) tumors. These results indicate that IST-FS 29 might be a suitable candidate as an orally administrable anticancer drug and support its further development in human tumor xenografts.

Animals↗
PubMed1984

Neuromuscular function and organotin compounds.

Mammalian exposure to toxic levels of the trialkyltin compounds, triethyltin (TET) and trimethyltin, results in pathological manifestations largely restricted to the nervous system. The remarkable features of TET toxicity are cerebral edema and muscular weakness. Rats exposed orally to TET (10-30mg TET Br/l of drinking water) progress through an increasingly compromised state beginning with mild ataxia and hindlimb weakness after one week, spastic paresis of the hindlimbs by two weeks; and hindlimb paraplegia and sensory changes by 3 weeks. Histopathological studies of chronic TET-exposed rats report minimal ultrastructural damage to distal peripheral nerves, myelin, and muscle. Chromatolytic reactions are observed in some alpha motor neurons; intramyelinic vacuolization in the ventral roots and horn is substantial by 3 weeks. Myelin vacuolization and degeneration are observed to a lesser extent in the dorsal roots of the spinal cord. Wet weights and myofiber diameters of EDL and soleus muscles are reduced during chronic TET intoxication, but no histopathology is evident using light microscopy. Conduction of compound action potentials in vivo along distal sensory fibers, ventral roots and distal motor fibers (in sciatic n.) is normal in 3 week TET rats as compared to control; however, nerve conduction velocity is decreased in the segment of the H-reflex arc involving the dorsal roots. Earlier studies by Stoner and coworkers led to suggestions that the neuromuscular junction may be preferentially affected by TET and could contribute, in part, to the symptoms of muscular weakness. In support of this hypothesis preliminary studies from our laboratory and others indicate that neurotransmission is functionally depressed at the myoneural junction following chronic TET treatment in vivo or when applied in vitro to isolated muscle preparations. Stimulated, but not unstimulated, release of acetylcholine from the vascular perfused rat phrenic nerve-hemidiaphragm preparation is decreased by TET especially at higher stimulation rates (20 Hz). In vitro administration of TET Br (10(-6)M) results in an irreversible decrease in the amplitude of evoked endplate potentials; chronic in vivo exposure to TET causes a decrease in the resting membrane potential of soleus muscle (in situ recordings) and provokes a peculiar post-stimulus (200Hz bursts) elevation of spontaneous miniature endplate potentials in isolated cut diaphragm preparations.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1990

Na+/K(+)-ATPase in rat brain and erythrocytes as a possible target and marker, respectively, for neurotoxicity: studies with chlordecone, organotins and mercury compounds.

Due to the inaccessibility of human nerve tissue for direct biochemical evaluation, there appears to be a need to identify peripheral markers which will reflect toxicity to the central nervous system by relatively non-invasive means. The aim of this study was to investigate whether the enzyme Na+/K(+)-ATPase in erythrocytes could be used as a marker for effects on the same enzyme in brain tissue. The compounds chosen to test this hypothesis were the pesticide chlordecone, the organotin compounds triethyltin and tributyltin, mercuric chloride and methyl mercury. All compounds were found to inhibit in vitro Na+/K(+)-ATPase activity in rat brain (IC50s = 0.9-56 microM) and in rat erythrocytes (IC50s = 1.2-66 microM) with similar potencies. However, administration of these compounds in vivo at high doses produced no significant inhibition of either brain or erythrocyte Na+/K(+)-ATPase activity, despite observed symptoms of neurotoxicity. Dialysis experiments indicated that dissociation of the compounds by dilution during tissue preparation was not responsible for the lack of detectable in vivo inhibition. Measurements of metal concentrations in brain by atomic absorption spectrometry after in vivo administration of triethyltin, mercuric chloride and methyl mercury indicated that levels of these compounds were too low to inhibit significantly NA+/K(+)-ATPase activity. These results suggest that inhibition of Na+/K(+)-ATPase activity might not represent the mechanism responsible for the neurotoxicity of these compounds, and that erythrocyte Na+/K(+)-ATPase activity is not a useful marker for neurotoxicity following acute exposures.

Animals↗
PubMedDate not supplied

Cytotoxicity in vitro and preliminary antitumor activity in vivo of a novel organotin compound.

The cytotoxic effect and antitumor activity induced by the novel organotin compound triethyltin(IV)lupinyisulfide hydrochloride, have been investigated. Different patterns of antiproliferative effects have been observed in a panel of human tumor cell lines in vitro. Toxicity studies in mice reported acute toxicity at the doses of 21 and 17.5 mg/kg which progressively disappeared at lower concentrations. On this basis, the doses of 3.5, 7 and 14 mg/kg were selected to assess the antitumor activity in vivo against the P388 leukemic cells xenografted in mice. This compound was able to induce a dose-dependent significant reduction of tumor volume, up to 46%, at the highest concentration (p = 0.0062) without important toxicity, as also confirmed by histological analysis of the main organ tissues. This preliminary study seems to hold interest for further investigations in different tumor models as well as for the evaluation of optimal drug route and schedule.

Animals↗
PubMed1998

Glutathione modifies the toxicity of triethyltin and trimethyltin in C6 glioma cells.

It has been demonstrated that exposure to mercury or cadmium compounds causes alterations in the glutathione system in a model glial cell line, C6. Here we report that two organic tin compounds, triethyltin (TET) and trimethyltin (TMT), are also toxic to these cells with EC50 values for cell death of c. 0.02 microM and 0.8 microM respectively. Exposure for 24 h to either of these compounds at sub-toxic concentrations caused increases in the amount of reduced glutathione (GSH) per cell. Increases in glutathione-S-transferase enzyme activity were also demonstrated after TET or TMT exposure. This suggests that glutathione increases occur in glial cells after toxic insults below that required to cause cell death, possibly acting as a protective mechanism. To test whether GSH plays a role in organotin-induced cell death we manipulated GSH in the culture media or via intracellular GSH and looked at the effects on sensitivity to TET or TMT toxicity. Adding GSH to the culture media did not protect the cells. Depletion of intracellular GSH with buthionine-[S,R] sulphoximine did not alter cytotoxicity of TET or TMT. However, pre-treatment with (-)-2-oxo-4-thiazolidine carboxylic acid (OTC), which increases intracellular GSH levels, protected the cells against both compounds. The EC50 for TMT was increased from 0.77 to 1.8 microM, a 2.3-fold shift, whereas the EC50 for TET was increased > 20-fold, from 0.022 to 0.47 microM. One interpretation of these results is that GSH protects cells against the toxicity of organic tin compounds without reacting directly with them to any significant extent. Under conditions where GSH is depleted, additional protective mechanisms may be active.

Animals↗
PubMed1998

Synthesis and biological activity of gold and tin compounds in ovarian cancer cells.

We have investigated the patterns of in vitro cytotoxicity, induced by six newly synthesized gold and tin compounds, in three human ovarian cancer cell lines (SW 626, IGROV 1 and OVCAR-3). Four gold compounds, i.e. gold(I)lupinylsulfide hydrochloride [1] (containing a naked gold atom), triethylphosphinogold(I)lupinylsulfide hydrochloride [2], triphenyl-phosphinogold(I)lupinylsulfide hydrochloride [3] and 1 ,2-bis(diphenylphosphino)ethane bis[gold(I)lupinylsulfide] dihydrochloride [4] (all containing a gold atom coordinated with different phosphines), were prepared. Moreover, the triethylphosphinogold(I)(2-diethylamino)ethylsulfide hydrochloride [5] in which the simple diethylaminoethylthiol replaced the bulky lupinylthiol was synthesized. The tin compound, triethyltin(IV)lupinylsulfide hydrochlorlde [6], was also studied. Comparative tests with cisplatin, the most widely used antitumor agent in ovarian cancer, were carried out in biological Investigations. In vitro cytotoxicity, by MTT assay, showed that compound [4] and compound [6] exhibited interesting antiproliferative activity in all the three cell lines (mean IC50=1.3 and 0.7 microM, respectively) compared to cisplatin (mean IC50=4.8 microM). In addition, the PA-1 cell line, more sensitive to cisplatin (IC50=0.6 microM), was included as a comparison in the study. Cell count assays confirmed the cytotoxic properties of compounds [4] and [6] against the four cell lines, reporting higher growth Inhibition potency than cisplatin, with IC50 values in the sub-micromolar range.

Antineoplastic Agents↗
PubMed1990

Acetazolamide inhibits the recovery from triethyl tin intoxication: putative role of carbonic anhydrase in dehydration of central myelin.

The vacuolar degeneration of central myelin was produced in Sprague-Dawley rats by oral administration of triethyl tin. The wet weight of brain stems which seems to reflect the degree of accumulation of water increased during the administration of the toxin, whereas the activity of 2', 3'-cyclic nucleotide 3'-phosphodiesterase altered less remarkably. When TET was withdrawn from the drinking water, the rats showed a dramatic clinical improvement along with reduction in wet weight of brain stems. Treatment with acetazolamide following TET inhibited the clinical improvement and reduction in wet weight of brain stems. The present results indicates that central myelin has plasticity in recovering from the vacuolar degeneration by removing the accumulated fluid and carbonic anhydrase is possibly involved in the dehydration of myelin in such a recovery phase.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1982

Triethyl tin-induced myelin oedema: an intermediate swelling state detected by X-ray diffraction.

X-ray diffraction was used to probe the effects of triethyl tin (TET) on the periodicity and amount of membrane disorientation in the lamellar myelin from respiring optic and sciatic nerves in vitro as well as from nerves of rats treated in vivo through their drinking water. The diffraction patterns show that in vitro TET at concentrations of 4-100 microM affects C.N.S. but not P.N.S. myelin structure. A planar, concentric membrane array with a 200 A period is detected in the C.N.S.; this ordered, swollen myelin contrasts with the vacuolar and vesicular structure seen in thin-sections in TET-induced oedema. No effects of short-term in vivo treatment with TET are observed in either the C.N.S. or P.N.S. The finding that carbonic anhydrase (CA) inhibitors have no effect on the TET-induced structural changes indicates that the swelling we observe is not related to a CA-dependent process. In comparison, the TET effect is prevented by replacing the mobile ions with isotonic sucrose. We conclude that TET-induced swelling in C.N.S. myelin arises from an increase in ion transport followed by obligatory fluid movement. Further, the ordered, swollen structure we detect may be an intermediate state that exists transiently in vivo in TET intoxication and that precedes the gross swelling and vacuolization usually observed.

Adenosine Triphosphatases↗