thiourea and Carcinoma--Ehrlich-Tumor

Previously, we showed that a nitric oxide synthase (NOS) inhibitor, compound T1023, induces transient hypoxia and prevents acute radiation syndrome (ARS) in mice. Significant efficacy (according to various tests, dose modifying factor (DMF)-1.6-1.9 against H-ARS/G-ARS) and safety in radioprotective doses (1/5-1/4 LD10) became the reason for testing its ability to prevent complications of tumor radiation therapy (RT). Research methods included studying T1023 effects on skin acute radiation reactions (RSR) in rats and mice without tumors and in tumor-bearing animals. The effects were evaluated using clinical, morphological and histological techniques as well as RTOG classification. T1023 administration prior to irradiation significantly limited the severity of acute RSR. This was due to a decrease in radiation alteration of the skin and underlying tissues, and the preservation of the functional activity of cell populations that are critical in the pathogenesis of radiation burn. The DMF values for T1023 for skin protection were 1.4-1.7. Moreover, its radioprotective effect was fully selective to normal tissues in RT models of solid tumors-T1023 reduced the severity of acute RSR and did not modify the antitumor effects of γ-radiation. The results indicate that T1023 can selectively protect the non-malignant tissues against γ-radiation due to hypoxic mechanism of action and potentiate opportunities of NOS inhibitors in RT complications prevention.

Topics: Animals; Carcinoma, Ehrlich Tumor; Female; Gamma Rays; Male; Mice; Mice, Inbred ICR; Nitric Oxide Synthase; Radiation Protection; Radiation-Protective Agents; Radiodermatitis; Rats; Rats, Sprague-Dawley; Sarcoma, Experimental; Thiourea

Combined chronic treatment of Ehrlich solid carcinoma (EC) with an NOS inhibitor 1-isobutanoyl-2-isopropylisothiourea hydrobromide (T1023) and a PDK1 inhibitor dichloroacetate was accompanied by statistically significant synergetic antitumor effects manifested in a significant and stable suppression of neoplasm growth (by 55-65%). Separate treatment with T1023 and dichloroacetate induced moderate short-term inhibition of tumor growth (by 30-35%) followed by weakening of tumor sensitivity to these substances. These results attest to synergetic antitumor effects NOS inhibitor T1023 and PDK1 inhibitor dichloroacetate producing antiangiogenic and hypoxia-targeted cytotoxic effects, during their combined administration, which allows overcoming the adaptive potential of the tumors.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Cell Line, Tumor; Dichloroacetic Acid; Female; Mice; Nitric Oxide Synthase; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Thiourea

A new series of isatin-β-thiocarbohydrazones was synthesized based on the pharmacophoric features of triapine required for metal chelation. Our strategy involved the modifications of triapine basic skeleton by replacing pyridinyl moiety with isatin which retains the tridentate feature of triapine needed for metal chelation. The new compounds were esteemed for their antitumor efficacy against cervical cancer (Hela) and kidney fibroblast cancer (COS-7) cell lines. Compounds 4c, 4d, 5c and 5e exhibited remarkable efficacy against Hela cell line. In addition, compounds 4c, 4k, 4e, 5c and 5e displayed an outstanding efficacy against COS-7 cell line. Compounds 4c, 4k, 4e, 5c and 5e were examined for their in vivo antitumor efficacy against Ehrlich ascites carcinoma (EAC) in mice. Pharmacophore mapping was performed to study the structural features of the synthesized compounds compared to triapine and to identify the essential moieties required for potent and selective antitumor activity.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Ehrlich Tumor; Cell Proliferation; Chlorocebus aethiops; COS Cells; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Hydrazines; Indoles; Isatin; Male; Mice; Microwaves; Structure-Activity Relationship; Thiourea

A novel series of optically active 2-aminobenzothiazole derivatives were synthesized by reaction of optically active amine (I) with thiophosgene to obtain optically active isothiocyanates (IIa-h) which on condensation with 4-fluoro-3-chloro aniline (III) yielded various optically active thioureas (IVa-h). Further oxidative cyclisation in the presence of bromine and chloroform yielded title compounds (Va-h). The structures of these compounds were established by IR, (1)H NMR, (13)C NMR, Mass and HRMS. The compounds (IVa-h and Va-h) were evaluated for in vitro cytotoxicity against mouse Ehrlich Ascites Carcinoma (EAC) and two human cancer cell lines (MCF-7 and HeLa). In preliminary MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cytotoxicity studies the optically active thiourea derivatives (IVe, IVf and IVh) were found most effective. In EAC cells the IC(50) values for IVe, IVf, IVh and Vg were found in the range of 10-24 microM, whereas in MCF-7 and HeLa cells the IC(50) values were observed in the range of 15-30 microM and 33-48 microM, respectively. In alkaline comet assay the compounds (IVe and IVf) showed dose-dependent DNA damaging activity.

Topics: Animals; Antineoplastic Agents; Benzothiazoles; Carcinoma, Ehrlich Tumor; Cell Line, Tumor; DNA Damage; Drug Design; Humans; Mice; Optical Phenomena; Thiourea; Time Factors

The effect of the flavonoid (+)-catechin and its hydrophilic derivative epicatechinsulphonate on the permeability of Ehrlich mouse ascites tumour cells (EMAT) was investigated. As a sensitive assay, the transmembrane fluxes of two different solutes were measured, the inwardly directed free diffusion of 14C-thiourea, and the carrier-mediated efflux of intracellularly accumulated 12C-1-aminocyclopentane-1-carboxylic acid. (+)-Catechn was found to reduce the permeability of EMAT membranes for both solutes. The primary target of the drug appears to be the membrane itself. The effectiveness of the drug was dependent on its concentration. Inhibition of fluxes was observed at 0.86 mM; the inhibition gradually increased as the concentration was increased. In contrast to (+)-catechin, epicatechinsulphonate was rather ineffective, even at a concentration as large as 10 mM. The effect of (+)-catechin was seen within a few minutes after its addition. However, it was considerably intensified as the incubation was prolonged. The effectivity of (+)-catechin decreased with increasing cell density. Thus, the drug appears to be absorbed by the cells. From the various data and the observation that incorporation of a strong lipophobic sulphonate residue into the moderately lipophilic catechin molecule markedly lowers the effectivity of the flavonoid, it is concluded that (+)-catechin, as a membrane stabilizing drug, interacts directly with certain constituents of the cell envelope, presumably membrane lipids.

Topics: Adsorption; Animals; Benzopyrans; Carcinoma, Ehrlich Tumor; Catechin; Cell Membrane; Cell Membrane Permeability; Cycloleucine; Diffusion; Female; Mice; Thiourea

Topics: Adenosine Triphosphate; Amino Acids; Animals; Ascitic Fluid; Biological Transport, Active; Carbon Isotopes; Carcinoma, Ehrlich Tumor; Dinitrophenols; Glycine; In Vitro Techniques; Kinetics; Leucine; Methionine; Mice; Sodium; Temperature; Thiourea

Topics: Animals; Biological Transport; Carcinoma, Ehrlich Tumor; Cell Membrane Permeability; Chlorides; Chlorine; Dinitrophenols; Ions; Membrane Potentials; Mice; Nitrates; Nitrogen; Osmosis; Oxygen; Potassium; Potassium Isotopes; Radioisotopes; Serum Albumin, Bovine; Sodium; Thiourea; Water

Topics: Animals; Carcinoma, Ehrlich Tumor; In Vitro Techniques; Insulin; Leucine; Leukemia L1210; Male; Methotrexate; Mice; Thiourea; Tritium

Topics: Animals; Antineoplastic Agents; Carcinoma; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Liver Neoplasms; Lymphoma, Non-Hodgkin; Male; Melanoma; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Osteosarcoma; Rats; Sarcoma, Experimental; Thiourea; Urea

Topics: Animals; Ascites; Carcinoma; Carcinoma, Ehrlich Tumor; Chemical Phenomena; Chemistry; Chromatography; Guanidines; Mercaptoethanol; Mercury; Oxidoreductases; Research; Spectrophotometry; Tetrahydrofolate Dehydrogenase; Thiourea

Topics: Animals; Biological Transport; Carbon Isotopes; Carcinoma, Ehrlich Tumor; Culture Techniques; Glycine; Hydrogen-Ion Concentration; Sulfur Isotopes; Taurine; Thiourea

Topics: Amino Acids; Animals; Ascites; Biological Transport; Carcinoma; Carcinoma, Ehrlich Tumor; Dinitrophenols; Glutamates; Glutamic Acid; Iodoacetates; Mice; Ouabain; Research; Thiourea