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At least 1,225 records · Page 68Linked to original sources
PubMed1988

Leukemia L1210 cell lines resistant to ribonucleotide reductase inhibitors.

Leukemia L1210 cell lines, ED1 and ED2, were generated which were resistant to the cytotoxic effects of deoxyadenosine/erythro-9-(2-hydroxyl-3-nonyl)adenine and deoxyadenosine/erythro-9-(2-hydroxyl-3-nonyl)adenine plus 2,3-dihydro-1H-pyrazole[2,3a]imidazole/Desferal, respectively. The ED1 and ED2 were characterized to show that these cell lines had increased levels of ribonucleotide reductase as measured by CDP reduction. The reductase activity in crude cell-free extracts from the ED1 and ED2 cells was not inhibited by dATP. For CDP reductase, the activation by adenylylimido diphosphate and inhibition by dGTP and dTTP in these extracts from the ED1 and ED2 cells were the same as for the wild-type L1210 cells. The ED1 and ED2 cells were highly cross-resistant, as measured by growth inhibition, to deoxyguanosine/8-aminoguanosine, 2-fluorodeoxyadenosine, and 2-fluoroadenine arabinoside. While the ED2 cells showed resistance to 2,3-dihydro-1H-pyrazole-[2,3a]-imidazole/Desferal (6-fold), the ED1 and ED2 cell lines showed less resistance to hydroxyurea, 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone, and the dialdehyde of inosine. These data indicate that the mechanisms of resistance to the ribonucleotide reductase inhibitors are related to the increased level of ribonucleotide reductase activity and to the decreased sensitivity of the effector-binding subunit to dATP.

Adenosine Deaminase↗
PubMedDate not supplied

Antiviral therapy.

The current status of antiviral therapy is reviewed, including discussion of older approaches together with more recently developed chemotherapy. Following the introduction dealing with pathophysiological aspects of virus disease, the different approaches to antiviral therapy are presented. The reasons for the slow progress in antiviral therapy are discussed. These include: 1. the necessity of intracellular penetration of drugs acting on viral replication; 2. the severe toxicity of most antiviral drugs; 3. the narrow antiviral spectrum of most of these agents; 4. the difficulty of making a rapid etiological diagnosis in view of the necessity of starting (specific?) treatment early in the course of the disease; 5. the difficult evaluation of beneficial as compared with deleterious effects of antiviral therapy. After a detailed review of clinically tested substances, including immunoglobulins, synthetic antiviral drugs (amantadine, nucleoside analogs, thiosemicarbazones and photodynamic dyes) and interferon, a guide concerning indications and application of specific antiviral therapy is presented. Although at present there are few indications, clinicians should be aware of the (present and future) possibilities of antiviral therapy.

Antibodies, Viral↗
PubMed1988

Biological characterization of three new spontaneous mouse lymphomas and comparison with the leukemia P388.

Three spontaneous lymphomas of 23- to 24-month-old (AB/Jena X DBA/2 Jena)F1 females were serially transplanted into syngeneic hosts. They were histologically classified as malignant lymphoblastic lymphomas (ABDt2 and ABDt5) and as a malignant lymphoma of histiocytic type (ABDt6). All lymphomas disseminated into the liver, spleen, and pancreas, whereas ABDt2 and ABDt5 additionally infiltrated the bone marrow and leptomeninx. None of the tumors showed a leukemic growth form, but extreme granulocytosis was observed in leukemia P388-bearing mice. Since the lymphomas ABDt2 and ABDt5 expressed T-cell differentiation antigens Ly-1, Ly-2, and Ly-3, they are thought to be of T-cell origin. On the contrary to the lymphocytes of parental mouse strain ABDt2 and ABDt5 cells reacted with anti H-2.23 allosera. All tumors have been found to be sensitive to at least 5/7 clinically used anticancer drugs. But only ABDt2- and P388-bearing mice survived longer than 60 days after treatment with the potent anticancer drug 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (ambazone). Successful chemotherapy of both tumors was accompanied with resistance of the hosts against the second transplant of the same tumor. Summarizing the characteristics of the newly established transplantation tumors it is concluded that they can be recommended as screening models in the search for new antineoplastic agents.

Animals↗
PubMed1987

Identification of drugs effective against Cowdria ruminantium using a mouse screening system.

Heartwater is a tick-transmitted rickettsial infection of ruminants, caused by Cowdria ruminantium. The tetracyclines are the only compounds available for therapy of the disease. A screen, using mice infected with C. ruminantium, was developed and used to identify new compounds with potential for the control of heartwater. A series of di-4-methyl-thiosemicarbazones was shown to be highly active in the mouse model and their efficacy was confirmed in further trials in sheep infected with C. ruminantium. The mouse screen was shown to be simple to operate and reliably predictive of activity against heartwater. Ways in which the screen may be improved are suggested.

Animals↗
PubMed1979

[Biologically active azomethines. Delépine reaction with 1-chloromethylisatin; preparation of some 1-aminomethylisatinazomethines (author's transl)].

The authors describe the synthesis of I-aminomethylisatin (3) from [I-chloromethylisatin] (1) by means of the Delépine reaction. On condensation with aromatic aldehydes, 3 yields the azomethines 5--7. The azomethine 5 is converted into the corresponding thiosemicarbazone 9. Testing for mitodepressive activity showed that the compounds 5--7 are active. On testing in vitro for tuberculostatic effects, the compound 9 proved exceptionally potent.

Antitubercular Agents↗
PubMed1975

[Sensitivity of m. kansasii strains to various antibiotics and chemotherapeutics in vitro and in vivo (author's transl)].

Sensitivity of 40 strains of M. kansasii (var. luciflava) to various antibiotics and chemotherapeutics in vitro and in vivo was examined. The strains showed considerable individual variability in their susceptibility in vitro, most were more resistant to isoniazid and PAS and about one half of the investigated strains to streptomycin, too, if correlated to "wild" strains of M. tuberculosis. Susceptibility to ethionamide, thiosemicarbazone (Conteben), viomycin, kanamycin and cycloserine appears to be the same as in the case of M. tuberculosis strains, but the resistance to pyrazinamide is higher. Good effect has been observed in vitro with rifampicin, ethambutol, capreomycin and phenazine derivative B 663. Oleandomycin and gentamycin are ineffectual in the dosages of drugs we used. The activity of most of these drugs was observed in experimental infections of white mice--in mono-therapy and in various combinations-provoked by different strains of M. kansasii. The main criterion of the effectivity of the treatment was the enumeration of viable mycobacterial units in the lungs of the mice in ten-days intervals; in one part of the experiments the histological examination of the various organs of the mice was performed. The drugs of the I. and II. line of antituberculotics were ineffective or showed only a slight effect. A very good effect of rifampicin, ethambutol and phenazine derivative B 663 in monotherapy and in multiply drug therapy was observed.

Animals↗
PubMed1977

Synthesis of some quinones of potential antitubercular activity.

Certain phthiocol derivatives of expected bactericidal action have been synthesized. These include the phthiocol moiety condensed with p-hydrazino-salicylic and -benzoic acids and their ethyl esters; phthiocol thiosemicarbazone and isonicotinyl hydrazidehydrazone. In another similar series the methyl group of phthiocol was replaced by carbethoxy, ethyl, butyl and isobutyl groups. Allyl and 1.2-epoxypropyl ethers of phthiocol being of high lipid dispersion were also synthesized.

Antitubercular Agents↗
PubMed1983

Direct photoaffinity labeling of the catalytic site of mouse ribonucleotide reductase by CDP.

Ribonucleotide reductase reduces all four ribonucleoside diphosphates to the deoxyribonucleotides required for DNA synthesis. The enzyme is composed of two nonidentical subunits, M1 and M2. The 89-kilodalton M1 subunit contains at least two allosteric sites which, by binding nucleotide effectors, regulate the catalytic activity and substrate specificity of the enzyme. We now show that in addition, protein M1 contains a substrate-binding (catalytic) site which is specifically photolabeled after UV irradiation in the presence of the natural substrate, [32P]CDP. The photolabeling of protein M1 by [32P]CDP required the presence of the second subunit, protein M2, and ATP, the positive allosteric effector for CDP reduction. The negative effectors, dATP, dGTP, and dTTP, inhibited the photolabeling of wild type protein M1. Deoxy-ATP did not inhibit the labeling of a mutant protein M1 that is resistant to feedback inhibition by dATP. In addition, hydroxyurea and 4-methyl-5-aminoisoquinoline thiosemicarbazone, two inhibitors of ribonucleotide reductase which affect protein M2, also inhibited the [32P]CDP labeling of protein M1. These data provide new insights into the role and interaction of the two ribonucleotide reductase subunits, proteins M1 and M2, and the mechanism of action of the allosteric effectors.

Affinity Labels↗
PubMed1984

Flow cytometric determination of estrogen receptors in intact cells.

Flow cytometry has been used to detect estrogen receptor (ER) in intact cells, using 1-(N)- fluoresceinyl estrone thiosemicarbazone ( 17FE ), a ligand shown to have sufficient affinity and specificity to identify high-affinity receptors. For each concentration of 17FE , two fluorescent distributions were obtained: (a) "total" fluorescence due to 17FE alone; and (b) diethylstilbestrol-inhibited fluorescence ("nonspecific"). The mean fluorescence intensity for both the "total" (MT) and "nonspecific" (MN) distributions was calculated at each ligand concentration by obtaining the total brightness of each sample, normalized to the number of cells analyzed. A specific binding curve was constructed over a broad range of 17FE concentrations (1.5 X 10(-9) to7 .5 X 10(-7) M) by plotting the mean specific fluorescence intensity (MS = MT-MN) at each 17FE concentration. Saturable binding was demonstrated for a known ER-positive cell line (MCF-7) at low ligand concentrations (5 to 10 X 10(-8) M), while no specific binding was obtained for a known ER-negative cell line (MDA-231). The Kd was estimated from the specific binding curve of MCF-7 cells as the concentration of 17FE at half-maximal binding. When corrected for the binding activity relative to estradiol, a Kd of 18 X 10(-10) M was obtained. The flow cytometer-generated distributions give a qualitative estimate of the proportions of ER-rich and ER-poor cells. Quantitation of ER heterogeneity will require a mathematical algorithm expressing the difference between the "total" and "nonspecific" distributions. These studies demonstrate that flow cytometry and an appropriate ligand can detect and partially describe ER heterogeneity in intact cells.

Breast Neoplasms↗
PubMedDate not supplied

[Antithyroid activity of various newly synthesized 1,3-thiazine derivatives].

Experiments were performed on rats. It was revealed that three newly-synthesized 1,3-thiazine derivative (1,3-thiazandithion-2,4, 1,3-thiazanthion-2-on-4-thiosemicarbazone-4, and 1,3-thiazandion-2,4) possessed and antithyroidal action in doses equal to 15% of LD50; in the two former preparations it was accompanied by an goiterogenic effect. 1,3-thiazandion-2,4 had the most antithyroidal action and relatively weak goiterogenic effect.

Animals↗
PubMed1980

Fatal progressive vaccinia in two immunodeficient infants.

Fatal progressive vaccinia developed in two infants, a girl and a boy, vaccinated at the age of 2 months. Immunodeficiencies comprised both humoral and cell-mediated immunity. In the girl low levels of immunoglobulins and a defect function of lymphocytes was demonstrated. The boy had hypogammaglobulinemia and lack of T-lymphocytes. There was a marked hypoplasia of thymus and lymphoid organs in both infants. Both infants had the haplotype A3, B8 and in the boy a crossing over had taken place within the HLA region. No effect was achieved with antivaccinia immunoglobulin and concomitant antiviral therapy (thiosemicarbazone, adenine arabinoside). Interferon therapy gave no clinical improvement, nor did transfer factor.

Agammaglobulinemia↗
PubMed1993

Antipyrine congeners as antidepressant agents.

1-(N-Antipyrinylglycyl)-3-arylideneamino)-2-thiobarbituric acids (III) were synthesized from 1-arylidene-4-(N-antipyrinyl glycyl)-3-thiosemicarbazones (II). Compounds II in turn were prepared from 4-amino antipyrine. Compounds III were finally converted into 1-(N-antipyrinylglycyl)-3-[(3'-chloro-4-aryl)azitidinyl]-2-t hiobarbituric acids (IV). 4-Aminoantipyrine was also treated with different N-protected amino acids in the presence of N,N'-dicyclohexylcarbodiimide to yield N-(antipyrinylcarbamoyl) substituted alkyl benzamides (V); their debenzoylation yielded 2-(amino-N-antipyrinyl) substituted acetamides (VI). The compounds were screened for their antidepressant activity. Compounds IIId, Va and Vb exhibited activity better than imipramine with less toxicity (ALD50 > 1000 mg/kg).

Amphetamine↗
PubMed1993

Thiazolidinone congeners as central nervous system active agents.

3-(Benzylidene amino)-2-imino-4-thiazolidinones (IIa-c) synthesized by cyclization of substituted thiosemicarbazones (Ia-c) were converted into 2-amino-3-(substituted benzylamino)-4-thiazolidinones (IIIa-c), 2-imino-3-(alpha-aryl azo benzylidene) amino-4-thiazolidinones (IVa-f) and 2-(2-amino-4-oxo-3-thiazolidinyl)-3-aryl-4-isothiazolidinones (VIa-c), IVa-f were finally converted into 5-(arylamino methyl)-2-imino-3-(alpha-aryl azobenzylidene)-amino-4-thiazolidinones (Va-l). These compounds III, V and VI were evaluated for their monoamine oxidase (MAO) inhibitory activity in vitro and various CNS activities in vivo. Some of the compounds exhibited promising CNS activity.

Amphetamine↗
PubMed1998

Chemotherapy for onchocerciasis: results of in vitro experiments with promising new compounds.

An improved short-term in vitro culture system was used for the routine screening of hundreds of promising new compounds with the target organism, the filarial nematode Onchocerca volvulus. The most active leads were identified among the pyrimidinylguanidines, amidine derivatives, the imidazolinylhydrazones, thiosemicarbazone derivatives and thiadiazole derivatives. Single compounds of these leads demonstrated strong macrofilaricidal efficacy in minimum effective dose trials down to 0.1 microM and in experiments evaluating the minimum time of exposure after less than 6 h exposure. In the group of the pyrimidinylguanidines we found a significant correlation of structure and activity: change of a single side-group in the molecules had dramatic influence on compound activity. Most of the new compounds that were active on the macrofilariae did not show significant activity on microfilariae (mf) in in vitro trials. Only one compound with significant activity against female O. volvulus worms killed mf at very low concentrations. Some of the promising leads will be processed in further trials on a preclinical level with predictive cattle models.

Animals↗
PubMed1998

[Inhibition of lipid peroxidation in erythrocytes by aminoguanidine, resorcylidine aminoguanidine and their oxygen and sulfur analogs in diabetic rats].

This study examined the effect of aminoguanidine (AG) and its structural analogs semicarbazide (SK) and thiosemicarbazide (TSK), as well as their condensation products with 2,4-dihydroxybenzaldehyde-resorcylidene aminoguanidine (RAG), resorcylidene thiosemicarbazone (RTSKon), and resorcylidene semicarbazone (RSKon) on erythrocyte lipid peroxidation in rats with diabetes mellitus induced by hydrogen peroxide. All of the tested compounds at concentrations 1 mmol.l-1 in incubation mixture significantly inhibited the formation of malondialdehyde (MDA), an end product of lipid peroxidation, as assessed by its thiobarbituric acid reactivity. AG and RAG were the most effective inhibitors of lipid peroxidation 90%). It was also found, that RSKon and RTSKon were more potent inhibitors of lipid peroxidation (70 and 80%) compared to Sk and TSK (50%). We suppose that this increase of inhibitory effect by compounds with resorcylidene group may be due to the formation of quinone structure.

Animals↗