Importance of genetic background of oxysterol signaling in cancer.

Oxysterols, oxygenated derivatives of cholesterol, are formed in the human body or ingested. Experimental evidence suggests that due to their diverse functions, e.g. modulating the activity of receptors such as liver X receptors, oxysterol-binding and metabolizing proteins, and several ATP binding cassette transporters, oxysterols may contribute to a number of human disorders including cancer. Genetic variability of oxysterol pathways represents another side of this process, affecting carcinogenesis and cancer progression. This review summarizes information about both the physiological role of oxysterol pathway genes and observed associations between their genetic variability and cancer incidence, progression, and therapy outcome. Besides candidate gene studies, results of genome-wide association studies are presented as well. The survey of available data shows some potential genetic biomarkers that, if clinically validated, may allow the stratification of individuals into genetically defined groups for prediction of individual cancer risk and subsequent screening strategies for early diagnosis.

[Significance of hysteroscopic resection in diagnostics of endometrial cancer]. / Význam resektoskopie v diagnostice karcinomu endometria.

OBJECTIVES: Endometrial cancer is the second most common malignancy of the female genital tract. Its incidence in the Czech Republic is 32/100 000 women and year with a permanent increasing tendency. In comparison with incidence, its mortality remains relatively low, with mortality ratio of 6.7 per 100,000 women and year. The decrease in mortality might be explained predominantly by early diagnostics. The most controversial issue is the potential risk of microscopic extrauterine dissemination of cancerous cells within the peritoneal cavity and circulation during hysteroscopy, and the question if the relatively high pressure of distension medium used during hysteroscopies may or may not multiply the risk. DESIGN: Retrospective study. MATERIALS AND METHODS: Totally, 400 endometrial biopsies were collected during years 2007-2009 at our clinic. In 56 patients, endometrial cancer was diagnosed. Afterwards, 44 women underwent surgery, during which peritoneal washing (lavage) and cytological examination were done. RESULTS: Fifty-six patients with histologically verified endometrial carcinoma were studied. The samples examined in the study were classified by grading as follows: G1 n=34, G1-2 n=10, G2 n=10, G3-4 n=2. In 44 cases that underwent radical surgery, no cancerous cells in peritoneal washings were found. Only in 1 case, the cytology obtained from peritoneal washing was considered to be suspicious. In 9 cases, carcinoma on the base of the polyp was detected, and in 2 cases, no residuum of cancer was observed after hysterectomy. CONCLUSION: In accordance with contemporary literature and based on our study, we suggest that hystero-resectoscopy does not increase the risk of dissemination of malignant cells within the peritoneal cavity and does not worsen the prognosis of the disease. On the contrary, the samples taken under visual control provide more precise and earlier diagnostics of endometrial cancer.

[New groups of potential antitubercular agents: 3-(4-ethoxythiocarbonylphenyl)-2-H-benzoxazin-2,4(3H)-diones and 3-(4-ethoxythiocarbonylphenyl)-4-thioxy-2H-benzoxazin-2(3H)-ones]. / Nové skupiny potenciálních antituberkulotik: 3-(4-ethoxythiokarbonylfenyl)-2-H-benzoxazin-2,4(3H)-diony a 3-(4-ethoxythiokarbonylfenyl)-4-thioxy-2H-benzoxazin-2(3H)-ony.

In connection with the search for new antituberculotics, the present authors prepared a group of derivatives of 3-(4-ethoxythiocarbonylphenyl)-2H-benzoxazin-2,4(3H)-dithione and 3-(4-ethoxythiocarbonylphenyl)-4-thioxy-2H-benzoxazin-2,4(3H)-one. The modifications of substituents were carried out on the benzoxazine ring. The study was based on the present authors' previous assumption that the substitution of the oxo group for the thioxo group was connected with an increase in antimycobacterial activity. The prepared substances were evaluated by the activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. However, it was concluded that there was no assumed increase in antimycobacterial activity in the groups of 3-(4-ethoxythiocarbonylphenyl)-4-thioxy-2H-benzoxazin-2,4(3H)-one and 3-(4-ethoxythiocarbonylphenyl)-2H-benzoxazin-2,4(3H)-dithione derivatives.

Antimycobacterial 3-aryl-2H-1,3-benzoxazine-2,4(3H)-diones.

A series of 153 derivatives of 3-phenyl-2H-benzoxazine-2,4(3H)-dione substituted in position 6 or 7 on benzoxazine and on the phenyl ring was synthesized. The compounds were evaluated in vitro for antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium. The activity of the compounds increases with increasing hydrophobicity and electron-withdrawing properties of the substituents on the phenyl ring, whereas the effect of the substituents on the benzoxazine ring seems to be more complex.

In vitro antifungal activity of 3-phenyl-2H-benzoxazine-2,4(3H)-diones.

A series of 81 3-phenyl-2H-benzoxazine-2,4(3H)-diones with substitution at C(6) on the benzoxazine ring and on the phenyl moiety was synthesized; the compounds were evaluated for antifungal activity against five strains of potentially pathogenic fungi (Absidia corymbifera, Aspergillus fumigatus, Candida albicans, Microsporum gypseum and Trichophyton mentagrophytes). Structure-activity relationships against T. mentagrophytes and M. gypseum were determined using the Free-Wilson method, which was further combined with the approach of Hansch. In vitro antifungal activity becomes higher with increasing electron-accepting ability of the substituents on the phenyl ring, and with increasing lipophilicity.

[Advances in the development of new antitubercular agents from a group of orthocondensed heterocyclic compounds. Part 2. Substances containing more nitrogen atoms in the 6-membered ring]. / Pokroky ve vývoji nových antituberkulotik ze skupiny orthokondenzovaných heterocyklických sloucenin. Cást 2. Látky obsahující v sesticlenném kruhu více atomu dusíku.

Tuberculosis and other mycobacterial diseases are considered to be one of the most important problems of contemporary health service. Since 1985 and particularly in the 1990s and at present the search for new structures of antimycobacterial agents have ranked among the foremost areas of chemotherapeutic research. The present review paper is already the 17th communication in a group of review papers about the development of new antituberculotics, the sixth about the development in recent 15 years and the second communication devoted in this series to ortho-condensed heterocyclic compounds. The classification of ortho-condensed compounds is based on six-membered heterocyclic substructural fragments. The literature search is based on the journal Chemical Abstracts, Current Awareness in Biomedicine, part Mycobacteria, and original papers. Current Awareness in Biomedicine is, however, a very imperfect literature search source, recording only a fraction of communications.

[Advances in the development of new antitubercular agents from a group of ortho-condensed heterocyclic compounds. Part 1. Compounds containing one heteroatom per six-membered ring]. / Pokroky ve vývoji nových antituberkulotik ze skupiny orthokondenzovaných heterocyklických sloucenin cást 1. Látky obsahující v sesticlenném kruhu jeden heteroatom.

Tuberculosis and other mycobacterial diseases are considered to be one of the most important problems of contemporary health service. Since 1985 and particularly in the 1990s and at present the search for new structures of antimycobacterial agents have ranked among the foremost areas of chemotherapeutic research. The present review paper is already the 16th communication in a group of review papers about the development of new antituberculotics in recent 15 years. The literature search is based on the journal Chemical Abstracts, Current Awareness in Biomedicine, part Mycobacteria, and original papers. Current Awareness in Biomedicine is, however, a very imperfect literature search source, recording only a fraction of communications. Though none of the ortho-condensed heterocyclic compounds has been introduced into practice, the in vitro evaluated activities of some of them equalled those of routine antituberculotics. Polycyclic systems make it possible to widely model the structures, and therefore the present review paper can inspire a search for new structures of antimycobacterial agents.

[Antimicrobial salicylanilides and 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones]. / Antimykobakteriální salicylanilidy a 3-fenyl-2H-1,3-benzoxazin-2,4(3H)-diony.

Salicylanilides and 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones are strong antimycobacterial substances which can be considered to be potential antituberculotics. In order to be able to verify the prognostics of the relationships between the structure and antimycobacterial activity, the series of previously evaluated substances was extended to include 4'-ethoxycarbonylsalicylanilide, 4'-trifluoromethylsalicylanilide, 4'-cyanidosalicylanilide, 4'-thiocarbamoylsalicylanilide, 3-(4-ethoxycarbonylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dione, 3-(4-trifluoromethylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dione, and 3-(4-cyanidophenyl)-2H-1,3-benzoxazine-2,4-(3H)-dione. The substances were evaluated against Mycobacterium tuberculosis, M. kansasii, and M. avium. In harmony with the previous study (see ref. 1), antimycobacterial activity increased with increasing lipophilicity and electron-acceptor properties of substituents. As the values of regression coefficients were not substantially changed after the complementation of the group, the present authors consider the problem under study to be solved.

[Advances in the development of new antitubercular agents from orthocondensed heterocyclic compounds. Part 3. Substances containing several types of heteroatoms in the six-membered ring]. / Pokroky ve vývoji nových antituberkulotik ze skupiny orthokondenzovaných heterocyklických sloucenin. Cást 3. Látky obsahující v sesticlenném kruhu více druhu heteroatomu.

Tuberculosis and other mycobacterial diseases are considered to be one of the most important problems of contemporary health service. Since 1985 and particularly in the 1990s and at present the search for new structures of antimycobacterial agents have ranked among the foremost areas of chemotherapeutic research. The present review paper is already the 18th communication in a group of review papers about substances with antituberculotic effects, and the third, final, communication devoted in this series about the development of new antimycobacterial agents to ortho-condensed heterocyclic compounds in recent 15 years. The classification of ortho-condensed compounds is based on six-membered heterocyclic substructural fragments and the present study deals with the substructural fragments containing a greater number of different heteroatoms. The literature search is based on the journal Chemical Abstracts, Current Awareness in Biomedicine, part Mycobacteria, and original papers. Current Awareness in Biomedicine is, however, a very imperfect literature search source, recording only a fraction of communications. Review papers about five-membered heterocyclic antituberculotic ortho-condensed compounds was published in the present journal in 1999.

[Advances in the development of new antitubercular agents from pyridine derivatives]. / Pokroky ve vývoji nových antituberkulotik ze skupiny derivátu pyridinu.

Tuberculosis and other mycobacterial diseases are considered to be one of the major health problems at present. Since 1985, and in particular in the 1990s, a search for new structures of antimycobacterial substances has been one of the priorities of chemotherapeutic research. Pyridine derivatives have always attracted the interest of research laboratories searching for new chemotherapeutic agents against tuberculosis. The present review paper, based on the journal Chemical Abstracts and original papers, surveys these attempts in recent fifteen years.

[Advances in the development of new antitubercular agents from a group of monocyclic 6-membered heterocyclic compounds with a greater number of nitrogen atoms]. / Pokroky ve vývoji nových antituberkulotik ze skupiny monocyklických sesticlenných heterocyklických sloucenin o více atomech dusíku.

Tuberculosis and other mycobacterial diseases are considered to be one of the major health problems at present. Since 1985, and in particular in the 1990s, a search for new structures of antimycobacterial substances has been one of the priorities of chemotherapeutic research. Pyrazine derivatives have always attracted the interest of research laboratories searching for new chemotherapeutic agents against tuberculosis. The present review paper, based on the journal Chemical Abstracts and original papers, surveys the attempts of the laboratories searching for new antituberculotic agents in the region of six-membered heterocyclic pyrimidine, pyrazine, and triazines compounds in recent fifteen years.

Organ distribution of fibrinogen-bound methotrexate in mice with Gardner lymphosarcoma.

The distribution of fibrinogen-bound 3H methotrexate was investigated in Gardner lymphosarcoma bearing mice. 3H labeled methotrexate (3H MTX) was covalently bound by means of aminopropyl carbodiimide to bovine and mouse fibrinogen (FBG). The preparations as well as the free 3H MTX were applied i.v. in a single dose to three groups of C3H mice on day 6 after the inoculation of Gardner lymphosarcoma. 3H MTX level was determined in the blood, spleen, tumor and liver. Sufficient amounts of MTX were released by proteolysis of FBG-MTX derivatives to induce chemotherapeutical effects. Protracted accumulation of MTX applied in the form of FBG-MTX derivatives was found in the spleen and in the liver, in contradistinction to free drug application, suggesting the proteolytic degradation as a directing step responsible for the prolonged persistence of FBG-MTX derivatives in the organs. In the tumor the highest amount of MTX was released from mouse FBG supporting the view of ready uptake of homologous FBG by tumors.

The effect of folate binding protein on the colony-forming activity of GM-CFC cells in vitro.

A modified method for the preparation of specific folate binding protein was described. The GM-CFC stimulating activity of this SFBP preparation was investigated on tissue cultures of human bone marrow cells. It has been found that in the presence of HPCM the cell proliferation was markedly increased by the SFBP. In the absence of HPCM, however, the cell proliferation has been influenced either positively or negatively presumably in dependence on the expression of folate receptors on the GM-CFC bone marrow cells.