BACKGROUND: We investigated the targeting of microtubules (MT) and F-actin cytoskeleton (AC) of the human pathogenic yeast Cryptococcus neoformans with agents for cancer therapy, in order to examine whether this yeast cytoskeleton could become a new antifungal target for the inhibition of cell division. METHODS: Cells treated with 10 cytoskeleton inhibitors in yeast extract peptone dextrose medium were investigated by phase-contrast and fluorescence microscopy, and growth inhibition was estimated by cell counts using a Bürker chamber and measuring absorbance for 6 days. RESULTS: Docetaxel, paclitaxel, vinblastine sulfate salt, cytochalasin D and chlorpropham [isopropyl N-(3-chlorophenyl) carbamate] did not inhibit proliferation. The MT inhibitors methyl benzimidazole-2-ylcarbamate (BCM), nocodazole, thiabendazole (TBZ) and vincristine (VINC) disrupted MT and inhibited mitoses, but anucleated buds emerged on cells that increased in size, vacuolated and seemed to die after 2 days. The response of the cells to the presence of the actin inhibitor latrunculin A (LA) included the disappearance of actin patches, actin cables and actin rings; this arrested budding and cell division. However, in 3-4 days, resistant budding cells appeared in all 5 inhibitors. Disruption of the MT and AC and inhibition of cell division and budding persisted only when the MT and AC inhibitors were combined, i.e. VINC + LA, BCM + LA or TBZ + LA. CONCLUSION: The MT and AC of C. neoformans are new antifungal targets for the persistent inhibition of cell division by combined F-actin and MT inhibitors.

• MeSH
• aktiny antagonisté a inhibitory   MeSH
• antifungální látky farmakologie   MeSH
• antitumorózní látky farmakologie   MeSH
• bicyklické sloučeniny heterocyklické farmakologie   MeSH
• buněčné dělení účinky léků   MeSH
• Cryptococcus neoformans účinky léků   MeSH
• fluorescenční mikroskopie MeSH
• lidé MeSH
• mikrofilamenta účinky léků   MeSH
• mikrotubuly účinky léků   MeSH
• racionální návrh léčiv MeSH
• thiazolidiny farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aktiny MeSH
• antifungální látky MeSH
• antitumorózní látky MeSH
• bicyklické sloučeniny heterocyklické MeSH
• latrunculin A MeSH Prohlížeč
• thiazolidiny MeSH

BACKGROUND: Cryptococcus neoformans is one of the most important human fungal pathogens. Its cells contain rich microtubules required for nuclear division and rich F-actin cytoskeletons for cell division. Disruption of microtubules by a microtubule inhibitor should block nuclear division, and disruption of F-actin by an actin inhibitor should block cell division. We investigated the effects of microtubule and actin inhibitors to find out whether the cytoskeletons of C. neoformans can become a new anti-fungal target for the inhibition of cell division, when examined at the ultrastructural level. METHODS: Cells treated with the microtubule inhibitors vincristine (VIN) and methyl benzimidazole-2-ylcarbamate (BCM) and the actin inhibitor latrunculin A (LA), in yeast extract peptone dextrose medium, were examined by scanning (SEM) and transmission electron microscopy (TEM), and the cell number was counted using a Bürker chamber. RESULTS: After 2 days of inhibition with VIN, BCM or LA, the cells did not divide, but later, resistant, proliferating cells appeared in all samples. With combined microtubule and actin inhibitors (VIN + LA or BCM + LA), cells did not divide during 6 or even 14 days, and no resistant cells originated. TEM showed that the inhibited cells were without cytoplasm and were dead; only empty cell walls persisted with reduced capsules, shown on SEM. CONCLUSION: Combined microtubule and actin inhibitors (VIN + LA or BCM + LA), have lethal effects on C. neoformans cells and no resistant cells originate.

• MeSH
• aktiny antagonisté a inhibitory   ultrastruktura   MeSH
• benzimidazoly farmakologie   MeSH
• bicyklické sloučeniny heterocyklické farmakologie   MeSH
• Cryptococcus neoformans účinky léků   ultrastruktura   MeSH
• karbamáty farmakologie   MeSH
• lidé MeSH
• mikroskopie elektronová rastrovací metody   MeSH
• mikrotubuly účinky léků   ultrastruktura   MeSH
• thiazolidiny farmakologie   MeSH
• transmisní elektronová mikroskopie metody   MeSH
• vinkristin farmakologie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aktiny MeSH
• benzimidazoly MeSH
• bicyklické sloučeniny heterocyklické MeSH
• carbendazim MeSH Prohlížeč
• karbamáty MeSH
• latrunculin A MeSH Prohlížeč
• thiazolidiny MeSH
• vinkristin MeSH

BACKGROUND: This basic research aimed to investigate the effects of the actin inhibitor latrunculin A (LA) on the human pathogen Cryptococcus neoformans, by freeze-substitution (FS) and electron microscopy (EM), to determine whether the actin cytoskeleton can become a new antifungal target for inhibition of cell division. METHODS: Cells treated with LA for 20 h in yeast-extract peptone dextrose medium were investigated by phase-contrast and fluorescent microscopy, FS and transmission EM, counted in a Bürker chamber and the absorbance was then measured. RESULTS: The disappearance of actin patches, actin cables and actin rings demonstrated the response of the cells of C. neoformans to the presence of the actin inhibitor LA. The removal of actin cables and patches arrested proliferation and led to the production of cells that had ultrastructural disorder, irregular morphology of the mitochondria and thick aberrant cell walls. Budding cells lysed in the buds and septa. CONCLUSION: LA exerts fungistatic, fungicidal and fungilytic effects on the human pathogenic yeast C. neoformans.

• MeSH
• aktiny antagonisté a inhibitory   MeSH
• antifungální látky farmakologie   MeSH
• bicyklické sloučeniny heterocyklické farmakologie   MeSH
• buněčná stěna účinky léků   metabolismus   MeSH
• buněčné dělení účinky léků   MeSH
• Cryptococcus neoformans účinky léků   metabolismus   MeSH
• elektronová mikroskopie metody   MeSH
• fluorescenční mikroskopie metody   MeSH
• kryptokokóza farmakoterapie   metabolismus   mikrobiologie   MeSH
• lidé MeSH
• mikrofilamenta účinky léků   metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• thiazolidiny farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aktiny MeSH
• antifungální látky MeSH
• bicyklické sloučeniny heterocyklické MeSH
• latrunculin A MeSH Prohlížeč
• thiazolidiny MeSH

BACKGROUND: Resistance of cancer cells to chemotherapeutic agents is a major cause of treatment failure in patients with cancer. The drug resistance of tumor cells can be significantly modified by specific features of tumor microenvironment, such as oxygen depletion (hypoxia), glucose/energy deprivation and acidosis. METHODS: The effects of acidic tumor-like microenvironment on cytotoxicity of antabuse (disulfiram, DSF)/Cu(2+) complexes to MCF-7 breast carcinoma and HT-29 colon carcinoma cells were studied. RESULTS: We show that acidic pH significantly potentiates toxicity of DSF/Cu(2+) complex to breast and colon cancer cells. This phenomenon is associated with changes in cell metabolism, altered Akt kinase and NFκB activity and increased reactive oxygen species production. CONCLUSION: Specific pH of tumor microenvironment enhances cytotoxicity of DSF/Cu(2+) to breast and colon cancer cells.

• MeSH
• antitumorózní látky chemická syntéza   chemie   toxicita   MeSH
• buňky HT-29 MeSH
• disulfiram chemie   MeSH
• fosforylace MeSH
• komplexní sloučeniny chemická syntéza   chemie   toxicita   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• měď chemie   MeSH
• MFC-7 buňky MeSH
• nádorové mikroprostředí účinky léků   MeSH
• nádory prsu metabolismus   patologie   MeSH
• nádory tračníku metabolismus   patologie   MeSH
• NF-kappa B metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• disulfiram MeSH
• komplexní sloučeniny MeSH
• měď MeSH
• NF-kappa B MeSH
• protoonkogenní proteiny c-akt MeSH
• reaktivní formy kyslíku MeSH

BACKGROUND: Dysfunction of the carnitine system in non-tumour tissue following anticancer therapy has been reported. In this setting, supplementation with carnitine derivatives might increase the general metabolic activity of normal cells so that they might better withstand the adverse effects of chemotherapy aimed at tumour cells. Here we investigated the effect of acetyl-L-carnitine (ALC) alone and in combination with the antineoplastic agent mitoxantrone (MX) in an animal cancer model. METHODS: The effects of MX and MX-ALC were assessed based on gain or loss of body weight and on local growth of a solid form of Ehrlich tumour inoculated into mice. We also performed biochemical analyses like serum activities of some enzymes signalling the functioning of the liver, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Total protein, albumin and bilirubin were also determined in serum. Under favourable conditions, the Ehrlich tumour readily forms metastases, and this is the reason why we performed histological studies of samples of both the liver and heart in order to identify changes that may have mediated the observed effect of the treatment. In addition to those studies, the survival time of treated animals against controls was also noted. RESULTS: MX monotherapy was associated with lower body weight gain, fewer metastases, smaller tumour size, and lower dissemination. ALC alone promoted survival, but had no potentiating effect on MX therapy in terms of survival. Serum biochemistry changes associated with MX-ALC treatment consisted of a significant (p < 0.05) increase in AST with MX at 6 or 9 mg·kg(-1) plus ALC 200 mg·kg(-1) and a significant (p < 0.05) reduction in total protein compared to the corresponding MX group; serum albumin and bilirubin remained unchanged. CONCLUSION: ALC in combination with MX, regardless of the dose of MX, led to higher occurrences of metastases with dissemination to the kidneys, lungs, heart, and mediastinum compared to MX treatment alone. These histological findings indicate that ALC is inappropriate to combine with MX in the treatment of a solid cancer. The protective effect of ALC in combination therapy with the cytostatic drug MX was not supported in this study by our findings that the agent did not improve the therapeutic outcomes of MX therapy.

• MeSH
• acylkarnitin terapeutické užití   MeSH
• antitumorózní látky terapeutické užití   MeSH
• bilirubin krev   MeSH
• Ehrlichův tumor farmakoterapie   patologie   MeSH
• experimentální nádory jater farmakoterapie   patologie   MeSH
• mitoxantron terapeutické užití   MeSH
• myši MeSH
• sérový albumin analýza   MeSH
• tělesná hmotnost MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acylkarnitin MeSH
• antitumorózní látky MeSH
• bilirubin MeSH
• mitoxantron MeSH
• sérový albumin MeSH

BACKGROUND: The aim of this basic study was to investigate by scanning electron microscopy the effects of cytoskeleton inhibitors on conidiogenesis and capsule in the yeast Fellomyces fuzhouensis CBS 8243, related to Cryptococcus neoformans. METHODS: Cells were treated by methyl benzimidazole-2-ylcarbamate (BCM) and latrunculin A (LAT) in yeast extract peptone dextrose medium and examined by scanning electron microscopy. RESULTS: During conidiogenesis, mother cells covered by capsule formed hypha-like stalks and at the hyphal tip yeast-like conidium developed. LAT blocked both stages of conidiogenesis. Inhibited mother cells and conidia became spherical and their capsule disappeared. BCM did not block formation of conidia that were neckless, or affect capsule. Combined application of LAT and BCM blocked both stages of conidiogenesis, cells became spherical and their capsule disappeared. CONCLUSION: Yeast cells with disrupted actin cytoskeleton do not reproduce by conidiogenesis and do not retain inherited cell shape and capsule.

• MeSH
• Basidiomycota účinky léků   ultrastruktura   MeSH
• bicyklické sloučeniny heterocyklické farmakologie   MeSH
• cytoskelet účinky léků   ultrastruktura   MeSH
• mikroskopie elektronová rastrovací metody   MeSH
• spory hub účinky léků   ultrastruktura   MeSH
• thiazolidiny farmakologie   MeSH
• tvar buňky účinky léků   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• bicyklické sloučeniny heterocyklické MeSH
• latrunculin A MeSH Prohlížeč
• thiazolidiny MeSH

BACKGROUND: The cytoskeleton was investigated as a potential target for the inhibition of cell division in Fellomyces fuzhouensis CBS 8243 related to Cryptococcus neoformans. METHODS: Vincristine, vinblastine, paclitaxel, methyl benzimidazole-2-yl carbamate (BCM), thiabendazole, cytochalasins A, B and D and latrunculin A were added to yeast extract peptone dextrose medium containing cells, investigated by phase contrast and fluorescence microscopy, counted in a Burker chamber and absorbance was measured. RESULTS: Vincristine, vinblastine, paclitaxel, cytochalasins A, B and D transiently blocked proliferation. BCM disrupted microtubules and inhibited mitosis, but F-actin patches and cables persisted and neck-less conidia appeared without stalks. Latrunculin disrupted F-actin, cells became spherical, and stalks and necks degenerated; microtubules persisted, but mitosis, cytokinesis and conidiogenesis were blocked. The combined application of latrunculin and BCM disrupted F-actin and microtubules, and inhibited cells became spherical and did not divide. CONCLUSIONS: Microtubules and F-actin are effective targets for permanent inhibition of nuclear and cell division and conidiogenesis by BCM and latrunculin A.

• MeSH
• antifungální látky farmakologie   MeSH
• Basidiomycota cytologie   účinky léků   MeSH
• bicyklické sloučeniny heterocyklické farmakologie   MeSH
• cytochalasiny farmakologie   MeSH
• cytokineze účinky léků   MeSH
• kvasinky cytologie   účinky léků   MeSH
• mikrofilamenta účinky léků   MeSH
• mikrotubuly účinky léků   MeSH
• modulátory tubulinu farmakologie   MeSH
• paclitaxel farmakologie   MeSH
• spory hub účinky léků   MeSH
• thiabendazol farmakologie   MeSH
• thiazolidiny farmakologie   MeSH
• vinblastin farmakologie   MeSH
• vinkristin farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antifungální látky MeSH
• bicyklické sloučeniny heterocyklické MeSH
• cytochalasiny MeSH
• latrunculin A MeSH Prohlížeč
• modulátory tubulinu MeSH
• paclitaxel MeSH
• thiabendazol MeSH
• thiazolidiny MeSH
• vinblastin MeSH
• vinkristin MeSH

BACKGROUND: Fluorescence correlation spectroscopy (FCS) can be used for the determination of diffusion coefficients of single molecules. Since diffusion coefficients are correlated with size and shape of the labeled species, FCS provides information on conformational changes in plasmids aggregates. METHODS: A 10-kbp plasmid stained with PicoGreen was condensed by spermine or liposomes formulated from cationic lipid and egg phosphatidylcholine. RESULTS: The diffusion coefficient of DNA increases from 1.0 x 10(-12) m2/s to 3.2 x 10(-12) m2/s by the addition of spermine, whereas the addition of cationic liposomes leads to complexes characterized by diffusion coefficients with values ranging from 1.7 to 1.9 x 10(-12) m2/s. CONCLUSIONS: FCS experiments allow determining the diffusion coefficients of DNA-containing aggregates which provide information regarding the topology and homogeneity of the aggregate.

• MeSH
• barvení a značení MeSH
• DNA chemie   MeSH
• fluorescenční barviva chemie   MeSH
• fluorescenční spektrometrie MeSH
• lidé MeSH
• lipidy chemie   MeSH
• organické látky chemie   MeSH
• plazmidy chemie   MeSH
• spermin chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH
• fluorescenční barviva MeSH
• lipidy MeSH
• organické látky MeSH
• PicoGreen MeSH Prohlížeč
• spermin MeSH

The diagnosis and assessment of the severity of intestinal mucosal damage in cancer patients treated with cytotoxic drugs still rely on anamnestic data. There is cumulative evidence that measurement of intestinal permeability may represent a sensitive indicator of intestinal damage by cytotoxic agents. The intestinal permeability testing is based on differential permeability of tight junctions along the crypt-villus axis to nonmetabolized sugars. Cytotoxic drugs induce flattening of villi, leading to increased exposure of luminal contents to crypts and increased disaccharide absorption. An increased disaccharide/monosaccharide ratio and decreased xylose absorption have been described in patients treated with different cytotoxic drugs across a spectrum of malignant tumors that correlated with clinical manifestations, and were used to monitor the effect of therapeutic interventions.

• MeSH
• antitumorózní látky škodlivé účinky   MeSH
• lidé MeSH
• mukozitida chemicky indukované   diagnóza   MeSH
• nádory komplikace   farmakoterapie   MeSH
• nemoci střev chemicky indukované   diagnóza   MeSH
• permeabilita MeSH
• střevní sliznice účinky léků   imunologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky MeSH

For the treatment of febrile episodes in granulocytopenic cancer patients, a combination of bactericidal and intravenously administered broad spectrum agents is recommended. An aminoglycoside plus a beta-lactame (piperacillin, azlocillin or IIIrd generation cephalosporins) are the drugs of first choice in an empiric approach. Because of frequent parenteral interventions (e.g. catheters, cannulations) in thrombopenic patients with multifactorial immunosuppression, we consider the application of once daily drugs, such as ceftriaxone, netilmicin or amikacin. For single dose treatment (1st day two applications), we used ceftriaxone in combination with netilmicin or amikacin as the first approach and retrospectively evaluated 47 patients for efficacy and safety.

• MeSH
• agranulocytóza komplikace   MeSH
• amikacin aplikace a dávkování   terapeutické užití   MeSH
• bakteriální infekce farmakoterapie   MeSH
• ceftriaxon aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• horečka farmakoterapie   MeSH
• kombinovaná farmakoterapie terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory komplikace   MeSH
• netilmicin aplikace a dávkování   terapeutické užití   MeSH
• retrospektivní studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• amikacin MeSH
• ceftriaxon MeSH
• netilmicin MeSH