Modifications of natural DNA in a cell-free medium by dinuclear bisplatinum complexes with equivalent coordination spheres, represented by the general formula [¿trans-PtCl(NH3)2¿2(H2N-R-NH2)]2+, where R is a propane or hexane, were studied by various methods of biochemical analysis or molecular biophysics. These methods include binding studies by means of differential-pulse polarography, measurements of melting curves with the aid of absorption spectrophotometry, measurements of CD spectra, ELISA with specific antibodies that recognize DNA modified by platinum complexes, interstrand cross-linking assay employing gel electrophoresis under denaturing conditions and mapping of DNA adducts by means of transcription assays. The results indicated that the major adduct of [¿trans-PtCl(NH3)2¿2(H2N-R-NH2)]2+ in DNA was an interstrand cross-link which was formed with a relatively short half-time (approximately 1 h). At least some types of these interstrand cross-links induced local denaturational changes in the DNA. The results of analyses of interactions of [¿trans-PtCl(NH3)2¿2(H2N-R-NH2)]2+ with linear DNA at relatively higher levels of the modification could be interpreted to mean that these dinuclear platinum complexes were also capable of intrastrand-cross-link formation between adjacent base residues in DNA. However, these intrastrand adducts of [¿trans-PtCl(NH3)2¿2(H2N-R-NH2)]2+ distorted DNA conformation in a way different from the DNA intrastrand adducts of cisplatin. In addition, the DNA adducts of the dinuclear platinum complexes inhibited DNA transcription in vitro. The length of the aliphatic linker chain affected the DNA-binding mode of [¿trans-PtCl(NH3)2¿2(H2N-R-NH2)]2+ and the resulting conformational changes in DNA. The extensive analysis of DNA interactions with [¿trans-PtCl(NH3)2¿2(H2N-R-NH2)]2+ described in this communication has provided further experimental support for previous suggestions [Farrell, N. (1991) in Platinum and other metal coordination compounds in cancer chemotherapy (Howell, S. B., ed.) pp. 81-91, Plenum Press, New York] that the binding of the dinuclear platinum complexes modifies DNA in a way that is different from the modification by antitumor cisplatin. Thus, the results of this work are consistent with the hypothesis that platinum drugs that bind to DNA in a manner fundamentally different from that of cisplatin can exhibit altered biological properties, including a different spectrum and intensity of antitumor activity.

• MeSH
• bakteriofág T7 metabolismus   MeSH
• cirkulární dichroismus MeSH
• cisplatina chemie   MeSH
• DNA řízené RNA-polymerasy metabolismus   MeSH
• DNA chemie   genetika   metabolismus   MeSH
• genetická transkripce MeSH
• imunochemie MeSH
• molekulární sekvence - údaje MeSH
• protinádorové látky chemie   MeSH
• reagencia zkříženě vázaná chemie   MeSH
• sekvence nukleotidů MeSH
• skot MeSH
• virové proteiny MeSH
• zvířata MeSH
• Check Tag
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bacteriophage T7 RNA polymerase MeSH Prohlížeč
• cisplatina MeSH
• DNA řízené RNA-polymerasy MeSH
• DNA MeSH
• protinádorové látky MeSH
• reagencia zkříženě vázaná MeSH
• transplatin MeSH Prohlížeč
• virové proteiny MeSH

The gold(I) mixed-ligand complexes involving O-substituted derivatives of 9-deazahypoxanthine (HLn) and triphenylphosphine (PPh3) with the general formula [Au(Ln)(PPh3)] (1-5) were prepared and thoroughly characterized by elemental analysis, FT-IR and multinuclear NMR spectroscopy, ESI+ mass spectrometry, single crystal X-ray (HL5 and complex 2) and TG/DTA analyses. Complexes 1-5 were evaluated for their in vitro antitumor activity against nine human cancer lines, i.e. MCF7 (breast carcinoma), HOS (osteosarcoma), A549 (adenocarcinoma), G361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) and THP-1 (monocytic leukaemia), for their in vitro anti-inflammatory activity using a model of LPS-activated macrophages, and for their in vivo antiedematous activity by λ-carrageenan-induced hind paw edema model on rats. The results showed that the complexes 1-5 exhibit selective in vitro cytotoxicity against MCF7, HOS, 22Rv1, A2780 and A2780R, with submicromolar IC50 values for 2 against the MCF7 (0.6 µM) and HOS (0.9 µM). The results of in vitro cytotoxicity screening on primary culture of human hepatocytes (HEP220) revealed up to 30-times lower toxicity of compounds against healthy cells as compared with cancer cells. Additionally, the complexes 1-5 significantly influence the secretion and expression of pro-inflammatory cytokines TNF-α and IL-1β by a similar manner as a commercially used anti-arthritic drug Auranofin. The tested complexes also significantly influence the rate and overall volume of the edema, caused by the intraplantar application of λ-carrageenan polysaccharide to rats. Based on these promising results, the presented compounds could qualify to become feasible candidates for advanced testing as potential antitumor and anti-inflammatory drug-like compounds.

• MeSH
• antiflogistika chemie   farmakologie   terapeutické užití   MeSH
• edém farmakoterapie   MeSH
• hepatocyty účinky léků   MeSH
• hypoxanthiny chemie   farmakologie   terapeutické užití   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   MeSH
• protinádorové látky chemie   farmakologie   terapeutické užití   MeSH
• spektroskopie infračervená s Fourierovou transformací MeSH
• zánět farmakoterapie   MeSH
• zlato chemie   farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 9-deazahypoxanthine MeSH Prohlížeč
• antiflogistika MeSH
• hypoxanthiny MeSH
• protinádorové látky MeSH
• zlato MeSH

A series of 6 substitutionally inert and luminescent iridium(iii) antitumor agents of the type [Ir(C∧N)2(N∧N)][PF6] containing a benzimidazole N∧N ligand with an ester group as a handle for further functionalization has been prepared. They exhibit IC50 values in the high nanomolar range in some ovarian and breast cancer cell lines (approximately 100× more cytotoxic than cisplatin (CDDP) in MDA-MB-231) and are located in the actin cortex predominantly as shown by confocal luminescence microscopy. This discovery could open the door to a new large family of drug bioconjugates with diverse and simultaneous functions.

• MeSH
• benzimidazoly chemie   farmakologie   MeSH
• iridium chemie   farmakologie   MeSH
• konfokální mikroskopie MeSH
• lidé MeSH
• ligandy MeSH
• luminiscence * MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• organokovové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzimidazole MeSH Prohlížeč
• benzimidazoly MeSH
• iridium MeSH
• ligandy MeSH
• organokovové sloučeniny MeSH
• protinádorové látky MeSH

A series of picolyl amides of betulinic acid (3a-3c and 6a-6c) was prepared and subjected to the cytotoxicity screening tests. Structure-activity relationships studies resulted in finding differences in biological activity in dependence on o-, m- and p-substitution of the pyridine ring in the target amides, when cytotoxicity data of 3a-3c and 6a-6c were obtained and compared. The amides 3b and 3a displayed cytotoxicity (given in the IC50 values) in G-361 (0.5 ± 0.1 μM and 2.4 ± 0.0 μM, respectively), MCF7 (1.4 ± 0.1 μM and 2.2 ± 0.2 μM, respectively), HeLa (2.4 ± 0.4 μM and 2.3 ± 0.5 μM, respectively) and CEM (6.5 ± 1.5 μM and 6.9 ± 0.4 μM, respectively) tumor cell lines, and showed weak effect in the normal human fibroblasts (BJ). Selectivity against all tested cancer cells was determined and compared to normal cells with therapeutic index (TI) between 7 and 100 for compounds 3a and 3b. The therapeutic index (TI = 100) was calculated for human malignant melanoma cell line (G-361) versus normal human fibroblasts (BJ). The cytotoxicity of other target amides (3c and 6a-6c) revealed lower effects than 3a and 3b in the tested cancer cell lines.

• Klíčová slova
• Amide, Betulinic acid, Cytotoxicity, Picolyl amine, Therapeutic index,
• MeSH
• amidy chemická syntéza   chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buněčné linie MeSH
• kyselina betulinová MeSH
• lidé MeSH
• molekulární struktura MeSH
• pentacyklické triterpeny MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• triterpeny chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amidy MeSH
• kyselina betulinová MeSH
• pentacyklické triterpeny MeSH
• protinádorové látky MeSH
• triterpeny MeSH

The ability to manipulate the structure and function of promising systems via external stimuli is emerging with the development of reconfigurable and programmable multifunctional materials. Increasing antifungal and antitumor activity requires novel, effective treatments to be diligently sought. In this work, the synthesis, characterization, and in vitro biological screening of pure α-Ag2WO4, irradiated with electrons and with non-focused and focused femtosecond laser beams are reported. We demonstrate, for the first time, that Ag nanoparticles/α-Ag2WO4 composite displays potent antifungal and antitumor activity. This composite had an extreme low inhibition concentration against Candida albicans, cause the modulation of α-Ag2WO4 perform the fungicidal activity more efficient. For tumor activity, it was found that the composite showed a high selectivity against the cancer cells (MB49), thus depleting the populations of cancer cells by necrosis and apoptosis, without the healthy cells (BALB/3T3) being affected.

• MeSH
• antifungální látky farmakologie   MeSH
• apoptóza MeSH
• buňky BALB 3T3 MeSH
• Candida albicans účinky léků   MeSH
• elektrony * MeSH
• kovové nanočástice aplikace a dávkování   chemie   účinky záření   MeSH
• lidé MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nádory močového měchýře farmakoterapie   patologie   MeSH
• oxidy chemie   účinky záření   MeSH
• proliferace buněk MeSH
• protinádorové látky farmakologie   MeSH
• stříbro chemie   účinky záření   MeSH
• wolfram chemie   účinky záření   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antifungální látky MeSH
• oxidy MeSH
• protinádorové látky MeSH
• stříbro MeSH
• tungsten oxide MeSH Prohlížeč
• wolfram MeSH

The effects of the two representatives of the antitumor transplatinum agents, trans-[PtCl2(methylamine)2] and trans-[PtCl2(NH3)(1-methyl-7-azaindole)] on bacterial growth were examined. The results show that these antitumor transplatinum agents can be grouped with the coordination Pt(II) compounds exhibiting antitumor activity and capable of inducing bacterial filamentation and initiate lysis in lysogenic bacteria. The results corroborate the thesis that DNA is the potential cellular target also for a class of antitumor derivatives of transplatin.

• Klíčová slova
• Antitumor, Bacterial cells, Bacterial filamentation, Cellular target, DNA, Prophage induction, Transplatinum,
• MeSH
• cisplatina chemie   farmakologie   MeSH
• DNA bakterií chemie   MeSH
• Escherichia coli účinky léků   MeSH
• organoplatinové sloučeniny chemie   farmakologie   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cisplatina MeSH
• DNA bakterií MeSH
• organoplatinové sloučeniny MeSH
• protinádorové látky MeSH
• transplatin MeSH Prohlížeč

The antitumor effect of ribonucleases was studied with animal ribonucleolytic enzymes, bovine pancreatic RNase A, bovine seminal RNase (BS-RNase), onconase and angiogenin. While bovine pancreatic RNase A exerts a minor antitumor effect, BS-RNase and onconase exert significant effects. Angiogenin, as RNase, works in an opposite way, it initiates vascularization of tumors and subsequent tumor growth. Ribonunclease inhibitors are not able to inhibit the antitumor effectiveness of BS-RNase or onconase. However, they do so in the case of pancreatic RNases. Conjugation of BS-RNase with antibodies against tumor antigens (preparation of immunotoxins) like the conjugation of the enzyme with polymers enhances the antitumor activity of the ribonuclease. After conjugation with polymers, the half-life of BS-RNase in blood is extended and its immunogenicity reduced. Recombinant RNases have the same functional activity as the native enzymes. The synthetic genes have also been modified, some of them with gene sequences typical for the BS-RNase parts. Recent experimental efforts are directed to the preparation of 'humanized antitumor ribonuclease' that would be structurally similar to human enzyme with minimal immunogenicity and side effects. The angiogenesis of tumors is attempted to be minimized by specific antibodies or anti-angiogenic substances.

• MeSH
• lidé MeSH
• nádorové buňky kultivované účinky léků   enzymologie   MeSH
• pankreatická ribonukleasa farmakologie   MeSH
• protinádorové látky farmakologie   MeSH
• ribonukleasy farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• pankreatická ribonukleasa MeSH
• protinádorové látky MeSH
• ribonukleasy MeSH

Unlike the bovine pancreatic ribonuclease (RNAase A), bovine seminal ribonuclease (BS RNAase) displays various biological activities including antitumor cytotoxicity. To learn more about its antitumor activity, we investigated BS RNAase effect on athymic nude mice bearing various tumors. BS RNAase (250 micrograms per mouse per day) was administered to the mice with prostate carcinoma for three weeks by three different routes (intraperitoneally--i.p., subcutaneously--s.c., and intratumorally-i.t.). Administration i.p. was ineffective, while s.c. administration reduced significantly size of tumors and i.t. administration abolished half of the tumors in treated mice. The i.t. administration of BS RNase to nude mice bearing melanoma showed even better results. Eighty % of mice were without tumors and in the other mice the tumors were significantly diminished. The best antitumor effect was obtained in case of seminoma. All mice bearing this tumor were cured after ten doses of BS RNAase.

• MeSH
• endoribonukleasy aplikace a dávkování   terapeutické užití   MeSH
• experimentální nádory farmakoterapie   MeSH
• melanom farmakoterapie   MeSH
• myši nahé MeSH
• myši MeSH
• nádory prostaty farmakoterapie   MeSH
• protinádorové látky aplikace a dávkování   terapeutické užití   MeSH
• screeningové testy protinádorových léčiv MeSH
• seminom farmakoterapie   MeSH
• skot MeSH
• transplantace heterologní MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• skot MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• endoribonukleasy MeSH
• protinádorové látky MeSH
• ribonuclease SPL MeSH Prohlížeč

Unlike the bovine pancreatic ribonuclease (RNaseA), bovine seminal ribonuclease (BS RNase) displays various biological activities, including antitumor activity, immunosuppressivity, spermatogenicity and embryotoxicity. To learn more about its antitumor effect we tested BS RNase on the growth of 16 cell lines derived from patients with various hematological malignancies. The cells of lymphoid origin were generally more susceptible to BS RNase, administered in the range of concentrations from 2 to 100 micrograms/ml, than the myeloid ones. RNaseA used at the same concentrations did not exert any inhibitory effect. The inhibitory effect of BS RNase persisted in cultured cells after three times wash in complete medium and cell recultivation in fresh medium free of BS RNase. Four cell lines were very little sensitive (KG-1 and U-937) or resistant (JOK and NAMALWA) to BS RNase regardless of their origin. The in vivo antitumor effect of BS RNase was tested on human prostate carcinoma transplanted to athymic nude mice. The daily dose of BS RNase (0.25 mg/20 g) was administered for three weeks except weekends (15 doses) by three different ways (intraperitoneally-i.p., subcutaneously-s.c. and intratumorally-i.t.). Whereas i.p. administration was ineffective, s.c. administration significantly reduced size of the tumors and i.t. administration abolished half of the tumors in treated mice. The average weight of treated mice decreased during the experiment by 10-15%.

• MeSH
• buněčné dělení účinky léků   MeSH
• endoribonukleasy farmakologie   MeSH
• HL-60 buňky účinky léků   MeSH
• leukemie farmakoterapie   MeSH
• lidé MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buňky kultivované účinky léků   MeSH
• nádory prostaty farmakoterapie   MeSH
• protinádorové látky farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• transplantace nádorů MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• endoribonukleasy MeSH
• protinádorové látky MeSH
• ribonuclease SPL MeSH Prohlížeč

One concept how to improve anticancer effects of conventional metallodrugs consists in conjugation of these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, biological effects, and mechanisms of action of new Pt(II) derivatives containing one or two nonsteroidal anti-inflammatory diclofenac (DCF) ligands also known for their antitumor effects. The antiproliferative properties of these metallic conjugates show that these compounds are potent and cancer cell selective cytotoxic agents exhibiting activity in cisplatin resistant and the COX-2 positive tumor cell lines. One of these compounds, compound 3, in which DCF molecules are coordinated to Pt(II) through their carboxylic group, is more potent than parental conventional Pt(II) drug cisplatin, free DCF and the congeners of 3 in which DCF ligands are conjugated to Pt(II) via a diamine. The potency of 3 is due to several factors including enhanced internalization that correlates with enhanced DNA binding and cytotoxicity. Mechanistic studies show that 3 combines multiple effects. After its accumulation in cells, it releases Pt(II) drug capable of binding/damaging DNA and DCF ligands, which affect distribution of cells in individual phases of the cell cycle, inhibit glycolysis and lactate transport, collapse mitochondrial membrane potential, and suppress the cellular properties characteristic of metastatic progression.

• MeSH
• antiflogistika nesteroidní chemie   farmakologie   MeSH
• diklofenak chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antiflogistika nesteroidní MeSH
• diklofenak MeSH
• organoplatinové sloučeniny MeSH
• protinádorové látky MeSH