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Antitumour Activity (antitumour + activity)
Selected AbstractsAntitumour Activity and Side Effects of Combined Treatment with Chitosan and Cisplatin in Sarcoma 180-Bearing MiceJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2000YOSHIYUKI KIMURA We examined the possible modulation by chitosan of the antitumour effects and side effects of cisplatin (cis-diaminedichloroplatinum, CDDP). The study showed that CDDP had potent antitumour activity when administered orally as well as intraperitoneally. We also compared the antitumour activity and side effects of orally administered CDDP plus orally administered chitosan versus intraperitoneally administered CDDP plus orally administered chitosan in sarcoma 180-bearing mice. When CDDP (1.25 mg kg,1 × 2 day,1) was intraperitoneally administered to sarcoma 180-bearing mice, myelotoxicity (the reduction of leucocyte and platelet numbers), nephrotoxicity (the increase of blood nitrogen urea level), immunotoxicity (the reduction of spleen and thymus weight) and a reduction in body weight resulted. These intraperitoneally administered CDDP-induced side effects were not prevented by oral administration of chitosan (150 mg kg,1 × 2 day,1 and 750 mg kg,1 × 2 day,1) for 14 consecutive days. On the other hand, the side effects such as the reductions of body and spleen weights induced by orally administered CDDP (1.25 mg kg,1 × 2 day,1) were prevented by the oral administration of chitosan (150 mg kg,1 × 2 day,1 and 750 mg kg,1 × 2 day,1). From these results, we conclude that the orally administered chitosan plus CDDP might be useful for the prevention of body weight reduction and immunotoxicity (the reduction of spleen weight) induced by the orally administered CDDP without diminishing antitumour activity. [source] Antitumour activity and specificity as a function of substitutions in the lipophilic sector of helical lactoferrin-derived peptideJOURNAL OF PEPTIDE SCIENCE, Issue 5 2003Nannan Yang Abstract A peptide L5 (PAWRKAFRWAWRMLKKAA), derived from the N -terminal ,-helical region of bovine lactoferrin (LFB 14,31), that is highly active against several tumour cell lines was reported earlier. In this study, a number of L5 analogues were designed in order to investigate how subsequent replacements of the aromatic amino acids in L5 with three amino acids representing different structural parameters influenced antitumour activity and tumour cell specificity relative to normal human cells. The Trp residues were substituted by Lys, Ile or Ala, while the Phe residue was substituted with Ala. The resulting peptides were investigated for their activity against prokaryotic cells, four tumour cell lines, human lung fibroblasts and human erythrocytes. Most of the peptides were highly active against both E. coli and S. aureus. The peptides were more active against the tumour cell lines than against normal eukaryotic cells but the activity against normal fibroblasts varied more among the peptides than did their antitumour activities. The results revealed that aromatic residues located opposite the cationic sector in L5 were more critical for antitumour activity than were aromatic residues located adjacent to the cationic sector. The biological responses for the peptides against tumour cell lines, fibroblasts, S. aureus (but not E. coli), were highly correlated with the amino acid descriptors used in our QSAR model. The result obtained from the QSAR study identified specific structural features that were important for lytic activity and membrane specificity. Certain structural properties in positions 3, 9 and 11 were shown to be important for antitumour activity, while additional structural properties in position 7 were found to be important with respect to tumour cell specificity. This information may offer a possibility for de novo design of an antitumour peptide with an improved therapeutic index. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd. [source] Antitumour activity of synthetic curcuminoid analogues (1,7-diaryl-1,6-heptadiene-3,5-diones) and their copper complexesAPPLIED ORGANOMETALLIC CHEMISTRY, Issue 8 2006V. D. John Abstract Four new curcuminoid analogues, 1,7-bis(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione, 1a; 1,7-di(2-furyl)-1,6-heptadiene-3,5-dione, 1b; 1,7-di(2-naphthyl)-1,6-heptadiene-3,5-dione, 1c; 1,7-bis(2-chlorophenyl)-1,6-heptadiene-3,5-dione, 1d; and their copper(II) complexes of ML2 stoichiometry were synthesized and characterized by UV, IR, 1H NMR, ESR and mass spectral data. The compounds were investigated for their possible cytotoxic and antitumour activities. It was found that copper chelates are remarkably active compared with free curcuminoid analogues. All the compounds were found to be cytotoxic towards Ehrlich ascites carcinoma cells and cultured L929 (lung fibroblast cells). In the case of culture studies, concentrations needed for 50% cell death were around 5 µg/ml for copper complexes and 10 µg/ml for curcuminoid analogues. Copper complex of 1a with hydroxyl group in the phenyl ring was found to be most active towards L929cells (1 µg/ml produced 43.3 ± 1.3% cell death). Compound 1b, which possesses a furyl ring system, was found to show least activity towards increase in life span of tumour-bearing mice (increase in life span 39.31%). Copper chelates of all curcuminoid analogues showed a significant reduction (p < 0.001) of solid tumour volume in mice. Copyright © 2005 John Wiley & Sons, Ltd. [source] Cyanobacteria from benthic mats of Antarctic lakes as a source of new bioactivitiesJOURNAL OF APPLIED MICROBIOLOGY, Issue 1 2008N. Biondi Abstract Aims:, To exploit the cyanobacterial diversity of microbial mats growing in the benthic environment of Antarctic lakes for the discovery of novel antibiotic and antitumour activities. Methods and results:, In all, 51 Antarctic cyanobacteria isolated from benthic mats were cultivated in the laboratory by optimizing temperature, irradiance and mixing. Productivity was generally very low (,60 mg l,1 d,1) with growth rates (,) in the range of 0·02,0·44 d,1. Growth rates were limited by photosensitivity, sensitivity to air bubbling, polysaccharide production or cell aggregation. Despite this, 126 extracts were prepared from 48 strains and screened for antimicrobial and cytotoxic activities. Seventeen cyanobacteria showed antimicrobial activity (against the Gram-positive Staphylococcus aureus, the filamentous fungus Aspergillus fumigatus or the yeast Cryptococcus neoformans), and 25 were cytotoxic. The bioactivities were not in accordance with the phylogenetic grouping, but rather strain-specific. One active strain was cultivated in a 10-l photobioreactor. Conclusions:, Isolation and mass cultivation of Antarctic cyanobacteria and LC-MS (liquid chromatography/mass spectrometry) fractionation of extracts from a subset of those strains (hits) that exhibited relatively potent antibacterial and/or antifungal activities, evidenced a chemical novelty worthy of further investigation. Significance and impact of the study:, Development of isolation, cultivation and screening methods for Antarctic cyanobacteria has led to the discovery of strains endowed with interesting antimicrobial and antitumour activities. [source] Involvement of calcium in the differential induction of heat shock protein 70 by heat shock protein 90 inhibitors, geldanamycin and radicicol, in human non-small cell lung cancer H460 cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2006Yuo-Sheng Chang Abstract Both geldanamycin (GA) and radicicol (RA) are HSP90 binding agents that possess antitumour activities. Although the in vitro data indicated that the inhibitory constant of RA is much bigger than that of GA, the in vivo data on drug efficacy might reveal different results. We have recently shown that treatment with GA induces a heat-shock response and that calcium mobilization may be involved in the process. By using induction of HSP70 as the endpoint assay, we found changes in upstream signaling mediators, including HSF1 and calcium mobilization, as well as possible involvement of protein kinase in human non-small cell lung cancer H460 cells treated with GA and RA. Our results demonstrated that calcium mobilization, a calcium dependent and H7-sensitive protein kinase, along with HSF1 activation by phosphorylation, are all involved in the HSP70 induction process triggered by the drugs. However, only GA, but not RA, can provoke a rapid calcium mobilization and thereby result in an instant induction of HSP70. Furthermore, the rapid calcium influx, followed by instant HSP induction, could be achieved in GA- or RA-treated cells placed in a medium containing excessive calcium while the response was completely abolished in cells depleted of calcium. Taken together, our findings suggest that differential calcium signaling may account for the differential induction of HSP and the action of GA and RA. J. Cell. Biochem. © 2005 Wiley-Liss, Inc. [source] Antitumour activity and specificity as a function of substitutions in the lipophilic sector of helical lactoferrin-derived peptideJOURNAL OF PEPTIDE SCIENCE, Issue 5 2003Nannan Yang Abstract A peptide L5 (PAWRKAFRWAWRMLKKAA), derived from the N -terminal ,-helical region of bovine lactoferrin (LFB 14,31), that is highly active against several tumour cell lines was reported earlier. In this study, a number of L5 analogues were designed in order to investigate how subsequent replacements of the aromatic amino acids in L5 with three amino acids representing different structural parameters influenced antitumour activity and tumour cell specificity relative to normal human cells. The Trp residues were substituted by Lys, Ile or Ala, while the Phe residue was substituted with Ala. The resulting peptides were investigated for their activity against prokaryotic cells, four tumour cell lines, human lung fibroblasts and human erythrocytes. Most of the peptides were highly active against both E. coli and S. aureus. The peptides were more active against the tumour cell lines than against normal eukaryotic cells but the activity against normal fibroblasts varied more among the peptides than did their antitumour activities. The results revealed that aromatic residues located opposite the cationic sector in L5 were more critical for antitumour activity than were aromatic residues located adjacent to the cationic sector. The biological responses for the peptides against tumour cell lines, fibroblasts, S. aureus (but not E. coli), were highly correlated with the amino acid descriptors used in our QSAR model. The result obtained from the QSAR study identified specific structural features that were important for lytic activity and membrane specificity. Certain structural properties in positions 3, 9 and 11 were shown to be important for antitumour activity, while additional structural properties in position 7 were found to be important with respect to tumour cell specificity. This information may offer a possibility for de novo design of an antitumour peptide with an improved therapeutic index. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd. [source] Synthesis and biological activity of phthalimide-based polymers containing 5-fluorouracilPOLYMER INTERNATIONAL, Issue 7 2002Neung-Ju Lee Abstract The attachment of anticancer agents to polymers is a promising approach towards reducing the toxic side-effects and retaining the potent antitumour activity of these agents. A new tetrahydrophthalimido monomer containing 5-fluorouracil (ETPFU) and its homopolymer and copolymers with acrylic acid (AA) and with vinyl acetate (VAc) have been synthesized and spectroscopically characterized. The ETPFU contents in poly(ETPFU- co -AA) and poly(ETPFU- co -VAc) obtained by elemental analysis were 21,mol% and 20,mol%, respectively. The average molecular weights of the polymers determined by gel permeation chromatography were as follows: Mn,=,8900,g,mol,1, Mw,= 13,300,g,mol,1, Mw/Mn,=,1.5 for poly(ETPFU); Mn,=,13,500,g,mol,1, Mw,=,16,600,g,mol,1, Mw/Mn,=,1.2 for poly(ETPFU- co -AA); Mn,=,8300,g,mol,1, Mw,=,11,600,g,mol,1, Mw/Mn,=,1.4 poly(ETPFU- co -VAc). The in vitro cytotoxicity of the compounds against FM3A and U937 cancer cell lines increased in the following order: ETPFU > 5-FU > poly(ETPFU) > poly(ETPFU- co -AA) > poly(ETPFU- co -VAc). The in vivo antitumour activities of all the polymers in Balb/C mice bearing the sarcoma 180 tumour cell line were greater than those of 5-FU and monomer at the highest dose (800,mg,kg,1). © 2002 Society of Chemical Industry [source] Antitumour activity of synthetic curcuminoid analogues (1,7-diaryl-1,6-heptadiene-3,5-diones) and their copper complexesAPPLIED ORGANOMETALLIC CHEMISTRY, Issue 8 2006V. D. John Abstract Four new curcuminoid analogues, 1,7-bis(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione, 1a; 1,7-di(2-furyl)-1,6-heptadiene-3,5-dione, 1b; 1,7-di(2-naphthyl)-1,6-heptadiene-3,5-dione, 1c; 1,7-bis(2-chlorophenyl)-1,6-heptadiene-3,5-dione, 1d; and their copper(II) complexes of ML2 stoichiometry were synthesized and characterized by UV, IR, 1H NMR, ESR and mass spectral data. The compounds were investigated for their possible cytotoxic and antitumour activities. It was found that copper chelates are remarkably active compared with free curcuminoid analogues. All the compounds were found to be cytotoxic towards Ehrlich ascites carcinoma cells and cultured L929 (lung fibroblast cells). In the case of culture studies, concentrations needed for 50% cell death were around 5 µg/ml for copper complexes and 10 µg/ml for curcuminoid analogues. Copper complex of 1a with hydroxyl group in the phenyl ring was found to be most active towards L929cells (1 µg/ml produced 43.3 ± 1.3% cell death). Compound 1b, which possesses a furyl ring system, was found to show least activity towards increase in life span of tumour-bearing mice (increase in life span 39.31%). Copper chelates of all curcuminoid analogues showed a significant reduction (p < 0.001) of solid tumour volume in mice. Copyright © 2005 John Wiley & Sons, Ltd. [source] Isoliquiritigenin, a natural anti-oxidant, selectively inhibits the proliferation of prostate cancer cellsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 8 2010Xiaoyu Zhang Summary 1.,Isoliquiritigenin (ISL) is a simple chalcone-type flavonoid derived from liquorice compounds. It has been reported to have anti-oxidative and antitumour activities. The aim of the present study was to investigate the antitumour effect of ISL on prostate cancer cells and to explore the possible signalling mechanisms involved. 2.,Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The fluorescent probe 2,,7,-dichlorofluorescein diacetate (H2DCF-DA) was used to measure intracellular levels of reactive oxygen species (ROS). Mitochondrial membrane potential (,m) was measured using the mitochondrial probe 5,5,,6,6,-tetrachloro-1,1,,3,3,-tetraethyl-benzimidazolylcarbocyanine iodide (JC-1). 3.,Isoliquiritigenin treatment (10,100 ,mol/L for 24 h) markedly inhibited the proliferation of both C4-2 and LNCaP prostate cancer cells in a dose-dependent manner. Intriguingly, ISL treatment (10,100 ,mol/L for 24 h) had no effect on the viability of IEC-6 normal epithelial cells. Treatment of C4-2 and IEC-6 cells with 87.0 ,mol/L ISL significantly decreased ROS levels and the ,m of C4-2 cells, but had no effect on either parameter in IEC-6 cells. Furthermore, AMP-activated protein kinase (AMPK) and extracellular-signal regulated kinase (ERK) levels were three to fourfold higher in IEC-6 cells than in C4-2 cells (P < 0.05). 4.,The results of the present study suggest that ISL, a natural anti-oxidant, selectively inhibits the proliferation of prostate cancer C4-2 cells, which may be attributed, in part, to defective AMPK and ERK signalling pathways in C4-2 compared with IEC-6 cells. [source] Mycelium cultivation, chemical composition and antitumour activity of a Tolypocladium sp. fungus isolated from wild Cordyceps sinensisJOURNAL OF APPLIED MICROBIOLOGY, Issue 2 2006P.H. Leung Abstract Aims:, To examine and illustrate the morphological characteristics and growth kinetics of Cs-HK1, a Tolypocladium fungus, isolated from wild Cordyceps sinensis in solid and liquid cultures, and the major chemical constituents and antitumour effects of Cs-HK1 mycelium. Methods and Results:, The Cs-HK1 fungus was isolated from the fruiting body of a wild C. sinensis and identified as a Tolypocladium sp. fungus. It grew rapidly at 22,25°C on a liquid medium containing glucose, yeast extract, peptone and major inorganic salts, with a specific growth rate of 1·1 day,1, reaching a cell density of 23·0 g dw l,1 in 7,9 days. Exopolysaccharides accumulated in the liquid culture to about 0·3 g l,1 glucose equivalent. In comparison with natural C. sinensis, the fungal mycelium had similar contents of protein (11·7,,g) and carbohydrate (654·6,,g) but much higher contents of polysaccharide (244·2 mg vs 129·5 mg), adenosine (1116·8,,g vs 264·6 ,g) and cordycepin (65·7 ,g vs 20·8 ,g) (per gram dry weight). Cyclosporin A, an antibiotic commonly produced by Tolypocladium sp., was also detected from the mycelium extract. The hot water extract of mycelium showed low cytotoxic effect on B16 melanoma cells in culture (about 25% inhibition) but significant antitumour effect in animal tests, causing 50% inhibition of B16 cell-induced tumour growth in mice. Conclusions:, The Tolypocladium sp. fungus, Cs-HK1, can be easily cultivated by liquid fermentation. The mycelium biomass contained the major bioactive compounds of C. sinensis, and the mycelium extract had significant antitumour activity. Significance and Impact of the Study:, The Cs-HK1 fungus may be a new and promising medicinal fungus and an effective and economical substitute of the wild C. sinensis for health care. [source] Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinomaJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8b 2009Hung Huynh Abstract Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Vascular endothelial growth factor, platelet derived growth factor and the Raf/mitogen-activated protein kinase/extracellular signal regulated kinase (Raf/MEK/ERK) signalling pathway regulates the growth, neovascularization, invasiveness and metastatic potential of HCC. In this study, we investigated the in vivo antitumour activity and mechanisms of action of sorafenib tosylate on four patient-derived HCC xenografts. Sorafenib dosed at 50 mg/kg and 100 mg/kg inhibited tumour growth by 85% and 96%, respectively. Sorafenib-induced growth suppression and apoptosis were associated with inhibition of angiogenesis, down-regulation of phospho-platelet-derived growth factor receptor , Tyr1021, phospho-eIF4E Ser209, phospho-c-Raf Ser259, c-Raf, Mcl-1, Bcl-2, Bcl-x and positive cell cycle regulators, up-regulation of apoptosis signalling kinase-1, p27 and p21. Expression of IGF-1R, and phosphorylation of c-Raf Ser338, MEK1/2 Ser217/221 and ERK1/2 Thr202/Tyr204 were increased by sorafenib treatment. Phosphorylation of mammalian target-of-rapamycin (mTOR) targets (p70S6K, S6R and 4EBP1) was reduced by sorafenib in sorafenib-sensitive lines but activated in sorafenib-less-sensitive 10,0505 xenograft. Sorafenib-induced phosphorylation of c-met, p70S6K and 4EBP1 was significantly reduced when 10,0505 cells were co-treated with anti-human anti-HGF antibody, suggesting that treatment with sorafenib leads to increased HGF secretion and activation of c-met and mTOR targets. Treatment of 10,0505 tumours with sorafenib plus rapamycin resulted in growth inhibition, inhibition of vascular endothelial growth factor receptor-2 phosphorylation, increased apoptosis and completely blocked sorafenib-induced phosphorylation of mTOR targets and cyclin B1 expression. These data also provide a strong rationale for clinical investigation of sorafenib in combination with mTOR inhibitors in patients with HCC. [source] Synthesis and further studies of chemical transformation of the 2-aryl-3-halogenoquinolin-4(1H)-one derivativesJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 2 2006Malose J. Mphahlele The C-3 brominated and iodinated derivatives were prepared from the corresponding 2-arylquinolin-4(1H)-ones and their NMe-4-oxo derivatives using pyridinium tribromide in acetic acid or iodine-Na2CO3 mixture in THF. The results of further studies of chemical transformation of the prepared ,-haloenones and preliminary antitumour activity of the 3-bromo NH-4-oxo and NMe-4-oxo derivatives are also described. [source] Antitumour activity and specificity as a function of substitutions in the lipophilic sector of helical lactoferrin-derived peptideJOURNAL OF PEPTIDE SCIENCE, Issue 5 2003Nannan Yang Abstract A peptide L5 (PAWRKAFRWAWRMLKKAA), derived from the N -terminal ,-helical region of bovine lactoferrin (LFB 14,31), that is highly active against several tumour cell lines was reported earlier. In this study, a number of L5 analogues were designed in order to investigate how subsequent replacements of the aromatic amino acids in L5 with three amino acids representing different structural parameters influenced antitumour activity and tumour cell specificity relative to normal human cells. The Trp residues were substituted by Lys, Ile or Ala, while the Phe residue was substituted with Ala. The resulting peptides were investigated for their activity against prokaryotic cells, four tumour cell lines, human lung fibroblasts and human erythrocytes. Most of the peptides were highly active against both E. coli and S. aureus. The peptides were more active against the tumour cell lines than against normal eukaryotic cells but the activity against normal fibroblasts varied more among the peptides than did their antitumour activities. The results revealed that aromatic residues located opposite the cationic sector in L5 were more critical for antitumour activity than were aromatic residues located adjacent to the cationic sector. The biological responses for the peptides against tumour cell lines, fibroblasts, S. aureus (but not E. coli), were highly correlated with the amino acid descriptors used in our QSAR model. The result obtained from the QSAR study identified specific structural features that were important for lytic activity and membrane specificity. Certain structural properties in positions 3, 9 and 11 were shown to be important for antitumour activity, while additional structural properties in position 7 were found to be important with respect to tumour cell specificity. This information may offer a possibility for de novo design of an antitumour peptide with an improved therapeutic index. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd. [source] Synthesis and in-vitro antitumour activity of new naphthyridine derivatives on human pancreatic cancer cellsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2009Irene Banti Abstract Objectives The aim of the study was to evaluate the antitumour effect in vitro of newly synthesized 7-substituted 2,3-dihydro-1,8-naphthyridines. Methods Characterization tools included cell viability assay, caspase 3/7 induction, DNA fragmentation, fibroblast growth factor type 1 receptor kinase inhibition, and in-vitro antiangiogenic analysis. Key findings Treatment of MIA PaCa-2 human pancreatic cancer cells with test compounds showed time- and concentration-dependent cytotoxicity with IC50 values in the micromolar range. Compounds with an aminoalkyl or a diaminoalkyl side chain at the 7-position exhibited remarkable cytotoxicity, whereas the presence of a methyl group or a cyclic amine in the same position led to a significant decrease in their biological activity. Cytotoxicity screening demonstrated that the most active was compound 11 (mean 50% inhibition of cell proliferation (IC50) 11 ,M). This compound had an in-vitro antitumour efficacy superior to 5-fluorouracil (the lowest cell viability value after treatment (Emax) 0.2% and 19%, respectively) and proved to be less toxic than 5-fluorouracil against non-cancerous human oral epithelial cells. In addition, compound 11 induced apoptosis in MIA PaCa-2 cells and it was able to promote antiangiogenic effects in vitro. Finally, its cytotoxicity was enhanced in pancreatic cancer cells stimulated with fibroblast growth factor, while no substantial effect was observed on human bronchial smooth muscle cells stimulated with the same growth factor. Conclusions These findings suggest that 1,8-naphthyridine derivatives are a promising class of compounds in cancer research. In particular, the antitumour activity of compound 11 is worth further investigation. [source] Cytotoxic activity of an octadecenoic acid extract from Euphorbia kansui (Euphorbiaceae) on human tumour cell strainsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2008Farong Yu We have investigated the cytotoxic and antitumour activity of an octadecenoic acid extract, mainly containing oleic and linoleic acids, from Euphorbia kansui on human gastric (SGC-7901), hepatocellular carcinoma (BEL-7402), and leukaemia (HL-60) tumour cell strains. Significant and dose-dependent antiproliferation effects were observed on tumour cells from the dose of 3.2 ,g mL,1, which were comparable with or better than those of the common antitumour agent 5-fluorouracil. Results from the clone formation assay and flow cytometry indicated that the mixture of octadecenoic acids resulted in a dose-dependent reduction in the number of tumour cells and significantly inhibited cell proliferation, with induced apoptosis and G0/G1 phase cell cycle arrest. Also, the octadecenoic acids could not only cause cell apoptosis/necrosis but also functionally and structurally damage the tumour cell membrane and cell ultra-structures. These observations encourage further clinical evaluation of the inhibitory effects of octadecenoic acids on various forms of cancer. [source] Antiproliferative, cytotoxic and antitumour activity of coumarins isolated from Calophyllum brasilienseJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2007César Ruiz-Marcial Among the eight Calophyllum species found on the American continent, Calophyllum brasiliense is the most widely distributed. Chemical analysis of this species has shown the presence of xanthones with cancer chemopreventive properties and antifungal activity. Recently, three new coumarins with antineoplastic properties have been found. In this study, we have evaluated the biological effects of the antiproliferative activity of coumarins isolated from C. brasiliense on the survival, cell cycle and apoptosis of cells in-vitro and their antitumour effects in mice. The cytological study showed that coumarins from C. brasiliense reduce the survival of BMK cells (baby mouse kidney cells) by inducing apoptosis and, to a lesser degree, necrosis. The cell cycle was arrested in S-phase and the division of BMK cells was inhibited. Coumarins had caused a reduction of experimental tumours in 83% of animals by the end of the treatment. Therefore, coumarins have the potential to be used alone or in combination with other antineoplastic drugs, and they might increase the effectiveness of other treatments for cancer. [source] Effect of monensin liposomes on the cytotoxicity of anti-My9-bR immunotoxinJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2003Madhu Sudhan Shaik The purpose of the study was to evaluate the utility of monensin liposomes in the enhancement of in-vitro cytotoxicity, apoptosis and in-vivo antitumour activity of anti-My9-bR immunotoxin. Monensin liposomes were prepared and studied for the enhancement of in-vitro cytotoxicity and apoptotic response of anti-My9-bR immunotoxin against both sensitive and resistant human promyelocytic leukemia HL-60 cells by MTS/PES method and acridine orange staining, respectively. Further, the in-vivo cytotoxicity enhancement of anti-My9-bR immunotoxin by monensin liposomes was studied in a survival model of severe combined immunodeficient (SCID) mice bearing intraperitoneal HL-60 tumours. The in-vitro cytotoxicity of anti-My9-bR immunotoxin was enhanced 580 fold and 4.7 fold against sensitive and resistant HL-60 cells, respectively, by monensin liposomes (5 times 10,8m). The combination of anti-My9-bR immunotoxin (50 ng mL,1) with monensin liposomes (5 times 10,8m) produced apoptosis in 40% of cells, whereas the apoptotic response was minimal (< 10%) in anti-My9-bR immunotoxin- or monensin liposome (alone)-treated HL-60 (resistant) cells. In SCID mice bearing HL-60 tumours, anti-My9-bR immunotoxin (75 ,g kg,1 administered intravenously every other day for a total of five courses) showed a median survival time of 20 days, which was no different than that of vehicle control- or monensin liposome-treated mice. However, anti-My9-bR immunotoxin (75 ,g kg,1) in combination with monensin liposomes (4 ,g kg,1 monensin), administered every other day for a total of five courses, was found to prolong the survival of 20% of mice for more than 46 days. Our results indicate that, despite anti-My9-bR immunotoxin being ineffective in the HL-60 tumour model, its combination with monensin liposomes could improve the antitumour response. [source] Antitumour Activity and Side Effects of Combined Treatment with Chitosan and Cisplatin in Sarcoma 180-Bearing MiceJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2000YOSHIYUKI KIMURA We examined the possible modulation by chitosan of the antitumour effects and side effects of cisplatin (cis-diaminedichloroplatinum, CDDP). The study showed that CDDP had potent antitumour activity when administered orally as well as intraperitoneally. We also compared the antitumour activity and side effects of orally administered CDDP plus orally administered chitosan versus intraperitoneally administered CDDP plus orally administered chitosan in sarcoma 180-bearing mice. When CDDP (1.25 mg kg,1 × 2 day,1) was intraperitoneally administered to sarcoma 180-bearing mice, myelotoxicity (the reduction of leucocyte and platelet numbers), nephrotoxicity (the increase of blood nitrogen urea level), immunotoxicity (the reduction of spleen and thymus weight) and a reduction in body weight resulted. These intraperitoneally administered CDDP-induced side effects were not prevented by oral administration of chitosan (150 mg kg,1 × 2 day,1 and 750 mg kg,1 × 2 day,1) for 14 consecutive days. On the other hand, the side effects such as the reductions of body and spleen weights induced by orally administered CDDP (1.25 mg kg,1 × 2 day,1) were prevented by the oral administration of chitosan (150 mg kg,1 × 2 day,1 and 750 mg kg,1 × 2 day,1). From these results, we conclude that the orally administered chitosan plus CDDP might be useful for the prevention of body weight reduction and immunotoxicity (the reduction of spleen weight) induced by the orally administered CDDP without diminishing antitumour activity. [source] Application of HPLC-NMR for the Rapid Chemical Profiling of a Southern Australian Sponge, Dactylospongia sp.JOURNAL OF SEPARATION SCIENCE, JSS, Issue 4 2009Daniel Anthony Dias Abstract Rapid chemical profiling of the antitumour active crude dichloromethane extract of the marine sponge, Dactylospongia sp. was undertaken. A combination of both offline (HPLC followed by NMR and MS) and on-line (on-flow and stop-flow HPLC-NMR) chemical profiling approaches was adopted to establish the exact nature of the major constituents present in the dichloromethane extract of this sponge. On-flow HPLC-NMR analysis was employed to initially identify components present in the dichloromethane extract, while stop-flow HPLC-NMR experiments were then conducted on the major component present, resulting in the partial identification of pentaprenylated p -quinol (5). Subsequent off-line RP semi-preparative HPLC isolation of 5 followed by detailed spectroscopic analysis using NMR and MS permitted the complete structure to be established. This included the first complete carbon NMR chemical shift assignment of 5 based on the heteronuclear 2-D NMR experiments, together with the first report of its antitumour activity. This study represents one of the few reports describing the application of HPLC-NMR to chemically profile secondary metabolites from a marine organism. [source] The knockdown of endogenous replication factor C4 decreases the growth and enhances the chemosensitivity of hepatocellular carcinoma cellsLIVER INTERNATIONAL, Issue 1 2009Masaaki Arai Abstract Aims: To identify differentially expressed genes and thereby detect potential molecular targets for future therapies directed against hepatocellular carcinoma (HCC). Methods: To isolate differentially expressed genes between HCC and adjacent non-cancerous liver tissues, cDNA microarray and quantitative reverse transcriptase polymerase chain reaction analyses were performed. Gene knockdown experiments in HepG2 cells were also performed using small interfering RNAs (siRNAs). Proteins were detected by immunostaining, and cell proliferation was analysed using the MTT/WST-8 assay. Apoptosis and cell cycle analyses were performed using flow cytometry. Results: After an intensive screening for differentially expressed genes in HCC tissues, we isolated 23 upregulated genes in these lesions. Among these, we focused on the replication factor C4 (RFC4) gene. The expression of endogenous RFC4 proteins in HepG2 cells was found to be significantly reduced by RFC4 -specific siRNA. This inhibition of RFC4 expression correlated with a decrease in cellular proliferation, increased levels of apoptosis and a sensitizing of the cells to the DNA-damaging chemotherapeutic agents, doxorubicin and camptothecin. Conclusion: The replication factor C4 gene may be a novel target for developing cancer therapeutics, which can enhance the antitumour activity of chemotherapeutic agents that induce DNA damage. [source] Involvement of p38 mitogen-activated protein kinase pathway in honokiol-induced apoptosis in a human hepatoma cell line (hepG2)LIVER INTERNATIONAL, Issue 10 2008Junfang Deng Abstract Background: Honokiol has been known to have antitumour activity. This study was conducted to evaluate the antiproliferative potential of honokiol against the hepG2 heptocellular cell line and its mechanism of action. Methods: hepG2 cells were treated with honokiol of 0,40 ,g/ml concentration. The cytotoxic effect of honokiol was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The apoptosis was evaluated by flow cytometry. Western blots were used to analyse the expression of various proteins (procaspase-9, procaspase-3, cleaved caspase-3, cytochrome c, Bcl-2, Bax, Bad, Bcl-XL and p38). Results: Honokiol induced apoptosis with a decreased expression of procaspase-3 and -9 and an increased expression of active caspase-3. Exposure of hepG2 cells to honokiol resulted in the downregulation of Bcl-XL and Bcl-2 expression and the release of mitochondrial cytochrome c to the cytosol. In addition, honokiol activated the p38 mitogen-activated protein kinase (MAPK) pathway, and the inhibition of this pathway by SB203580 reduced honokiol-induced apoptosis and activation of caspase-3. Conclusion: Honokiol induces apoptosis of hepG2 human hepatocellular carcinoma cells through activation of the p38 MAPK pathway, and, in turn, activation of caspase-3. [source] Bioactive brominated diterpenes from the marine red alga Jania Rubens (L.) Lamx.PHYTOTHERAPY RESEARCH, Issue 4 2004Nagwa E. Awad Abstract Seven brominated diterpenes of the parguerene and isoparguerene series were isolated for the ,rst time from the red alga Jania rubens (L.) Lamx., collected from the Red Sea coast at Hurghada, Egypt. The diterpenes were identi,ed as isoparguerol (1), isoparguerol-16-acetate (2), isoparguerol-7,16-diacetate (3), parguerol-16-acetate (4), parguerol-7,16-diacetate (5), deoxyparguerol (6) and deoxyparguerol-7-acetate (7). The isolated diterpenes had a marked antitumour activity. Isoparguerol derivatives were slightly more effective than parguerol derivatives. Moreover, the data implied that the cytotoxicity of these compounds were dependent on the number of acetoxy groups. Also, anthelmintic activities of the isolated compounds on earthworms (Allolobophora caliginosa) were studied. Copyright © 2004 John Wiley & Sons, Ltd. [source] Recuperative effect of Semecarpus anacardium linn. nut milk extract on carbohydrate metabolizing enzymes in experimental mammary carcinoma-bearing ratsPHYTOTHERAPY RESEARCH, Issue S1 2002Venugopal Sujatha Abstract Semecarpus anacardium Linn. of the family Anacardiaceae has many applications in the Ayurvedic and Siddha systems of medicine. We have tested the antitumour activity of Semecarpus anacardium nut extract against experimental mammary carcinoma in animals. As there is a direct relationship between the proliferation of tumour cells and the activities of the glycolytic and gluconeogenic enzymes, we studied changes in the activities of enzymes involved in this metabolic pathway in the liver and kidney. The enzymes investigated were glycolytic enzymes, namely hexokinase, phosphoglucoisomerase, aldolase and the gluconeogenic enzymes, namely glucose-6-phosphatase and fructose-1,6-biphosphatase in experimental rats. A significant rise in glycolytic enzyme activities and a simultaneous fall in gluconeogenic enzyme activities were found in mammary carcinoma bearing rats. Drug administration returned these enzyme activities to their respective control activities. Copyright © 2002 John Wiley & Sons, Ltd. [source] Synthesis and biological activity of phthalimide-based polymers containing 5-fluorouracilPOLYMER INTERNATIONAL, Issue 7 2002Neung-Ju Lee Abstract The attachment of anticancer agents to polymers is a promising approach towards reducing the toxic side-effects and retaining the potent antitumour activity of these agents. A new tetrahydrophthalimido monomer containing 5-fluorouracil (ETPFU) and its homopolymer and copolymers with acrylic acid (AA) and with vinyl acetate (VAc) have been synthesized and spectroscopically characterized. The ETPFU contents in poly(ETPFU- co -AA) and poly(ETPFU- co -VAc) obtained by elemental analysis were 21,mol% and 20,mol%, respectively. The average molecular weights of the polymers determined by gel permeation chromatography were as follows: Mn,=,8900,g,mol,1, Mw,= 13,300,g,mol,1, Mw/Mn,=,1.5 for poly(ETPFU); Mn,=,13,500,g,mol,1, Mw,=,16,600,g,mol,1, Mw/Mn,=,1.2 for poly(ETPFU- co -AA); Mn,=,8300,g,mol,1, Mw,=,11,600,g,mol,1, Mw/Mn,=,1.4 poly(ETPFU- co -VAc). The in vitro cytotoxicity of the compounds against FM3A and U937 cancer cell lines increased in the following order: ETPFU > 5-FU > poly(ETPFU) > poly(ETPFU- co -AA) > poly(ETPFU- co -VAc). The in vivo antitumour activities of all the polymers in Balb/C mice bearing the sarcoma 180 tumour cell line were greater than those of 5-FU and monomer at the highest dose (800,mg,kg,1). © 2002 Society of Chemical Industry [source] Epidermal growth factor receptor targeted therapy with gefitinib in locally advanced and metastatic primary lung adenocarcinomaRESPIROLOGY, Issue 3 2006Chong-Kin LIAM Objective: To describe the efficacy of monotherapy with the epidermal growth factor receptor-tyrosine kinase inhibitor, gefitinib in patients with locally advanced and metastatic primary lung adenocarcinoma. Methods: A retrospective analysis was undertaken of patients who had locally advanced or metastatic lung adenocarcinoma treated with gefitinib 250 mg orally once daily until disease progression. All patients had either been previously treated with systemic cytotoxic chemotherapy and/or radiotherapy or had declined chemotherapy or were medically not fit for cytotoxic chemotherapy. Results: A total of 23 patients (13 men) (15 never smokers) with a median age of 51 years (range 35,79 years) received gefitinib monotherapy. Disease control occurred in 14 patients (61%); there was a reduction in the size of the primary and/or metastatic tumours (partial response (PR)) in 11 patients (48%), and 3 patients (13%) had stable disease. The response rate was significantly higher in those who had never smoked (10 of 15 (67%)) compared with that of smokers (1 of 8 (13%)) (odds ratio (95% confidence interval), 14.0 (1.33,147.43) P = 0.027). In total, 11 of 18 patients (61%) with a WHO performance status 1 or 2 showed a PR, whereas none with a performance status 3 or 4 responded (P = 0.037). Response was not affected by the patient's age, gender, disease stage, prior chemotherapy treatment, interval between diagnosis and commencement of gefitinib or the development of skin toxicity. The median time to symptom improvement was 1.5 (range 0.5,6) weeks. The median progression-free survival time was: 60 (range 15,138) weeks in patients with PR and 34 (range 7,38) weeks in patients with stable disease (P = 0.368). Conclusion: When given alone, gefitinib showed significant antitumour activity in patients with locally advanced and metastatic primary lung adenocarcinoma. An objective response was observed more frequently in never smokers and exclusively in patients with good performance status. [source] Di- n -butyltin(IV) derivatives of bis(carboxymethyl)benzylamines: synthesis, NMR and X-ray structure characterization and in vitro antitumour propertiesAPPLIED ORGANOMETALLIC CHEMISTRY, Issue 7 2001Teresa Mancilla Abstract Four di- n -butyltin(IV) derivatives of bis(carboxymethyl)benzylamines were synthesized and their structure characterized by 1H,13C and 117/119Sn NMR, Mössbauer spectroscopy and mass spectrometry. The derivative substituted in the meta position by a methyl group has been further characterized by X-ray crystallography. This compound exhibits a distorted trigonal bipyramidal geometry at tin. The NMR data in solution, as well as other spectroscopic results in the solid state, confirm this structure for all the compounds. Evidence is provided to show that the compounds are more highly associated in concentrated solution than in the solid state. Their in vitro antitumour activity is reported. Copyright © 2001 John Wiley & Sons, Ltd. [source] Crystallization of agglutinin from the seeds of Abrus precatoriusACTA CRYSTALLOGRAPHICA SECTION D, Issue 7 2000Kaliyamoorthy Panneerselvam Agglutinin protein purified from the seeds of Abrus precatorius has a high antitumour activity and was crystallized at room temperature with polyethylene glycol 8000 as the precipitant. The agglutinin crystal diffracted to 3.45,Å and belongs to one of two possible tetragonal space groups, P41212 or P43212, with unit-cell parameters a = b = 141.91, c = 105.63,Å. The asymmetric unit contains a heterotetrameric protein molecule of molecular weight 134,kDa and has a solvent content of approximately 38%. [source] Crystallization and preliminary X-ray crystallographic analysis of human phosphodiesterase 12ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 5 2010Tetsuya Kohno Phosphodiesterase PDE12 is a medically important esterase-family member that hydrolyzes 2,,5,-linked oligoadenylates (2-5A), which are involved in the regulation of biological processes related to the antiviral and antitumour activity that can be induced by interferons. Here, cloning, purification and crystallization of the C-terminal endonuclease/exonuclease/phosphatase-homology domain of human PDE12 is reported. The crystals belonged to space group P3121 or P3221, with unit-cell parameters a = b = 111.3, c = 192.4,Å, and diffracted to 2.5,Å resolution. Assuming the presence of three molecules in the asymmetric unit, the solvent content was estimated to be about 44.0%. [source] Studies on the Synthesis and Activity of Three Tripalladium Complexes Containing Planaramine LigandsCHEMMEDCHEM, Issue 11 2009Mohammad Farhad Abstract The present study deals with the synthesis, characterization and activity against human cancer cell lines: A2780, A2780cisR and A2780ZD0473R of three tripalladium complexes, MH3, MH4 and MH5, that each have two planaramine ligands bound to the central metal ion. Cellular uptake levels, extent of DNA binding, and nature of interaction with salmon sperm and pBR322 plasmid DNA were determined for each complex. Palladium compounds are much more reactive than their corresponding platinum derivatives, which makes them therapeutically inactive but toxic. However, the results of the present study suggest that significant antitumour activity can be introduced in palladium complexes by lessening their reactivity by the introduction of sterically hindered ligands such as 2-hydroxypyridine, 3-hydroxypyridine and 4-hydroxypyridine. When bound to the central palladium ion, 4-hydroxypyridine appears to be more activating than 2-hydroxypyridine and 3-hydroxypyridine, suggesting that noncovalent interactions, such as hydrogen bonding, may also be key determinants of antitumour activity in addition to the steric effect. While cisplatin binds with DNA to form intrastrand GG adducts that causes local bending of a DNA strand, these planaramine-derived palladium complexes are expected to bind with DNA and form a number of long-range interstrand GG adducts that would cause a global change in DNA conformation, provided the tripalladium cations in MH3, MH4 and MH5 persist under physiological conditions. [source] Syntheses and Crystal Structure of Six-coordinated Diorgnotin Complexes with 2, 5-Dimercapto-4-phenyl-1, 3,4-thiodiazoIe,CHINESE JOURNAL OF CHEMISTRY, Issue 7 2003Chun-Lin Ma Abstract The reactions of diorganotin dichloride [Ph2SnCl2, (PhCH2)2 -SnCl2 or (n -Bu)2SnCl2] with potassium salt of 2, 5-dimercapto-4-phenyl-1, 3, 4-thiodiazole gave complexes R2Sn (S3N2C8H5)2 (4: R = Ph; 5: R = PhCH2 and 6: R = n -Bu), respectively. Characterizations were carried out for all complexes by IR, 1H NMR spectra and X-ray crystallography analysis. Including the Sn,N interaction, the three complexes all have six-coordinated distorted octahedral geometry. Based on the requence of stereochemical constraint sequence, phenyl,benzyl > n -butyl, the less the effect of the stereochemical constraint of R groups, the shorter the Sn,N length. In complexes 5 and 6, there exist S,S weak intra-molecular interactions, through which the complexes are dissociated into loose 2D polymers. All three complexes show antitumour activity in bioactivity measurements. [source] | ||||||||||||||||