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Vitro Cytotoxicity (vitro + cytotoxicity)
Selected AbstractsThe Presence of a Ferrocenyl Unit on an Estrogenic Molecule is Not Always Sufficient to Generate in,vitro CytotoxicityCHEMMEDCHEM, Issue 11 2006Anne Vessičres Dr. Abstract We recently reported the dual (antihormonal and cytotoxic) functionality of ferrocifens, which are organometallic complexes derived from hydroxytamoxifen, the standard molecule in the treatment of hormone-dependent breast cancers. To test the hypothesis that the presence of a ferrocenyl substituent on molecules with an affinity for the estrogen receptor is sufficient to give them cytotoxic properties in,vitro, we prepared complexes derived from estradiol with a ferrocenyl substituent at positions 7, and 17,. The complexes thus obtained retain a satisfactory level of affinity for the estrogen receptor (RBA values higher than 12,%). At low concentrations (0.1,1,,M) the complexes show an estrogenic effect in,vitro equivalent to that of estradiol on hormone-dependent (MCF-7) breast cancer cells, and no cytotoxic effect on hormone-independent (MDA-MB-231) breast cancer cells. At high concentrations (up to 50,,M) the 17, -ethynylferrocenyl estradiol and 7, -ferrocenylmethylthio estradiol become cytotoxic (IC50=13.2,,M and 18.8,,m, respectively) while the 17, -ferrocenylestradiol remains non toxic. The low toxicity of these compounds support our hypothesis that electronic communication between the ferrocenyl and phenol moieties in the hydroxyferrocifens series is a key parameter in the generation of cytotoxic effects at submicromolar concentrations. [source] Antheraea assama Silk Fibroin-Based Functional Scaffold with Enhanced Blood Compatibility for Tissue Engineering Applications,ADVANCED ENGINEERING MATERIALS, Issue 5 2010Naresh Kasoju Abstract The architecture and surface chemistry of a scaffold determine its utility in tissue engineering (TE). Conventional techniques have limitations in fabricating a scaffold with control over both architecture and surface chemistry. To ameliorate this, in this report, we demonstrate the fabrication of an Antheraea assama silk fibroin (AASF)-based functional scaffold. AASF is a non-mulberry variety having superior qualities to mulberry SF and is largely unexplored in the context of TE. First, a 3D scaffold with biomimetic architecture is fabricated. The scaffold is subsequently made blood compatible by modifying the surface chemistry through a simple sulfation reaction. EDX and FTIR analysis demonstrate the successful sulfation of the scaffold. SEM observations reveal that sulfation has no any effect on the scaffold architecture. TGA reveals that it has increased thermal stability. The sulfation reaction significantly improves the overall hydrophilicity of the scaffold, as is evident from the increase in water holding capacity; this possibly enhances the blood compatibility. The enhancement in blood compatibility of the sulfated scaffold is determined from in vitro haemolysis, protein adsorption and platelet adhesion studies. The sulfated scaffold is non-toxic and supports cell adhesion and growth, as revealed by indirect and direct contact-based in vitro cytotoxicity assays. This study reveals that the AASF-based functional scaffold, which has biomimetic architecture and blood-compatible surface chemistry, could be suitable for TE applications. [source] Functional analysis of DM64, an antimyotoxic protein with immunoglobulin-like structure from Didelphis marsupialis serumFEBS JOURNAL, Issue 24 2002Surza L. G. Rocha Bothrops snake venoms are known to induce local tissue damage such as hemorrhage and myonecrosis. The opossum Didelphis marsupialis is resistant to these snake venoms and has natural venom inhibitors in its plasma. The aim of this work was to clone and study the chemical, physicochemical and biological properties of DM64, an antimyotoxic protein from opossum serum. DM64 is an acidic protein showing 15% glycosylation and with a molecular mass of 63 659 Da when analysed by MALDI-TOF MS. It was cloned and the amino acid sequence was found to be homologous to DM43, a metalloproteinase inhibitor from D. marsupialis serum, and to human ,1B-glycoprotein, indicating the presence of five immunoglobulin-like domains. DM64 neutralized both the in vivo myotoxicity and the in vitro cytotoxicity of myotoxins I (mt-I/Asp49) and II (mt-II/Lys49) from Bothrops asper venom. The inhibitor formed noncovalent complexes with both toxins, but did not inhibit the PLA2 activity of mt-I. Accordingly, DM64 did not neutralize the anticoagulant effect of mt-I nor its intracerebroventricular lethality, effects that depend on its enzymatic activity, and which demonstrate the dissociation between the catalytic and toxic activities of this Asp49 myotoxic PLA2. Furthermore, despite its similarity with metalloproteinase inhibitors, DM64 presented no antihemorrhagic activity against Bothrops jararaca or Bothrops asper crude venoms, and did not inhibit the fibrinogenolytic activity of jararhagin or bothrolysin. This is the first report of a myotoxin inhibitor with an immunoglobulin-like structure isolated and characterized from animal blood. [source] Monocytes in the rat: Phenotype and function during acute allograft rejectionIMMUNOLOGICAL REVIEWS, Issue 1 2001Birte Steiniger Summary: Cells of the monocyte/macrophage system originate from the bone marrow, reach the organs via the blood, immigrate through post-capillary venules and further differentiate into organ-specific tissue macrophages. In rats and other species, activated monocytes/macrophages aggravate autoimmune reactions, rejection of non-vascularized allografts and chronic allograft rejection. It is very likely that they also contribute to acute allograft destruction. So far it has been impossible to distinguish the function of monocytes from that of macrophages, because cell phenotypes and their alterations upon activation are ill-defined. We have thus begun to characterize the ex vivo phenotype and function of rat monocytes in the normal state and during renal allograft rejection. Monocytes are recovered from both the central and the marginal blood pool by perfusing either the recipient's circulation or the allograft vasculature. Rat monocytes have a unique surface phenotype. During allograft rejection or after infusion of interferon-, they up-regulate class II MHC molecules, CD161 (NKR-P1A), CD62L and CD8, while CD4 and CD43 are down-modulated. Activated perfusate monocytes exert increased in vitro cytotoxicity against tumour targets, which differs from that of NK cells. We speculate that activated monocytes contribute to kidney allograft destruction by directly damaging endothelial cells or by promoting intravascular coagulation. [source] Silencing of APAF-1 in B-CLL results in poor prognosis in the case of concomitant p53 mutationINTERNATIONAL JOURNAL OF CANCER, Issue 9 2006Isrid Sturm Abstract Apoptosis protease-activating factor 1 (APAF-1), a transcriptional target of p53, is a cytosolic adaptor protein that links the mitochondrial apoptosis pathway to the caspase cascade. Here, we aimed to study the impact of APAF-1 expression levels on cell death induced by anticancer drugs or ionizing irradiation (IR) and disease prognosis in B-type chronic lymphocytic leukemia (B-CLL) patients. Samples from 138 patients with B-CLL were investigated for APAF-1 expression and p53 mutations. The results were related to survival data, in vitro cytotoxicity of various cytotoxic drugs and IR and clinico-pathological data. Variable APAF-1 expression was observed in all investigated B-CLL samples. Reduction in APAF-1 expression was observed at both mRNA and protein level indicating transcriptional silencing whereas mutation of p53 or the immunoglobulin heavy chain variable genes (IgHV) had no impact on APAF-1 expression. Surprisingly, APAF-1 loss did not result in resistance to cytotoxic therapies. Likewise, APAF-1 downregulation on its own showed no impact on disease prognosis. Nevertheless, a poor prognosis was observed in patients with loss of APAF-1 expression and additional p53 mutation. Thus, loss of APAF-1 may become relevant when additional core apoptosis signaling components are disrupted. © 2005 Wiley-Liss, Inc. [source] Polycarbonate microspheres containing tumor necrosis factor-, genes and magnetic powder as potential cancer therapeuticsJOURNAL OF APPLIED POLYMER SCIENCE, Issue 5 2008Bin Hu Abstract Amphiphilic polycarbonate copolymers including methoxy-terminated poly(ethylene glycol)- co -poly (5,5-dimethyl trimethylene carbonate) [Poly(PEG- b -TMC)] and poly(ethylene glycol)- co -poly(trimethylene carbonate) [Poly(PEG- b -DTC)] were synthesized. The water-in-oil-in-water (W/O/W) solvent evaporation technique was adopted to produce anticancer magnetic Poly(PEG- b -DTC) microspheres containing tumor necrosis factor-, (TNF-,) genes and Fe3O4 magnetic ultrafine powder. Drug release studies showed that the microspheres can sustain a steady release rate of TNF-, genes in 0.1M phosphate buffer saline solution in vitro for up to 60 h. In vitro cytotoxicity assays demonstrated that the microspheres have high inhibition and antitumor action to human hepatocellular carcinoma (Bel-7204) cells in vitro. In vivo inhibition on the growth of hepatic carcinomas and histopathologic observation indicated that the microspheres possess a markedly high antitumor activity to human hepatocellular carcinoma (Bel-7204). © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008 [source] In vitro cytotoxicity of dental composites based on new and traditional polymerization chemistries,JOURNAL OF BIOMEDICAL MATERIALS RESEARCH, Issue 2 2007M. Goël Brackett Abstract The biological response to dental restorative polymer composites is mediated by the release of unpolymerized residual monomers. Several new composite formulations claim to reduce unpolymerized residual mass. The current study assessed the cytotoxic responses to several of these new formations and compared them with more traditional formulations. Our hypothesis predicted that if these new polymerization chemistries reduce unpolymerized residual mass, the cytotoxicity of these materials also should be reduced relative to traditional formulations. Methods: Materials (HerculiteXRV, Premise, Filtek Supreme, CeramxDuo, Hermes, and Quixfil) were tested in vitro in direct contact with Balb mouse fibroblasts, initially, then after aging in artificial saliva for 0, 1, 3, 5, or 8 weeks. The toxicity was determined by using the MTT assay to the estimate SDH activity. Knoop hardness of the materials also was measured at 0 and 8 weeks to determine whether surface breakdown of the materials in artificial saliva contributed to cytotoxic responses. Results: Materials with traditional methacrylate chemistries (Herculite, Premise, Filtek Supreme) were severely (>50%) cytotoxic throughout the 8-week interval, but materials with newer chemistries or filling strategies (Hermes, CeramXDuo, and Quixfil) improved over time of aging in artificial saliva. Hermes showed the least cytotoxicity at 8 weeks, and was statistically equivalent to Teflon® negative controls. Hardness of the materials was unaffected by exposure to artificial saliva. Conclusions: Newer polymerization and filling strategies for dental composites show promise for reducing the release of unpolymerized components and cytotoxicity. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006 [source] The sodium pump ,1 sub-unit: a disease progression,related target for metastatic melanoma treatmentJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 9b 2009Véronique Mathieu Abstract Melanomas remain associated with dismal prognosis because they are naturally resistant to apoptosis and they markedly metastasize. Up-regulated expression of sodium pump , sub-units has previously been demonstrated when comparing metastatic to non-metastatic melanomas. Our previous data revealed that impairing sodium pump ,1 activity by means of selective ligands, that are cardiotonic steroids, markedly impairs cell migration and kills apoptosis-resistant cancer cells. The objective of this study was to determine the expression levels of sodium pump , sub-units in melanoma clinical samples and cell lines and also to characterize the role of ,1 sub-units in melanoma cell biology. Quantitative RT-PCR, Western blotting and immunohistochemistry were used to determine the expression levels of sodium pump , sub-units. In vitro cytotoxicity of various cardenolides and of an anti-,1 siRNA was evaluated by means of MTT assay, quantitative videomicroscopy and through apoptosis assays. The in vivo activity of a novel cardenolide UNBS1450 was evaluated in a melanoma brain metastasis model. Our data show that all investigated human melanoma cell lines expressed high levels of the ,1 sub-unit, and 33% of human melanomas displayed significant ,1 sub-unit expression in correlation with the Breslow index. Furthermore, cardenolides (notably UNBS1450; currently in Phase I clinical trials) displayed marked anti-tumour effects against melanomas in vitro. This activity was closely paralleled by decreases in cMyc expression and by increases in apoptotic features. UNBS1450 also displayed marked anti-tumour activity in the aggressive human metastatic brain melanoma model in vivo. The ,1 sodium pump sub-unit could represent a potential novel target for combating melanoma. [source] Antibacterial activity of silver inorganic agent YDA fillerJOURNAL OF ORAL REHABILITATION, Issue 4 2004S. Ohashi summary, YDA filler is an antibacterial agent that is currently in commercial dental use. In this study, we attempted to determine whether it exerts an antibacterial effect on human saliva bacteria, and to determine whether it can be used in dental materials. CFUs in 1 mL stimulated human saliva were examined using blood agar and mitis salivarius agar after immersion, with or without YDA filler. The antibacterial effect was compared with that of Ketac-Silver. Dental materials containing 5% wt YDA filler were prepared for in vitro testing on S. mutans and A. viscosus. Furthermore, we examined the in vitro cytotoxicity of experimental MMA resin containing YDA filler on HeLa cells. Human saliva bacteria and mutans streptococci showed reduced viability following exposure to YDA filler after 12 h. The concentration of silver ions released by YDA filler was below 1 ppm after 12 h. Two tested strains showed reduced viability following exposure to dental materials containing YDA filler. In another experiment, MMA resin containing YDA filler did not show cytotoxicity on HeLa cells after 24- and 48-h exposure. Thus, YDA filler may help in the development of antibacterial dental materials, such as composite resin, glass,ionomer or temporary cement. [source] A comparison of the in vitro cytotoxicity of two root canal sealersJOURNAL OF ORAL REHABILITATION, Issue 4 2003M. Dartar Öztan summary, The purpose of this study was to compare the cytotoxicity of an epoxy resin-based sealer (AH Plus) and a silicone-based sealer (Roeko Seal Automix, RSA). Cytotoxicity was assessed using the MTT assay for mitochondrial enzyme activity and haemocytometer viable cell counting after 24, 48 and 72-h exposure to L929 cells. AH Plus and RSA showed no statistically significant difference in the degree of toxicity. Both sealers had a low toxic influence on the cells during the experimental period. This study indicates that epoxy resin-based sealer AH Plus and the silicone-based sealer RSA have similar levels of cytotoxicity to mouse fibroblasts. [source] Solubilizing efficiency and in vitro cytotoxicity of Peptoad GJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2010Radhakrishna K. Maroju Abstract A novel non-ionic surfactant, Peptoad G, is evaluated for its solubilizing capacity and cytotoxicity in order to explore its possible use in aqueous formulation of hydrophobic drugs. Solubility studies were carried out using ten model hydrophobic drugs, and cytotoxicity of the surfactant was evaluated in three different cell lines using the MTT assay. It was shown that peptoad G enhances the solubility of the ten model drugs to different extents, ranging from 20- to 1100-fold, which correlated with the number of hydrogen-bonding sites on the drug molecules. The in vitro cytotoxicity studies revealed comparable cytotoxicity of peptoad G to that of cremophor EL. The results suggest peptoad G possesses potential as an alternative to conventional solubilizers in hydrophobic drug formulations. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2196,2198, 2010 [source] Analysis of FimX, a phosphodiesterase that governs twitching motility in Pseudomonas aeruginosaMOLECULAR MICROBIOLOGY, Issue 4 2006Barbara I. Kazmierczak Summary Type IV pili (Tfp) are polar surface structures of Pseudomonas aeruginosa required for twitching motility, biofilm formation and adherence. One protein required for the assembly of tfp is FimX, which possesses both GGDEF and EAL domains characteristic of diguanylate cyclases and phosphodiesterases respectively. In this work we demonstrate that FimX has phosphodiesterase activity towards bis-(3,-5,)-cyclic dimeric guanosine monophosphate (c-di-GMP), but does not show diguanylate cyclase activity. Instead, the imperfect GGDEF domain of FimX likely serves to activate phosphodiesterase activity when bound to GTP, as has recently been described for the Caulobacter crescentus composite GGDEF-EAL protein, CC3396. Bacteria expressing FimX in which either the GGDEF or EAL domain is deleted or mutated have phenotypes indistinguishable from a ,fimX strain, demonstrating the importance of both domains to function. Previous work has shown that FimX localizes to the bacterial pole. In this work we show that restriction of FimX to a single pole requires intact GGDEF and EAL domains. Deletion of the amino-terminal REC domain of FimX, which contains a putative polar localization signal, results in a protein that still supports intermediate levels of pilus assembly and function. RFP,FimX,REC, unlike RFP,FimX, is no longer localized to the bacterial pole, while transmission electron microscopy shows that surface pili can originate from non-polar sites in this mutant. Although ,fimX mutants show limited in vitro cytotoxicity, they are as virulent as the wild-type strain in a murine model of acute pneumonia. [source] Cranberry proanthocyanidins are cytotoxic to human cancer cells and sensitize platinum-resistant ovarian cancer cells to paraplatinPHYTOTHERAPY RESEARCH, Issue 8 2009Ajay P. Singh Abstract Polyphenolic extracts of the principal flavonoid classes present in cranberry were screened in vitro for cytotoxicity against solid tumor cells lines, identifying two fractions composed principally of proanthocyanidins (PACs) with potential anticancer activity. Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF-MS) analysis of the proanthocyanidins (PACs) fractions indicated the presence of A-type PACs with 1,4 linkages containing between 2,8 epicatechin units with a maximum of 1 epigallocatechin unit. PACs exhibited in vitro cytotoxicity against platinum-resistant human ovarian, neuroblastoma and prostate cancer cell lines (IC50 = 79,479 µg/mL) but were non-cytotoxic to lung fibroblast cells (IC50 > 1000 µg/ml). SKOV-3 ovarian cancer cells treated with PACs exhibited classic apoptotic changes. PACs acted synergistically with paraplatin in SKOV-3 cells. Pretreatment of SKOV-3 cells with PACs (106 µg/ml) resulted in a significant reduction of the paraplatin IC50 value. Similarly, in a BrdU incorporation assay, co-treatment of SKOV-3 cells with PACs and paraplatin revealed reduced cell proliferation at lower concentrations than with either individually. In SKOV-3 cell cultures co-treated with PAC-1 and paraplatin, an HPLC analysis indicated differential quantitative presence of various PAC oligomers such as DP-8, -9, -11 and -14 indicating either selective binding or uptake. Cranberry proanthocyanidins exhibit cell-line specific cytotoxicity, induce apoptotic markers and augment cytotoxicity of paraplatin in platinum-resistant SKOV-3 ovarian cancer cells. Copyright © 2009 John Wiley & Sons, Ltd. [source] Synthesis, characterization, in vitro degradation and cytotoxicity of polyphosphazenes containing N -ethoxypyrrolidone side groupsPOLYMER INTERNATIONAL, Issue 2 2010Yunmei Bi Abstract A new biodegradable polyphosphazene (PYRMP) containing N -ethoxypyrrolidone and methoxyethoxyethoxy side groups was synthesized via a route of macromolecular substitution. The synthetic method of poly{bis[2-(2-oxo-1-pyrrolidinyl)ethoxy]phosphazene} (PYRP) was improved. The thermal properties of the polymers were investigated using differential scanning calorimetry. Degradation studies were carried out in vitro with varying pH conditions. The in vitro cytotoxicity of PYRMP and its hydrolysis products was evaluated using the methyl tetrazolium (MTT) cytotoxicity test in HepG2 cell culture. PYRMP and PYRP have low glass transition temperatures of ,68.8 and ,59.6 °C, respectively. The polymers show a higher degradation rate at pH = 5.0 than at both pH = 7.4 and 8.0. The degradation process of PYRMP in different buffer solutions is discussed. The MTT test reveals that PYRMP at concentrations below 800 µg mL,1 and its hydrolysis products are non-toxic to HepG2 cells. Moreover, the hydrolysis products diluted 10 times are able to promote cell proliferation. This study shows that polyphosphazene containing N -ethoxypyrrolidone subsituents provides interesting perspectives for various biomedical applications. Copyright © 2009 Society of Chemical Industry [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] Recent advances in rational gene transfer vector design based on poly(ethylene imine) and its derivativesTHE JOURNAL OF GENE MEDICINE, Issue 8 2005Michael Neu Abstract The continually increasing wealth of knowledge about the role of genes involved in acquired or hereditary diseases renders the delivery of regulatory genes or nucleic acids into affected cells a potentially promising strategy. Apart from viral vectors, non-viral gene delivery systems have recently received increasing interest, due to safety concerns associated with insertional mutagenesis of retro-viral vectors. Especially cationic polymers may be particularly attractive for the delivery of nucleic acids, since they allow a vast synthetic modification of their structure enabling the investigation of structure-function relationships. Successful clinical application of synthetic polycations for gene delivery will depend primarily on three factors, namely (1) an enhancement of the transfection efficiency, (2) a reduction in toxicity and (3) an ability of the vectors to overcome numerous biological barriers after systemic or local administration. Among the polycations presently used for gene delivery, poly(ethylene imine), PEI, takes a prominent position, due to its potential for endosomal escape. PEI as well as derivatives of PEI currently under investigation for DNA and RNA delivery will be discussed. This review focuses on structure-function relationships and the physicochemical aspects of polyplexes which influence basic characteristics, such as complex formation, stability or in vitro cytotoxicity, to provide a basis for their application under in vivo conditions. Rational design of optimized polycations is an objective for further research and may provide the basis for a successful cationic polymer-based gene delivery system in the future. Copyright © 2005 John Wiley & Sons, Ltd. [source] Anticancer activity of hydrophobic peptides from soy proteinsBIOFACTORS, Issue 1-4 2000Song E Kim Abstract An anticancer peptide from soy protein was purified and isolated. Defatted soy protein was hydrolyzed with thermoase and hydrophobic peptides were extracted with ethanol. The peptide extract was fractionated by XAD-2 hydrophobic, gel filtration chromatography, and different C18 HPLCs. Anticancer activity of each fraction was assayed by measuring in vitro cytotoxicity on P388D1, a mouse monocyte macrophage cell line. IC50 value of a peptide fraction from Sephadex G-25 chromatography was 0.16 mg/ml. This peptide fraction at 1 mg/ml significantly affected cell cycle progression by arresting P388D1 at G2/M phases. Finally purified peptide from analytical C18 HPLC was nonapeptide of which molecular weight was 1157 Da and the sequence was X-Met-Leu-Pro-Ser-Tye-Ser-Pro-Tyr. [source] Antitumor activity of sugar-modified cytosine nucleosidesCANCER SCIENCE, Issue 2 2004Akira Matsuda Nucleoside analogues which show antimetabolic activity in cells have been successfully used in the treatment of various tumors. Nucleosides such as 1-,-D-arabinofuranosylcytosine (araC), 6-mercaptopurine, fludarabine and cladribine play an important role in the treatment of leukemias, while gemcitabine, 5-fluorouracil and its prodrugs are used extensively in the treatment of many types of solid tumors. All of these compounds are metabolized similarly to endogenous nucleosides and nucleotides. Active metabolites interfere with the de novo synthesis of nucleosides and nucleotides or inhibit the DNA chain elongation after being incorporated into the DNA strand as terminators. Furthermore, nucleoside antimetabolites incorporated into the DNA strand induce strand-breaks and finally cause apoptosis. Nucleoside antimetabolites target one or more specific enzyme(s). The mode of inhibitory action on the target enzyme is not always similar even among nucleoside antimetabolites which have the same nucleoside base, such as araC and gemcitabine. Although both nucleosides are phosphorylated by deoxycytidine kinase and are also good substrates of cytidine deaminase, only gemcitabine shows antitumor activity against solid tumors. This suggests that differences in the pharmacological activity of these nucleoside antimetabolites may reflect different modes of action on target molecules. The design, in vitro cytotoxicity, in vivo antitumor activity, metabolism and mechanism of action of sugar-modified cytosine nucleosides, such as (2,S)-2,-deoxy-2,-C-methylcytidine (SMDC), 1-(2-deoxy-2-methylene-,-D-erythro-pentofuranosyl)cytosine (DMDC), 1-(2-C-cyano-2-deoxy-1-,-D-arabino-pentofuranosyl)cytosine (CNDAC) and 1-(3-C-ethynyl-,-D-ribo-pentofuranosyl)cytosine (ECyd), developed by our groups, are discussed here. [source] Liposome Formulations for Effective Administration of Lipophilic Malonatoplatinum(II) ComplexesCANCER SCIENCE, Issue 11 2002Insook Han For effective administration of lipophilic trans(±)-l,2-diaminocyclohexaneplatinum(II) complexes of malonate derivatives [(dach)PtL, L=allylmalonate (AM), diallylmalonate (DAM), allylbenzyl-malonate (ABM), or dibenzylmalonate (DBM)] in aqueous solution, we have applied three different liposome formulations and evaluated their physical and chemical properties, along with their in vitro cytotoxicity. The liposome formulations were composed of DMPC/DMPG [DMPC=1,2-dimyristoyl- sn -glycero-3-phosphocholine, DMPG=l,2-dimyristoyl- sn -glycero-3-(phospho- rac -l-glycerol) (sodium salt)] in different molar ratios (7/3 or 3/7) or an equimolar DOTAP/DOPE formulation (DOTAP=l,2-dioleoyl-3-trimethylammonium propane, DOPE=l,2-dioleoyl- sn -glycero-3-phosphoethanolamine). Preliposomal powders of the platinum complexes were prepared by lyophilization, and reconstituted in aqueous solution to obtain the final liposomal platinum complexes. Due to the lipophilicity of the malonatoplatinum complexes, the entrapment efficiency of drugs within the liposomes was over 90% except for the AM complex, and platinum drug stability was also satisfactory (>90%) in these liposomal systems. In vitro cytotoxicity was tested in human ovarian carcinoma cells sensitive (A2780) and resistant to cisplatin (A2780/PDD). In both cell lines, the liposomal DBM complex was much more cytotoxic than the corresponding DAM and ABM complexes, which means that the more hydrophobic benzyl substituent affords higher cytotoxicity than the allyl substituent in the malonato leaving group. Furthermore, the DBM complex in DMPC/DMPG formulations was effective against both sensitive and resistant A2780 cells (resistance indexes (RI)=1.10,1.49), showing lack of cross-resistance to cisplatin. Therefore, the liposomal DBM complex in the DMPC/DMPG formulations is a promising candidate for stable pharmaceutical liposomal platinum complexes. [source] Selective Treatment of Cancer: Synthesis, Biological Evaluation and Structural Elucidation of Novel Analogues of the Antibiotic CC-1065 and the DuocarmycinsCHEMISTRY - A EUROPEAN JOURNAL, Issue 16 2007Abstract Novel diastereomerically pure ,- D -galactosidic prodrugs (+)- 12,a,e of the cytotoxic antibiotics CC-1065 and the duocarmycins were prepared for an antibody directed enzyme prodrug therapy (ADEPT) using 4 as a substrate via a radical cyclization to give rac - 5 and rac - 6 followed by a chromatographic resolution of the enantiomers of rac - 5, glycosidation and linkage to the DNA-binding units 10,a,e. These only slightly toxic compounds can be toxified enzymatically by an antibody,,- D -galactosidase conjugate at the surface of malignant cells to give the cytotoxic drugs, which then alkylate DNA. The new prodrugs were tested in in vitro cytotoxicity assays showing excellent QIC50 values of 4800 and 4300 for (+)- 12,a and (+)- 12,b, respectively. The absolute configuration of precursor (+)- 5 was determined by comparison of the experimental CD spectrum with the theoretically predicted CD spectra and by X-ray structure analysis. [source] Synthesis of 9,9-Dialkyl-4,5-diazafluorene Derivatives and Their Structure,Activity Relationships Toward Human Carcinoma Cell LinesCHEMMEDCHEM, Issue 4 2010Qiwei Wang Abstract A homologous set of 9,9-dialkyl-4,5-diazafluorene compounds were prepared by alkylation of 4,5-diazafluorene with the appropriate alkyl bromide and under basic conditions. The structures of these simple organic compounds were confirmed by spectroscopic techniques (FTIR, NMR, and FABMS). Their biological effects toward a panel of human carcinoma cells, including Hep3B hepatocellular carcinoma, MDAMB-231 breast carcinoma, and SKHep-1 hepatoma cells, were investigated; a structure,activity correlation was established with respect to the length of the alkyl chain and the fluorene ring structure. The relationship between the mean potency [log(1/IC50)] and alkyl chain length was systematically studied. The results show that compounds with butyl, hexyl, and octyl chains exhibit good growth inhibitory effects toward these three human carcinoma cell lines, and the 9,9-dihexyl-4,5-diazafluorene further exhibits antitumor activity in athymic nude mice Hep3B xenograft models. For the structurally related dialkylfluorenes that lack the diaza functionality, in,vitro cytotoxicity was not observed at clinically relevant concentrations. [source] | |||||||||||||||||||