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Anticancer Drugs (anticancer + drug)
Kinds of Anticancer Drugs Terms modified by Anticancer Drugs Selected AbstractsClick Chelators for Platinum-Based Anticancer DrugsEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 2 2008Aurélie Maisonial Abstract Triazoles from "click chemistry" are convenient ligands for the formation of platinum complexes bearing combined triazole,amine or triazole,carboxylate moieties. Striking differences in the chelation modes are observed between the two series. One of the triazole,amine platinum complexes exhibits selective cytotoxicity against breast cancer cells lines. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) [source] Structural Models and Binding Site Prediction of the C-terminal Domain of Human Hsp90: A New Target for Anticancer DrugsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2008Miriam Sgobba Heat shock protein 90 is a valuable target for anticancer drugs because of its role in the activation and stabilization of multiple oncogenic signalling proteins. While several compounds inhibit heat shock protein 90 by binding the N-terminal domain, recent studies have proved that the C-terminal domain is important for dimerization of the chaperone and contains an additional binding site for inhibitors. Heat shock protein 90 inhibition achieved with molecules binding to the C-terminal domain provides an additional and novel opportunity to design and develop drugs. Therefore, for the first time, we have investigated the structure and the dynamic behaviour of the C-terminal domain of human heat shock protein 90 with and without the small-middle domain, using homology modelling and molecular dynamics simulations. In addition, secondary structure predictions and peptide folding simulations proved useful to investigate a putative additional ,-helix located between H18 and ,20 of the C-terminal domain. Finally, we used the structural information to infer the location of the binding site located in the C-terminal domain by using a number of computational tools. The predicted pocket is formed by two grooves located between helix H18, the loop downstream of H18 and the loop connecting helices H20 and H21 of each monomer of the C-terminal domain, with only two amino acids contributing from each middle domain. [source] Organometallic Ruthenium Inhibitors of Glutathione- S -Transferase P1-1 as Anticancer DrugsCHEMMEDCHEM, Issue 12 2007Han Ang Dr. Abstract Ruthenium,arene complexes conjugated to ethacrynic acid were prepared as part of a strategy to develop novel glutathione- S -transferase (GST) inhibitors with alternate modes of activity through the organometallic fragment, ultimately to provide targeted ruthenium-based anticancer drugs. Enzyme kinetics and electrospray mass spectrometry experiments using GST P1-1 and its cysteine-modified mutant forms revealed that the complexes are effective enzyme inhibitors, but they also rapidly inactivate the enzyme by covalent binding at Cys,47 and, to a lesser extent, Cys,101. They are highly effective against the GST Pi-positive A2780 and A2780cisR ovarian carcinoma cell lines, are among the most effective ruthenium complexes reported so far, and target ubiquitous GST Pi overexpressed in many cancers. [source] Preclinical evaluation of antisense bcl -2 as a chemosensitizer for patients with gastric carcinomaCANCER, Issue 10 2004Ph.D., Ryungsa Kim M.D. Abstract BACKGROUND Because bcl -2 is a critical factor for anticancer drug-induced apoptosis, the authors conducted a preclinical evaluation of antisense (AS) bcl -2 as an enhancer of the chemotherapeutic effect in the treatment of patietns with gastric carcinoma. METHODS AS bcl -2 was used with 18-mer phosphorothiated oligonucleotides in the MKN-45 gastric carcinoma cell line. Drug sensitivity in vitro was evaluated using the methyl-thiazoldiphenyl tetrazolium assay, and antitumor effects in vivo were evaluated using the nude mouse xenograft. Apoptosis was determined with the terminal deoxyuridine triphosphate nick-end labeling assay. AS bcl -2 in vitro was treated with lipofectin, whereas it was administered intraperitoneally for 6 consecutive days twice every 2 weeks in vivo. Anticancer drugs were administered intraperitoneally four times per week. RESULTS bcl -2 was down-regulated to 60% of its initial value after treatment with 1.0 ,M AS bcl -2 compared with the controls of random and mismatched oligonucleotides. Drug sensitivity to doxorubicin, cisplatin, and paclitaxel (TXL) was increased 3,4-fold when used in combination with AS bcl -2, which was determined with 50% inhibitory concentration values, compared with the control group. Increased drug sensitivity was associated with apoptosis, which increased in Bax and poly-adenosine diphosphate (ADP-ribose) polymerase and decreased in phosphorylated Akt (pAkt). The antitumor effect of cisplatin and TXL in vivo was enhanced significantly in combination with AS bcl -2. Down-regulation of bcl -2 was observed on Day 4 after the treatment with AS bcl -2. CONCLUSIONS Combination treatment with AS bcl -2 and anticancer drugs, including cisplatin and TXL, may be a new strategy for enhancing chemotherapeutic effects in the treatment of gastric carcinoma. Cancer 2004. © 2004 American Cancer Society. [source] Lectin-aided separation of circulating tumor cells and assay of their response to an anticancer drug in an integrated microfluidic deviceELECTROPHORESIS, Issue 18 2010Li Li Abstract Metastasis caused by the entry of circulating tumor cells (CTCs) into the bloodstream or lymphatic vessels is a major factor contributing to death in cancer patients. Separation of CTCs and studies on CTC,drug interactions are very important for prognostic and therapeutic implications of metastatic cancer. In this study, an integrated microfluidic device for CTC separation through the combination of lectin and microstructure is presented. This microfluidic device and lectin concanavalin A were utilized for the separation of K562 cells in whole blood samples. The results showed that the separation efficiency can reach 84%, which is much higher than that of an experiment without concanavalin A treatment. To further demonstrate the feasibility of this microfluidic device application in sequential studies after target cells were separated, the interactions of K562 cells and an anticancer drug, cytarabine, were also examined. After 6,h on-chip treatment with cytarabine, the viabilities of K562 cells were 85.29, 77.05, and 40% for drug concentration levels of 0.25, 0.5, and 1.0,g/L, respectively. This system can facilitate the rapid and efficient in vitro investigation of CTC separation and CTC-related studies. [source] Structure of a human telomeric DNA sequence stabilized by 8-bromoguanosine substitutions, as determined by NMR in a K+ solutionFEBS JOURNAL, Issue 14 2007Akimasa Matsugami The structure of human telomeric DNA is controversial; it depends upon the sequence contexts and the methodologies used to determine it. The solution structure in the presence of K+ is particularly interesting, but the structure is yet to be elucidated, due to possible conformational heterogeneity. Here, a unique strategy is applied to stabilize one such structure in a K+ solution by substituting guanosines with 8-bromoguanosines at proper positions. The resulting spectra are cleaner and led to determination of the structure at a high atomic resolution. This demonstrates that the application of 8-bromoguanosine is a powerful tool to overcome the difficulty of nucleic acid structure determination arising from conformational heterogeneity. The obtained structure is a mixed-parallel/antiparallel quadruplex. The structure of telomeric DNA was recently reported in another study, in which stabilization was brought about by mutation and resultant additional interactions [Luu KN, Phan AT, Kuryavyi V, Lacroix L & Patel DJ (2006) Structure of the human telomere in K+ solution: an intramolecular (3+1) G-quadruplex scaffold. J Am Chem Soc 128, 9963,9970]. The structure of the guanine tracts was similar between the two. However, a difference was seen for loops connecting guanine tracts, which may play a role in the higher order arrangement of telomeres. Our structure can be utilized to design a small molecule which stabilizes the quadruplex. This type of molecule is supposed to inhibit a telomerase and thus is expected to be a candidate anticancer drug. [source] Experimental design comparison of studies evaluating doxorubicin nanoparticles in breast cancer therapyHUMAN FACTORS AND ERGONOMICS IN MANUFACTURING & SERVICE INDUSTRIES, Issue 3 2008Farman A. Moayed Background The unique properties of nanoparticles (NP) qualify these colloidal systems for a wide range of medical applications, including diagnosis and treatment. Particularly in cancer therapy, NP have significantly enhanced the potential of conventional imaging, radiotherapy, and chemotherapy and, consequently, offered new avenues for early interventions. So far, breast cancer has been one of the most studied cancer types with NP research, which can benefit the occupational breast cancer for the increasing number of women in the labor force in industry. Objectives The objective of this study is to compare the experimental designs of preclinical studies that assessed the effect of doxorubicin NP (DOX-NP) on the estrogen-dependent MCF-7 breast cancer cell line using a recently established quantitative Experimental Appraisal Instrument (ExpAI). Methods A systematic review of research articles published between August 2004 and August 2005 on NP and breast cancer treatment with doxorubicin was performed using various online databases and indexes available through the University of Cincinnati. Restrictive inclusion and exclusion criteria were defined leading to selection of four relevant articles that used comparable experimental designs. Critical appraisal of those studies was performed by five independent assessors using the ExpAI version 2.0 and the results were summarized in a table of evidence. Results The study design in the selected articles was either between groups or mixed, with sample sizes varying from n = 3,6, and the evaluation of the effect of DOX-NP either in vitro or in vivo. The cytotoxic drug doxorubicin was the input variable in all studies, whereas different end points such as pharmacokinetic parameters, cytotoxicity surrogates (e.g., growth inhibition, mitochondrial activity), and quantitative analysis of messenger RNA were used as output variables. Conclusions Although the articles assessed in this article were preclinical experimental studies, the results showed that doxorubicin NP drugs can be used effectively to enhance the delivery process in MCF-7 breast cancer cells by increasing the circulation time and targeting the tumor tissues. Considering the rising number of women in the labor force and the risk of occupational breast cancer, it can be concluded that DOX-NP may potentially be used as an effective anticancer drug on humans, but further research and studies are required to understand how DOX-NP drugs might react in the human body before using it on breast cancer patients. © 2008 Wiley Periodicals, Inc. [source] Click-Engineered, Bioresponsive, Drug-Loaded PEG SpheresADVANCED MATERIALS, Issue 43 2009Heng Pho Yap A click-chemistry approach to synthesize bioresponsive poly(ethylene glycol acrylate) particles is described. The particles are loaded with a model anticancer drug (doxorubicin, DOX), and undergo simultaneous particle deconstruction and DOX release upon specific activation by the simulated environment of the cellular cytoplasm. [source] Identification of stemonamide synthetic intermediates as a novel potent anticancer drug with an apoptosis-inducing abilityINTERNATIONAL JOURNAL OF CANCER, Issue 2 2010Ying-Yi Li Abstract We previously demonstrated that Pim-3, a protooncogene with serine/threonine kinase activity, was aberrantly expressed in malignant lesions but not in normal tissues of endoderm-derived organs, including pancreas, liver, colon and stomach. Moreover, aberrantly expressed Pim-3 can prevent tumor cell apoptosis by inactivating a proapoptotic molecule, Bad, and enhancing the expression of an antiapoptotic molecule, Bcl-XL. These observations prompted us to speculate that a chemical targeting Pim-3 kinase may be a good candidate for a novel type of anticancer drug. Hence, we screened various low-molecule compounds by examining their capacity to inhibit Pim-3 kinase activity in vitro. We observed that some synthetic intermediates of stemonamide can inhibit in vitro activities of Pim-3 kinase and its related kinases, such as Pim-1 and Pim-2. Moreover, these compounds inhibit in vitro cell proliferation of various human pancreatic, hepatocellular and colon cancer cell lines. Furthermore, the compounds can induce apoptosis of human pancreatic cancer cell lines in vitro by reducing the amount of phospho-Ser112 -Bad, but not total amounts of Bad and Pim-3. Finally, when the compound was administered to nude mice injected with a human pancreatic cancer cell line, it retarded tumor growth by increasing apoptotic cell numbers and decreasing proliferating cell numbers without causing serious adverse effects on blood counts. These observations indicate that the chemicals and its related compounds may be effective for the treatment of tumors of endoderm-derived organs, particularly the pancreas. [source] DNA Designer Defects in Photonic Crystals: Optically Monitored Biochemistry,ADVANCED MATERIALS, Issue 18 2006F. Fleischhaker Biomolecules have been incorporated as designed planar defect layers in colloidal photonic crystals using self- assembly techniques (see figure). Through shifts of the photonic intragap defect mode, for example, DNA conformational changes and the enantioselective intercalation of a chiral anticancer drug can be optically monitored. This newfound capability for optically monitoring biochemistry bodes well for the development of a new generation of simple on-the-spot color readout biosensors. [source] Copper-Catalyzed Stereoselective Hydroarylation of 3-Aryl-2- propynenitriles with Arylboronic AcidsADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 9 2009Yoshihiko Yamamoto Abstract The selective synthesis of 3,3-diarylacrylonitriles has been achieved by copper-catalyzed hydroarylation of 3-aryl-2-propynenitriles with arylboronic acids. The starting cyanoalkynes were efficiently prepared from the appropriate aromatic aldehydes and diethyl cyanomethylphosphonate in two steps. The hydroarylation of the obtained cyanoalkyne substrates proceeded in methanol at ambient temperature to produce 3,3-diarylacrylonitriles in good to high yields with excellent syn selectivity. The present method was successfully applied to the regiospecific synthesis of both stereoisomers of CC-5079, which was recently reported as a potent anticancer drug. [source] Injectable and thermosensitive poly(organophosphazene) hydrogels for a 5-fluorouracil deliveryJOURNAL OF APPLIED POLYMER SCIENCE, Issue 6 2009Sun Mi Lee Abstract The drug solubility and its release profiles of an anticancer drug from an injectable thermosensitive poly(organophosphazene) hydrogel bearing hydrophobic L -isoleucine ethyl ester and hydrophilic ,-amino-,-methoxy-poly(ethylene glycol) with and without hydrolysis-sensitive glycyl lactate ethyl ester or functional glycyl glycine have been investigated. 5-Fluorouracil (5-FU) was used as a model anticancer drug. The aqueous solutions of 5-FU incorporated poly(organophosphazenes) were an injectable fluid state at room temperature and formed a transparent gel at body temperature. The poly(organophosphazene) solution could enhance the solubility of 5-FU and its solubility (34.26 mg/mL) was increased up to 10-fold compared to that in phosphate-buffered saline (3.39 mg/mL, pH 7.4, 4°C). The in vitro drug release profiles from poly(organophosphazene) hydrogels were established in phosphate-buffered saline at pH 7.4 at 37°C and the release of 5-FU was significantly affected by the diffusion-controlled stage. The results suggest that the injectable and thermosensitive poly(organophosphazene) hydrogel is a potential carrier for 5-FU to increase its solubility, control a relatively sustained and localized release at target sites and thus decrease systemic side effects. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009 [source] Increase of lipid peroxidation by cisplatin in WI38 cells but not in SV40-transformed WI38 cellsJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 1 2003Hsiu-Chuan Yen Abstract Cisplatin (CPT) is an effective anticancer drug that causes cumulative toxicity to normal tissues. It has been suggested that CPT damages normal cells by causing oxidative stress, but it is not known whether it can induce similar oxidative damage to tumor cells. In this study, by using normal human lung fibroblast (W138) cells and SV40-transformed WI38 (VA13) cells as a model, we compared the effect of CPT on cytotoxicity, apoptosis, lipid peroxidation, and mitochondrial gene expression, which could be regulated by oxidative stress, between normal and tumor cells. CPT induced greater growth inhibition and percentage of apoptotic cells in VA13 cells. However, levels of esterified F2 -isoprostanes and 4-hydroxy-2-nonenal, two specific products of lipid peroxidation, were increased by CPT in WI38 cells, but not in VA13 cells. Furthermore, the transcript level of mitochondrial 12S rRNA was augmented by CPT in both cells, but to a higher degree in WI38 cells. The data suggest a correlation between lipid peroxidation and cytotoxicity or increased mitochondrial transcript levels in WI38 cells but not in VA13 cells. The results also indicate an altered response of oxidative damage and mitochondrial gene regulation to CPT in the transformed phenotype of WI38 cells. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:39,46, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10059 [source] A simple and rapid high-performance liquid chromatographic (HPLC) method for 5-fluorouracil (5-FU) assay in plasma and possible detection of patients with impaired dihydropyrimidine dehydrogenase (DPD) activityJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2004J. Ciccolini PharmD PhD Summary Background:, Dihydropyrimidine dehydrogenase (DPD) gene polymorphism may lead to severe toxicity with 5-fluorouracil (5-FU), a major anticancer drug extensively used in clinical oncology. Drug monitoring combined with early detection of patients at risk would enable timely dose adaptation so as to maintain drug concentrations within a therapeutic window. However, the best method to identify such patients remains to be determined. Objective:, The aim of this study was to develop a rapid and simple high-performance liquid chromatographic (HPLC) method for estimating uracil/dihydrouracil (U/UH2) ratio in plasma, as an index of DPD status, and for assaying 5-FU as part of drug level monitoring. Method:, Assay of 5-FU, and U/UH2 detection were performed on a HPLC system equipped with UV detector. Analytes were separated at room temperature using a 5 ,m particles, 25 cm RP-18 X-Terra column. The mobile-phase consisted of a KH2PO4 salt solution (0·05 m) + 0·1% triethylamine (TEA) pumped at 0·4 mL/min. Detection of 5-FU and 5-bromouracil were performed at 254 nm; U and UH2 elution was monitored at 210 nm. Results:, The method was sensitive and specific for assaying 5-FU within the 5,500 ng/mL concentration range, which covers exposure levels currently met in clinical practice. The method was simple, and relatively cheap, and rapid, with an analytical run time of about 30 min. Data from a patient with 5-FU toxicity suggest that the method was capable of identifying DPD metabolic phenotype in cancer patients, based on measurement of plasma U/UH2 ratio. Conclusion:, The method described should be suitable both for detecting patients at high risk of 5-FU toxicity, and for drug level monitoring during chemotherapy. [source] Characterization of in vitro and in vivo metabolic pathways of the investigational anticancer agent, 2-methoxyestradiolJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2007Nehal J. Lakhani Abstract The aim of this study was to characterize the metabolic pathways of 2-methoxyestradiol (2ME2), an investigational anticancer drug. In vitro metabolism studies were performed by incubation of 2ME2 with human liver microsomes under various conditions and metabolite identification was performed using liquid chromatography-tandem mass spectrometry. In microsomal mixtures, four major oxidative metabolites and two glucuronic acid conjugates were observed originating from 2ME2. Human liver S9 protein fraction was used to screen for in vitro sulfation but no prominent conjugates were observed. The total hepatic clearance as estimated using the well-stirred model was approximately 712 mL/min. In vivo metabolism, assessed using 24-h collections of urine from cancer patients treated with 2ME2 revealed that <0.01% of the total administered dose of 2ME2 is excreted unchanged in urine and about 1% excreted as glucuronides. Collectively, this suggests that glucuronidation and subsequent urinary excretion are elimination pathways for 2ME2. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1821,1831, 2007 [source] Reversal of cancer multidrug resistance by green tea polyphenolsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2004Yuying Mei The aim of this study was to examine the effect and mechanism of green tea polyphenols (TP) on reversal of multidrug resistance (MDR) in a carcinoma cell line. Using the MTT assay, TP was examined for its modulating effects on the drug-resistant KB-A-1 cells and drug-sensitive KB-3,1 cells. When 10 ,g mL,1 (-)-epigallocatechin gallate (EGCG) or 40 ,g mL,1 TP were present simultaneously with doxorubicin (DOX), the IC50 of DOX on KB-A-1 cells decreased from 10.3 ± 0.9 ,g mL,1 to 4.2 ± 0.2 and 2.0 ± 0.1 ,g mL,1, respectively. TP and EGCG enhanced the DOX cytotoxicity on KB-A-1 cells by 5.2-and 2.5-times, respectively, but did not show a modulating effect on KB-3,1 cells. This indicated that both TP and EGCG had reversal effects on the MDR phenotype in-vitro. A KB-A-1 cell xenograft model was established, and the effect of TP on reversing MDR in-vivo was determined. Mechanistic experiments were conducted to examine the uptake, efflux and accumulation of DOX. Cloning and expression of the nucleotide binding domain of the human MDR1 gene in Escherichia coli was established, and by using colorimetry to examine the activity of ATPase to hydrolyse ATP, the ATPase activity of target nucleotide binding domain protein was determined. TP exerted its reversal effects through the inhibition of ATPase activity, influencing the function of P-glycoprotein, and causing a decreased extrusion of anticancer drug and an increased accumulation of anticancer drug in drug resistant cells. Using reverse transcription-polymerase chain reaction, the inhibitory effect of TP on MDR1 gene expression was investigated. Down-regulation of MDR1 gene expression was the main effect, which resulted in the reversal effect of TP on the MDR phenotype. TP is a potent MDR modulator with potential in the treatment of P-glycoprotein mediated MDR cancers. [source] Effect of berberine on proliferation, cell cycle and apoptosis in HeLa and L1210 cellsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2003a Jantová Previous studies on the anticancer activity of protoberberine alkaloids against a variety of cancer cell lines were extended to human tumour HeLa and murine leukemia L1210 cell lines. An attempt was also made to investigate the relationship between the cytotoxic activity of berberine and its molecular mechanism of action. Cytotoxicity was measured in-vitro using a primary biochemical screening according to Oyama and Eagle, and the growth inhibition assay. The in-vitro cytotoxic techniques were complemented by cell cycle analysis and determination of apoptotic DNA fragmentation in L1210 cells. Berberine acted cytotoxically on both tumour cell lines. The sensitivity of leukemia L1210 cells to the berberine was higher than that of HeLa cells. The IC100 was below 100 ,g mL,1 for HeLa cells and approached a 10 , mL,1 limit for the leukemia L1210 cells. For both cell lines the IC50 was found to be less than 4 ,g mL,1, a limit put forward by the National Cancer Institute (NCI) for classification of the compound as a potential anticancer drug. In L1210 cells treated with 10,50 , mL,1 berberine, G0/G1 cell cycle arrest was observed. Futhermore, a concentration-dependent decrease of cells in S phase and increase in G2/M phase was detected. In addition, apoptosis detected as sub-G0 cell population in cell cycle measurement was proved in 25,100 ,g mL,1 berberine-treated cells by monitoring the apoptotic DNA fragmentation (DNA ladder) using agarose gel electrophoresis. [source] The Effect of Different Dosing Schedules of UCN-01 on its Pharmacokinetics and Cardiohaemodynamics in DogsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2000N. KURATA 7-Hydroxy-staurosporine (UCN-01) is now under development as a novel anticancer drug. In clinical studies, different infusion schedules are being investigated in the USA and Japan. To examine the effect of different infusion schedules on the pharmacokinetics and cardiohaemodynamics of UCN-01, dogs were treated with UCN-01 as either a 3-h or a 24-h constant intravenous infusion. Blood pressure and heart rate, together with UCN-01 concentrations during and after infusion, were monitored. To analyse the relationship between the pharmacokinetics and cardiohaemodynamics of UCN-01, the plasma concentration of UCN-01 at the end of infusion (Cend), the area under the plasma concentration versus time curves (AUC0-,) and the mean residence time (MRT) were used. As indices of cardiohaemodynamic changes, the area under decreasing systolic blood pressure and increasing heart rate versus time curves (dAUCpressure and AUCheart rate) were calculated by the trapezoidal method. For the 3-h (0.22 and 0.65 mgkg,1) and 24-h infusion (0.81 to 6.48 mgkg,1), systolic and diastolic blood pressures fell after or during infusions, accompanied by a dose-dependent increase in heart rate for both infusions. During both infusion schedules, the plasma concentrations of UCN-01 gradually increased and Cend showed a dose-proportional increase. After that, UCN-01 was eliminated bi-exponentially with an elimination half-life of 5.14 ± 1.12 to 8.32 ± 1.80 h. The total clearance (CLtotal) ranged from 0.383 to 0.666 ± 0.149L h,1kg,1. There was no significant difference in these parameters among the doses in each infusion schedule, indicating that UCN-01 has a linear pharmacokinetic profile over the dose range examined for each infusion, and there were also no significant differences between the 3-h and 24-h infusion except for MRT. The pharmacokinetic parameters of Cend, AUC0-, and slope0-3h exhibited a degree of correlation with the AUCheart rate in the 3-h infusion and correlated significantly with the dAUCpressure in the 24-h infusion. The MRT did not correlate with cardiohaemodynamic changes during either infusion. In conclusion, the pharmacokinetic profile of UCN-01 after the shorter infusion is similar to that after the longer one. However, a longer dosing period of UCN-01 increased the residence time in comparison with the shorter infusion. This may be due to the effect on the circulatory function in dogs. [source] Density functional study on the structural conformations and intramolecular charge transfer from the vibrational spectra of the anticancer drug combretastatin-A2JOURNAL OF RAMAN SPECTROSCOPY, Issue 4 2009L. Padmaja Abstract Combretastatin-A2 (CA2), a potential anticancer drug in advanced preclinical development, is extracted from the medicinal plant Combretum caffrum. The NIR-FT Raman and FT-IR spectral studies of the molecule were carried out and ab initio calculations performed at the B3LYP/6-31G(d) level to derive the equilibrium geometry as well as the vibrational wavenumbers and intensities of the spectral bands. The vibrational analysis showed that the molecule has a similar geometry as that of cis-stilbene, and has undergone steric repulsion resulting in twisting of the phenyl ring with respect to the ethylenic plane. Vibrational analysis was used to investigate the lowering of the stretching modes, and enhancement of infrared band intensities of the C,H stretching modes of Me2 may be attributed to the electronic effects caused by back-donation and induction from the oxygen atom. Analysis of phenyl ring modes shows that the CA2 stretching mode 8 and the aromatic C,H in-plane bending mode are equally active as strong bands in both IR and Raman spectra, which can be interpreted as the evidence of intramolecular charge transfer (ICT) between the OH and OCH3groups via conjugated ring path and is responsible for bioactivity of the molecule. Copyright © 2008 John Wiley & Sons, Ltd. [source] EXAFS characterization of oxaliplatin anticancer drug and its degradation in chloride mediaJOURNAL OF SYNCHROTRON RADIATION, Issue 6 2006Diane Bouvet Oxaliplatin is a second-generation platinum-based anticancer drug. Its degradation is studied in solution, in the presence of chloride ions (in neutral or acidic media) in excess. In both cases the degradation product precipitates immediately. The EXAFS spectra of these products show that they are identical. EXAFS modeling and refinement of the first coordination sphere shows that two light atoms are replaced by two chloride ions. The complete refinement of the local structure is possible by studying the multiple-scattering signal. The results show that the main multiple-scattering contribution is due to the binding oxalato group and that the degradation product is [Cl2 -(diaminocyclohexane)-Pt(II)]. [source] A novel technique to monitor carboxypeptidase G2 expression in suicide gene therapy using 19F magnetic resonance spectroscopyNMR IN BIOMEDICINE, Issue 5 2009Laura Mancini Abstract Development and evaluation of new anticancer drugs are expedited when minimally invasive biomarkers of pharmacokinetic and pharmacodynamic behaviour are available. Gene-directed enzyme prodrug therapy (GDEPT) is a suicide gene therapy in which the anticancer drug is activated in the tumor by an exogenous enzyme previously targeted by a vector carrying the gene. GDEPT has been evaluated in various clinical trials using several enzyme/prodrug combinations. The key processes to be monitored in GDEPT are gene delivery and expression, as well as prodrug delivery and activation. {4-[bis(2-chloroethyl)amino]-3,5-difluorobenzoyl}-L-glutamic acid, a prodrug for the GDEPT enzyme carboxypeptidase-G2 (CPG2; Km,=,1.71,µM; kcat,=,732,s,1), was measured with 19F magnetic resonance spectroscopy (MRS). The 1,ppm chemical shift separation found between the signals of prodrug and activated drug (4-[bis(2-chloroethyl)amino]-3,5-difluorobenzoic acid) is sufficient for the detection of prodrug activation in vivo. However, these compounds hydrolyze rapidly, and protein binding broadens the MR signals. A new CPG2 substrate was designed with hydroxyethyl instead of chloroethyl groups (Km,=,3.5,µM, kcat,=,747,s,1). This substrate is nontoxic and stable in solution, has a narrow MRS resonance in the presence of bovine and foetal bovine albumin, and exhibits a 1.1,ppm change in chemical shift upon cleavage by CPG2. In cells transfected to express CPG2 in the cytoplasm (MDA MB 361 breast carcinoma cells and WiDr colon cancer cells), well-resolved 19F MRS signals were observed from clinically relevant concentrations of the new substrate and its nontoxic product. The MRS conversion half-life (470,min) agreed with that measured by HPLC (500,min). This substrate is, therefore, suitable for evaluating gene delivery and expression prior to administration of the therapeutic agent. Copyright © 2009 John Wiley & Sons, Ltd. [source] Matrix-assisted laser desorption/ionization imaging mass spectrometry of oxaliplatin derivatives in heated intraoperative chemotherapy (HIPEC)-like treated rat kidneyRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 4 2010Amina Bouslimani Oxaliplatin [1,2-diaminocyclohexane (dach)-Pt complex] is a platinum anticancer drug which is mainly used in the treatment of advanced colorectal cancer, particularly in Heated Intraoperative Chemotherapy (HIPEC) for the treatment of colorectal peritoneal carcinomatosis. In order to better understand the penetration of oxaliplatin in treated tissues we performed a direct imaging of tissue sections from HIPEC-like treated rat kidney using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. This procedure allowed the detection and localization of oxaliplatin and its metabolites, the monocysteine and monomethionine complexes, in kidney sections. Specifically, oxaliplatin and its metabolites were localized exclusively in the kidney cortex, suggesting that it did not penetrate deeply into the organ. Based on these results, an imaging analysis of human tumors collected after HIPEC is currently in progress to assess the distribution of oxaliplatin and/or metabolites with the aim of defining clinical conditions to improve drug penetration. Copyright © 2010 John Wiley & Sons, Ltd. [source] Mass spectrometry study of hemoglobin-oxaliplatin complexes in colorectal cancer patients and potential association with chemotherapeutic responsesRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 17 2006Rupasri Mandal Oxaliplatin is the most active platinum (Pt)-containing anticancer drug for the treatment of advanced colorectal cancer. We report here the study of potential association of the levels of oxaliplatin-protein complexes in 19 cancer patients with treatment efficacy using size-exclusion high-performance liquid chromatography with inductively coupled plasma mass spectrometry (HPLC/ICPMS) and nanoelectrospray ionization mass spectrometry (nanoESI-MS) techniques. Blood samples from 19 colorectal cancer patients were collected at 1 and 48,h after the first infusion of oxaliplatin. HPLC/ICPMS quantification of the oxaliplatin-protein complexes showed that the levels of Pt-protein complexes in plasma samples at 48,h were reduced by approximately 50% compared to those at 1,h, whereas those in hemolysates did not change significantly. The concentrations of hemoglobin (Hb)-oxaliplatin complexes determined by HPLC/ICPMS ranged from 3.1 to 8.7,µM. NanoESI-MS analysis of the patient hemolysates showed three distinct mass spectral profiles of the Hb-oxaliplatin complexes: (1) 1:1, (2) 1:1 with 1:2, and (3) multiple complexes of 1:1, 1:2, 1:3, and 1:4, corresponding to the Hb-oxaliplatin complex concentrations determined by HPLC/ICPMS. Potential association of variables including Hb-oxaliplatin complex concentrations with time to progress as the treatment efficacy indicator was analyzed using the Cox model. Multivariate analysis of the potential predictors showed that the statistically significant variables were Hb-oxaliplatin complex concentration (p,=,0.02), performance status (p,=,0.02), baseline neutrophil count (p,=,0.05), and the site of the primary cancer (colon vs. rectal, p,=,0.01). The hazard ratio for the concentration of the Hb-oxaliplatin complexes was 2.4, suggesting that the risk of cancer progression significantly increased with increasing of Hb-oxaliplatin complexes in patients. These results demonstrate that the level of the Hb-oxaliplatin complexes in erythrocytes is a potential biomarker for indicating inter-patient variations in oxaliplatin treatment efficacy. Copyright © 2006 John Wiley & Sons, Ltd. [source] Angiogenesis in the Caprine Caruncles in Non-Pregnant and Pregnant Normal and Swainsonine-Treated DoesTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 7 2007S.A. Hafez Abstract Microvascular corrosion casts of caruncles from non-pregnant and pregnant doe goats at 4, 7, 10, 13, 16, and 18 weeks were examined with scanning electron microscopy. The internal convex surface of the caruncles of non-pregnant does was covered with capillary meshes of regular diameter and form, without crypts. As pregnancy advanced the complexity of the vasculature increased: at 4 weeks the surface showed a pattern of ridges separated by troughs. At later stages, branches of radial arteries penetrated the periphery forming an extensive mesh of capillaries on the concave surface. Capillary diameters increased significantly during pregnancy, especially after 4 weeks, when large flattened sinusoids formed. These sinusoids had a great deal of surface area for potential contact with the fetal component. The caprine placenta is usually considered to have increased interhemal distance compared with endotheliochorial and hemochorial types: our results suggest that the very extensive development of sinusoids and crypts may compensate for any negative consequences of the placental architecture. Placental angiogenesis, which is physiologically normal, may serve as a general model of this process in other circumstances, such as tumor. The effect of swainsonine (active compound of locoweed and a potential anticancer drug) on vascular development showed no differences in sinusoidal diameters at 7 weeks, but a decrease in capillary density was noted. Swainsonine caused a great distortion to the vasculature at 18 weeks. The effects of this compound on the vascular development lend credibility to its potential as an anticancer agent. Anat Rec, 2007. © 2007 Wiley-Liss, Inc. [source] Adenoviral-mediated gene transfer of Gadd45a results in suppression by inducing apoptosis and cell cycle arrest in pancreatic cancer cellTHE JOURNAL OF GENE MEDICINE, Issue 1 2009Yunfeng Li Abstract Background The extremely poor prognosis of patients with pancreatic ductal adenocarcinoma indicates the need for novel therapeutic approaches. The growth arrest and DNA damage-inducible (Gadd) gene Gadd45a is a member of a group of genes that are induced by DNA damaging agents and growth arrest signals. Methods We evaluated the biological activity of Gadd45a in pancreatic ductal adenocarcinoma cancer-derived cell lines and assessed the efficacy of a combined treatment with adenoviral-mediated expression of Gadd45a (Ad-G45a) and anticancer drug (Etoposide, cisplatin, 5-fluorouracil, respectively) for the PANC1 cell line. Results Gadd45a is variously expressed in cell lines derived from pancreatic ductal adenocarcinoma cancer and adenoviral-mediated expression of Gadd45a (Ad-G45a) in these cells results in apoptosis via caspase activation and cell-cycle arrest in the G2/M phase. Gadd45a significantly increased the chemosensitivity of PANC1, which may be due to abundant apoptosis induction and cell cycle arrest. By combinational treatment of Ad-G45a infection and chemotherapeutics, Gadd45a expression was elevated to a higher extent in cancer cells with wild-type p53 than in that with knocked-out p53 status, indicating a higher chemosensitivity to cancer chemotherapy. Conclusions Gadd45a may be a promising candidate for use in cancer gene therapy in combination with chemotherapeutic agents. Copyright © 2008 John Wiley & Sons, Ltd. [source] Synthesis of New Quinoline Derivatives as Inhibitors of Human Tumor Cells GrowthARCHIV DER PHARMAZIE, Issue 8 2010Aymn E. Rashad Abstract A series of new 8-[(2H -tetrazol-5-yl)methoxy]quinoline derivatives, their sugar hydrazones, and their N -glycoside derivatives were synthesized. Furthermore, the 1,2,4-triazole-3-one derivatives 3 and 4 were synthesized from the amidrazone derivative 2. Some of the newly prepared compounds demonstrated inhibitory effects on the growth of MCF-7 human breast cancer cells as compared with the activity of the commonly used anticancer drug, cisplatin. The results of antitumor evaluation revealed that compounds 2,5, 8b, and 12 inhibited the growth of cancer cells through their effect as free-radical regulators by increasing the activity of superoxide dismutase and depletion of intracellular levels of reduced glutathione, catalase and glutathione peroxidase activities, accompanied with a high production of hydrogen peroxide, nitric oxide, and other free radicals causing the killing of tumor cells. The results suggested that the prepared compounds possess significant anticancer activity comparable to cisplatin and the antitumor activity of these prepared compounds was accompanied with a reduction in the levels of protein and nucleic acids. [source] Synthesis and in-vitro Cytotoxicity of Poly-functionalized 4-(2-Arylthiazol-4-yl)-4H -chromenesARCHIV DER PHARMAZIE, Issue 7 2010Majid Mahmoodi Abstract A new series of 4-aryl-4H -chromenes bearing a 2-arylthiazol-4-yl moiety at the 4-position were prepared as potential cytotoxic agents. The in-vitro cytotoxic activity of the synthesized 4-aryl-4H -chromenes was investigated in comparison with etoposide, a well-known anticancer drug, using MTT colorimetric assay. Among them, the 2-(2-chlorophenyl)thiazol-4-yl analog 4b showed the most potent activity against nasopharyngeal epidermoid carcinoma KB, medulloblastoma DAOY, and astrocytoma 1321N1, and compound 4d bearing a 2-(4-chlorophenyl)thiazol-4-yl moiety at the 4-position of the chromene ring exhibited the best inhibitory activity against breast cancer cells MCF-7, lung cancer cells A549, and colon adenocarcinoma cells SW480 with IC50 values less than 5 ,M. The ability of compound 4b to induce apoptosis was confirmed in a nuclear morphological assay by DAPI staining in the KB and MCF-7 cells. [source] Proline Analogue of Nitrosourea as a New Cytotoxic ProdrugARCHIV DER PHARMAZIE, Issue 11 2009Anna Stankiewicz-Kranc Abstract Carmustine is frequently used as anticancer drug. High toxicity and low selectivity reduces the application of this drug. Though, there is a necessity to find new compounds characterized by similar therapeutic effects but a higher selectivity and safety. As a result, the proline analogue of nitrosourea, N -[N,-(2-bromophenyl)- N,-nitrosocarbamoyl]proline (AC), has been synthesized. The aim of this study was to compare the influence of carmustine and the proline analogue of nitrosourea on the antioxidant abilities of fibroblasts and leukemia cells, MOLT4. It was shown that carmustine as well as AC cause an increase in hydrogen peroxide concentration in normal and neoplastic cells. Incubation with both compounds led to a diminution of the activity of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and reductase. Changes in activity / level of antioxidant parameters were accompanied by augmentation of lipid and oxidative protein modifications. In conclusion, carmustine and AC cause changes in the antioxidative system of normal and MOLT4 cells and are a reason of oxidative stress formation. [source] Influence of Hyperglycaemia on Chemical-Induced Toxicity: Study with Cyclophosphamide in RatBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2009Kalavatala Saandeep Hyperglycaemia perturbs the critical balance between oxidative stress and anti-oxidant defence mechanisms in the body and thereby alters the response of biological system towards various toxic chemicals. Cyclophosphamide (CP) is a widely prescribed anticancer drug, well-known genotoxic agent as well as used in the development of immunocompromised animal models. The present study investigated the modulating effect of diabetes on the cyclophosphamide-induced cytotoxicity and genotoxicity. The study was performed on male Sprague-Dawley rats (200 ± 10 g). Cyclophosphamide (10 mg/kg) was administered five consecutive days in a week for 3 weeks to both control and diabetic rats. Thiobarbituric acid reactive substances (TBARS) levels were measured in the plasma, liver, kidney and lung tissues. DNA damaging potential of cyclophosphamide under diabetic condition was evaluated using comet and halo assay as an endpoint. To further ascertain the mode of cell death, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay and immunohistochemical evaluation of p53 was performed. Significant increase in DNA damage was revealed by the comet assay parameters, halo assay indicated the level of cytotoxicity and the oxidative stress was measured using the TBARS assay in the diabetic rats receiving cyclophosphamide treatment. The toxic effects were more prominent in diabetic animals as compared to non-diabetic rats. Cyclophosphamide treatment and diabetic condition per se led to increase in the p53 + and TUNEL + cells in the liver and kidney of rats. Under diabetic condition, further increase in the p53 + and TUNEL + cells was observed in response to cyclophosphamide. In the present study, we report that hyperglycaemic condition exaggerates the cyclophosphamide-induced toxicity and the response was found to be tissue specific. [source] Effect of millimeter wave irradiation on tumor metastasisBIOELECTROMAGNETICS, Issue 4 2006Mahendra K. Logani Abstract One of the major side effects of chemotherapy in cancer treatment is that it can enhance tumor metastasis due to suppression of natural killer (NK) cell activity. The present study was undertaken to examine whether millimeter electromagnetic waves (MMWs) irradiation (42.2 GHz) can inhibit tumor metastasis enhanced by cyclophosphamide (CPA), an anticancer drug. MMWs were produced with a Russian-made YAV-1 generator. Peak SAR and incident power density were measured as 730,±,100 W/kg and 36.5,±,5 mW/cm2, respectively. Tumor metastasis was evaluated in C57BL/6 mice, an experimental murine model commonly used for metastatic melanoma. The animals were divided into 5 groups, 10 animals per group. The first group was not given any treatment. The second group was irradiated on the nasal area with MMWs for 30 min. The third group served as a sham control for group 2. The fourth group was given CPA (150 mg/kg body weight, ip) before irradiation. The fifth group served as a sham control for group 4. On day 2, all animals were injected, through a tail vein, with B16F10 melanoma cells, a tumor cell line syngeneic to C57BL/6 mice. Tumor colonies in lungs were counted 2 weeks following inoculation. CPA caused a marked enhancement in tumor metastases (fivefold), which was significantly reduced when CPA-treated animals were irradiated with MMWs. Millimeter waves also increased NK cell activity suppressed by CPA, suggesting that a reduction in tumor metastasis by MMWs is mediated through activation of NK cells. Bioelectromagnetics 27:258,264, 2006. © 2006 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||