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Sample records for active chemotherapeutic agents

  1. [Chemotherapeutic agents under study].

    PubMed

    Kawahara, S

    1998-12-01

    The development of new drugs with strong antituberculous activity and fewer side effects which are not cross-resistant to conventional antituberculosis drugs is urgently desired now. The chemotherapeutic agents under study which are considered a candidate for a new antituberculosis drug are listed below. 1) Rifamycin derivatives: rifabutin, rifapentin, KRM-1648, FCE-22250, 22807, CGP-7040, 27557, 29035, 29861, P-DEA, SPA-S-565, R-76-1. 2) New quinolones: ofloxacin, ciprofloxacin, levofloxacin, sparfloxacin, gatifloxacin, CS-940, Du-6859a. 3) Phenazines: clofazimine, B746, B4101, B4154, B4157. 4) Pyrazinamide derivatives: N-hydroxy pyrazinamide, N-hydroxy pyrazinamide-4-oxide. 5) Nitroimidazole derivatives: metronidazole et al.

  2. Hormetic Effect of Berberine Attenuates the Anticancer Activity of Chemotherapeutic Agents.

    PubMed

    Bao, Jiaolin; Huang, Borong; Zou, Lidi; Chen, Shenghui; Zhang, Chao; Zhang, Yulin; Chen, Meiwan; Wan, Jian-Bo; Su, Huanxing; Wang, Yitao; He, Chengwei

    2015-01-01

    Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents. Our results demonstrated that berberine at low dose range (1.25 ~ 5 μM) promoted cell proliferation to 112% ~170% of the untreated control in various cancer cells, while berberine at high dose rage (10 ~ 80 μM) inhibited cell proliferation. Further, we observed that co-treatment with low dose berberine could significantly attenuate the anticancer activity of chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX). The hormetic effect and thereby the attenuated anticancer activity of chemotherapeutic drugs by berberine may attributable to the activated protective stress response in cancer cells triggered by berberine, as evidenced by up-regulated MAPK/ERK1/2 and PI3K/AKT signaling pathways. These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer.

  3. Nrf2 inhibition sensitizes cholangiocarcinoma cells to cytotoxic and antiproliferative activities of chemotherapeutic agents.

    PubMed

    Samatiwat, Papavee; Prawan, Auemduan; Senggunprai, Laddawan; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol

    2016-08-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor regulating antioxidant, cytoprotective, and metabolic enzymes, plays important roles in drug resistance and proliferation in cancer cells. The present study was aimed to examine the expression of Nrf2 in connection with chemotherapeutic drug sensitivity on cholangiocarcinoma (CCA) cells. The basal levels of Nrf2 protein in cytosol and nuclear fractions of CCA cells were determined using Western blot analysis. Nrf2 mRNA expression of KKU-M156 and KKU-100 cells, representatives of low and high-Nrf2-expressing CCA cells, were silenced using siRNA. After knockdown of Nrf2, the sensitivity of those cells to the cytotoxicity of cisplatin (Cis) was enhanced in association with the increased release of AIF and downregulation of Bcl-xl in both cells. Also, knockdown of Nrf2 suppressed the replicative capability of those cells in colony-forming assay and enhanced their sensitivity to antiproliferative activity of Cis and 5-fluorouracil. The chemosensitizing effect was associated with the suppressed expression of Nrf2-regulated and Cis-induced antioxidant and metabolic genes including NQO1, HO-1, GCLC, TXN, MRP2, TKT, and G6PD. In cell cycle analysis, Nrf2 knockdown cells were arrested at G0/G1 phase and combination with Cis increased the accumulation of cells at S phase. The suppression of KKU-M156 cell proliferation was associated with the downregulation of cyclin D1 and increased level of p21. Inhibition of Nrf2 could be a novel strategy in enhancing antitumor activity of chemotherapeutic agent in control of resistant cancer.

  4. Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy.

    PubMed

    Siemann, Dietmar W; Mercer, Emma; Lepler, Sharon; Rojiani, Amyn M

    2002-05-01

    The utility of combining the vascular targeting agents 5,6-dimethyl-xanthenone-4 acetic acid (DMXAA) and combretastatin A-4 disodium phosphate (CA4DP) with the anticancer drugs cisplatin and cyclophosphamide (CP) was evaluated in experimental rodent (KHT sarcoma), human breast (SKBR3) and ovarian (OW-1) tumor models. Doses of the vascular targeting agents that led to rapid vascular shutdown and subsequent extensive central tumor necrosis were identified. Histologic evaluation showed morphologic damage of tumor cells within a few hours after treatment, followed by extensive hemorrhagic necrosis and dose-dependent neoplastic cell death as a result of prolonged ischemia. Whereas these effects were induced by a range of CA4DP doses (10-150 mg/kg), the dose response to DMXAA was extremely steep; doses < or = 15 mg/kg were ineffective and doses > or = 20 mg/kg were toxic. DMXAA also enhanced the tumor cell killing of cisplatin, but doses > 15 mg/kg were required. In contrast, CA4DP increased cisplatin-induced tumor cell killing at all doses studied. This enhancement of cisplatin efficacy was dependent on the sequence and interval between the agents. The greatest effects were achieved when the vascular targeting agents were administered 1-3 hr after cisplatin. When CA4DP (100 mg/kg) or DMXAA (17.5 mg/kg) were administered 1 hr after a range of doses of cisplatin or CP, the tumor cell kill was 10-500-fold greater than that seen with chemotherapy alone. In addition, the inclusion of the antivascular agents did not increase bone marrow stem cell toxicity associated with these anticancer drugs, thus giving rise to a therapeutic gain.

  5. Activation of the human immune system by chemotherapeutic or targeted agents combined with the oncolytic parvovirus H-1

    PubMed Central

    2011-01-01

    Background Parvovirus H-1 (H-1PV) infects and lyses human tumor cells including melanoma, hepatoma, gastric, colorectal, cervix and pancreatic cancers. We assessed whether the beneficial effects of chemotherapeutic agents or targeted agents could be combined with the oncolytic and immunostimmulatory properties of H-1PV. Methods Using human ex vivo models we evaluated the biological and immunological effects of H-1PV-induced tumor cell lysis alone or in combination with chemotherapeutic or targeted agents in human melanoma cells +/- characterized human cytotoxic T-cells (CTL) and HLA-A2-restricted dendritic cells (DC). Results H-1PV-infected MZ7-Mel cells showed a clear reduction in cell viability of >50%, which appeared to occur primarily through apoptosis. This correlated with viral NS1 expression levels and was enhanced by combination with chemotherapeutic agents or sunitinib. Tumor cell preparations were phagocytosed by DC whose maturation was measured according to the treatment administered. Immature DC incubated with H-1PV-induced MZ7-Mel lysates significantly increased DC maturation compared with non-infected or necrotic MZ7-Mel cells. Tumor necrosis factor-α and interleukin-6 release was clearly increased by DC incubated with H-1PV-induced SK29-Mel tumor cell lysates (TCL) and was also high with DC-CTL co-cultures incubated with H-1PV-induced TCL. Similarly, DC co-cultures with TCL incubated with H-1PV combined with cytotoxic agents or sunitinib enhanced DC maturation to a greater extent than cytotoxic agents or sunitinib alone. Again, these combinations increased pro-inflammatory responses in DC-CTL co-cultures compared with chemotherapy or sunitinib alone. Conclusions In our human models, chemotherapeutic or targeted agents did not only interfere with the pronounced immunomodulatory properties of H-1PV, but also reinforced drug-induced tumor cell killing. H-1PV combined with cisplatin, vincristine or sunitinib induced effective immunostimulation via a

  6. Bitter melon extracts enhance the activity of chemotherapeutic agents through the modulation of multiple drug resistance

    PubMed Central

    Kwatra, Deep; Venugopal, Anand; Standing, David; Ponnurangam, Sivapriya; Dhar, Animesh; Mitra, Ashim; Anant, Shrikant

    2014-01-01

    Recently we demonstrated that extracts of bitter melon (BME) can be used as a preventive/therapeutic agent in colon cancers. Here, we determined BME effects on anticancer activity and bioavailability of doxorubicin (DOX) in colon cancer cells. BME enhanced the effect of DOX on cell proliferation and sensitized the cells towards DOX upon pretreatment. Furthermore, there was both increased drug uptake and reduced drug efflux. We also observed a reduction in the expression of Multidrug resistance conferring proteins (MDRCP) P-glycoprotein, MRP-2 and BCRP. Further BME suppressed DOX efflux in MDCK cells overexpressing the three efflux proteins individually, suggesting that BME is a potent inhibitor of MDR function. Next, we determined the effect of BME on PXR, a xenobiotic sensing nuclear receptor and a transcription factor that controls the expression of the three MDR genes. BME suppressed PXR promoter activity thereby suppressing its expression. Finally, we determined the effect of AMPK pathway on drug efflux because we have previously demonstrated that BME affects the pathway. However, inhibiting AMPK did not affect drug resistance, suggesting that BME may use different pathways for the anticancer and MDR modulating activities. Together, these results suggest that BME can enhance the bioavailability and efficacy of conventional chemotherapy. PMID:24129966

  7. GTP depletion synergizes the anti-proliferative activity of chemotherapeutic agents in a cell type-dependent manner

    SciTech Connect

    Lin, Tao; Meng, Lingjun; Tsai, Robert Y.L.

    2011-10-22

    Highlights: {yields} Strong synergy between mycophenolic acid (MPA) and 5-FU in MDA-MB-231 cells. {yields} Cell type-dependent synergy between MPA and anti-proliferative agents. {yields} The synergy of MPA on 5-FU is recapitulated by RNA polymerase-I inhibition. {yields} The synergy of MPA on 5-FU requires the expression of nucleostemin. -- Abstract: Mycophenolic acid (MPA) depletes intracellular GTP by blocking de novo guanine nucleotide synthesis. GTP is used ubiquitously for DNA/RNA synthesis and as a signaling molecule. Here, we made a surprising discovery that the anti-proliferative activity of MPA acts synergistically with specific chemotherapeutic agents in a cell type-dependent manner. In MDA-MB-231 cells, MPA shows an extremely potent synergy with 5-FU but not with doxorubicin or etoposide. The synergy between 5-FU and MPA works most effectively against the highly tumorigenic mammary tumor cells compared to the less tumorigenic ones, and does not work in the non-breast cancer cell types that we tested, with the exception of PC3 cells. On the contrary, MPA shows the highest synergy with paclitaxel but not with 5-FU in SCC-25 cells, derived from oral squamous cell carcinomas. Mechanistically, the synergistic effect of MPA on 5-FU in MDA-MB-231 cells can be recapitulated by inhibiting the RNA polymerase-I activity and requires the expression of nucleostemin. This work reveals that the synergy between MPA and anti-proliferative agents is determined by cell type-dependent factors.

  8. Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats

    PubMed Central

    Rahn, E J; Makriyannis, A; Hohmann, A G

    2007-01-01

    Background and purpose: The ability of cannabinoids to suppress mechanical hypersensitivity (mechanical allodynia) induced by treatment with the chemotherapeutic agent vincristine was evaluated in rats. Sites of action were subsequently identified. Experimental approach: Mechanical hypersensitivity developed over the course of ten daily injections of vincristine relative to groups receiving saline at the same times. Effects of the CB1/CB2 receptor agonist WIN55,212-2, the receptor-inactive enantiomer WIN55,212-3, the CB2-selective agonist (R,S)-AM1241, the opiate agonist morphine and vehicle on chemotherapy-induced neuropathy were evaluated. WIN55,212-2 was administered intrathecally (i.t.) or locally in the hindpaw to identify sites of action. Pharmacological specificity was established using competitive antagonists for CB1 (SR141716) or CB2 receptors (SR144528). Key results: Systemic administration of WIN55,212-2, but not WIN55,212-3, suppressed vincristine-evoked mechanical allodynia. A leftward shift in the dose-response curve was observed following WIN55,212-2 relative to morphine treatment. The CB1 (SR141716) and CB2 (SR144528) antagonists blocked the anti-allodynic effects of WIN55,212-2. (R,S)-AM1241 suppressed vincristine-induced mechanical hypersensitivity through a CB2 mechanism. Both cannabinoid agonists suppressed vincristine-induced mechanical hypersensitivity without inducing catalepsy. Spinal sites of action are implicated in cannabinoid modulation of chemotherapy-induced neuropathy. WIN55,212-2, but not WIN55,212-3, administered i.t. suppressed vincristine-evoked mechanical hypersensitivity at doses that were inactive following local hindpaw administration. Spinal coadministration of both the CB1 and CB2 antagonists blocked the anti-allodynic effects of WIN55,212-2. Conclusions and implications: Cannabinoids suppress the maintenance of vincristine-induced mechanical allodynia through activation of CB1 and CB2 receptors. These anti-allodynic effects

  9. Anti-tubercular and antioxidant activities of C-glycosyl carbonic anhydrase inhibitors: towards the development of novel chemotherapeutic agents against Mycobacterium tuberculosis.

    PubMed

    Zaro, María J; Bortolotti, Ana; Riafrecha, Leonardo E; Concellón, Analía; Morbidoni, Héctor R; Colinas, Pedro A

    2016-12-01

    During the treatment of tuberculosis infection, oxidative stress due to anti-tubercular drugs may result in tissue inflammation. It was suggested that treatment with antioxidant drugs could be beneficial as an adjunct to anti-tuberculosis drug therapy. Recently our group has shown that several C-glycosides are inhibitors of Mycobacterium tuberculosis β-carbonic anhydrases (CAs, EC 4.2.1.1). In an effort to develop novel chemotherapeutic agents against tuberculosis, the anti-tubercular and antioxidant activities of a series of C-glycosides containing the phenol or the methoxyaryl moiety were studied. Many compounds showed inhibition of growth of M. tuberculosis H37Rv strain and good antioxidant ability. A glycomimetic incorporating the 3-hydroxyphenyl moiety showed the best activity profile and therefore this functionality represents lead for the development of novel anti-tubercular agents with dual mechanisms of action.

  10. Inhibition of DNA helicase, ATPase and DNA-binding activities of E. coli RecQ helicase by chemotherapeutic agents.

    PubMed

    Zhang, Bo; Zhang, Ai-hua; Chen, Lei; Xi, Xu Guang

    2008-06-01

    RecQ helicases play an essential role in maintaining genetic integrity in all organisms from Escherichia coli to humans. Defects to these enzymes are responsible for three distinct human diseases: Werner syndrome, Bloom syndrome and Rothmund-Thomson syndrome. All three diseases are characterized by a predisposition to cancer due to increased genomic instability. Previous studies on the effects of non-covalent DNA modifications on the catalytic activity of purified Werner and Bloom DNA helicases have shown that both enzymes have similar sensitivity profiles to these DNA-binding agents and are most strongly inhibited by the minor groove binder distamycin A. In this study, we show that the sensitivity profiles of E. coli RecQ to a number of DNA-binding ligands are different to those observed for WRN and Bloom helicases. These observations may give insights into the differences in molecular mechanisms underlying efficient motor function of RecQ helicases.

  11. Inhibition of constitutively activated phosphoinositide 3-kinase/AKT pathway enhances antitumor activity of chemotherapeutic agents in breast cancer susceptibility gene 1-defective breast cancer cells.

    PubMed

    Yi, Yong Weon; Kang, Hyo Jin; Kim, Hee Jeong; Hwang, Jae Seok; Wang, Antai; Bae, Insoo

    2013-09-01

    Loss or decrease of wild type BRCA1 function, by either mutation or reduced expression, has a role in hereditary and sporadic human breast and ovarian cancers. We report here that the PI3K/AKT pathway is constitutively active in BRCA1-defective human breast cancer cells. Levels of phospho-AKT are sustained even after serum starvation in breast cancer cells carrying deleterious BRCA1 mutations. Knockdown of BRCA1 in MCF7 cells increases the amount of phospho-AKT and sensitizes cells to small molecule protein kinase inhibitors (PKIs) targeting the PI3K/AKT pathway. Restoration of wild type BRCA1 inhibits the activated PI3K/AKT pathway and de-sensitizes cells to PKIs targeting this pathway in BRCA1 mutant breast cancer cells, regardless of PTEN mutations. In addition, clinical PI3K/mTOR inhibitors, PI-103, and BEZ235, showed anti-proliferative effects on BRCA1 mutant breast cancer cell lines and synergism in combination with chemotherapeutic drugs, cisplatin, doxorubicin, topotecan, and gemcitabine. BEZ235 synergizes with the anti-proliferative effects of gemcitabine by enhancing caspase-3/7 activity. Our results suggest that the PI3K/AKT pathway can be an important signaling pathway for the survival of BRCA1-defective breast cancer cells and pharmacological inhibition of this pathway is a plausible treatment for a subset of breast cancers.

  12. Current Research and Development of Chemotherapeutic Agents for Melanoma

    PubMed Central

    Hsan, Kyaw Minn; Chen, Chun-Chieh; Shyur, Lie-Fen

    2010-01-01

    Cutaneous malignant melanoma is the most lethal form of skin cancer and an increasingly common disease worldwide. It remains one of the most treatment-refractory malignancies. The current treatment options for patients with metastatic melanoma are limited and in most cases non-curative. This review focuses on conventional chemotherapeutic drugs for melanoma treatment, by a single or combinational agent approach, but also summarizes some potential novel phytoagents discovered from dietary vegetables or traditional herbal medicines as alternative options or future medicine for melanoma prevention. We explore the mode of actions of these natural phytoagents against metastatic melanoma. PMID:24281076

  13. In vitro sensitivity of human ovarian tumours to chemotherapeutic agents.

    PubMed Central

    Wilson, A. P.; Neal, F. E.

    1981-01-01

    The in vitro chemosensitivity of primary monolayer cultures of human ovarian tumours to a wide range of chemotherapeutic agents has been determined using 3H-leucine incorporation as an index of cytotoxicity. Of 67 specimens received, 35 have been successfully cultured and tested for chemosensitivity. Drugs tested included alkylating agents, antibiotics, antimitotics, antimetabolites and progestogens. The overall incidence of efficacy of the drugs corresponded with the incidence which might be expected from data on the clinical response rates produced by the various drugs. Cultures from the tumour cells of treated patients generally showed greater resistance than tumours of untreated patients. Correlation between in vitro results and in vivo response was positive in all 8 patients receiving first-line chemotherapy and in 57% (4/7) patients receiving second-line chemotherapy. PMID:6791675

  14. Natural products as a source of potential cancer chemotherapeutic and chemopreventive agents.

    PubMed

    Cassady, J M; Baird, W M; Chang, C J

    1990-01-01

    Recent advances in the chemistry of novel bioactive natural products are reported. This research is directed to the exploration of plants with confirmed activity in bioassays designed to detect potential cancer chemotherapeutic and chemopreventive agents. Structural work and chemical studies are reported for several cytotoxic agents from the plants Annona densicoma, Annona reticulata, Claopodium crispifolium, Polytrichum obioense, and Psorospermum febrifugum. Studies are also reported based on development of a mammalian cell culture benzo[a]pyrene metabolism assay for the detection of potential anticarcinogenic agents from natural products. In this study a number of isoflavonoids and flavonoids with antimutagenic activity have been discovered.

  15. Cinnamaldehyde/chemotherapeutic agents interaction and drug-metabolizing genes in colorectal cancer.

    PubMed

    Yu, Chen; Liu, Shen-Lin; Qi, Ming-Hao; Zou, Xi

    2014-02-01

    Cinnamaldehyde is an active monomer isolated from the stem bark of Cinnamomum cassia, a traditional oriental medicinal herb, which is known to possess marked antitumor effects in vitro and in vivo. The aim of the present study was to examine the potential advantages of using cinnamaldehyde in combination with chemotherapeutic agents commonly used in colorectal carcinoma (CRC) therapy, as well as to investigate the effect of cinnamaldehyde on chemotherapeutic-associated gene expression. The synergistic interaction of cinnamaldehyde and chemotherapeutic agents on human CRC HT-29 and LoVo cells was evaluated using the combination index (CI) method. The double staining with Annexin V conjugated to fluorescein-isothiocyanate and phosphatidylserine was employed for apoptosis detection. The expression of drug-metabolizing genes, including excision repair cross‑complementing 1 (ERCC1), orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), breast cancer susceptibility gene 1 (BRCA1) and topoisomerase 1 (TOPO1), all in HT-29 and LoVo cells, with or without the addition of cinnamaldehyde, was examined by quantitative polymerase chain reaction (PCR). Cinnamaldehyde had a synergistic effect on the chemotherapeutic agents cytotoxicity in HT-29 and LoVo cells. In addition, cinnamaldehyde suppressed BRCA1, TOPO1, ERCC1 and TS mRNA expression, except for OPRT expression, which was markedly upregulated. Our findings indicate that cinnamaldehyde appears to be a promising candidate as an adjuvant in combination therapy with 5-fluorouracil (5-FU) and oxaliplatin (OXA), two chemotherapeutic agents used in CRC treatment. The possible mechanisms of its action may involve the regulation of drug‑metabolizing genes.

  16. Chemosensitization of Breast Cancer Cells to Chemotherapeutic Agents by 3,3’-Diindolylmethane (DIM)

    DTIC Science & Technology

    2007-08-01

    protects against covalent binding of benzo [ a ] pyrene and N -nitrosodimethylamine metabolites to mouse liver macromolecules. Chem Biol Interact 1984;48...by ANSI Std. Z39.18 Constitutive activation of Akt or NF-κB has been reported to play a role in de novo resistance of cancer cells to...chemotherapeutic agents, which is a major cause of treatment failure in cancer chemotherapy. Previous studies have shown that 3, 3’-diindolylmethane (DIM), a

  17. Graphene Oxide Induced Perturbation to Plasma Membrane and Cytoskeletal Meshwork Sensitize Cancer Cells to Chemotherapeutic Agents.

    PubMed

    Zhu, Jianqiang; Xu, Ming; Gao, Ming; Zhang, Zhihong; Xu, Yong; Xia, Tian; Liu, Sijin

    2017-03-28

    The outstanding physicochemical properties endow graphene materials (e.g., graphene oxide, GO) with beneficial potentials in diverse biomedical fields such as bioimaging, drug delivery, and biomolecular detection. GO recently emerged as a chemosensitizer; however, the detailed molecular basis underlying GO-conducted sensitization and corresponding biological effects are still elusive. Based on our recent findings that GO treatment at sublethal concentrations could impair the general cellular priming state, including disorders of plasma membrane and cytoskeleton construction, we aimed here to explore the mechanism of GO as a sensitizer to make cancer cells more susceptible to chemotherapeutic agents. We discovered that GO could not only compromise plasma membrane and cytoskeleton in J774A.1 macrophages and A549 lung cancer cells at sublethal concentrations without incurring significant cell death but also dampen a number of biological processes. Using the toxicogenomics approaches, we laid out the gene expression signature affected by GO and further defined those genes involved in membrane and cytoskeletal impairments responding to GO. The mechanistic investigation uncovered that the interactions of GO-integrin occurred on the plasma membrane and consequently activated the integrin-FAK-Rho-ROCK pathway and suppressed the expression of integrin, resulting in compromised cell membrane and cytoskeleton and a subsequent cellular priming state. By making use of this mechanism, the efficacy of chemotherapeutic agents (e.g., doxorubicin and cisplatin) could be enhanced by GO pretreatment in killing cancer cells. This study unveiled a feature of GO in cancer therapeutics: sensitizing cancer cells to chemotherapeutic agents by undermining the resistance capability of tumor cells against chemotherapeutic agents, at least partially, by compromising plasma membrane and cytoskeleton meshwork.

  18. Noscapine and its Analogs as Chemotherapeutic Agent: Current updates.

    PubMed

    Tomar, Vartika; Kukreti, Shrikant; Prakash, Satya; Madan, Jitender; Chandra, Ramesh

    2017-01-01

    Recently, noscapine was reported as anticancer drug. Unlike, colchicine and podophyllotoxin, noscapine did not depolymerize microtubules even at stoichiometric concentrations but rather only mitigated their dynamics. Other microtubule-interacting chemotherapeutics, although quite effective, have therapy-limiting toxicities including immunosuppression and peripheral neuropathies. Recurrent cancers often become resistant. Noscapine however remains effective in some such instances, e.g., taxane-resistant ovarian cancer. Noscapine and analogs also do not show signs of neurotoxicity or immunosuppression. In addition, 9-bromo noscapine, Red-9-Br-Nos and other analogs were characterized for their structure and further studied in detail. On the other hand, noscapine was shown to be neuroprotective in mouse model of neurodegenerative disease and in stroke patients. Like low doses of colchicine, noscapine and its analog 9-Br-Noscapine also show anti-inflammatory activities. There are indications of a preventive use of noscapine in ischemiareperfusion injury and fibrosis. The entire biosynthetic pathway of noscapine is encoded as gene cluster within 401 kilo bases of genomic DNA, opening up opportunities for the large-scale biotechnological production of noscapine for medicinal needs. Thus, noscapine and its derivatives (noscapinoids) might be cost-effective and safe components for cancer chemotherapy. Owing to its low toxicity, it also might be useful for preventive use in high-risk situations. This brief review is an update of current research activity and patents on noscapine and its analogs.

  19. Assessment of the significance of mitochondrial DNA damage by chemotherapeutic agents.

    PubMed

    Lo, Soo; Tolner, Berend; Taanman, Jan-Willem; Cooper, J Mark; Gu, Mei; Hartley, John A; Schapira, Anthony H V; Hochhauser, Daniel

    2005-08-01

    The pathways which are activated following damage to nuclear DNA in cancer cells are well understood. There is evidence that treatment with several chemotherapeutic agents may result in damage to mitochondrial DNA. This study investigated the contribution of mitochondrial DNA to cytotoxicity of DNA-interactive agents. To understand the significance of drug interactions with mitochondrial DNA, we investigated A549 non-small cell lung cancer cell lines and their rho0 derivatives in which mitochondrial DNA has been eradicated. The parental cell line showed increased sensitivity to the anthracycline daunorubicin when compared with the A549 rho0 line. In addition, the A549 rho0 line was resistant to the rhodacyanine derivative, MKT-077, which has been shown to interact with mitochondrial DNA. Southern blotting demonstrated that MKT-077 mediated damage to mitochondrial but not nuclear DNA. Restoration of mitochondrial DNA by formation of cybrids restored sensitivity to these agents. The mitochondrial DNA damage, following treatment of A549 rho0 cells with MKT-077, resulted in G2 arrest which was not mediated by expression of p53. Mitochondrial DNA is a critical target for MKT-077 and daunorubicin, and is a potential target for novel chemotherapeutic agents.

  20. Synthesis and biological activity of NOSH-naproxen (AVT-219) and NOSH-sulindac (AVT-18A) as potent anti-inflammatory agents with chemotherapeutic potential

    PubMed Central

    Kodela, Ravinder; Chattopadhyay, Mitali; Kashfi, Khosrow

    2013-01-01

    Nitric oxide- (NO) and hydrogen sulfide- (H2S) releasing naproxen (NOSH-naproxen) and NO and H2S-releasing sulindac (NOSH-sulindac) were synthesized and their cell growth inhibitory properties were evaluated in four different human cancer cell lines. These cell lines are of adenomatous (colon, pancreas), epithelial (breast), and lymphocytic (leukemia) origin. Using HT-29 human colon cancer cells, NOSH-naproxen and NOSH-sulindac increased apoptosis, and inhibited proliferation. NOSH-naproxen caused a G0/G1 whereas NOSH-sulindac caused a G2/M block in the cell cycle. Both compounds exhibited significant anti-inflammatory properties, using the carrageenan rat paw edema model. Reconstitution and structure-activity studies representing a fairly close approximation to the intact molecule showed that NOSH-naproxen was approximately 8000-fold more potent than the sum of its parts in inhibiting cell growth. Our data suggest that these compounds merit further investigation as potential anti-cancer agents. PMID:24273639

  1. The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents.

    PubMed

    Yu, Yan; Xie, Yangchun; Cao, Lizhi; Yang, Liangchun; Yang, Minghua; Lotze, Michael T; Zeh, Herbert J; Kang, Rui; Tang, Daolin

    2015-01-01

    Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Development of resistance to chemotherapeutic agents is a major hurdle in the effective treatment of patients with AML. The quinazolinone derivative erastin was originally identified in a screen for small molecules that exhibit synthetic lethality with expression of the RAS oncogene. This lethality was subsequently shown to occur by induction of a novel form of cell death termed ferroptosis. In this study we demonstrate that erastin enhances the sensitivity of AML cells to chemotherapeutic agents in an RAS-independent manner. Erastin dose-dependently induced mixed types of cell death associated with ferroptosis, apoptosis, necroptosis, and autophagy in HL-60 cells (AML, NRAS_Q61L), but not Jurkat (acute T-cell leukemia, RAS wild type), THP-1 (AML, NRAS_G12D), K562 (chronic myelogenous leukemia, RAS wild type), or NB-4 (acute promyelocytic leukemia M3, KRAS_A18D) cells. Treatment with ferrostatin-1 (a potent ferroptosis inhibitor) or necrostatin-1 (a potent necroptosis inhibitor), but not with Z-VAD-FMK (a general caspase inhibitor) or chloroquine (a potent autophagy inhibitor), prevented erastin-induced growth inhibition in HL-60 cells. Moreover, inhibition of c-JUN N-terminal kinase and p38, but not of extracellular signal-regulated kinase activation, induced resistance to erastin in HL-60 cells. Importantly, low-dose erastin significantly enhanced the anticancer activity of 2 first-line chemotherapeutic drugs (cytarabine/ara-C and doxorubicin/adriamycin) in HL-60 cells. Collectively, the induction of ferroptosis and necroptosis contributed to erastin-induced growth inhibition and overcame drug resistance in AML cells.

  2. Some characteristics of activity of potential chemotherapeutics--benzimidazole derivatives.

    PubMed

    Błaszczak-Świątkiewicz, Katarzyna; Mikiciuk-Olasik, Elżbieta

    2015-03-01

    In this work, the biological activity of some benzimidazoles and benzimidazole-4,7-diones was compared. These two groups of compounds were evaluated as potential chemotherapeutics and their characteristic relationship structure to biological activity was discussed. The authors compared their effect into the cytotoxic, apoptosis and DNA destruction approach. Their cytotoxic effect on the human lung adenocarcinoma A549 cells line was determined by WST-1 test. Next the cytotoxic way of tumor cells death was determined by caspase 3/7 test. The last point referred to the DNA destruction of A549 cells and test in situ DNA Assay Kit was applied. Two of the examined compounds (B2 and D2) show a very good correlation of the cytotoxic effect normoxia to hypoxia and they have been found as the potential agents of the DNA damage. The most cytotoxic feature possesses N-oxide benzimidazole derivatives (D and B groups). The screening test of the DNA damage established that N-oxide benzimidazole derivatives (D and B groups) can be more potent as the hypoxia-selective agents for tumor cells than benzimidazole derivatives (A and C groups). Additionally, the test of the caspase-dependent apoptosis proved that the exposure of benzimidazole-4,7-diones against A549 cells, especially in hypoxia, promotes apoptotic cell death.

  3. 2,3-DIPHENYL-1,4-NAPHTHOQUINONE: A POTENTIAL CHEMOTHERAPEUTIC AGENT AGAINST TRYPANOSOMA CRUZI

    PubMed Central

    Ramos, Enrique I.; Garza, Kristine M.; Krauth-Siegel, R. L.; Bader, Julia; Martinez, Luiz E.; Maldonado, Rosa A.

    2010-01-01

    Chagas disease, caused by Trypanosoma cruzi, is a wide spread infection in Latin America. Currently, only 2 partially effective and highly toxic drugs, i.e., benznidazole and nifurtimox, are available for the treatment of this disease and several efforts are underway in the search for better chemotherapeutic agents. Here, we have determined the trypanocidal activity of 2,3-diphenyl-1,4-naphthoquinone (DPNQ), a novel quinone derivative. In vitro, DPNQ was highly cytotoxic at a low, micromolar concentration (LD50 = 2.5 μM) against epimastigote, cell-derived trypomastigote, and intracellular amastigote forms of T. cruzi, but not against mammalian cells (LD50 = 130 μM). In vivo studies on the murine model of Chagas disease revealed that DPNQ-treated animals (3 doses of 10 mg/kg/day) showed a significant delay in parasitemia peak and higher (up to 60%) survival rate 70 days post-infection, when compared to control group (infected, untreated). We also observed a 2-fold decrease in the parasitemia between the control group (infected, untreated) and the treated group (infected, treated). No apparent drug toxicity effects were noticed in the control group (uninfected, treated). In addition, we determined that DPNQ is the first competitive inhibitor of T. cruzi lipoamide dehydrogenase (TcLipDH) thus far described. Our results indicate that DPNQ is a promising chemotherapeutic agent against T. cruzi. PMID:18788881

  4. [The sensitivity of anaerobic bacteria to chemotherapeutic agents (Zurich, 1991)].

    PubMed

    Wüst, J; Hardegger, U

    1991-12-27

    There have been numerous reports on resistance of anaerobic bacteria against antimicrobial agents. Therefore, to assess the situation in Zurich, 187 anaerobic strains of various bacterial genera, isolated from clinical specimens during winter 1990/91, were tested for their susceptibility to antimicrobial agents active against anaerobic bacteria. Besides the Bacteroides fragilis group, which is naturally resistant against penicillin, 30% of isolates of other Bacteroides species were also resistant against penicillin. In general, anaerobes have remained susceptible to cefoxitin, chloramphenicol, clindamycin, imipenem, the 5-nitroimidazoles (metronidazole, ornidazole) as well as combinations of beta-lactam antibiotics with beta-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam). Because rare strains resistant against cefoxitin, clindamycin and beta-lactams plus beta-lactamase inhibitors can be found, at least isolates from specific clinical situations should be tested for antimicrobial susceptibility. These are strains isolated from patients with brain abscess, endocarditis, osteomyelitis, arthritis, infected implants and prosthesis as well as those from persisting or recurrent bacteremia. Because the agar diffusion test yields unreliable results, minimal inhibitory concentration should be determined. Maybe the new 'E test' or the spiral gradient procedure can be used after evaluation.

  5. Nobiletin enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cancer cells

    PubMed Central

    Ma, Wenzhe; Feng, Senling; Yao, Xiaojun; Yuan, Zhongwen; Liu, Liang; Xie, Ying

    2015-01-01

    Multidrug resistance (MDR) is the major obstacle to the successful chemotherapy treatment of many cancers. Here we found that nobiletin, a citrus methoxyflavone, significantly sensitized ABCB1 overexpressing cells A2780/T and A549/T to chemotherapeutic agents such as paclitaxel (a 433-fold reversal of MDR to PTX at 9 μM), doxorubicin (DOX), docetaxel and dounorubicin. Nobiletin profoundly inhibited ABCB1 transporter activity since it significantly increased the intracellular accumulation of DOX and Flutax-2 in A2780/T cells and decreased the efflux of ABCB1 substrates in Caco2 cells without altering the mRNA and protein expression of ABCB1. Moreover, nobiletin stimulated ATPase activity and inhibited verapamil-stimulated ATPase activity in a concentration-dependent manner, indicating a direct interaction with the transporter. Consistent with these findings, molecular docking analysis also identified favorable binding of nobiletin with the transmemberane region site 1 of homology modeled human ABCB1 transporter. Moreover, the Nrf2 protein expression and phosphorylation levels of AKT/ERK were suppressed by co-treated with nobiletin and PTX at the reversal concentrations, suggesting that inhibition of the AKT/ERK/Nrf2 pathway was associated with the sensitizing effect of nobiletin. These findings encourage further animal and clinical MDR studies with the combination therapy of nobiletin and chemotherapeutic drugs. PMID:26689156

  6. Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment

    PubMed Central

    Kang, Lin; Gao, Zhonggao; Huang, Wei; Jin, Mingji; Wang, Qiming

    2015-01-01

    The efficacy of chemotherapeutic drug in cancer treatment is often hampered by drug resistance of tumor cells, which is usually caused by abnormal gene expression. RNA interference mediated by siRNA and miRNA can selectively knock down the carcinogenic genes by targeting specific mRNAs. Therefore, combining chemotherapeutic drugs with gene agents could be a promising strategy for cancer therapy. Due to poor stability and solubility associated with gene agents and drugs, suitable protective carriers are needed and have been widely researched for the co-delivery. In this review, we summarize the most commonly used nanocarriers for co-delivery of chemotherapeutic drugs and gene agents, as well as the advances in co-delivery systems. PMID:26579443

  7. Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.

    PubMed

    Pace, Jennifer R; DeBerardinis, Albert M; Sail, Vibhavari; Tacheva-Grigorova, Silvia K; Chan, Kelly A; Tran, Raymond; Raccuia, Daniel S; Wechsler-Reya, Robert J; Hadden, M Kyle

    2016-04-28

    Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.

  8. Inhibition of HIV replication in vitro by clinical immunosuppressants and chemotherapeutic agents

    PubMed Central

    2013-01-01

    Background Recent studies have suggested that a functional cure for HIV-1 infection, purportedly resultant from allogeneic bone marrow transplantation, may be possible. Additionally, the first such patient was treated with whole-body irradiation, immunosuppressants, and the chemotherapeutic, cytarabine. However, the precise role of the coinciding medical interventions in diminishing detectable HIV reservoirs remains unstudied. Findings In this article, we demonstrate that the immunosuppressants, mycophenolic acid and cyclosporine, and the chemotherapeutic, cytarabine, are potent antiretroviral agents at clinically relevant dosages. These drugs strongly inhibit HIV-1 replication in a GFP indicator T cell line and peripheral blood mononuclear cells (PBMC). Conclusions Our study suggests that certain clinical immunosuppressants and chemotherapeutic agents may act combinatorially to inhibit HIV infection. Additionally, chemotherapy-mediated cytotoxicity may also affect the stability of viral reservoirs. Thus, further study is needed to examine potential therapeutic value of these interventions in patients. PMID:23672887

  9. Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach.

    PubMed

    Lee, Kuo-Hsiung

    2010-03-26

    Medicinal plants have long been an excellent source of pharmaceutical agents. Accordingly, the long-term objectives of the author's research program are to discover and design new chemotherapeutic agents based on plant-derived compound leads by using a medicinal chemistry approach, which is a combination of chemistry and biology. Different examples of promising bioactive natural products and their synthetic analogues, including sesquiterpene lactones, quassinoids, naphthoquinones, phenylquinolones, dithiophenediones, neo-tanshinlactone, tylophorine, suksdorfin, DCK, and DCP, will be presented with respect to their discovery and preclinical development as potential clinical trial candidates. Research approaches include bioactivity- or mechanism of action-directed isolation and characterization of active compounds, rational drug design-based modification and analogue synthesis, and structure-activity relationship and mechanism of action studies. Current clinical trial agents discovered by the Natural Products Research Laboratories, University of North Carolina, include bevirimat (dimethyl succinyl betulinic acid), which is now in phase IIb trials for treating AIDS. Bevirimat is also the first in a new class of HIV drug candidates called "maturation inhibitors". In addition, an etoposide analogue, GL-331, progressed to anticancer phase II clinical trials, and the curcumin analogue JC-9 is in phase II clinical trials for treating acne and in development for trials against prostate cancer. The discovery and development of these clinical trial candidates will also be discussed.

  10. Effects of St. John’s Wort and Vitamin E on Breast Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2002-05-01

    Johns wort may decrease peak levels of doxorubicin. Further studies will help to determine whether important interactions occur between these nutrients and cancer chemotherapeutic agents....doxorubicin. Our studies suggest that even relatively high doses of vitamin E do not adversely affect the toxicity of doxorubicin. On the other hand, St

  11. [Experience with vaginal suppositories containing chemotherapeutic agents (author's transl)].

    PubMed

    Török, J; Kószó, E; Altmayer, P; Mezey, G

    1981-01-01

    The authors determined the release of chloramphenicol, oxytetracycline, neomycin and sulphadimidine from different bases (polyoxethene mass, solid fat, 95% solid fat +5% Span 20). The diffusion of chloramphenicol and sulphadimidine was best from hydrophilic bases; that of oxytetracycline and neomycin, from emulsifier-containing lipophil bases. This may be explained by the solubilities of the pharmaca and by interactions between base and active substance.

  12. Synergistic interaction of telomerase-specific oncolytic virotherapy and chemotherapeutic agents for human cancer.

    PubMed

    Fujiwara, Toshiyoshi; Kagawa, Shunsuke; Tazawa, Hiroshi

    2012-07-01

    Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis through the maintenance of telomeres, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector, in which the hTERT promoter element drives expression of E1 genes, OBP-301 (Telomelysin). Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. OBP-301 alone exhibited substantial antitumor effects both in animal models and in clinical trials; data regarding combination therapy with OBP-301 and chemotherapeutic agents are preliminary but encouraging. This article reviews synergistic interaction of virotherapy and chemotherapy, and illustrates the potential application for the treatment of human cancer.

  13. Dacarbazine in melanoma: from a chemotherapeutic drug to an immunomodulating agent.

    PubMed

    Ugurel, Selma; Paschen, Annette; Becker, Jürgen C

    2013-02-01

    Chemotherapeutic drugs are clinically used to treat cancer because of their cytotoxic activities against tumor cells. Recently, however, evidence is accumulating-including the report of Hervieu et al. (2012) in the current issue of The Journal of Investigative Dermatology-indicating that at least some of these drugs have broader activities and that they should also be considered immunomodulatory agents. Indeed, Hervieu demonstrates that dacarbazine (DTIC) exerts immunostimulatory effects by inducing local activation of natural killer (NK) and T cells, suggesting that upon treatment with DTIC, the tumor participates in the initiation of an immune response: (i) DTIC treatment elicits the expression of ligands of the immunoreceptor NKG2D on melanoma cells; (ii) engagement of the ligands by NKG2D on NK cells leads to their activation, allowing enhanced tumor-cell killing and the release of IFN-γ; and (iii) IFN-γ in turn upregulates major histocompatibility complex class I expression on tumor cells, which favors their recognition by cytotoxic CD8+ T lymphocytes (CTLs).

  14. Identification of plumbagin and sanguinarine as effective chemotherapeutic agents for treatment of schistosomiasis☆

    PubMed Central

    Zhang, Si-Ming; Coultas, Kristen A.

    2012-01-01

    Schistosomiasis, a snail-borne parasitic disease, affects more than 200 million people worldwide. Currently the treatment of schistosomiasis relies on a single therapy of praziquantel, a drug developed over 30 years ago. Thus, there is an urgent need to develop alternative antischistosomal drugs. In the pursuit of novel antischistosomal drugs, we examined the antischistosomal activities of 45 compounds that had been reported to exhibit antimicrobial and/or antiparasitic activities. Two plant-derived compounds, plumbagin and sanguinarine, were found to possess potent antischistosomal activities in vitro. For both the compounds, a concentration of 10 μM (equivalent to 1.88 μg/ml for plumbagin and 3.68 μg/ml for sanguinarine) resulted in 100% mortality at 48 h, which meets the World Health Organization’s (WHO) criterion of “hit” compounds for the control of schistosomiasis. Morphological changes and tegumental alterations of the dead worms treated by the two compounds were quite different. The significant morphological changes of worms after treatment by the two compounds suggest the two compounds target different biological pathways, both of which result in parasite’s death. This study provides evidence to suggest plumbagin and sanguinarine have real potential as effective alternative chemotherapeutic agents for the treatment of schistosomiasis. PMID:23641325

  15. Chemosensitization of Breast Cancer Cells to Chemotherapeutic Agents by 3,3’diindolylmethane (DIM)

    DTIC Science & Technology

    2006-08-01

    carbinol protects against covalent binding of benzo [ a ] pyrene and N -nitrosodimethylamine metabolites to mouse liver macromolecules. Chem Biol Interact...TκB has been reported to play a role in de novo resistance of cancer cells to chemotherapeutic agents, which is a major cause for treatment failure in... cancer chemotherapy. Previous studies have shown that 3,3’-diindolylmethane (DIM), a major in vivo acid- catalyzed condensation product of Indole-3

  16. Genome-Wide Mutational Signature of the Chemotherapeutic Agent Mitomycin C in Caenorhabditis elegans.

    PubMed

    Tam, Annie S; Chu, Jeffrey S C; Rose, Ann M

    2015-11-12

    Cancer therapy largely depends on chemotherapeutic agents that generate DNA lesions. However, our understanding of the nature of the resulting lesions as well as the mutational profiles of these chemotherapeutic agents is limited. Among these lesions, DNA interstrand crosslinks are among the more toxic types of DNA damage. Here, we have characterized the mutational spectrum of the commonly used DNA interstrand crosslinking agent mitomycin C (MMC). Using a combination of genetic mapping, whole genome sequencing, and genomic analysis, we have identified and confirmed several genomic lesions linked to MMC-induced DNA damage in Caenorhabditis elegans. Our data indicate that MMC predominantly causes deletions, with a 5'-CpG-3' sequence context prevalent in the deleted regions of DNA. Furthermore, we identified microhomology flanking the deletion junctions, indicative of DNA repair via nonhomologous end joining. Based on these results, we propose a general repair mechanism that is likely to be involved in the biological response to this highly toxic agent. In conclusion, the systematic study we have described provides insight into potential sequence specificity of MMC with DNA.

  17. The chemotherapeutic agent paclitaxel selectively impairs learning while sparing source memory and spatial memory.

    PubMed

    Smith, Alexandra E; Slivicki, Richard A; Hohmann, Andrea G; Crystal, Jonathon D

    2017-03-01

    Chemotherapeutic agents are widely used to treat patients with systemic cancer. The efficacy of these therapies is undermined by their adverse side-effect profiles such as cognitive deficits that have a negative impact on the quality of life of cancer survivors. Cognitive side effects occur across a variety of domains, including memory, executive function, and processing speed. Such impairments are exacerbated under cognitive challenges and a subgroup of patients experience long-term impairments. Episodic memory in rats can be examined using a source memory task. In the current study, rats received paclitaxel, a taxane-derived chemotherapeutic agent, and learning and memory functioning was examined using the source memory task. Treatment with paclitaxel did not impair spatial and episodic memory, and paclitaxel treated rats were not more susceptible to cognitive challenges. Under conditions in which memory was not impaired, paclitaxel treatment impaired learning of new rules, documenting a decreased sensitivity to changes in experimental contingencies. These findings provide new information on the nature of cancer chemotherapy-induced cognitive impairments, particularly regarding the incongruent vulnerability of episodic memory and new learning following treatment with paclitaxel.

  18. Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

    SciTech Connect

    Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.; Conn, Charlotte E.; Kimpton, Kathleen; Waddington, Lynne J.; Krodkiewska, Irena; Drummond, Calum J.

    2014-09-24

    We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

  19. Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

    NASA Astrophysics Data System (ADS)

    Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.; Conn, Charlotte E.; Kimpton, Kathleen; Waddington, Lynne J.; Krodkiewska, Irena; Drummond, Calum J.

    2011-03-01

    We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

  20. Interactions of human leukocyte interferon with vinca alkaloids and other chemotherapeutic agents against human tumors in clonogenic assay.

    PubMed

    Aapro, M S; Alberts, D S; Salmon, S E

    1983-01-01

    Purified human leukocyte interferon produced by recombinant techniques (IFN-alpha A) was tested in vitro with chemotherapeutic drugs, vinblastine (VLB), vincristine (VCR), vindesine (VDS), vinzolidine (VZL), cis-platinum (PLAT), doxorubicin (DOXO), etoposide (VP-16), and melphalan (MEL). The activity of these agents alone or in combination was tested against various human tumor cell lines, using a modified soft agar clonogenic assay. Three human tumor cell lines (myeloma, RPMI 8226; breast, MCF-7; and colon, WiDR) showed sensitivity to these agents at clinically achievable drug concentrations. Statistically significant synergistic activity against in vitro colony formation was observed with the combination of VLB and IFN-alpha A. An additive or sub-additive effect was usually observed with the other agents tested. Continuous exposure of the 8226 myeloma cell line to both IFN-alpha A and PLAT showed evidence of a more significant potentiation. It is hypothesized that the synergistic effect observed between VLB and IFN-alpha A is due to some of their common mechanisms of action.

  1. High-frequency induction of chromosomal rearrangements in mouse germ cells by the chemotherapeutic agent chlorambucil.

    PubMed

    Rinchik, E M; Flaherty, L; Russell, L B

    1993-12-01

    Recent mutagenesis studies have demonstrated that the chemotherapeutic agent, chlorambucil (CHL), is highly mutagenic in male germ cells of the mouse. Post-meiotic germ cells, and especially early spermatids, are the most sensitive to the cytotoxic and mutagenic effects of this agent. Genetic, cytogenetic and molecular analyses of many induced mutations have shown that, in these germ-cell stages, CHL induces predominantly chromosomal rearrangements (deletions and translocations), and mutation-rate studies show that, in terms of tolerated doses, CHL is perhaps five to ten times more efficient in inducing rearrangements than is radiation exposure. Appropriate breeding protocols, along with knowledge of the advantages and limitations associated with the use of CHL, can be used to expand the current resource of chromosomal rearrangements in the mouse and to provide new phenotype-associated mutations amenable to positional-cloning techniques. The analysis of CHL-induced mutations has also contributed to understanding the factors that affect the yield and nature of chemically induced germline mutations in mammals.

  2. Treatment of cancer using pulsed electric field in combination with chemotherapeutic agents or genes.

    PubMed

    Nishi, T; Dev, S B; Yoshizato, K; Kuratsu, J; Ushio, Y

    1997-03-01

    Electroporation is a standard laboratory technique originally developed for in vitro transfer of molecules into cells. It involves application of electrical pulses ranging from micro- to milliseconds that create transient pores in the cell membrane allowing intracellular access of exogenous molecules. This technique has been successfully applied to regress tumors in animal models by combining electroporation with chemotherapeutic agents--a process known as electrochemotherapy (ECT) which substantially enhance cytotoxicity of some antineoplastic agents. Recently ECT has moved into clinical arena and patients with cutaneous tumors and head and neck cancers have been treated very effectively with ECT. Parallel to ECT, a technique has also been developed which makes it possible to inject plasmid DNA and combine it with in vivo electroporation--electro--genetherapy (EGT)--to deliver in a highly efficient manner both marker and functional genes into target tissue and achieve gene expression. Thus, in vivo electroporation is contributing to the development of a new strategy for cancer treatment with both drugs and genes.

  3. Long-term consequences of chemotherapeutic agents on hematopoiesis: development of altered radiation tolerance.

    PubMed

    Kovacs, C J; Evans, M J; Hooker, J L; Johnke, R M

    1988-01-01

    The long-term effects of chemotherapeutic agents on subsequent radiation tolerance of the hematopoietic marrow were studied after a single injection of doxorubicin, 5-fluorouracil, or cyclophosphamide at a maximum tolerated dose. At designated intervals following drug treatment, drug-treated and age-matched control male B6D2F1 mice were exposed to 4.5 Gy of total-body irradiation, and the recovery kinetics of the stem cell (assayed at days 8 and 13 colony-forming spleen units) and progenitor (burst-forming erythroid units, and colony-forming erythroid and granulocyte/macrophage units) compartments were established. Response deficits were calculated for each compartment by comparison of treated and control recovery curves at 5 intervals over 32 weeks. Based on these response deficits, a number of conclusions were drawn: 1) There is selective drug specificity for the more primitive (13d) and mature (8d) CFUs subpopulations; 2) these sensitivities determine the temporal consequences of drug treatment on subsequent radiation tolerance in the marrow (e.g., acute, delayed, or long term); and 3) drugs that influence long-term radiation tolerance of the marrow are dose dependent and initially affect the more primitive stem cells. The data suggest that the initial lesion in the stem cell compartment, resulting in long-term enhancement of radiosensitivity, involves a major restriction (either in cell number or in genetic functionality) of the proliferative potential necessary for recovery from subsequent radiation insult.

  4. Synergistic Anticancer Effect of Tocotrienol Combined with Chemotherapeutic Agents or Dietary Components: A Review

    PubMed Central

    Eitsuka, Takahiro; Tatewaki, Naoto; Nishida, Hiroshi; Nakagawa, Kiyotaka; Miyazawa, Teruo

    2016-01-01

    Tocotrienol (T3), unsaturated vitamin E, is gaining a lot of attention owing to its potent anticancer effect, since its efficacy is much greater than that of tocopherol (Toc). Various factors are known to be involved in such antitumor action, including cell cycle arrest, apoptosis induction, antiangiogenesis, anti-metastasis, nuclear factor-κB suppression, and telomerase inhibition. Owing to a difference in the affinity of T3 and Toc for the α-tocopherol transfer protein, the bioavailability of orally ingested T3 is lower than that of Toc. Furthermore, cellular uptake of T3 is interrupted by coadministration of α-Toc in vitro and in vivo. Based on this, several studies are in progress to screen for molecules that can synergize with T3 in order to augment its potency. Combinations of T3 with chemotherapeutic drugs (e.g., statins, celecoxib, and gefitinib) or dietary components (e.g., polyphenols, sesamin, and ferulic acid) exhibit synergistic actions on cancer cell growth and signaling pathways. In this review, we summarize the current status of synergistic effects of T3 and an array of agents on cancer cells, and discuss their molecular mechanisms of action. These combination strategies would encourage further investigation and application in cancer prevention and therapy. PMID:27669218

  5. Antinuclear antibodies with nucleosome-restricted specificity for targeted delivery of chemotherapeutic agents.

    PubMed

    Torchilin, Vladimir P

    2010-08-01

    Circulating antinuclear autoantibodies (ANAs) are well known to accompany various pathological conditions and can be artificially induced by immunization. Research and clinical data permit us to hypothesize a definite connection between cancer and ANAs. Based on the available data, my group's research suggested that exogenous ANAs may be used as anticancer therapeutics. Among these ANAs, nucleosome-specific ANAs may be particularly useful. Advances in cancer immunotherapy with monoclonal antibodies re-emphasized the role of humoral immunity in neoplasia control. The development of a universal antibody targeting diverse cancers is of clear importance. We showed that certain natural ANAs recognize the surface of numerous tumor cells but not normal cells via cell surface-bound nucleosomes originating from the apoptotically dying neighboring tumor cells, mediate antibody-dependent cellular cytotoxicity of tumor cells in vitro and inhibit the development of murine tumor in syngeneic mice. A single monoclonal antinuclear nucleosome-specific autoantibody, mAb 2C5, specifically recognizes multiple unrelated human tumor cell lines and accumulates at a high tumor-to-normal cell ratio in various human tumors in nude mice. Immunotherapy with mAb 2C5 resulted in significant suppression of the growth of several human tumors. In addition, mAb 2C5, when used in subtherapeutic quantities, can serve as a highly efficient specific ligand to target various drug- or diagnostic agent-loaded pharmaceutical nanocarriers, such as liposomes and polymeric micelles, to various tumors. Here, the data (accumulated predominantly in our laboratory over several years) on mAb 2C5-mediated tumor targeting of chemotherapeutic agents is reviewed.

  6. Repurposing the FDA-Approved Pinworm Drug Pyrvinium as a Novel Chemotherapeutic Agent for Intestinal Polyposis

    PubMed Central

    Giambelli, Camilla; Fei, Dennis Liang; Han, Lu; Hang, Brian I.; Bai, Feng; Pei, Xin-Hai; Nose, Vania; Burlingame, Oname; Capobianco, Anthony J.; Orton, Darren; Lee, Ethan; Robbins, David J.

    2014-01-01

    Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes. PMID:25003333

  7. Improved Chemotherapeutic Activity by Morus alba Fruits through Immune Response of Toll-Like Receptor 4

    PubMed Central

    Chang, Bo Yoon; Kim, Seon Beom; Lee, Mi Kyeong; Park, Hyun; Kim, Sung Yeon

    2015-01-01

    Morus alba L. fruits have long been used in traditional medicine by many cultures. Their medicinal attributes include cardiovascular, hepatoprotective, neuroprotective and immunomodulatory actions. However, their mechanism of macrophage activation and anti-cancer effects remain unclear. The present study investigated the molecular mechanisms of immune stimulation and improved chemotherapeutic effect of M. alba L. fruit extract (MFE). MFE stimulated the production of cytokines, nitric oxide (NO) and tumor necrosis factor-α (TNF-α) and tumoricidal properties of macrophages. MFE activated macrophages through the mitogen-activated protein kinase (MAPKinase) and nuclear factor-κB (NF-κB) signaling pathways downstream from toll-like receptor (TLR) 4. MFE was shown to exhibit cytotoxicity of CT26 cells via the activated macrophages, even though MFE did not directly affect CT26 cells. In a xenograft mouse model, MFE significantly enhanced anti-cancer activity combined with 5-fluorouracil and markedly promoted splenocyte proliferation, natural killer (NK) cell activity, cytotoxic T lymphocyte (CTL) activity and IFN-γ production. Immunoglobulin G (IgG) antibody levels were significantly increased. These results indicate the indirect anti-cancer activity of MFE through improved immune response mediated by TLR4 signaling. M. alba L. fruit extract might be a potential anti-tumor immunomodulatory candidate chemotherapy agent. PMID:26473845

  8. Tissue levels of chemotherapeutic agents for hepatic metastasis during hepatic arterial and portal injection.

    PubMed

    Kaneko, A; Naomoto, Y; Aoyama, M; Tanaka, N

    1999-01-01

    Hepatic metastasis is one of the most important prognostic factors in digestive organ cancer, and hepatic arterial infusion is aggressively performed for therapy of nonresectable metastatic liver cancer. Although comparatively high response rates have been attained in some cases, this treatment has been ineffective in not a few cases because these metastatic tumors are frequently hypovascular in nature. To develop better methods of administering chemotherapeutic agents, we performed basic experiments concerning intraportal administration which has been regarded as having a generally negative effect, focusing on a report indicating that portal supply is dominant along the borders of metastatic liver cancer tumors. VX2 carcinoma cells were inoculated into the hepatic parenchyma beneath the capsule of juvenile Japanese white rabbits. Drugs were infused 2 weeks after the inoculation, then tissue and blood were sequentially sampled. Mitomycin C (1.7 mg/kg) was infused either by bolus injection to the hepatic artery (arterial infusion group) or by bolus injection to the portal vein (portal infusion group). Five-fluorouracil (9.5 mg/kg) and Cisplatin (1.6 mg/kg) were likewise infused continuously over 60 min, and tissue levels of the drugs were compared between the two groups. Mitomycin C and 5-fluorouracil levels were measured by HPLC and Cisplatin levels were measured by atomic absorption spectrophotometry. As a result, the levels of every drug in VX2 tumor tissue did not significantly differ between the arterial infusion group and the portal infusion group, while the levels were significantly higher than those in the intravenous infusion group. Using portal infusion, we observed a drug transition which was not inferior to that of arterial infusion, suggesting that an imported antitumoral effect may be obtained with this method compared with intravenous infusion.

  9. Chemotherapeutic agent CPT-11 eliminates peritoneal resident macrophages by inducing apoptosis.

    PubMed

    Huang, Mei-Yun; Pan, Hao; Liang, Yi-Dan; Wei, Hong-Xia; Xu, Li-Hui; Zha, Qing-Bing; He, Xian-Hui; Ouyang, Dong-Yun

    2016-02-01

    CPT-11 (Irinotecan) is a first-line chemotherapeutic agent in clinic, but it may induce side effects including diarrhea and enteritis in patients. The underlying mechanism of CPT-11's intestinal toxicity is unclear. Peritoneal resident macrophages have been reported to be important for the maintenance of intestinal homeostasis. In this study, we evaluated the cytotoxic effects of CPT-11 on mouse peritoneal resident macrophages. CPT-11 was administered intraperitoneally to mice and their peritoneal exudate cells were isolated for evaluation. CPT-11 treatment strikingly decreased the ratio of F4/80(hi)MHCII(low) large peritoneal macrophages (LPMs), which are regarded as prenatally-originated peritoneal resident macrophages. Consistent with this, the transcription factor GATA6 specifically expressed in LPMs was barely detectable in the macrophages from CPT-11-treated mice, indicative of elimination of LPMs. Such elimination of LPMs was at least partly due to CPT-induced apoptosis in macrophages, because inhibition of apoptosis by caspase-3 inhibitor z-DEVD-fmk significantly diminished the loss of GATA6(+) LPMs. As GATA6 is a transcription factor that controls expression of multiple genes regulating peritoneal B-1 cell development and translocation, elimination of GATA6(+) LPMs led to a great reduction in B-1 cells in the peritoneal cavity after CPT-11 treatment. These results indicated that CPT-11-induced apoptosis contributed to the elimination of peritoneal resident macrophages, which might in turn impair the function of peritoneal B-1 cells in maintaining intestinal homeostasis. Our findings may at least partly explain why CPT-11 treatment in cancer patients induces diarrhea and enteritis, which may provide a novel avenue to prevent such side effects.

  10. CHEMICAL AGENTS IN NEOPLASTIC DISEASES—An Evaluation of Chemotherapeutic Substances for Clinical Management

    PubMed Central

    Bierman, Howard R.

    1953-01-01

    The rapid appearance of many new chemical substances which possess some antineoplastic effects has created a complex problem for the practicing physician. These agents which have shown promise in man and lower animals are grouped according to their modes of action. Each substance is discussed thoroughly with regard to its structure, activity, and influence upon the neoplasms of man. Key references are cited, and the practical value of each chemical agent is defined. The proper methods of administration of the compounds recommended for use are carefully described. In addition a section on agents whose therapeutic value has been disproven is also included. ImagesFigure 1. PMID:13009518

  11. Combination of conventional chemotherapeutics with redox-active cerium oxide nanoparticles--a novel aspect in cancer therapy.

    PubMed

    Sack, Maren; Alili, Lirija; Karaman, Elif; Das, Soumen; Gupta, Ankur; Seal, Sudipta; Brenneisen, Peter

    2014-07-01

    Nanotechnology is becoming an important field of biomedical and clinical research and the application of nanoparticles in disease may offer promising advances in treatment of many diseases, especially cancer. Malignant melanoma is one of the most aggressive forms of cancer and its incidence is rapidly increasing. Redox-active cerium oxide nanoparticles (CNP) are known to exhibit significant antitumor activity in cells derived from human skin tumors in vitro and in vivo, whereas CNP is nontoxic and beyond that even protective (antioxidative) in normal, healthy cells of the skin. As the application of conventional chemotherapeutics is associated with harmful side effects on healthy cells and tissues, the clinical use is restricted. In this study, we addressed the question of whether CNP supplement a classical chemotherapy, thereby enhancing its efficiency without additional damage to normal cells. The anthracycline doxorubicin, one of the most effective cancer drugs, was chosen as reference for a classical chemotherapeutic agent in this study. Herein, we show that CNP enhance the antitumor activity of doxorubicin in human melanoma cells. Synergistic effects on cytotoxicity, reactive oxygen species generation, and oxidative damage in tumor cells were observed after co-incubation. In contrast to doxorubicin, CNP do not cause DNA damage and even protect human dermal fibroblasts from doxorubicin-induced cytotoxicity. A combination of classical chemotherapeutics with nongenotoxic but antitumor active CNP may provide a new strategy against cancer by improving therapeutic outcome and benefit for patients.

  12. Plasma and cerebrospinal fluid pharmacokinetics of select chemotherapeutic agents following intranasal delivery in a non-human primate model.

    PubMed

    League-Pascual, James C; Lester-McCully, Cynthia M; Shandilya, Shaefali; Ronner, Lukas; Rodgers, Louis; Cruz, Rafael; Peer, Cody J; Figg, William D; Warren, Katherine E

    2017-03-13

    The blood-brain barrier (BBB) limits entry of most chemotherapeutic agents into the CNS, resulting in inadequate exposure within CNS tumor tissue. Intranasal administration is a proposed means of delivery that can bypass the BBB, potentially resulting in more effective chemotherapeutic exposure at the tumor site. The objective of this study was to evaluate the feasibility and pharmacokinetics (plasma and CSF) of intranasal delivery using select chemotherapeutic agents in a non-human primate (NHP) model. Three chemotherapeutic agents with known differences in CNS penetration were selected for intranasal administration in a NHP model to determine proof of principle of CNS delivery, assess tolerability and feasibility, and to evaluate whether certain drug characteristics were associated with increased CNS exposure. Intravenous (IV) temozolomide (TMZ), oral (PO) valproic acid, and PO perifosine were administered to adult male rhesus macaques. The animals received a single dose of each agent systemically and intranasally in separate experiments, with each animal acting as his own control. The dose of the agents administered systemically was the human equivalent of a clinically appropriate dose, while the intranasal dose was the maximum achievable dose based on the volume limitation of 1 mL. Multiple serial paired plasma and CSF samples were collected and quantified using a validated uHPLC/tandem mass spectrometry assay after each drug administration. Pharmacokinetic parameters were estimated using non-compartmental analysis. CSF penetration was calculated from the ratio of areas under the concentration-time curves for CSF and plasma (AUCCSF:plasma). Intranasal administration was feasible and tolerable for all agents with no significant toxicities observed. For TMZ, the degrees of CSF drug penetration after intranasal and IV administration were 36 (32-57) and 22 (20-41)%, respectively. Although maximum TMZ drug concentration in the CSF (Cmax) was lower after intranasal

  13. Noscapine, a benzylisoquinoline alkaloid, sensitizes leukemic cells to chemotherapeutic agents and cytokines by modulating the NF-kappaB signaling pathway.

    PubMed

    Sung, Bokyung; Ahn, Kwang Seok; Aggarwal, Bharat B

    2010-04-15

    Noscapine, a benzylisoquinoline alkaloid derived from opium, was recently reported to exhibit activity against a variety of cancers through a poorly understood mechanism. Because the transcription factor NF-kappaB has been linked with inflammation, survival, proliferation, invasion, and angiogenesis in tumors, we hypothesized that noscapine mediates its effects by modulating the NF-kappaB activation pathway. We found that noscapine potentiates apoptosis induced by cytokines and chemotherapeutic agents in tumor cells. Noscapine alone suppressed proliferation of human leukemia and myeloma cells and downregulated the constitutive expression of cell survival proteins. Noscapine also abrogated the inducible expression of proteins involved in survival, proliferation, invasion, and angiogenesis, all of which are regulated by NF-kappaB. Noscapine suppressed both inducible and constitutive NF-kappaB activation in tumor cells through inhibition of IkappaB kinase, leading to inhibition of phosphorylation and degradation of IkappaBalpha. Noscapine also suppressed phosphorylation and nuclear translocation of p65, leading to inhibition of NF-kappaB reporter activity induced by various components of the NF-kappaB activation pathway. Activity of the NF-kappaB-containing cyclooxygenase-2 promoter was also inhibited by noscapine. Thus, noscapine inhibits the proliferation of leukemia cells and sensitizes them to tumor necrosis factor and chemotherapeutic agents by suppressing the NF-kappaB signaling pathway.

  14. Nanocarrier mediated Delivery of siRNA/miRNA in Combination with Chemotherapeutic Agents for Cancer Therapy: Current Progress and Advances

    PubMed Central

    Gandhi, Nishant S.; Tekade, Rakesh K.; Chougule, Mahavir B.

    2014-01-01

    Chemotherapeutic agents have certain limitations when it comes to treating cancer, the most important being severe side effects along with multidrug resistance developed against them. Tumor cells exhibits drug resistance due to activation of various cellular level processes viz. activation of drug efflux pumps, anti-apoptotic defense mechanisms etc. Currently, RNA interference (RNAi) based therapeutic approaches are under vibrant scrutinization to seek cancer cure. Especially small interfering RNA (siRNA) and micro RNA (miRNA), are able to knock down the carcinogenic genes by targeting the mRNA expression, which underlies the uniqueness of this therapeutic approach. Recent research focus in the regime of cancer therapy involves the engagement of targeted delivery of siRNA/miRNA in combinations with other therapeutic agents (such as gene, DNA or chemotherapeutic drug) for targeting permeability glycoprotein (P-gp), Multidrug resistant protein 1(MRP-1), B-cell lymphoma (BCL-2) and other targets that are mainly responsible for resistance in cancer therapy. RNAi-chemotherapeutic drug combinations have also been found to be effective against different molecular targets as well and can increase the sensitization of cancer cells to therapy several folds. However, due to stability issues associated with siRNA/miRNA suitable protective carrier is needed and nanotechnology based approaches have been widely explored to overcome these drawbacks. Furthermore, it has been univocally advocated that the co-delivery of siRNA/miRNA with other chemodrugs significantly enhances their capability to overcome cancer resistance compared to naked counterparts. The objective of this article is to review recent nanocarrier based approaches adopted for the delivery of siRNA/miRNA combinations with other anticancer agents (siRNA/miRNA/pDNA/chemodrugs) to treat cancer. PMID:25204288

  15. Linifanib (ABT-869) Potentiates the Efficacy of Chemotherapeutic Agents through the Suppression of Receptor Tyrosine Kinase-Mediated AKT/mTOR Signaling Pathways in Gastric Cancer

    PubMed Central

    Chen, Jing; Guo, Jiawei; Chen, Zhi; Wang, Jieqiong; Liu, Mingyao; Pang, Xiufeng

    2016-01-01

    Gastric cancer, highly dependent on tumor angiogenesis, causes uncontrolled lethality, in part due to chemoresistance. Here, we demonstrate that linifanib (ABT-869), a novel multi-targeted receptor tyrosine kinase inhibitor, markedly augments cytotoxicity of chemotherapies in human gastric cancer. ABT-869 and chemotherapeutic agents exhibited a strong synergy to inhibit the viability of several gastric cancer cell lines, with combination index values ranging from 0.017 to 0.589. Additionally, the combination of ABT-869 and chemotherapeutic agents led to remarkable suppression of vascular endothelial growth factor (VEGF)-induced angiogenesis in vitro and in vivo. Importantly, in a preclinical gastric cancer xenograft mouse model, drug co-treatments led to increased mouse survival as well as a synergistic reduction in tumor size and the inhibition of tumor angiogenesis. Mechanistic studies further revealed that all of the co-treatments containing ABT-869 resulted in decreased activation of the VEGF receptor, the epidermal growth factor receptor and the insulin growth factor receptor. Inhibition of these receptor tyrosine kinases consequently attenuated the activation of the downstream AKT/mTOR signaling pathway both in cultured gastric cancer cells and in gastric cancer xenografts. Collectively, our findings suggest that the addition of ABT-869 to traditional chemotherapies may be a promising strategy for the treatment of human gastric cancer. PMID:27387652

  16. The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species

    PubMed Central

    Ruefli, Astrid A.; Ausserlechner, Michael J.; Bernhard, David; Sutton, Vivien R.; Tainton, Kellie M.; Kofler, Reinhard; Smyth, Mark J.; Johnstone, Ricky W.

    2001-01-01

    Many chemotherapeutic agents induce mitochondrial-membrane disruption to initiate apoptosis. However, the upstream events leading to drug-induced mitochondrial perturbation have remained poorly defined. We have used a variety of physiological and pharmacological inhibitors of distinct apoptotic pathways to analyze the manner by which suberoylanilide hydroxamic acid (SAHA), a chemotherapeutic agent and histone deacetylase inhibitor, induces cell death. We demonstrate that SAHA initiates cell death by inducing mitochondria-mediated death pathways characterized by cytochrome c release and the production of reactive oxygen species, and does not require the activation of key caspases such as caspase-8 or -3. We provide evidence that mitochondrial disruption is achieved by means of the cleavage of the BH3-only proapoptotic Bcl-2 family member Bid. SAHA-induced Bid cleavage was not blocked by caspase inhibitors or the overexpression of Bcl-2 but did require the transcriptional regulatory activity of SAHA. These data provide evidence of a mechanism of cell death mediated by transcriptional events that result in the cleavage of Bid, disruption of the mitochondrial membrane, and production of reactive oxygen species to induce cell death. PMID:11535817

  17. Small-Molecule Procaspase-3 Activation Sensitizes Cancer to Treatment with Diverse Chemotherapeutics

    PubMed Central

    2016-01-01

    Conventional chemotherapeutics remain essential treatments for most cancers, but their combination with other anticancer drugs (including targeted therapeutics) is often complicated by unpredictable synergies and multiplicative toxicities. As cytotoxic anticancer chemotherapeutics generally function through induction of apoptosis, we hypothesized that a molecularly targeted small molecule capable of facilitating a central and defining step in the apoptotic cascade, the activation of procaspase-3 to caspase-3, would broadly and predictably enhance activity of cytotoxic drugs. Here we show that procaspase-activating compound 1 (PAC-1) enhances cancer cell death induced by 15 different FDA-approved chemotherapeutics, across many cancer types and chemotherapeutic targets. In particular, the promising combination of PAC-1 and doxorubicin induces a synergistic reduction in tumor burden and enhances survival in murine tumor models of osteosarcoma and lymphoma. This PAC-1/doxorubicin combination was evaluated in 10 pet dogs with naturally occurring metastatic osteosarcoma or lymphoma, eliciting a biologic response in 3 of 6 osteosarcoma patients and 4 of 4 lymphoma patients. Importantly, in both mice and dogs, coadministration of PAC-1 with doxorubicin resulted in no additional toxicity. On the basis of the mode of action of PAC-1 and the high expression of procaspase-3 in many cancers, these results suggest the combination of PAC-1 with cytotoxic anticancer drugs as a potent and general strategy to enhance therapeutic response. PMID:27610416

  18. STAT3 Inhibition by Microtubule-Targeted Drugs: Dual Molecular Effects of Chemotherapeutic Agents

    PubMed Central

    Walker, Sarah R.; Chaudhury, Mousumi; Frank, David A.

    2011-01-01

    To improve the effectiveness of anti-cancer therapies, it is necessary to identify molecular targets that are essential to a tumor cell but dispensable in a normal cell. Increasing evidence indicates that the transcription factor STAT3, which regulates the expression of genes controlling proliferation, survival, and self-renewal, constitutes such a target. Recently it has been found that STAT3 can associate with the cytoskeleton. Since many of the tumors in which STAT3 is activated, such as breast cancer and ovarian cancer, are responsive to drugs that target microtubules, we examined the effect of these compounds on STAT3. We found that microtubule stabilizers, such as paclitaxel, or microtubule inhibitors, such as vinorelbine, decrease the activating tyrosine phosphorylation of STAT3 in tumor cells and inhibit the expression of STAT3 target genes. Paclitaxel decreases the association between STAT3 and microtubules, and appears to decrease STAT3 phosphorylation through induction of a negative feedback regulator. The cytotoxic activity of paclitaxel in breast cancer cell lines correlates with its ability to decrease STAT3 phosphorylation. However, consistent with the necessity for expression of a negative regulator, treatment of resistant MDA-MB-231 cells with the DNA demethylating agent 5-azacytidine restores the ability of paclitaxel to block STAT3-dependent gene expression. Finally, the combination of paclitaxel and agents that directly target STAT3 has beneficial effects in killing STAT3-dependent cell lines. Thus, microtubule-targeted agents may exert some of their effects by inhibiting STAT3, and understanding this interaction may be important for optimizing rational targeted cancer therapies. PMID:21949561

  19. Targeted concurrent and sequential delivery of chemotherapeutic and antiangiogenic agents to the brain by using drug-loaded nanofibrous membranes

    PubMed Central

    Tseng, Yuan-Yun; Yang, Tao-Chieh; Wang, Yi-Chuan; Lee, Wei-Hwa; Chang, Tzu-Min; Kau, Yi-Chuan; Liu, Shih-Jung

    2017-01-01

    Glioblastoma is the most frequent and devastating primary brain tumor. Surgery followed by radiotherapy with concomitant and adjuvant chemotherapy is the standard of care for patients with glioblastoma. Chemotherapy is ineffective, because of the low therapeutic levels of pharmaceuticals in tumor tissues and the well-known tumor-cell resistance to chemotherapy. Therefore, we developed bilayered poly(d,l)-lactide-co-glycolide nanofibrous membranes that enabled the sequential and sustained release of chemotherapeutic and antiangiogenic agents by employing an electrospinning technique. The release characteristics of embedded drugs were determined by employing an in vitro elution technique and high-performance liquid chromatography. The experimental results showed that the fabricated nanofibers showed a sequential drug-eluting behavior, with the release of high drug levels of chemotherapeutic carmustine, irinotecan, and cisplatin from day 3, followed by the release of high concentrations of the antiangiogenic combretastatin from day 21. Biodegradable multidrug-eluting nanofibrous membranes were then dispersed into the cerebral cavity of rats by craniectomy, and the in vivo release characteristics of the pharmaceuticals from the membranes were investigated. The results suggested that the nanofibrous membranes released high concentrations of pharmaceuticals for more than 8 weeks in the cerebral parenchyma of rats. The result of histological analysis demonstrated developmental atrophy of brains with no inflammation. Biodegradable nanofibrous membranes can be manufactured for long-term sequential transport of different chemotherapeutic and anti-angiogenic agents in the brain, which can potentially improve the treatment of glioblastoma multiforme and prevent toxic effects due to systemic administration. PMID:28243088

  20. PHB-Based Gels as Delivery Agents of Chemotherapeutics for the Effective Shrinkage of Tumors.

    PubMed

    Wu, Yun-Long; Wang, Han; Qiu, Ying-Kun; Liow, Sing Shy; Li, Zibiao; Loh, Xian Jun

    2016-10-01

    Injectable thermogel to deliver chemotherapeutics in a minimally invasive manner and to achieve their long term sustained release at tumor sites to minimize side effects is attractive for chemotherapy and precision medicine, but its rational design remains a challenge. In this work, a copolymer with natural biodegradable poly[(R)-3-hydroxybutyrate] (PHB), hydrophilic poly(ethylene glycol), and temperature sensitive poly(propylene glycol) blocks linked by urethane linkages is designed to show thermogelling characteristics which are beneficial for minimally invasive injection and safe degradation. This thermogelling polymer possesses in vitro biocompatibility with very low cyto-toxicity in HEK293 cells. Furthermore, it is able to form the gel to achieve the controllable release of paclitaxel (PTX) and doxorubicin (DOX) by adjusting polymer concentrations. A rodent model of hepatocarcinoma has been performed to demonstrate the in vivo applications of this PHB-based thermogel. The drug-loaded thermogel has been intratumorally injected and both PTX-loaded and DOX-loaded thermogel have significantly slowed down tumor growth. This work represents the first time that injectable PHB thermogels have possessed good controllable release effect of chemotherapeutics against the in vivo model of tumors and will benefit various applications, including on-demand drug delivery and personalized medicine.

  1. Hantzsch-Type dihydropyridines and Biginelli-type tetra-hydropyrimidines: a review of their chemotherapeutic activities.

    PubMed

    Sepehri, Saghi; Sanchez, Horacio Perez; Fassihi, Afshin

    2015-01-01

    Years after the first report on 1,4-dihydropyridines (1,4-DHPs) and 1,2,3,4-tetrahydropyrimidines (1,2,3,4-THPMs) appeared, they are revisited as plausible therapeutic agents. This is mainly due to the convenient methods that exist for their synthesis and the diverse pharmacologic properties that these scaffolds present. 1,4-Dihydropyridines and 1,2,3,4-tetrahydropyrimidines are usually regarded as analogous in several aspects. They are both prepared in multi-component reactions using very similar starting materials and synthesis protocols. This leads to common structural features between 1,4-DHPs and 1,2,3,4-THPMs, as well several related biological effects. For example, they share many pharmacological features such as analgesic, anti-tumor, antioxidant, anti-inflammatory, antitubercular, antibacterial, cardiovascular and adrenoceptor blocking activities. Numerous reviews have been devoted to the chemistry and cardiovascular effects of these compounds. However, the lack of a comprehensive literature overview on the chemotherapeutic ability of these scaffolds is behind the present attempt to provide a detailed survey of 1,4-DHPs and 1,2,3,4-THPMs and their structural features as chemotherapeutic agents.

  2. Enriched environment housing enhances the sensitivity of mouse pancreatic cancer to chemotherapeutic agents.

    PubMed

    Wu, Yufeng; Gan, Yu; Yuan, Hui; Wang, Qing; Fan, Yingchao; Li, Guohua; Zhang, Jian; Yao, Ming; Gu, Jianren; Tu, Hong

    2016-04-29

    Living in an enriched housing environment is an established model of eustress and has been consistently shown to reduce the growth of transplanted tumors, including pancreatic cancer. Here, we further investigate the influence of an enriched environment (EE) on the efficacy of chemotherapy in pancreatic cancer. Male C57BL/6 mice were housed in EE or standard environment (SE) conditions and transplanted with syngeneic Panc02 pancreatic cancer cells. Tumor-bearing mice were treated with 5-fluorouracil (5-FU) or gemcitabine (GEM) to examine their sensitivities to chemotherapy. The results showed that both 5-FU and GEM exerted the dose dependent inhibition of tumor growth. The tumor inhibition rates of low-dose 5-FU and GEM were improved from 17.7% and 23.6% to 46.3% and 49.9% by EE housing. Importantly, tumor cells isolated from the pancreatic cancer xenografts of EE mice had significantly enhanced sensitivities to both 5-FU and GEM (IC50 for 5-FU: 2.8 μM versus 27.3 μM; IC50 for GEM: 0.8 μM versus 5.0 μM). Furthermore, using microarray analyses, we identified the "ATP-binding cassette (ABC) transporter" that was overrepresented among EE-induced down-regulated genes in pancreatic cancer. Particularly, the tumoral expression of ABC transporter A8b (ABCA8b) was confirmed to be significantly decreased by EE. Over-expression of ABCA8b in mouse pancreatic cancer cells led to a marked decrease in the sensitivity to chemotherapeutic drugs both in vitro and in vivo. In conclusion, our data indicate that benign stressful stimulation can synergistically boost the efficiency of chemotherapeutics in pancreatic cancer, which suggests a novel strategy for adjuvant cancer therapy.

  3. Enterobacter and Klebsiella species isolated from fresh vegetables marketed in Valencia (Spain) and their clinically relevant resistances to chemotherapeutic agents.

    PubMed

    Falomir, María Pilar; Rico, Hortensia; Gozalbo, Daniel

    2013-12-01

    Occurrence of antibiotic-resistant pathogenic or commensal enterobacteria in marketed agricultural foodstuffs may contribute to their incorporation into the food chain and constitutes an additional food safety concern. In this work, we have determined the clinically relevant resistances to 11 common chemotherapeutic agents in Enterobacter and Klebsiella isolates from fresh vegetables from various sources (supermarkets and greengrocers' shops in Valencia, Spain). A total of 96 isolates were obtained from 160 vegetables analyzed (50% positive samples): 68 Enterobacter isolates (59 E. cloacae, two E. aerogenes, two E. cancerogenus, one E. gergoviae, and four E. sakazakii, currently Cronobacter spp.), and 28 Klebsiella isolates (19 K. oxytoca and 9 K. pneumoniae). Only seven isolates were susceptible to all agents tested, and no resistances to ceftazidime, ciprofloxacin, gentamicin, and chloramphenicol were detected. Most isolates were resistant to amoxicillin/clavulanic acid (74 [58 Enterobacter and 16 Klebsiella]) or to ampicillin (80 [55/25]). Other resistances were less frequent: nitrofurantoin (13 isolates [12/1]), tetracycline (6 [5/1]), co-trimoxazole (3 [3/0]), cefotaxime (1 [1/0]), and streptomycin (2 [1/1]). Multiresistant isolates to two (56 [41/15]), three (10 E. cloacae isolates), four (one E. cloacae and one K. pneumoniae isolate), and five (two E. cloacae isolates) chemotherapeutic agents were also detected. The presence of potential pathogens points to marketed fresh produce, which often is eaten raw, as a risk factor for consumer health. In addition, these results support the usefulness of these bacterial species as indicators of the spreading of antibiotic resistances into the environment, particularly in the food chain, and suggest their role as carriers of resistance determinants from farms to consumers, which may constitute an additional "silent" food safety concern. Therefore, there is a need to improve the hygienic quality of marketed fresh

  4. A Novel Agent Enhances the Chemotherapeutic Efficacy of Doxorubicin in MCF-7 Breast Cancer Cells

    PubMed Central

    Wang, Liang; Chan, Judy Y.; Zhou, Xinhua; Cui, Guozhen; Yan, Zhixiang; Wang, Li; Yan, Ru; Di, Lijun; Wang, Yuqiang; Hoi, Maggie P.; Shan, Luchen; Lee, Simon M.

    2016-01-01

    We have previously demonstrated that DT-010, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), displays anti-tumor effects in breast cancer cells both in vitro and in vivo. In the present study, we investigated whether DT-010 enhances the chemotherapeutic effect of doxorubicin (Dox) in MCF-7 breast cancer cells and exerts concurrent cardioprotective benefit at the same time. Our findings showed that DT-010 was more potent than TMP, DSS, or their combination in potentiating Dox-induced toxicity in MCF-7 cells. Co-treatment with DT-010 and Dox increased apoptosis in MCF-7 cells relative to Dox alone. Further study indicated that glycolytic capacity, glycolytic reserve and lactate level of MCF-7 cells were significantly inhibited after DT-010 treatment. DT-010 also increased the expression of the pro-survival protein GRP78, which was inhibited by co-treatment with Dox. Both endoplasmic reticulum stress inhibitor 4-PBA and knockdown of the expression of GRP78 protein potentiated DT-010-mediated apoptosis in MCF-7 cells. Moreover, DT-010 inhibited Dox-induced cardiotoxicity in H9c2 myoblasts. In conclusion, DT-010 and Dox confer synergistic anti-tumor effect in MCF-7 breast cancer cells through downregulation of the glycolytic pathway and inhibition of the expression of GRP78. Meanwhile, DT-010 also protects against Dox-induced cardiotoxicity. PMID:27559313

  5. A Novel Agent Enhances the Chemotherapeutic Efficacy of Doxorubicin in MCF-7 Breast Cancer Cells.

    PubMed

    Wang, Liang; Chan, Judy Y; Zhou, Xinhua; Cui, Guozhen; Yan, Zhixiang; Wang, Li; Yan, Ru; Di, Lijun; Wang, Yuqiang; Hoi, Maggie P; Shan, Luchen; Lee, Simon M

    2016-01-01

    We have previously demonstrated that DT-010, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), displays anti-tumor effects in breast cancer cells both in vitro and in vivo. In the present study, we investigated whether DT-010 enhances the chemotherapeutic effect of doxorubicin (Dox) in MCF-7 breast cancer cells and exerts concurrent cardioprotective benefit at the same time. Our findings showed that DT-010 was more potent than TMP, DSS, or their combination in potentiating Dox-induced toxicity in MCF-7 cells. Co-treatment with DT-010 and Dox increased apoptosis in MCF-7 cells relative to Dox alone. Further study indicated that glycolytic capacity, glycolytic reserve and lactate level of MCF-7 cells were significantly inhibited after DT-010 treatment. DT-010 also increased the expression of the pro-survival protein GRP78, which was inhibited by co-treatment with Dox. Both endoplasmic reticulum stress inhibitor 4-PBA and knockdown of the expression of GRP78 protein potentiated DT-010-mediated apoptosis in MCF-7 cells. Moreover, DT-010 inhibited Dox-induced cardiotoxicity in H9c2 myoblasts. In conclusion, DT-010 and Dox confer synergistic anti-tumor effect in MCF-7 breast cancer cells through downregulation of the glycolytic pathway and inhibition of the expression of GRP78. Meanwhile, DT-010 also protects against Dox-induced cardiotoxicity.

  6. Trk inhibition reduces cell proliferation and potentiates the effects of chemotherapeutic agents in Ewing sarcoma

    PubMed Central

    Heinen, Tiago Elias; dos Santos, Rafael Pereira; da Rocha, Amanda; dos Santos, Michel Pinheiro; da Costa Lopez, Patrícia Luciana; Filho, Marco Aurélio Silva; Souza, Bárbara Kunzler; da Rosa Rivero, Luís Fernando; Becker, Ricardo Gehrke; Gregianin, Lauro José; Brunetto, Algemir Lunardi; Brunetto, André Tesainer; de Farias, Caroline Brunetto; Roesler, Rafael

    2016-01-01

    Ewing sarcoma (ES) is a highly aggressive pediatric cancer that may arise from neuronal precursors. Neurotrophins stimulate neuronal devlopment and plasticity. Here, we found that neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as well as their receptors (TrkA and TrkB, respectively) are expressed in ES tumors. Treatment with TrkA (GW-441756) or TrkB (Ana-12) selective inhibitors decreased ES cell proliferation, and the effect was increased when the two inhibitors were combined. ES cells treated with a pan-Trk inhibitor, K252a, showed changes in morphology, reduced levels of β-III tubulin, and decreased mRNA expression of NGF, BDNF, TrkA and TrkB. Furthermore, combining K252a with subeffective doses of cytotoxic chemotherapeutic drugs resulted in a decrease in ES cell proliferation and colony formation, even in chemoresistant cells. These results indicate that Trk inhibition may be an emerging approach for the treatment of ES. PMID:27145455

  7. Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo.

    PubMed

    Chen, Zhen; Chen, Yifan; Xu, Meng; Chen, Likun; Zhang, Xu; To, Kenneth Kin Wah; Zhao, Hongyun; Wang, Fang; Xia, Zhongjun; Chen, Xiaoqin; Fu, Liwu

    2016-08-01

    The overexpression of ATP-binding cassette (ABC) transporters has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. In our study, we investigated whether osimertinib (AZD9291), a third-generation irreversible tyrosine kinase inhibitor of both activating EGFR mutations and resistance-associated T790M point mutation, could reverse MDR induced by ABCB1 and ABCG2 in vitro, in vivo, and ex vivo Our results showed that osimertinib significantly increased the sensitivity of ABCB1- and ABCG2-overexpressing cells to their substrate chemotherapeutic agents in vitro and in the model of ABCB1-overexpressing KBv200 cell xenograft in nude mice. Mechanistically, osimertinib increased the intracellular accumulations of doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, osimertinib stimulated the ATPase activity of both ABCB1 and ABCG2 and competed with the [(125)I] iodoarylazidoprazosin photolabeling bound to ABCB1 or ABCG2, but did not alter the localization and expression of ABCB1 or ABCG2 in mRNA and protein levels nor the phosphorylations of EGFR, AKT, and ERK. Importantly, osimertinib also enhanced the cytotoxicity of DOX and intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. Overall, these findings suggest osimertinib reverses ABCB1- and ABCG2-mediated MDR via inhibiting ABCB1 and ABCG2 from pumping out chemotherapeutic agents and provide possibility for cancer combinational therapy with osimertinib in the clinic. Mol Cancer Ther; 15(8); 1845-58. ©2016 AACR.

  8. Activation of multiple chemotherapeutic prodrugs by the natural enzymolome of tumour-localised probiotic bacteria.

    PubMed

    Lehouritis, Panos; Stanton, Michael; McCarthy, Florence O; Jeavons, Matthieu; Tangney, Mark

    2016-01-28

    Some chemotherapeutic drugs (prodrugs) require activation by an enzyme for efficacy. We and others have demonstrated the ability of probiotic bacteria to grow specifically within solid tumours following systemic administration, and we hypothesised that the natural enzymatic activity of these tumour-localised bacteria may be suitable for activation of certain such chemotherapeutic drugs. Several wild-type probiotic bacteria; Escherichia coli Nissle, Bifidobacterium breve, Lactococcus lactis and Lactobacillus species, were screened against a panel of popular prodrugs. All strains were capable of activating at least one prodrug. E. coli Nissle 1917 was selected for further studies because of its ability to activate numerous prodrugs and its resistance to prodrug toxicity. HPLC data confirmed biochemical transformation of prodrugs to their toxic counterparts. Further analysis demonstrated that different enzymes can complement prodrug activation, while simultaneous activation of multiple prodrugs (CB1954, 5-FC, AQ4N and Fludarabine phosphate) by E. coli was confirmed, resulting in significant efficacy improvement. Experiments in mice harbouring murine tumours validated in vitro findings, with significant reduction in tumour growth and increase in survival of mice treated with probiotic bacteria and a combination of prodrugs. These findings demonstrate the ability of probiotic bacteria, without the requirement for genetic modification, to enable high-level activation of multiple prodrugs specifically at the site of action.

  9. Testing chemotherapeutic agents in the feather follicle identifies a selective blockade of cell proliferation and a key role for sonic hedgehog signaling in chemotherapy-induced tissue damage.

    PubMed

    Xie, Guojiang; Wang, Hangwei; Yan, Zhipeng; Cai, Linyan; Zhou, Guixuan; He, Wanzhong; Paus, Ralf; Yue, Zhicao

    2015-03-01

    Chemotherapeutic agents induce complex tissue responses in vivo and damage normal organ functions. Here we use the feather follicle to investigate details of this damage response. We show that cyclophosphamide treatment, which causes chemotherapy-induced alopecia in mice and man, induces distinct defects in feather formation: feather branching is transiently and reversibly disrupted, thus leaving a morphological record of the impact of chemotherapeutic agents, whereas the rachis (feather axis) remains unperturbed. Similar defects are observed in feathers treated with 5-fluorouracil or taxol but not with doxorubicin or arabinofuranosyl cytidine (Ara-C). Selective blockade of cell proliferation was seen in the feather branching area, along with a downregulation of sonic hedgehog (Shh) transcription, but not in the equally proliferative rachis. Local delivery of the Shh inhibitor, cyclopamine, or Shh silencing both recapitulated this effect. In mouse hair follicles, those chemotherapeutic agents that disrupted feather formation also downregulated Shh gene expression and induced hair loss, whereas doxorubicin or Ara-C did not. Our results reveal a mechanism through which chemotherapeutic agents damage rapidly proliferating epithelial tissue, namely via the cell population-specific, Shh-dependent inhibition of proliferation. This mechanism may be targeted by future strategies to manage chemotherapy-induced tissue damage.

  10. Modification of in vitro and in vivo BCG cell wall-induced immunosuppression by treatment with chemotherapeutic agents or indomethacin

    SciTech Connect

    DeSilva, M.A.; Wepsic, H.T.; Mizushima, Y.; Nikcevich, D.A.; Larson, C.H.

    1985-04-01

    The in vitro inhibition of spleen cell blastogenesis response and the in vivo enhancement of tumor growth are phenomena associated with BCG cell wall (BCGcw) immunization. What effect treatment with chemotherapeutic agents and the prostaglandin inhibitor indomethacin would have on the in vitro and in vivo responses to BCGcw immunization was evaluated. In vitro blastogenesis studies showed that chemotherapy pretreatment prior to immunization with BCGcw resulted in a restoration of the spleen cell blastogenesis response. In blastogenesis addback studies, where BCGcw-induced irradiated splenic suppressor cells were admixed with normal cells, less inhibition of blastogenesis occurred when spleen cells were obtained from rats that had received the combined treatment of chemotherapy and BCGcw immunization versus only BCGcw immunization. The cocultivation of spleen cells from BCGcw-immunized rats with indomethacin resulted in a 30-40% restoration of the blastogenesis response. In vivo studies showed that BCGcw-mediated enhancement of intramuscular tumor growth of the 3924a ACI rat tumor could be abrogated by either pretreatment with busulfan or mitomycin or by the feeding of indomethacin.

  11. In-vitro susceptibility of Giardia lamblia to albendazole, mebendazole and other chemotherapeutic agents.

    PubMed

    Cedillo-Rivera, R; Muñoz, O

    1992-09-01

    The susceptibility of a strain of Giardia lamblia to benzimidazole carbamates, 5-nitroimidazoles, nitrofurans and other drugs was studied in vitro. Albendazole was the most active compound, with a 50% inhibitory concentration (IC50) of 0.01 mg/L and a minimal lethal concentration (MLC) of less than 0.04 mg/L; the IC50 of mebendazole was 0.06 mg/L and the MLC less than 0.5 mg/L. Among the 5-nitroimidazoles tested, ornidazole was the most effective (IC50 0.12 mg/L); tinidazole, metronidazole, secnidazole and hemezole were less active. Nifuroxazide, etofamide and nalidixic acid exhibited modest anti-giardial activity; quinfamide did not inhibit the growth of the parasite at a concentration of 200 mg/L. Albendazole and mebendazole are promising candidates for clinical use and should be further evaluated.

  12. Selenium is a Chemotherapeutic Agent for the Treatment of Prostate Cancer

    DTIC Science & Technology

    2006-02-01

    receptor activity by a hammerhead ribozyme . Mol Endrocrinol 1998;12:1558-1566. 10. Ko YJ, Devi GR, London CA, et al. Androgen receptor down-regulation...Strategic targeting of the AR with ribozymes , antisense oligomers, and small interfering RNAs has been shown to significantly inhibit prostate cancer

  13. Enhanced X ray sensitivity of human colon tumor cells by combination of N-methylformamide with chemotherapeutic agents

    SciTech Connect

    Leith, J.T.; Lee, E.S.; Leite, D.V.; Glicksman, A.S.

    1986-08-01

    The responses of human colon tumor cells (clone A) to graded doses of x-irradiation were studied in combination with conventional chemotherapeutic drugs (bleomycin and 5-fluorouracil) after induction of commitment to differentiation by chronic exposure to N-methylformamide (NMF). NMF treated cells show increased radiation sensitivity, particularly in the low dose region of the survival curve. When doses of bleomycin (Bleo) and 5-fluorouracil (5-FU) were used that were subtoxic, both agents enhanced the cytotoxicity of x-irradiation by factors of about 1.25 and 1.10, respectively (at the 10% level of survival), and little sequence dependence was seen. However, in NMF treated cells, the combination of these drugs produced enhancement of X ray killing by factors of about 1.6 (x + bleo), 2.5 (bleo + x), 1.4 (x + 5-FU), and 1.6 (5-FU + x). Drug exposures were for 1 hr duration at 37/sup 0/C; 0.05 microgram/ml for Bleo, and 20 micrograms/ml for 5-FU. Since the X ray dose enhancement factor for NMF alone was about 1.3, the increased toxicity seen is probably additive in nature for the NMF + 5-FU + x experiments, but more than additive for the NMF + Bleo + x experiments. Also, complete removal of the shoulder was seen in the NMF + Bleo + X ray experiments. These data indicate that the use of differentiation-inducing agents in combination with other cytotoxic therapies might be important in yielding major decreases in the neoplastic cell burden, while avoiding the major morbidity seen in aggressive cancer therapy.

  14. Environmental and chemotherapeutic agents induce breakage at genes involved in leukemia-causing gene rearrangements in human hematopoietic stem/progenitor cells

    PubMed Central

    Thys, Ryan G.; Lehman, Christine E.; Pierce, Levi C.T.

    2016-01-01

    Hematopoietic stem and progenitor cells (HSPCs) give rise to all of the cells that make up the hematopoietic system in the human body, making their stability and resilience especially important. Damage to these cells can severely impact cell development and has the potential to cause diseases, such as leukemia. Leukemia-causing chromosomal rearrangements have largely been studied in the context of radiation exposure and are formed by a multi-step process, including an initial DNA breakage and fusion of the free DNA ends. However, the mechanism for DNA breakage in patients without previous radiation exposure is unclear. Here, we investigate the role of non-cytotoxic levels of environmental factors, benzene, and diethylnitrosamine (DEN), and chemotherapeutic agents, etoposide, and doxorubicin, in generating DNA breakage at the patient breakpoint hotspots of the MLL and CBFB genes in human HSPCs. These conditions represent exposure to chemicals encountered daily or residual doses from chemotherapeutic drugs. Exposure of HSPCs to non-cytotoxic levels of environmental chemicals or chemotherapeutic agents causes DNA breakage at preferential sites in the human genome, including the leukemia-related genes MLL and CBFB. Though benzene, etoposide, and doxorubicin have previously been linked to leukemia formation, this is the first study to demonstrate a role for DEN in the generation of DNA breakage at leukemia-specific sites. These chemical-induced DNA breakpoints coincide with sites of predicted topoisomerase II cleavage. The distribution of breakpoints by exposure to non-cytotoxic levels of chemicals showed a similar pattern to fusion breakpoints in leukemia patients. Our findings demonstrate that HSPCs exposed to non-cytotoxic levels of environmental chemicals and chemotherapeutic agents are prone to topoisomerase II-mediated DNA damage at the leukemia-associated genes MLL and CBFB. These data suggest a role for long-term environmental chemical or residual

  15. Environmental and chemotherapeutic agents induce breakage at genes involved in leukemia-causing gene rearrangements in human hematopoietic stem/progenitor cells.

    PubMed

    Thys, Ryan G; Lehman, Christine E; Pierce, Levi C T; Wang, Yuh-Hwa

    2015-09-01

    Hematopoietic stem and progenitor cells (HSPCs) give rise to all of the cells that make up the hematopoietic system in the human body, making their stability and resilience especially important. Damage to these cells can severely impact cell development and has the potential to cause diseases, such as leukemia. Leukemia-causing chromosomal rearrangements have largely been studied in the context of radiation exposure and are formed by a multi-step process, including an initial DNA breakage and fusion of the free DNA ends. However, the mechanism for DNA breakage in patients without previous radiation exposure is unclear. Here, we investigate the role of non-cytotoxic levels of environmental factors, benzene, and diethylnitrosamine (DEN), and chemotherapeutic agents, etoposide, and doxorubicin, in generating DNA breakage at the patient breakpoint hotspots of the MLL and CBFB genes in human HSPCs. These conditions represent exposure to chemicals encountered daily or residual doses from chemotherapeutic drugs. Exposure of HSPCs to non-cytotoxic levels of environmental chemicals or chemotherapeutic agents causes DNA breakage at preferential sites in the human genome, including the leukemia-related genes MLL and CBFB. Though benzene, etoposide, and doxorubicin have previously been linked to leukemia formation, this is the first study to demonstrate a role for DEN in the generation of DNA breakage at leukemia-specific sites. These chemical-induced DNA breakpoints coincide with sites of predicted topoisomerase II cleavage. The distribution of breakpoints by exposure to non-cytotoxic levels of chemicals showed a similar pattern to fusion breakpoints in leukemia patients. Our findings demonstrate that HSPCs exposed to non-cytotoxic levels of environmental chemicals and chemotherapeutic agents are prone to topoisomerase II-mediated DNA damage at the leukemia-associated genes MLL and CBFB. These data suggest a role for long-term environmental chemical or residual

  16. Identification of lead chemotherapeutic agents from medicinal plants against blood flukes and whipworms

    PubMed Central

    Wangchuk, Phurpa; Giacomin, Paul R.; Pearson, Mark S.; Smout, Michael J.; Loukas, Alex

    2016-01-01

    Schistosomiasis and trichuriasis are two of the most common neglected tropical diseases (NTD) that affect almost a billion people worldwide. There is only a limited number of effective drugs to combat these NTD. Medicinal plants are a viable source of parasiticides. In this study, we have investigated six of the 19 phytochemicals isolated from two Bhutanese medicinal plants, Corydalis crispa and Pleurospermum amabile, for their anthelmintic properties. We used the xWORM technique and Scanning Electron Microscope-based imaging to determine the activity of the compounds. Of the six compounds tested, isomyristicin and bergapten showed significant anthelmintic activity against Schistosoma mansoni and Trichuris muris with bergapten being the most efficacious compound one against both parasites (S. mansoni IC50 = 8.6 μg/mL and T. muris IC50 = 10.6 μg/mL) and also against the schistosomulum stage of S. mansoni. These two compounds induced tegumental damage to S. mansoni and affected the cuticle, bacillary bands and bacillary glands of T. muris. The efficacy against multiple phylogenetically distinct parasites and different life stages, especially the schistosomulum where praziquantel is ineffective, makes isomyristicin and bergapten novel scaffolds for broad-spectrum anthelmintic drug development that could be used for the control of helminths infecting humans and animals. PMID:27572696

  17. Identification of lead chemotherapeutic agents from medicinal plants against blood flukes and whipworms.

    PubMed

    Wangchuk, Phurpa; Giacomin, Paul R; Pearson, Mark S; Smout, Michael J; Loukas, Alex

    2016-08-30

    Schistosomiasis and trichuriasis are two of the most common neglected tropical diseases (NTD) that affect almost a billion people worldwide. There is only a limited number of effective drugs to combat these NTD. Medicinal plants are a viable source of parasiticides. In this study, we have investigated six of the 19 phytochemicals isolated from two Bhutanese medicinal plants, Corydalis crispa and Pleurospermum amabile, for their anthelmintic properties. We used the xWORM technique and Scanning Electron Microscope-based imaging to determine the activity of the compounds. Of the six compounds tested, isomyristicin and bergapten showed significant anthelmintic activity against Schistosoma mansoni and Trichuris muris with bergapten being the most efficacious compound one against both parasites (S. mansoni IC50 = 8.6 μg/mL and T. muris IC50 = 10.6 μg/mL) and also against the schistosomulum stage of S. mansoni. These two compounds induced tegumental damage to S. mansoni and affected the cuticle, bacillary bands and bacillary glands of T. muris. The efficacy against multiple phylogenetically distinct parasites and different life stages, especially the schistosomulum where praziquantel is ineffective, makes isomyristicin and bergapten novel scaffolds for broad-spectrum anthelmintic drug development that could be used for the control of helminths infecting humans and animals.

  18. FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents.

    PubMed

    Patil, Abhijit A; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D; Roylance, Anthony; Kriplani, Deepti H; Myers, Katie N; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A; Collis, Spencer J

    2014-08-15

    Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge, where survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome.

  19. FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents

    PubMed Central

    Patil, Abhijit A.; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D.; Roylance, Anthony; Kriplani, Deepti H.; Myers, Katie N.; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A.; Collis, Spencer J.

    2014-01-01

    Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge. GBM survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome. PMID:25071006

  20. Targeting pyrimidine pathway of Plasmodium knowlesi: new strategies towards identification of novel antimalarial chemotherapeutic agents.

    PubMed

    Rashmi, Mayank; Yadav, Manoj Kumar; Swati, D

    2017-03-15

    Plasmodium knowlesi has been recently recognized as a human malarial parasite, particularly in the region of south-east Asia. The effective prevention and treatment of this disease is increasingly bound to fail due to the emergence of drug resistance. Hence, design of new drugs against known targets is gaining importance. Pyrimidine pathway is a crucial metabolic pathway in P. knowlesi, and the enzymes involved are also unique in terms of their structure and function as compared to its human counterpart. Thus targeting Dihydroorotase, an enzyme involved in the pyrimidine pathway, provides a promising route for novel drug development. The 3D structure of P. knowlesi Dihydroorotase is not available. The structural homologues of the enzyme are not available in the database, so a threading approach is used to predict the structure. The steric clashes of the predicted model are removed by running a MD simulation of 20 ns. Then the resulting structure is validated by using Ramachandran plot and G-factor analysis. The active sites are predicted and they show interactions with His13, His15, Asp256, Lys97, His134 and His169 for two Zn atoms, and Arg17, Asn42, Thr43, Pro100, His260 and Lys271 for the Dihydroorotate. Interactions between the ligand and binding pocket residues are extracted to create a structure-based pharmacophore model of the docked complex. A four point based pharmacophore model, with four H-bond acceptors and one negative carboxyl ion, was used as a 3D query for screening against 2,664,779 standard lead compounds, obtained from freely available ZINC database. Top 15 compounds with higher pharmacophore-fit score were considered for further study. Among these, only four compounds show desired drug-like properties, and follow the Lipinski's rule of five. Two compounds (ZINC22066495, ZINC20136046) that are negatively charged are found to be more suitable for interaction with positively charged active site of enzyme. Molecular dynamics simulation is used to

  1. Induction of immunogenic cell death by chemotherapeutic platinum complexes.

    PubMed

    Wong, Daniel Yuan Qiang; Ong, Wendy Wei Fang; Ang, Wee Han

    2015-05-26

    There is compelling evidence suggesting that the immune-modulating effects of many conventional chemotherapeutics, including platinum-based agents, play a crucial role in achieving clinical response. One way in which chemotherapeutics can engage a tumor-specific immune response is by triggering an immunogenic mode of tumor cell death (ICD), which then acts as an "anticancer vaccine". In spite of being a mainstay of chemotherapy, there has not been a systematic attempt to screen both existing and upcoming Pt agents for their ICD ability. A library of chemotherapeutically active Pt agents was evaluated in an in vitro phagocytosis assay, and no correlation between cytotoxicity and phagocytosis was observed. A Pt(II) N-heterocyclic carbene complex was found to display the characteristic hallmarks of a type II ICD inducer, namely focused oxidative endoplasmic reticulum (ER) stress, calreticulin exposure, and both HMGB1 and ATP release, and thus identified as the first small-molecule immuno-chemotherapeutic agent.

  2. Targeted Delivery of Chemotherapeutic Agents Using Improved Radiosensitive Liquid Core Microcapsules and Assessment of Their Antitumor Effect

    SciTech Connect

    Harada, Satoshi Ehara, Shigeru; Ishii, Keizo; Yamazaki, Hiromichi; Matsuyama, Shigeo; Sato, Takahiro; Oikawa, Shyoichi; Kamiya, Tomihiro; Arakawa, Kazuo; Yokota, Wataru; Sera, Koichiro; Ito, Jyun

    2009-10-01

    Purpose: Radiation-sensitive microcapsules composed of alginate and hyaluronic acid are being developed. We report the development of improved microcapsules that were prepared using calcium- and yttrium-induced polymerization. We previously reported on the combined antitumor effect of carboplatin-containing microcapsules and radiotherapy. Methods and Materials: We mixed a 0.1% (wt/vol) solution of hyaluronic acid with a 0.2% alginate solution. Carboplatin (l mg) and indocyanine green (12.5 {mu}g) were added to this mixture, and the resultant material was used for capsule preparation. The capsules were prepared by spraying the material into a mixture containing a 4.34% CaCl{sub 2} solution supplemented with 0-0.01% yttrium. These capsules were irradiated with single doses of 0.5, 1.0, 1.5, or 2 Gy {sup 60}Co {gamma}-rays. Immediately after irradiation, the frequency of microcapsule decomposition was determined using a microparticle-induced X-ray emission camera. The amount of core content released was estimated by particle-induced X-ray emission and colorimetric analysis with 0.25% indocyanine green. The antitumor effect of the combined therapy was determined by monitoring its effects on the diameter of an inoculated Meth A fibrosarcoma. Results: Microcapsules that had been polymerized using a 4.34% CaCl{sub 2} solution supplemented with 5.0 x 10{sup -3}% (10{sup -3}% meant or 10%{sup -3}) yttrium exhibited the maximal decomposition, and the optimal release of core content occurred after 2-Gy irradiation. The microcapsules exhibited a synergistic antitumor effect combined with 2-Gy irradiation and were associated with reduced adverse effects. Conclusion: The results of our study have shown that our liquid core microcapsules can be used in radiotherapy for targeted delivery of chemotherapeutic agents.

  3. Warming Effect on Miriplatin-Lipiodol Suspension as a Chemotherapeutic Agent for Transarterial Chemoembolization for Hepatocellular Carcinoma: Preliminary Clinical Experience

    SciTech Connect

    Kora, Shinn-ichi; Urakawa, Hiroshi; Mitsufuji, Toshimichi; Osame, Akinobu; Higashihara, Hideyuki; Yoshimitsu, Kengo

    2013-08-01

    PurposeTo retrospectively elucidate the preliminary clinical impact of warmed miriplatin-lipiodol suspension (MPT-LPD) when used as a chemotherapeutic agent for transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).Materials and MethodsBetween June and December 2010, TACE was performed with MPT-LPD at room temperature (RT group), and after January 2011, TACE with MPT-LPD warmed to 40 Degree-Sign C was performed (W group). The intraarterial appearance of MPT-LPD immediately after injection through microcatheters at the second-order branches was compared between the two groups with a 5-point grading system. Local therapeutic effects of HCCs as assessed by follow-up computed tomography (CT) obtained 1-3 months after TACE were compared between the groups with a 4-point grading system (TE1-TE4). After April 2011, angiography-assisted CT was routinely performed at TACE, and HCCs that revealed apparent corona enhancement (CE) were retrospectively selected. The degree of concordance between CE and MPT-LPD accumulation as assessed by CT immediately after TACE was assessed with a 3-point grading scale.ResultsMPT-LPD therapy resulted in a smooth and continuous appearance in the W group (grades 1, 2, 3, 4, and 5 were, respectively, 1, 2, 11, 18, and 4) compared to the RT group (4, 0, 1, 2, and 0). The W group (TE1, TE2, TE3, and TE4 were 1, 9, 11, and 12) revealed better local therapeutic effects than the RT group (6, 3, 9, and 0) (p < 0.05). CE was found in 26 HCC nodules, and concordance between CE and MPT-LPD accumulation was observed in 66 % (grades 1, 2, and 3 were, respectively, 2, 8, and 19).ConclusionWarmed MPT-LPD flowed more smoothly within vascular lumen, passed through tumor sinusoid of HCC, and had better local therapeutic effects at short-term observation than MPT-LPD at room temperature.

  4. Impairment of stress granule assembly via inhibition of the eIF2alpha phosphorylation sensitizes glioma cells to chemotherapeutic agents.

    PubMed

    Vilas-Boas, Fabrício de Almeida Souza; da Silva, Aristóbolo Mendes; de Sousa, Lirlândia Pires; Lima, Kátia Maciel; Vago, Juliana Priscila; Bittencourt, Lucas Felipe Fernandes; Dantas, Arthur Estanislau; Gomes, Dawidson Assis; Vilela, Márcia Carvalho; Teixeira, Mauro Martins; Barcelos, Lucíola Silva

    2016-04-01

    Malignant gliomas are a lethal type of brain tumors that poorly respond to chemotherapeutic drugs. Several therapy resistance mechanisms have been characterized. However, the response to stress through mRNA translational control has not been evaluated for this type of tumor. A potential target would involve the alpha subunit of eukaryotic translation initiation factor (eIF2α) that leads to assembly of stress granules (SG) which are cytoplasmic granules mainly composed by RNA binding proteins and untranslated mRNAs. We assessed whether glioma cells are capable of assembling SG after exposure to different classes of chemotherapeutic agents through evaluation of the effects of interfering in this process by impairing the eIF2α signaling. C6 and U87MG cells were exposed to bortezomib, cisplatin, or etoposide. Forced expression of a dominant negative mutant of eIF2α (eIF2α(DN)) was employed to block this pathway. We observed that exposure to drugs stimulated SG assembly. This was reduced in eIF2α(DN)-transfected cells and this strategy enhanced chemotherapeutically-induced cell death for all drugs. Our data suggest that SG assembly occurs in glioma cells in response to chemotherapeutic drugs in an eIF2α-dependent manner and this response is relevant for drug resistance. Interfering with eIF2α signaling pathway may be a potential strategy for new co-adjuvant therapies to treat gliomas.

  5. Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor

    PubMed Central

    Li, Xiaoyu; Wu, Meiying; Pan, Limin; Shi, Jianlin

    2016-01-01

    To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4) and a chemotherapeutic drug (doxorubicin) and conjugate with targeting molecules (iRGD peptide) for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors. PMID:26766908

  6. Therapeutic potential and critical analysis of trastuzumab and bevacizumab in combination with different chemotherapeutic agents against metastatic breast/colorectal cancer affecting various endpoints.

    PubMed

    Wahid, Mohd; Mandal, Raju K; Dar, Sajad A; Jawed, Arshad; Lohani, Mohtashim; Areeshi, Mohammad Y; Akhter, Naseem; Haque, Shafiul

    2016-08-01

    Researchers are working day and night across the globe to eradicate or at least lessen the menace of cancer faced by the mankind. The two very frequently occurring cancers faced by the human beings are metastatic breast cancer and metastatic colorectal cancer. The various chemotherapeutic agents like anthracycline, cyclophosphamide, paclitaxel, irinotecan, fluorouracil and leucovorin etc., have been used impressively for long. But the obstinate character of metastatic breast cancer and metastatic colorectal cancer needs more to tackle the threat. So, the scientists found the use of monoclonal antibodies trastuzumab (Herceptin(®)) and bevacizumab (Avastin(®)) for the same. The current study critically investigates the therapeutic potential of trastuzumab and bevacizumab in combination with various chemotherapeutic agents against metastatic breast cancer and metastatic colorectal cancer. To the best of our knowledge, this is the very first critical analysis showing percent wise increase in various positive endpoints like median time to disease progression, median survival, and progression free survival etc. for the treatment of metastatic breast/colorectal cancer using trastuzumab and bevacizumab in combination with different chemotherapeutic agents and provides the rational for the success and failure of the selected monoclonal antibodies.

  7. Evaluation of uttroside B, a saponin from Solanum nigrum Linn, as a promising chemotherapeutic agent against hepatocellular carcinoma

    PubMed Central

    Nath, Lekshmi R.; Gorantla, Jaggaiah N.; Thulasidasan, Arun Kumar T.; Vijayakurup, Vinod; Shah, Shabna; Anwer, Shabna; Joseph, Sophia M.; Antony, Jayesh; Veena, Kollery Suresh; Sundaram, Sankar; Marelli, Udaya K.; Lankalapalli, Ravi S.; Anto, Ruby John

    2016-01-01

    We report, for the first time, the remarkable efficacy of uttroside B, a potent saponin from Solanum nigrum Linn, against liver cancer. The compound has been isolated and characterized from the leaves of Solanum nigrum Linn, a plant widely used in traditional medicine and is a rich resource of several anticancer molecules. Uttroside B, that comprises of β-D-glucopyranosyl unit at C-26 of the furostanol and β-lycotetraosyl unit at C-3, is ten times more cytotoxic to the liver cancer cell line, HepG2 (IC50: 0.5 μM) than sorafenib (IC50: 5.8 μM), the only FDA-approved drug for liver cancer. Moreover, it induces cytotoxicity in all liver cancer cell lines, irrespective of their HBV status, while being non-toxic to normal immortalized hepatocytes. It induces apoptosis in HepG2 cells by down-regulating mainly the activation of MAPK and mTOR pathways. The drastic reduction in HepG2-xenograft tumor size achieved by uttroside B in NOD-SCID mice and substantiation of its biological safety through both acute and chronic toxicity studies in Swiss albino mice warrants clinical validation of the molecule against hepatic cancer, for which, the chemotherapeutic armamentarium currently has limited weapons. PMID:27808117

  8. Liposomal chemotherapeutics.

    PubMed

    Gentile, Emanuela; Cilurzo, Felisa; Di Marzio, Luisa; Carafa, Maria; Ventura, Cinzia Anna; Wolfram, Joy; Paolino, Donatella; Celia, Christian

    2013-12-01

    Currently, six liposomal chemotherapeutics have received clinical approval and many more are in clinical trials or undergoing preclinical evaluation. Liposomes exhibit low toxicity and improve the biopharmaceutical features and therapeutic index of drugs, thereby increasing efficacy and reducing side effects. In this review we discuss the advantages of using liposomes for the delivery of chemotherapeutics. Gemcitabine and paclitaxel have been chosen as examples to illustrate how the performance of a metabolically unstable or poorly water-soluble drug can be greatly improved by liposomal incorporation. We look at the beneficial effects of liposomes in a variety of solid and blood-borne tumors, including thyroid cancer, pancreatic cancer, breast cancer and multiple myeloma.

  9. Endoscopic spectral domain optical coherence tomography of murine colonic morphology to determine effectiveness of chemopreventive and chemotherapeutic agents in colorectal cancer

    NASA Astrophysics Data System (ADS)

    LeGendre-McGhee, Susan; Rice, Photini F. S.; Wall, R. Andrew; Klein, Justin; Luttman, Amber; Sprute, Kyle; Gerner, Eugene; Barton, Jennifer K.

    2012-02-01

    Optical coherence tomography (OCT) is a minimally-invasive imaging modality capable of tracking the development of individual colonic adenomas. As such, OCT can be used to evaluate the mechanisms and effectiveness of chemopreventive and chemotherapeutic agents in colorectal cancer models. The data presented here represent part of a larger study evaluating α-difluoromethylornithine (DFMO) and Sulindac as chemopreventive and chemotherapeutic agents using mice treated with the carcinogen azoxymethane (AOM). 27 A/J mice were included in the chemoprevention study, subdivided into four treatment groups (No Drug, DFMO, Sulindac, DFMO/Sulindac). 30 mm lateral images of each colon at eight different rotations were obtained at five different time points using a 2 mm diameter spectral domain OCT endoscopy system centered at 890 nm with 3.5 μm axial resolution in air and 5 μm lateral resolution. Images were visually analyzed to determine number and size of adenomas. Gross photos of the excised colons and histology provided gold standard confirmation of the final imaging time point. Preliminary results show that 100% of mice in the No Drug group developed adenomas over the course of the chemoprevention study. Incidence was reduced to 71.43% in mice given DFMO, 85.71% for Sulindac and 0% for DFMO/Sulindac. Discrete adenoma size did not vary significantly between experimental groups. Additional experiments are currently under way to verify these results and evaluate DFMO and Sulindac for chemotherapeutic applications.

  10. Apoptosis-like cell death pathways in the unicellular parasite Toxoplasma gondii following treatment with apoptosis inducers and chemotherapeutic agents: a proof-of-concept study.

    PubMed

    Ni Nyoman, Ayu Dewi; Lüder, Carsten G K

    2013-06-01

    Ancient pathways of an apoptosis-like cell death have been identified in unicellular eukaryotes including protozoan parasites. Here, we examined programmed cell death in the apicomplexan Toxoplasma gondii which is a common intracellular pathogen of humans and warm-blooded animals. Treatment of extracellular T. gondii with various pro-apoptotic stimuli significantly induced DNA strand breaks as revealed by TUNEL and flow cytometry. Using staurosporine or miltefosine as pro-apoptotic stimuli, parasites also presented a reduced cell size, i.e. pyknosis and externalized phosphatidylserine while the plasma membrane remained intact. Importantly, staurosporine also induced DNA strand breaks in intracellular T. gondii. Data mining of the Toxoplasma genome resource identified 17 putative cell death-associated genes encoding proteases, a nuclease and several apoptosis regulators. Staurosporine-treated parasites but not controls strongly up-regulated several of these genes in a time-dependent fashion with a putative PDCD2 protein being more than 100-fold up-regulated. However, the mitochondrial membrane potential (ΔΨ(m)) remained intact and caspase-like activity increased only slightly during staurosporine-triggered cell death. As compared to staurosporine, the transcriptional response of parasites to miltefosine was more restricted but PDCD2 was again strongly induced. Furthermore, T. gondii lost their ΔΨ(m) and rapidly presented strong caspase-like activity during miltefosine treatment. Consequently, protease inhibitors abrogated miltefosine-induced but not staurosporine-induced Toxoplasma cell death. Finally, toxoplasmacidal drugs triggered DNA strand breaks in extracellular T. gondii. Interestingly, clindamycin also induced markers of an apoptosis-like cell death in intracellular parasites. Together, the data indicate that T. gondii possesses ancient apoptosis-like cell death machinery which can be triggered by chemotherapeutic agents.

  11. 1,3-Bis(2-chloroethyl)-1-nitrosourea-loaded bovine serum albumin nanoparticles with dual magnetic resonance–fluorescence imaging for tracking of chemotherapeutic agents

    PubMed Central

    Wei, Kuo-Chen; Lin, Feng-Wei; Huang, Chiung-Yin; Ma, Chen-Chi M; Chen, Ju-Yu; Feng, Li-Ying; Yang, Hung-Wei

    2016-01-01

    To date, knowing how to identify the location of chemotherapeutic agents in the human body after injection is still a challenge. Therefore, it is urgent to develop a drug delivery system with molecular imaging tracking ability to accurately understand the distribution, location, and concentration of a drug in living organisms. In this study, we developed bovine serum albumin (BSA)-based nanoparticles (NPs) with dual magnetic resonance (MR) and fluorescence imaging modalities (fluorescein isothiocyanate [FITC]-BSA-Gd/1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU] NPs) to deliver BCNU for inhibition of brain tumor cells (MBR 261-2). These BSA-based NPs are water dispersible, stable, and biocompatible as confirmed by XTT cell viability assay. In vitro phantoms and in vivo MR and fluorescence imaging experiments show that the developed FITC-BSA-Gd/BCNU NPs enable dual MR and fluorescence imaging for monitoring cellular uptake and distribution in tumors. The T1 relaxivity (R1) of FITC-BSA-Gd/BCNU NPs was 3.25 mM−1 s−1, which was similar to that of the commercial T1 contrast agent (R1 =3.36 mM−1 s−1). The results indicate that this multifunctional drug delivery system has potential bioimaging tracking of chemotherapeutic agents ability in vitro and in vivo for cancer therapy. PMID:27601895

  12. Sec61β Controls Sensitivity to Platinum-Containing Chemotherapeutic Agents through Modulation of the Copper-Transporting ATPase ATP7A

    PubMed Central

    Larson, Christopher A.; Manorek, Gerald; Adams, Preston; Howell, Stephen B.

    2012-01-01

    The Sec61 protein translocon is a multimeric complex that transports proteins across lipid bilayers. We discovered that the Sec61β subunit modulates cellular sensitivity to chemotherapeutic agents, particularly the platinum drugs. To investigate the mechanism, expression of Sec61β was constitutively knocked down in 2008 ovarian cancer cells. Sec61β knockdown (KD) resulted in 8-, 16.8-, and 9-fold resistance to cisplatin (cDDP), carboplatin, and oxaliplatin, respectively. Sec61β KD reduced the cellular accumulation of cDDP to 67% of that in parental cells. Baseline copper levels, copper uptake, and copper cytotoxicity were also reduced. Because copper transporters and chaperones regulate platinum drug accumulation and efflux, their expression in 2008 Sec61β-KD cells was analyzed; ATP7A was found to be 2- to 3-fold overexpressed, whereas there was no change in ATP7B, ATOX1, CTR1, or CTR2 levels. Cells lacking ATP7A did not exhibit increased cDDP resistance upon knockdown of Sec61β. Sec61β-KD cells also exhibited altered ATP7A cellular distribution. We conclude that Sec61β modulates the cytotoxicity of many chemotherapeutic agents, with the largest effect being on the platinum drugs. This modulation occurs through effects of Sec61β on the expression and distribution of ATP7A, which was shown previously to control platinum drug sequestration and cytotoxicity. PMID:22710939

  13. Sec61β controls sensitivity to platinum-containing chemotherapeutic agents through modulation of the copper-transporting ATPase ATP7A.

    PubMed

    Abada, Paolo B; Larson, Christopher A; Manorek, Gerald; Adams, Preston; Howell, Stephen B

    2012-09-01

    The Sec61 protein translocon is a multimeric complex that transports proteins across lipid bilayers. We discovered that the Sec61β subunit modulates cellular sensitivity to chemotherapeutic agents, particularly the platinum drugs. To investigate the mechanism, expression of Sec61β was constitutively knocked down in 2008 ovarian cancer cells. Sec61β knockdown (KD) resulted in 8-, 16.8-, and 9-fold resistance to cisplatin (cDDP), carboplatin, and oxaliplatin, respectively. Sec61β KD reduced the cellular accumulation of cDDP to 67% of that in parental cells. Baseline copper levels, copper uptake, and copper cytotoxicity were also reduced. Because copper transporters and chaperones regulate platinum drug accumulation and efflux, their expression in 2008 Sec61β-KD cells was analyzed; ATP7A was found to be 2- to 3-fold overexpressed, whereas there was no change in ATP7B, ATOX1, CTR1, or CTR2 levels. Cells lacking ATP7A did not exhibit increased cDDP resistance upon knockdown of Sec61β. Sec61β-KD cells also exhibited altered ATP7A cellular distribution. We conclude that Sec61β modulates the cytotoxicity of many chemotherapeutic agents, with the largest effect being on the platinum drugs. This modulation occurs through effects of Sec61β on the expression and distribution of ATP7A, which was shown previously to control platinum drug sequestration and cytotoxicity.

  14. Multi-Chemotherapeutic Schedules Containing the pan-FGFR Inhibitor ARQ 087 are Safe and Show Antitumor Activity in Different Xenograft Models.

    PubMed

    Chilà, Rosaria; Hall G, Terence; Abbadessa, Giovanni; Broggini, Massimo; Damia, Giovanna

    2017-02-02

    ARQ 087 is a multi-tyrosine kinase inhibitor with potent activity against the FGFR receptor family, currently in Phase I clinical studies for the treatment of advanced solid tumors. The compound has a very safe profile and induces tumor regressions in FGFR-driven models. The feasibility of combining ARQ 087 with chemotherapy was investigated in FGFR deregulated human xenografts. Nude mice were transplanted subcutaneously with H1581, and when tumor masses reached 150 mg, were randomized to receive vehicle, ARQ 087, paclitaxel, carboplatin as single agents or in combination. Similar experimental conditions were applied in nude mice bearing SNU16 and MFE296 xenografts, with the inclusion of capecitabine in the former xenograft model. In the different xenograft models, the drugs given as single agents ranged from very active to partially active. The double combinations were more active than the single ones, but the triple combinations were the most active. In particular, the combination of ARQ 087 + paclitaxel + carboplatin in H1581 bearing mice was able to induce tumor regression in all the mice, with 6/8 mice tumor free at day 140 after tumor transplant. Of note, no toxic deaths nor premature stopping or delaying of drug administration were observed. The data herein reported demonstrated the feasibility of using xenografts models for poli-chemotherapeutic trials mimicking the best standard of care in treatment of specific tumor type and that ARQ 087, a new pan-FGFR inhibitor, can be safely combined with standard cytotoxic chemotherapeutic drugs with apparently no sign of cumulative toxicity and an associated increased antitumor effect.

  15. Natural and Synthetic Flavonoids: Structure-Activity Relationship and Chemotherapeutic Potential for the Treatment of Leukemia.

    PubMed

    Menezes, José C J M D S; Orlikova, Barbora; Morceau, Franck; Diederich, Marc

    2016-07-29

    Flavonoids and their derivatives are polyphenolic secondary metabolites with an extensive spectrum of pharmacological activities, including antioxidants, antitumor, anti-inflammatory, and antiviral activities. These flavonoids can also act as chemopreventive agents by their interaction with different proteins and can play a vital role in chemotherapy, suggesting a positive correlation between a lower risk of cancer and a flavonoid-rich diet. These agents interfere with the main hallmarks of cancer by various individual mechanisms, such as inhibition of cell growth and proliferation by arresting the cell cycle, induction of apoptosis and differentiation, or a combination of these mechanisms. This review is an effort to highlight the therapeutic potential of natural and synthetic flavonoids as anticancer agents in leukemia treatment with respect to the structure-activity relationship (SAR) and their molecular mechanisms. Induction of cell death mechanisms, production of reactive oxygen species, and drug resistance mechanisms, including p-glycoprotein efflux, are among the best-described effects triggered by the flavonoid polyphenol family.

  16. Determination of six chemotherapeutic agents in municipal wastewater using online solid-phase extraction coupled to liquid chromatography-tandem mass spectrometry.

    PubMed

    Rabii, Farida W; Segura, Pedro A; Fayad, Paul B; Sauvé, Sébastien

    2014-07-15

    Due to the increased consumption of chemotherapeutic agents, their high toxicity, carcinogenicity, their occurrence in the aquatic environment must be properly evaluated. An analytical method based on online solid-phase extraction coupled to liquid chromatography-tandem mass spectrometry was developed and validated. A 1 mL injection volume was used to quantify six of the most widely used cytotoxic drugs (cyclophosphamide, gemcitabine, ifosfamide, methotrexate, irinotecan and epirubicin) in municipal wastewater. The method was validated using standard additions. The validation results in wastewater influent had coefficients of determination (R(2)) between 0.983 and 0.998 and intra-day precision ranging from 7 to 13% (expressed as relative standard deviation %RSD), and from 9 to 23% for inter-day precision. Limits of detection ranged from 4 to 20 ng L(-1) while recovery values were greater than 70% except for gemcitabine, which is the most hydrophilic compound in the selected group and had a recovery of 47%. Matrix effects were interpreted by signal suppression and ranged from 55 to 118% with cyclophosphamide having the highest value. Two of the target anticancer drugs (cyclophosphamide and methotrexate) were detected and quantified in wastewater (effluent and influent) and ranged from 13 to 60 ng L(-1). The proposed method thus allows proper monitoring of potential environmental releases of chemotherapy agents.

  17. Assessment of the inhibitory effects of different radiation qualities or chemotherapeutic agents on a human melanoma cell line.

    PubMed

    Ristić-Fira, Aleksandra M; Petrović, Ivan M; Korićanac, Lela B; Valastro, Lucia M; Privitera, Giuseppe; Cuttone, Giacomo

    2008-12-01

    The correlation between time dependent viabilities, after applying two radiation qualities and two alkylating agents on HTB140 melanoma cells, has been studied. Irradiations were performed with gamma-rays and 62 MeV protons, close to the Bragg peak maximum, delivering doses of 8-24 Gy. Treatments with fotemustine (FM) and dacarbazine (DTIC) were carried out with concentrations of 0.05-2mM. High radio-resistance of HTB140 cells revealed by a clonogenic assay was confirmed by microtetrasolium and sulforhodamine B, through the surviving fraction at 2 Gy (SF2), being 0.961-0.956 for gamma-rays and 0.931-0.887 for protons. A better efficiency of protons was illustrated by relative biological effectiveness at 2 Gy (RBE), ranging from 1.69 to 1.89. A kinetic study of concentration dependent cytotoxicity indicated that the best effect of the drugs, estimated as the concentration that produces 50% of growth inhibition (IC(50)), was obtained at 48 h, having values of 76 microM for DTIC and 145 microM for FM. The cytostatic ability of the drugs pointed out that the presence of DTIC at 24h, compared to FM, was insufficient to produce an effect. Protons and FM demonstrated their pro apoptotic capacity. Cross-resistance between treatments applied to the HTB140 cells was observed, protons being the most efficient, while DTIC, FM and gamma-rays demonstrated a lower level of cell inactivation.

  18. Using Agent-Based Modelling to Predict the Role of Wild Refugia in the Evolution of Resistance of Sea Lice to Chemotherapeutants.

    PubMed

    McEwan, Gregor F; Groner, Maya L; Fast, Mark D; Gettinby, George; Revie, Crawford W

    2015-01-01

    A major challenge for Atlantic salmon farming in the northern hemisphere is infestation by the sea louse parasite Lepeophtheirus salmonis. The most frequent method of controlling these sea louse infestations is through the use of chemical treatments. However, most major salmon farming areas have observed resistance to common chemotherapeutants. In terrestrial environments, many strategies employed to manage the evolution of resistance involve the use of refugia, where a portion of the population is left untreated to maintain susceptibility. While refugia have not been deliberately used in Atlantic salmon farming, wild salmon populations that migrate close to salmon farms may act as natural refugia. In this paper we describe an agent-based model that explores the influence of different sizes of wild salmon populations on resistance evolution in sea lice on a salmon farm. Using the model, we demonstrate that wild salmon populations can act as refugia that limit the evolution of resistance in the sea louse populations. Additionally, we demonstrate that an increase in the size of the population of wild salmon results in an increased effect in slowing the evolution of resistance. We explore the effect of a population fitness cost associated with resistance, finding that in some cases it substantially reduces the speed of evolution to chemical treatments.

  19. Chemotherapeutic agents circumvent emergence of dasatinib-resistant BCR-ABL kinase mutations in a precise mouse model of Philadelphia chromosome-positive acute lymphoblastic leukemia.

    PubMed

    Boulos, Nidal; Mulder, Heather L; Calabrese, Christopher R; Morrison, Jeffrey B; Rehg, Jerold E; Relling, Mary V; Sherr, Charles J; Williams, Richard T

    2011-03-31

    The introduction of cultured p185(BCR-ABL)-expressing (p185+) Arf (-/-) pre-B cells into healthy syngeneic mice induces aggressive acute lymphoblastic leukemia (ALL) that genetically and phenotypically mimics the human disease. We adapted this high-throughput Philadelphia chromosome-positive (Ph(+)) ALL animal model for in vivo luminescent imaging to investigate disease progression, targeted therapeutic response, and ALL relapse in living mice. Mice bearing high leukemic burdens (simulating human Ph(+) ALL at diagnosis) entered remission on maximally intensive, twice-daily dasatinib therapy, but invariably relapsed with disseminated and/or central nervous system disease. Although relapse was frequently accompanied by the eventual appearance of leukemic clones harboring BCR-ABL kinase domain (KD) mutations that confer drug resistance, their clonal emergence required prolonged dasatinib exposure. KD P-loop mutations predominated in mice receiving less intensive therapy, whereas high-dose treatment selected for T315I "gatekeeper" mutations resistant to all 3 Food and Drug Administration-approved BCR-ABL kinase inhibitors. The addition of dexamethasone and/or L-asparaginase to reduced-intensity dasatinib therapy improved long-term survival of the majority of mice that received all 3 drugs. Although non-tumor-cell-autonomous mechanisms can prevent full eradication of dasatinib-refractory ALL in this clinically relevant model, the emergence of resistance to BCR-ABL kinase inhibitors can be effectively circumvented by the addition of "conventional" chemotherapeutic agents with alternate antileukemic mechanisms of action.

  20. Differential Interactions of Cytochrome P450 3A5 and 3A4 with Chemotherapeutic Agent-Vincristine: A Comparative Molecular Dynamics Study.

    PubMed

    Saba, Nikhat; Bhuyan, Rajabrata; Nandy, Suman Kumar; Seal, Alpana

    2015-01-01

    The chemotherapeutic agent vincristine, used for treatment of acute lymphoblastic leukemia is metabolized preferentially by polymorphic cytochrome P450 3A5 (CYP3A5) with higher clearance rate than cytochrome P450 3A4 (CYP3A4). As a result, CYP3A5 expressers have a reduced amount of vincristine-induced peripheral neuropathy than non-expressers. We modeled the structure of CYP3A5 and its interaction with vincristine, compared with CYP3A4-vincristine complex using molecular docking and simulation studies. This relative study helped us to understand the molecular mechanisms behind the interaction at the atomic level through interaction energy, binding free energy, hydrogen bond and solvent accessible surface area analysis - giving an insight into the binding mode and the main residues involved in this particular interaction. Our results show that the interacting groups get closer in CYP3A5-vincristine complex due to different orientation of vincristine. This leads to higher binding affinity of vincristine towards CYP3A5 compared to CYP3A4 and explains the preferential metabolism of vincristine by CYP3A5. We believe that, the results of the current study will be helpful for future studies on structure-based drug design in this area.

  1. Inhibition of phosphatidylinositol 3-kinase promotes tumor cell resistance to chemotherapeutic agents via a mechanism involving delay in cell cycle progression

    SciTech Connect

    McDonald, Gail T.; Sullivan, Richard; Pare, Genevieve C.; Graham, Charles H.

    2010-11-15

    Approaches to overcome chemoresistance in cancer cells have involved targeting specific signaling pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway, a stress response pathway known to be involved in the regulation of cell survival, apoptosis and growth. The present study determined the effect of PI3K inhibition on the clonogenic survival of human cancer cells following exposure to various chemotherapeutic agents. Treatment with the PI3K inhibitors LY294002 or Compound 15e resulted in increased survival of MDA-MB-231 breast carcinoma cells after exposure to doxorubicin, etoposide, 5-fluorouracil, and vincristine. Increased survival following PI3K inhibition was also observed in DU-145 prostate, HCT-116 colon and A-549 lung carcinoma cell lines exposed to doxorubicin. Increased cell survival mediated by LY294002 was correlated with a decrease in cell proliferation, which was linked to an increase in the proportion of cells in the G{sub 1} phase of the cell cycle. Inhibition of PI3K signaling also resulted in higher levels of the cyclin-dependent kinase inhibitors p21{sup Waf1/Cip1} and p27{sup Kip1}; and knockdown of p27{sup kip1} with siRNA attenuated resistance to doxorubicin in cells treated with LY294002. Incubation in the presence of LY294002 after exposure to doxorubicin resulted in decreased cell survival. These findings provide evidence that PI3K inhibition leads to chemoresistance in human cancer cells by causing a delay in cell cycle; however, the timing of PI3K inhibition (either before or after exposure to anti-cancer agents) may be a critical determinant of chemosensitivity.

  2. A Quinoxaline Derivative as a Potent Chemotherapeutic Agent, Alone or in Combination with Benznidazole, against Trypanosoma cruzi

    PubMed Central

    Rodrigues, Jean Henrique da Silva; Ueda-Nakamura, Tânia; Corrêa, Arlene Gonçalves; Sangi, Diego Pereira; Nakamura, Celso Vataru

    2014-01-01

    Background Chagas’ disease is a condition caused by the protozoan Trypanosoma cruzi that affects millions of people, mainly in Latin America where it is considered endemic. The chemotherapy for Chagas disease remains a problem; the standard treatment currently relies on a single drug, benznidazole, which unfortunately induces several side effects and it is not successful in the cure of most of the chronic patients. In order to improve the drug armamentarium against Chagas’ disease, in the present study we describe the synthesis of the compound 3-chloro-7-methoxy-2-(methylsulfonyl) quinoxaline (quinoxaline 4) and its activity, alone or in combination with benznidazole, against Trypanosoma cruzi in vitro. Methodology/Principal Findings Quinoxaline 4 was found to be strongly active against Trypanosoma cruzi Y strain and more effective against the proliferative forms. The cytotoxicity against LLCMK2 cells provided selective indices above one for all of the parasite forms. The drug induced very low hemolysis, but its anti-protozoan activity was partially inhibited when mouse blood was added in the experiment against trypomastigotes, an effect that was specifically related to blood cells. A synergistic effect between quinoxaline 4 and benznidazole was observed against epimastigotes and trypomastigotes, accompanied by an antagonistic interaction against LLCMK2 cells. Quinoxaline 4 induced several ultrastructural alterations, including formations of vesicular bodies, profiles of reticulum endoplasmic surrounding organelles and disorganization of Golgi complex. These alterations were also companied by cell volume reduction and maintenance of cell membrane integrity of treated-parasites. Conclusion/Significance Our results demonstrated that quinoxaline 4, alone or in combination with benznidazole, has promising effects against all the main forms of T. cruzi. The compound at low concentrations induced several ultrastructural alterations and led the parasite to an

  3. Chemical Validation of Phosphodiesterase C as a Chemotherapeutic Target in Trypanosoma cruzi, the Etiological Agent of Chagas' Disease▿ †

    PubMed Central

    King-Keller, Sharon; Li, Minyong; Smith, Alyssa; Zheng, Shilong; Kaur, Gurpreet; Yang, Xiaochuan; Wang, Binghe; Docampo, Roberto

    2010-01-01

    Trypanosoma cruzi phosphodiesterase (PDE) C (TcrPDEC), a novel and rather unusual PDE in which, unlike all other class I PDEs, the catalytic domain is localized in the middle of the polypeptide chain, is able to hydrolyze cyclic GMP (cGMP), although it prefers cyclic AMP (cAMP), and has a FYVE-type domain in its N-terminal region (S. Kunz et al., FEBS J. 272:6412-6422, 2005). TcrPDEC shows homology to the mammalian PDE4 family members. PDE4 inhibitors are currently under development for the treatment of inflammatory diseases, such as asthma, chronic pulmonary diseases, and psoriasis, and for treating depression and serving as cognitive enhancers. We therefore tested a number of compounds originally synthesized as potential PDE4 inhibitors on T. cruzi amastigote growth, and we obtained several useful hits. We then conducted homology modeling of T. cruzi PDEC and identified other compounds as potential inhibitors through virtual screening. Testing of these compounds against amastigote growth and recombinant TcrPDEC activity resulted in several potent inhibitors. The most-potent inhibitors were found to increase the cellular concentration of cAMP. Preincubation of cells in the presence of one of these compounds stimulated volume recovery after hyposmotic stress, in agreement with their TcrPDEC inhibitory activity in vitro, providing chemical validation of this target. The compounds found could be useful tools in the study of osmoregulation in T. cruzi. In addition, their further optimization could result in the development of new drugs against Chagas' disease and other trypanosomiases. PMID:20625148

  4. Effects of Streptococcus thermophilus TH-4 on intestinal mucositis induced by the chemotherapeutic agent, 5-Fluorouracil (5-FU).

    PubMed

    Whitford, Eleanor J; Cummins, Adrian G; Butler, Ross N; Prisciandaro, Luca D; Fauser, Jane K; Yazbeck, Roger; Lawrence, Andrew; Cheah, Ker Y; Wright, Tessa H; Lymn, Kerry A; Howarth, Gordon S

    2009-03-15

    Beneficial bacteria (probiotics) and probiotic-derived factors have the potential to ameliorate disorders of the intestine. The aim of this study was to compare live Streptococcus thermophilus TH-4 (TH-4), dead TH-4 and TH-4 supernatant in rats treated with 5-Fluorouracil. Rats were randomly allocated to five treatment groups (n=8-10): Saline+Water; 5-FU+Skim Milk; 5-FU+Live TH-4; 5-FU+Supernatant TH-4; and 5-FU+Dead TH-4. 5-FU (150mg.kg(-1)) was administered by a single intraperitoneal injection on day 0; animals were killed on day 4. Treatments were administered daily from days -2 to 3 via oro-gastric gavage. Metabolic parameters were measured daily. Blood was obtained by cardiac puncture, and intestinal tissues removed for quantitative and qualitative histological assessment, including: villous height and area; crypt depth and area, mitotic count and crypt fission; biochemical determination of sucrase and myeloperoxidase (MPO) activity; and disease severity scoring. One-way ANOVA statistical analyses were conducted for the majority of outcome measures. Live TH-4 significantly reduced disease severity score by 13% (p< 0.05), and partially normalised mitotic counts compared with 5-FU+Skim milk controls. Live and supernatant TH-4 reduced crypt fission by 69% and 48% (p< 0.05), respectively, compared to 5-FU+Skim Milk controls. No significant differences (p> 0.05) in the occurrence of bacteraemia were evident across all groups. Live TH-4 partially normalised mitotic count and histological severity score in 5-FU treated rats. The inhibitory effect of live TH-4 and TH-4 supernatant on crypt fission suggests therapeutic utility in the prevention of disorders characterised by increased crypt fission, such as colorectal carcinoma.

  5. Effects of Streptococcus thermophilus TH-4 on intestinal mucositis induced by the chemotherapeutic agent 5-Fluorouracil (5-FU).

    PubMed

    Whitford, Eleanor J; Cummins, Adrian G; Butler, Ross N; Prisciandaro, Luca D; Fauser, Jane K; Yazbeck, Roger; Lawrence, Andrew; Cheah, Ker Y; Wright, Tessa H; Lymn, Kerry A; Howarth, Gordon S

    2009-03-15

    Beneficial bacteria (probiotics) and probiotic-derived factors have the potential to ameliorate disorders of the intestine. The aim of this study was to compare live Streptococcus thermophilus TH-4 (TH-4), dead TH-4 and TH-4 supernatant in rats treated with 5-Fluorouracil. Rats were randomly allocated to five treatment groups (n = 8–10): Saline + Water; 5-FU + Skim Milk; 5-FU+ Live TH-4; 5-FU + Supernatant TH-4; and 5-FU + Dead TH-4.5-FU (150 mg.kg-1) was administered by a single intraperitoneal injection on day zero; animals were killed on day four. Treatments were administered daily from days -2 to +3 via oro-gastric gavage. Metabolic parameters were measured daily. Blood was obtained by cardiac puncture, and intestinal tissues removed for quantitative and qualitative histological assessment, including: villus height and area; crypt depth and area, mitotic count and crypt fission;biochemical determination of sucrase and myeloperoxidase (MPO)activity; and disease severity scoring. One-way ANOVA statistical analyses were conducted for the majority of outcome measures. Live TH-4 significantly reduced disease severity score by 13% (p< 0.05), and partially normalized mitotic counts compared with 5-FU + Skim Milk controls. Live and Supernatant TH-4 reduced crypt fission by 69% and 48% (p < 0.05), respectively, compared to 5-FU + Skim Milk controls. No significant differences (p > 0.05) in the occurrence of bacteraemia were evident across all groups. Live TH-4 partially normalized mitotic count and histological severity score in 5-FU treated rats. The inhibitory effect of live TH-4 and TH-4 Supernatant on crypt fission suggests therapeutic utility in the prevention of disorders characterized by increased crypt fission,such as colorectal carcinoma.

  6. Nanospheric Chemotherapeutic and Chemoprotective Agents

    DTIC Science & Technology

    2008-09-01

    targeting the drug-nanosphere complex to diseased cells, thereby minimizing unwanted effects on healthy cells. This report describes the optimization of...military and civilian requirements for effective breast cancer chemotherapy : nontoxic administration, increased bioavailability, prolonged circulation...provide highly effective delivery of hydrophobic paclitaxel to human tumor cells in vitro; (b) tyrosine-derived nanospheres exhibit no toxicity as

  7. Lessons from Nature: Sources and Strategies for Developing AMPK Activators for Cancer Chemotherapeutics.

    PubMed

    Arkwright, Richard T; Deshmukh, Rahul; Adapa, Nikhil; Stevens, Ryan; Zonder, Emily; Zhang, Zhongyu; Farshi, Pershang; Ahmed, Reda Saber Ibrahim; El-Banna, Hossny Awad; Chan, Tak-Hang; Dou, Q Ping

    2015-01-01

    Adenosine Monophosphate-Activated Protein Kinase or AMPK is a highly-conserved master-regulator of numerous cellular processes, including: Maintaining cellular-energy homeostasis, modulation of cytoskeletaldynamics, directing cell growth-rates and influencing cell-death pathways. AMPK has recently emerged as a promising molecular target in cancer therapy. In fact, AMPK deficiencies have been shown to enhance cell growth and proliferation, which is consistent with enhancement of tumorigenesis by AMPK-loss. Conversely, activation of AMPK is associated with tumor growth suppression via inhibition of the Mammalian Target of Rapamycin Complex-1 (mTORC1) or the mTOR signal pathway. The scientific communities' recognition that AMPK-activating compounds possess an anti-neoplastic effect has contributed to a rush of discoveries and developments in AMPK-activating compounds as potential anticancer-drugs. One such example is the class of compounds known as Biguanides, which include Metformin and Phenformin. The current review will showcase natural compounds and their derivatives that activate the AMPK-complex and signaling pathway. In addition, the biology and history of AMPK-signaling and AMPK-activating compounds will be overviewed, their anticancer-roles and mechanisms-of-actions will be discussed, and potential strategies for the development of novel, selective AMPK-activators with enhanced efficacy and reduced toxicity will be proposed.

  8. Application of homology modeling to generate CYP1A1 mutants with enhanced activation of the cancer chemotherapeutic prodrug dacarbazine.

    PubMed

    Lewis, Benjamin C; Mackenzie, Peter I; Miners, John O

    2011-11-01

    The chemotherapeutic prodrug dacarbazine (DTIC) has limited efficacy in human malignancies and exhibits numerous adverse effects that arise from systemic exposure to the cytotoxic metabolite. DTIC is activated by CYP1A1 and CYP1A2 catalyzed N-demethylation. However, structural features of these enzymes that confer DTIC N-demethylation have not been characterized. A validated homology model of CYP1A1 was employed to elucidate structure-activity relationships and to engineer CYP1A1 enzymes with altered DTIC activation. In silico docking demonstrated that DTIC orientates proximally to Ser122, Phe123, Asp313, Ala317, Ile386, Tyr259, and Leu496 of human CYP1A1. The site of metabolism is positioned 5.6 Å from the heme iron at an angle of 105.3°. Binding in the active site is stabilized by H-bonding between Tyr259 and the N(2) position of the imidazole ring. Twenty-seven CYP1A1 mutants were generated and expressed in Escherichia coli in yields ranging from 9 to 225 pmol P450/mg. DTIC N-demethylation by the E161K, E256K, and I458V mutants exhibited Michaelis-Menten kinetics, with decreases in K(m) (183-249 μM) that doubled the catalytic efficiency (p < 0.05) relative to wild-type CYP1A1 (K(m), 408 ± 43 μM; V(max), 28 ± 4 pmol · min(-1) · pmol of P450(-1)). The generation of enzymes with catalytically enhanced DTIC activation highlights the potential use of mutant CYP1A1 proteins in P450-based gene-directed enzyme prodrug therapy for the treatment of metastatic malignant melanoma.

  9. Essential oils as active ingredients of lipid nanocarriers for chemotherapeutic use.

    PubMed

    Severino, Patricia; Andreani, Tatiana; Chaud, Marco V; Benites, Cibelem I; Pinho, Samantha C; Souto, Eliana B

    2015-01-01

    Essential oils have increased interest as promising ingredients for novel pharmaceutical dosage forms. These oils are reported to provide synergistic effects of their active ingredients, in parallel with their biodegradable properties. In addition, essential oils may also have therapeutic effects in diabetes, inflammation, cancer and to treat microbial infections. However, there are some physicochemical properties that may limit their use as active compounds in several formulations, such as high volatility, low-appealing organoleptic properties, low bioavailability and physicochemical instability, as result of exposure to light, oxygen and high temperatures. To overcome these limitations, lipid colloidal carriers (e.g. liposomes, solid lipid nanoparticles (SLN), self nanoemulsified drug delivery systems (SNEDDS)) have been pointed out as suitable carriers to improve bioavailability, low solubility, taste, flavor and long-term storage of sensitive compounds. This paper reviews the potential beneficial effects of formulating essential oils in pharmaceutical applications using colloidal carriers as delivery systems.

  10. Modification of polyethylene glycol onto solid lipid nanoparticles encapsulating a novel chemotherapeutic agent (PK-L4) to enhance solubility for injection delivery

    PubMed Central

    Fang, Yi-Ping; Wu, Pao-Chu; Huang, Yaw-Bin; Tzeng, Cherng-Chyi; Chen, Yeh-Long; Hung, Yu-Han; Tsai, Ming-Jun; Tsai, Yi-Hung

    2012-01-01

    Background The synthetic potential chemotherapeutic agent 3-Chloro-4-[(4-methoxyphenyl) amino]furo[2,3-b]quinoline (PK-L4) is an analog of amsacrine. The half-life of PK-L4 is longer than that of amsacrine; however, PK-L4 is difficult to dissolve in aqueous media, which is problematic for administration by intravenous injection. Aims To utilize solid lipid nanoparticles (SLNs) modified with polyethylene glycol (PEG) to improve the delivery of PK-L4 and investigate its biodistribution behavior after intravenous administration. Results The particle size of the PK-L4-loaded SLNs was 47.3 nm and the size of the PEGylated form was smaller, at 28 nm. The entrapment efficiency (EE%) of PK-L4 in SLNs with and without PEG showed a high capacity of approximately 100% encapsulation. Results also showed that the amount of PK-L4 released over a prolonged period from SLNs both with and without PEG was comparable to the non-formulated group, with 16.48% and 30.04%, respectively, of the drug being released, which fit a zero-order equation. The half-maximal inhibitory concentration values of PK-L4-loaded SLNs with and those without PEG were significantly reduced by 45%–64% in the human lung carcinoma cell line (A549), 99% in the human breast adenocarcinoma cell line with estrogen receptor (MCF7), and 95% in the human breast adenocarcinoma cell line (MDA-MB-231). The amount of PK-L4 released by SLNs with PEG was significantly higher than that from the PK-L4 solution (P < 0.05). After intravenous bolus of the PK-L4-loaded SLNs with PEG, there was a marked significant difference in half-life alpha (0.136 ± 0.046 hours) when compared with the PK-L4 solution (0.078 ± 0.023 hours); also the area under the curve from zero to infinity did not change in plasma when compared to the PK-L4 solution. This demonstrated that PK-L4-loaded SLNs were rapidly distributed from central areas to tissues and exhibited higher accumulation in specific organs. The highest deposition of PK-L4-loaded SLNs

  11. In vitro DNA binding profile of enantiomeric dinuclear Cu(II)/Ni(II) complexes derived from l-/d-histidine-terepthaldehyde reduced Schiff base as potential chemotherapeutic agents.

    PubMed

    Yousuf, Imtiyaz; Arjmand, Farukh

    2016-11-01

    New chiral reduced Schiff base ligands, L1 and L2 derived from l-/d-histidine and terepthaldehyde, and their Cu(II) and Ni(II) dinuclear complexes 1 &2 (a and b) were synthesized and thoroughly characterized by various spectroscopic techniques. Comparative binding profile of both l-/d-enantiomeric Cu(II) and Ni(II) complexes with ct-DNA was studied by employing optical and spectroscopic techniques to evaluate their enantiopreferential selectivity towards molecular target DNA and thereby explore their relative chemotherapeutic potential. Quantitative assessment of DNA binding propensity was ascertained by calculating Kb, K and Ksv values of 1 &2 (a and b) which demonstrated higher binding affinity of l-enantiomeric Cu(II) complex, 1a and followed the order as 1a>1b>2a>2b. Scanning electron microscopy (SEM) was used to analyze the morphological changes of the DNA condensate in presence of complexes 1 (a and b). The SEM micrographs condensates revealed morphological transitions and formation of different structural features implicating the condensation process between the complexes and biomolecule occurred to form compact massive structures. The gel electrophoretic assay of complex 1a was carried out with pBR322 plasmid DNA which revealed an efficient cleaving ability of the complex via oxidative pathway with the involvement of singlet oxygen ((1)O2) and the superoxide anion (O2(•-)) radicals as the ROS responsible the cleavage reactions. Molecular docking studies of 1 (a and b) with DNA revealed selective recognition of G-C residues of the narrow minor groove of the DNA duplex and complex 1a demonstrated binding affinity towards DNA ascertained from its higher binding energy values. Furthermore, the cytotoxic assessment of 1a was examined on a panel of cancer cell lines of different histological origin employing SRB assay which revealed remarkably good cytotoxic activity towards HL60, HeLa and MCF7 cancer cell lines.

  12. Augmentation of Chemotherapeutic Infusion Effect by TSU-68, an Oral Targeted Antiangiogenic Agent, in a Rabbit VX2 Liver Tumor Model

    SciTech Connect

    Kim, Hyo-Cheol; Chung, Jin Wook Choi, Seung Hong; Im, Seock-Ah; Yamasaki, Yasundo; Jun, Suryoung; Jae, Hwan Jun; Park, Jae Hyung

    2012-02-15

    Purpose: This study was designed to investigate the in vivo effects of combination therapy with TSU-68 and chemotherapeutic infusion in a rabbit VX2 liver tumor model. Methods: This study was approved by the animal care committee at our institute. Three weeks before chemotherapeutic infusion, VX2 carcinoma was implanted into the livers of 32 rabbits. One week after chemotherapeutic infusion, vehicle was administered orally for 3 weeks in the control group (n = 16), and TSU-68 was administered orally at a daily dose of 200 mg/kg for 3 weeks in the treated group (n = 16). Computed tomography (CT) was performed before and 1, 2, 3, and 4 weeks after chemotherapeutic infusion. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) on CT scan. The maximum thickness of viable tumor was measured on microscopic sections. Results: According to the RECIST, stable disease was observed in 9 (56%) rabbits and progressive disease in 7 (44%) in the control group, whereas partial response was observed in 1 (6%) rabbit and stable disease in 15 (94%) in the treated group. On pathologic examination, a viable lesion was present in 12 (75%) rabbits in the control group and in 6 (38%) rabbits in the treated group (P = 0.073). The mean maximum thickness of viable tumor in the treated group was significantly smaller than that in the control group (0.74 mm vs. 3.39 mm; P = 0.02). Conclusions: Oral administration of TSU-68 augmented the effect of chemotherapeutic infusion in a rabbit VX2 liver tumor model.

  13. Pro-oxidant activity of dietary chemopreventive agents: an under-appreciated anti-cancer property.

    PubMed

    Azmi, Asfar S; Sarkar, Fazlul H; Hadi, S M

    2013-01-01

    " Let food be thy medicine and medicine be thy food" was quoted by Hippocrates more than two thousand years ago and since ancient times the health benefits of different natural agents have been exploited. In modern research, the disease preventive benefits of many such natural agents, particularly dietary compounds and their derivatives, has been attributed to their well recognized activity as the regulators of redox state of the cell. Nevertheless, most of these studies have focused on their antioxidant activity. A large body of evidence indicates that a major fraction of these agents can elicit pro-oxidant (radical generating) behavior which has been linked to their anti-cancer effects. This editorial provides an overview of the under-appreciated pro-oxidant activity of natural products, with a special focus on their ability to generate reactive oxygen species in the presence of transition metal ions, and discusses their possible use as cancer chemotherapeutic agents.

  14. Field Agent Activities: Level 1.

    ERIC Educational Resources Information Center

    Gussett, James

    One of a series of monographs providing information about the Delaware Model: A Systems Approach to Science Education (Del Mod System), this monograph describes the role of field agents. These agents are responsible for individual teachers who express a desire for involvement in improving teacher effectiveness and to be involved in the teaching of…

  15. Blockade of constitutively activated ERK signaling enhances cytotoxicity of microtubule-destabilizing agents in tumor cells.

    PubMed

    Tanimura, Susumu; Uchiyama, Aya; Watanabe, Kazushi; Yasunaga, Masahiro; Inada, Yoshiyuki; Kawabata, Takumi; Iwashita, Ken-Ichi; Noda, Sinji; Ozaki, Kei-Ichi; Kohno, Michiaki

    2009-01-16

    The extracellular signal-regulated kinase (ERK) signaling pathway is constitutively activated in many human tumor cell types. Given the cytoprotective role of this pathway, we examined whether its specific blockade might sensitize human tumor cells to the induction of apoptosis by various anticancer drugs. Although blockade of ERK signaling alone did not induce substantial cell death, it resulted in marked and selective enhancement of the induction of apoptosis by microtubule-destabilizing agents in tumor cells in which the ERK pathway is constitutively activated. The synergistic activation of c-Jun NH(2)-terminal kinase by the combination of an ERK pathway inhibitor and a microtubule-destabilizing agent appeared to be responsible, at least in part, for this effect. These results suggest that administration of the combination of an ERK pathway inhibitor and a microtubule-destabilizing agent is a potential chemotherapeutic strategy for the treatment of tumor cells with constitutive activation of the ERK pathway.

  16. Screening of promising chemotherapeutic candidates against human adult T-cell leukemia/lymphoma from plants: active principles from Physalis pruinosa and structure-activity relationships with withanolides.

    PubMed

    Nakano, Daisuke; Ishitsuka, Kenji; Hatsuse, Takahiro; Tsuchihashi, Ryota; Okawa, Masafumi; Okabe, Hikaru; Tamura, Kazuo; Kinjo, Junei

    2011-07-01

    Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell lymphotropic virus type I (HTLV-1). Clinical manifestations of ATL range from smoldering to chronic, lymphoma and acute subtypes. Patients with acute and lymphoma-type ATL require therapeutic intervention. Conventional chemotherapeutic regimens used against other malignant lymphoma have been administered to ATL patients, but the therapeutic outcomes of acute and lymphoma-type ATL remain very poor. In this study, 214 extracts from 162 plants belonging to 65 families were screened for the purpose of elucidating the anti-proliferative effect against HTLV-1-infected T-cell lines. Extracts from aerial parts of Physalis pruinosa showed potent inhibitory effect. We isolated five withanolides from the extracts by activity-guided fractionation and examined the structure-activity relationships. The presence of a 5β,6β-epoxy function is suggested to be essential for the activity, and the most active principle showed selective toxicity to HTLV-1-infected T-cell lines.

  17. N-acetylaspartate (NAA) induces neuronal differentiation of SH-SY5Y neuroblastoma cell line and sensitizes it to chemotherapeutic agents

    PubMed Central

    Mazzoccoli, Carmela; Ruggieri, Vitalba; Tataranni, Tiziana; Agriesti, Francesca; Laurenzana, Ilaria; Fratello, Angelo; Capitanio, Nazzareno; Piccoli, Claudia

    2016-01-01

    Neuroblastoma is the most commonly extra-cranial solid tumor of childhood frequently diagnosed. The nervous system-specific metabolite N-acetylaspartate (NAA) is synthesized from aspartate and acetyl-CoA in neurons, it is among the most abundant metabolites present in the central nervous system (CNS) and appears to be involved in many CNS disorders. The functional significance of the high NAA concentration in the brain remains uncertain, but it confers to NAA a unique clinical significance exploited in magnetic resonance spectroscopy. In the current study, we show that treatment of SH-SY5Y neuroblastoma-derived cell line with sub-cytotoxic physiological concentrations of NAA inhibits cell growth. This effect is partly due to enhanced apoptosis, shown by decrease of the anti-apoptotic factors survivin and Bcl-xL, and partly to arrest of the cell-cycle progression, linked to enhanced expression of the cyclin-inhibitors p53, p21Cip1/Waf1 and p27Kip1. Moreover, NAA-treated SH-SY5Y cells exhibited morphological changes accompanied with increase of the neurogenic markers TH and MAP2 and down-regulation of the pluripotency markers OCT4 and CXCR4/CD184. Finally, NAA-pre-treated SH-SY5Y cells resulted more sensitive to the cytotoxic effect of the chemotherapeutic drugs Cisplatin and 5-fluorouracil. To our knowledge, this is the first study demonstrating the neuronal differentiating effects of NAA in neuroblastoma cells. NAA may be a potential preconditioning or adjuvant compound in chemotherapeutic treatment. PMID:27036033

  18. Activity Recognition for Agent Teams

    DTIC Science & Technology

    2007-07-01

    correspond to a real team, but is rather a visual illusion caused by a coincidental configuration of agents. 50 CHAPTER 4. STABR The behavior...each frame-pair were only classified with 76% accuracy, such a method would hallucinate false action transitions at unacceptable rates). Fortunately

  19. Scalable Production of Recombinant Membrane Active Peptides and Its Potential as a Complementary Adjunct to Conventional Chemotherapeutics

    PubMed Central

    Rothan, Hussin A.; Ambikabothy, Jamunaa; Abdulrahman, Ammar Y.; Bahrani, Hirbod; Golpich, Mojtaba; Amini, Elham; A. Rahman, Noorsaadah; Teoh, Teow Chong; Mohamed, Zulqarnain; Yusof, Rohana

    2015-01-01

    The production of short anticancer peptides in recombinant form is an alternative method for costly chemical manufacturing. However, the limitations of host toxicity, bioactivity and column purification have impaired production in mass quantities. In this study, short cationic peptides were produced in aggregated inclusion bodies by double fusion with a central protein that has anti-cancer activity. The anticancer peptides Tachiplicin I (TACH) and Latarcin 1 (LATA) were fused with the N- and C-terminus of the MAP30 protein, respectively. We successfully produced the recombinant TACH-MAP30-LATA protein and MAP30 alone in E. coli that represented 59% and 68% of the inclusion bodies. The purified form of the inclusion bodies was prepared by eliminating host cell proteins through multiple washing steps and semi-solubilization in alkaline buffer. The purified active protein was recovered by inclusive solubilization at pH 12.5 in the presence of 2 M urea and refolded in alkaline buffer containing oxides and reduced glutathione. The peptide-fusion protein showed lower CC50 values against cancer cells (HepG2, 0.35±0.1 μM and MCF-7, 0.58±0.1 μM) compared with normal cells (WRL68, 1.83±0.2 μM and ARPE19, 2.5±0.1 μM) with outstanding activity compared with its individual components. The presence of the short peptides facilitated the entry of the peptide fusion protein into cancer cells (1.8 to 2.2-fold) compared with MAP30 alone through direct interaction with the cell membrane. The cancer chemotherapy agent doxorubicin showed higher efficiency and selectivity against cancer cells in combination with the peptide- fusion protein. This study provides new data on the mass production of short anticancer peptides as inclusion bodies in E. coli by fusion with a central protein that has similar activity. The product was biologically active against cancer cells compared with normal cells and enhanced the activity and selective delivery of an anticancer chemotherapy agent

  20. New agents with antimycobacterial activity.

    PubMed

    Marco-Contelles, José; Gómez-Sánchez, Elena

    2005-11-01

    In this paper, we report that a series of structurally simple a-halogenoacetamides show potent and excellent antimycobacterial activities against drug-sensitive Mycobacterium tuberculosis H(37)Rv and drug-resistant M. avium.

  1. Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models.

    PubMed

    Perera, Yasser; Toro, Neylen Del; Gorovaya, Larisa; Fernandez-DE-Cossio, Jorge; Farina, Hernan G; Perea, Silvio E

    2014-11-01

    CIGB-300 is a novel clinical-stage synthetic peptide that impairs the casein kinase 2 (CK2)-mediated phosphorylation of B23/nucleophosmin in different experimental settings and cancer models. As a single agent, CIGB-300 induces apoptosis in vitro and in vivo and modulates an array of proteins that are mainly involved in drug resistance, cell proliferation and apoptosis, as determined by proteomic analysis. However, the clinical oncology practice and cumulative knowledge on tumor biology suggest that drug combinations are more likely to cope with tumor complexity compared to single agents. In this study, we investigated the antiproliferative effect of CIGB-300 when combined with different anticancer drugs, such as cisplatin (alkylating), paclitaxel (antimitotic), doxorubicin (antitopoisomerase II) or 5-fluorouracil (DNA/RNA antimetabolite) in cell lines derived from lung and cervical cancer. Of note, using a Latin square design and subsequent analysis by CalcuSyn software, we observed that paclitaxel and cisplatin exhibited the best synergistic/additive profile when combined with CIGB-300, according to the combination and dose reduction indices. Such therapeutically favorable profiles may be explained by a direct cytotoxic effect and also by the observed cell cycle impairment following incubation of tumor cells with selected drug combinations. Importantly, on in vivo dose-finding schedules in human cervical tumors xenografted in nude mice, we observed that concomitant administration of CIGB-300 and cisplatin increased mice survival compared to single-agent treatment. Collectively, these findings provide a rationale for combining the anti-CK2 CIGB-300 peptide with currently available anticancer agents in the clinical setting and indicate platins and taxanes as compounds with major perspectives.

  2. Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models

    PubMed Central

    PERERA, YASSER; TORO, NEYLEN DEL; GOROVAYA, LARISA; FERNANDEZ-DE-COSSIO, JORGE; FARINA, HERNAN G.; PEREA, SILVIO E.

    2014-01-01

    CIGB-300 is a novel clinical-stage synthetic peptide that impairs the casein kinase 2 (CK2)-mediated phosphorylation of B23/nucleophosmin in different experimental settings and cancer models. As a single agent, CIGB-300 induces apoptosis in vitro and in vivo and modulates an array of proteins that are mainly involved in drug resistance, cell proliferation and apoptosis, as determined by proteomic analysis. However, the clinical oncology practice and cumulative knowledge on tumor biology suggest that drug combinations are more likely to cope with tumor complexity compared to single agents. In this study, we investigated the antiproliferative effect of CIGB-300 when combined with different anticancer drugs, such as cisplatin (alkylating), paclitaxel (antimitotic), doxorubicin (antitopoisomerase II) or 5-fluorouracil (DNA/RNA antimetabolite) in cell lines derived from lung and cervical cancer. Of note, using a Latin square design and subsequent analysis by CalcuSyn software, we observed that paclitaxel and cisplatin exhibited the best synergistic/additive profile when combined with CIGB-300, according to the combination and dose reduction indices. Such therapeutically favorable profiles may be explained by a direct cytotoxic effect and also by the observed cell cycle impairment following incubation of tumor cells with selected drug combinations. Importantly, on in vivo dose-finding schedules in human cervical tumors xenografted in nude mice, we observed that concomitant administration of CIGB-300 and cisplatin increased mice survival compared to single-agent treatment. Collectively, these findings provide a rationale for combining the anti-CK2 CIGB-300 peptide with currently available anticancer agents in the clinical setting and indicate platins and taxanes as compounds with major perspectives. PMID:25279177

  3. Design, synthesis and structure--activity relationship (SAR) studies of imidazo[4,5-b]pyridine derived purine isosteres and their potential as cytotoxic agents.

    PubMed

    Sajith, Ayyiliath M; Abdul Khader, K K; Joshi, Nithin; Reddy, Manchala Nageswar; Syed Ali Padusha, M; Nagaswarupa, H P; Nibin Joy, M; Bodke, Yadav D; Karuvalam, Ranjith P; Banerjee, Rinti; Muralidharan, A; Rajendra, P

    2015-01-07

    Drug resistance to chemotherapeutic agents paved the way to develop novel synthetic molecules which are active on MDR cancer cell lines. Regio-isomeric imidazo[4,5-b]pyridine analogues were synthesized and evaluated for their cytotoxic activity against a range of cancer cell lines. The structure-activity relationship (SAR) studies of the imidazopyridine analogues are also described. Analogue 6b displayed strong cytotoxicity and good microsomal stability.

  4. Socialization Agents and Activities of Young Adolescents

    ERIC Educational Resources Information Center

    Arnon, Sara; Shamai, Shmuel; Ilatov, Zinaida

    2008-01-01

    Research examined the relative importance of peer groups for young adolescents as compared with diverse adult socialization agents--family, school, and community. The factors involved were teenagers' activities, preferences, feelings, and thoughts as to how they spend their leisure time, their preferences for help providers, and their sense of…

  5. Experimental FT-IR, Laser-Raman and DFT spectroscopic analysis of a potential chemotherapeutic agent 6-(2-methylpropyl)-4-oxo-2-sulfanylidene-1,2,3,4-tetrahydropyrimidine-5-carbonitrile.

    PubMed

    Sert, Yusuf; Al-Turkistani, Abdulghafoor A; Al-Deeb, Omar A; El-Emam, Ali A; Ucun, Fatih; Çırak, Çağrı

    2014-01-01

    In this study, the experimental and theoretical vibrational frequencies of a newly synthesized potential chemotherapeutic agent namely, 6-(2-methylpropyl)-4-oxo-2-sulfanylidene-1,2,3,4-tetrahydropyrimidine-5-carbonitrile have been investigated. The experimental FT-IR (4000-400 cm(-1)) and Laser-Raman spectra (4000-100 cm(-1)) of the molecule in solid phase have been recorded. The theoretical vibrational frequencies and optimized geometric parameters (bond lengths and bond angles) have been calculated by using density functional theory (DFT/B3LYP: Becke, 3-parameter, Lee-Yang-Parr) and M06-2X (the highly parametrized, empirical exchange correlation function) quantum chemical methods with 6-311++G(d,p) basis set by Gaussian 09 W software, for the first time. The assignments of the vibrational frequencies have been done by potential energy distribution (PED) analysis by using VEDA 4 software. The theoretical optimized geometric parameters and vibrational frequencies have been found to be in good agreement with the corresponding experimental data, and with the results in the literature. In addition, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energies and the other related molecular energy values have been calculated and depicted.

  6. Double-Walled Microparticles-Embedded Self-Cross-Linked, Injectable, and Antibacterial Hydrogel for Controlled and Sustained Release of Chemotherapeutic Agents.

    PubMed

    Davoodi, Pooya; Ng, Wei Cheng; Yan, Wei Cheng; Srinivasan, Madapusi P; Wang, Chi-Hwa

    2016-09-07

    First-line cancer chemotherapy has been prescribed for patients suffered from cancers for many years. However, conventional chemotherapy provides a high parenteral dosage of anticancer drugs over a short period, which may cause serious toxicities and detrimental side effects in healthy tissues. This study aims to develop a new drug delivery system (DDS) composed of double-walled microparticles and an injectable hydrogel for localized dual-agent drug delivery to tumors. The uniform double-walled microparticles loaded with cisplatin (Cis-DDP) and paclitaxel (PTX) were fabricated via coaxial electrohydrodynamic atomization (CEHDA) technique and subsequently were embedded into injectable alginate-branched polyethylenimine. The findings show the uniqueness of CEHDA technique for simply swapping the place of drugs to achieve a parallel or a sequential release profile. This study also presents the simulation of CEHDA technique using computational fluid dynamics (CFD) that will help in the optimization of CEHDA's operating conditions prior to large-scale production of microparticles. The new synthetic hydrogel provides an additional diffusion barrier against Cis-DDP and confines premature release of drugs. In addition, the hydrogel can provide a versatile tool for retaining particles in the tumor resected cavity during the injection after debulking surgery and preventing surgical site infection due to its inherent antibacterial properties. Three-dimensional MDA-MB-231 (breast cancer) spheroid studies demonstrate a superior efficacy and a greater reduction in spheroid growth for drugs released from the proposed composite formulation over a prolonged period, as compared with free drug treatment. Overall, the new core-shell microparticles embedded into injectable hydrogel can serve as a flexible controlled release platform for modulating the release profiles of anticancer drugs and subsequently providing a superior anticancer response.

  7. Quantum Speedup for Active Learning Agents

    NASA Astrophysics Data System (ADS)

    Paparo, Giuseppe Davide; Dunjko, Vedran; Makmal, Adi; Martin-Delgado, Miguel Angel; Briegel, Hans J.

    2014-07-01

    Can quantum mechanics help us build intelligent learning agents? A defining signature of intelligent behavior is the capacity to learn from experience. However, a major bottleneck for agents to learn in real-life situations is the size and complexity of the corresponding task environment. Even in a moderately realistic environment, it may simply take too long to rationally respond to a given situation. If the environment is impatient, allowing only a certain time for a response, an agent may then be unable to cope with the situation and to learn at all. Here, we show that quantum physics can help and provide a quadratic speedup for active learning as a genuine problem of artificial intelligence. This result will be particularly relevant for applications involving complex task environments.

  8. Human toxoplasmosis-Searching for novel chemotherapeutics.

    PubMed

    Antczak, Magdalena; Dzitko, Katarzyna; Długońska, Henryka

    2016-08-01

    The protozoan Toxoplasma gondii, an obligate intracellular parasite, is an etiological agent of human and animal toxoplasmosis. Treatment regimens for T. gondii-infected patients have not essentially changed for years. The most common chemotherapeutics used in the therapy of symptomatic toxoplasmosis are a combination of pyrimethamine and sulfadiazine plus folinic acid or a combination of pyrimethamine with lincosamide or macrolide antibiotics. To protect a fetus from parasite transplacental transmission, therapy of pregnant women is usually based on spiramycin, which is quite safe for the organism, but not efficient in the treatment of infected children. Application of recommended drugs limits replication of T. gondii, however, it may be associated with numerous an severe adverse effects. Moreover, medicines have no impact on the tissue cysts of the parasite located predominantly in a brain and muscles. Thus, there is urgent need to develop new drugs and establish "gold standard" treatment. In this review classical treatment of toxoplasmosis as well as potential compounds active against T. gondii have been discussed. For two last decades studies on the development of new anti-T. gondii medications have been focused on both natural and novel synthetic compounds based on existing chemical scaffolds. They have revealed several promising drug candidates characterized by a high selectivity, the low IC50 (the half maximal inhibitory concentration) and low cytotoxicity towards host cells. These drugs are expected to replace or supplement current anti-T. gondii drug arsenal soon.

  9. Activation of ATM by DNA Damaging Agents

    DTIC Science & Technology

    2005-09-01

    serine 139. Pretreatment of cells with NAC partially, peroxide dismutase and glutathione peroxidase - 1 (37). This but significantly, attenuated the... Gy , concentrations of wortmannin (lanes 3-5) for 30 min prior to the addi- 2 h) (Fig. 4A). tion of 1 gm doxorubicin (lanes 2-5) and further incubation...AD Award Number: DAMD17-02- 1 -0318 TITLE: Activation of ATM by DNA Damaging Agents PRINCIPAL INVESTIGATOR: Ebba U. Kurz, Ph.D. Susan P. Lees-Miller

  10. Effect of a novel oral chemotherapeutic agent containing a combination of trifluridine, tipiracil and the novel triple angiokinase inhibitor nintedanib, on human colorectal cancer xenografts

    PubMed Central

    Suzuki, Norihiko; Nakagawa, Fumio; Matsuoka, Kazuaki; Takechi, Teiji

    2016-01-01

    Trifluridine/tipiracil (TFTD) is a combination drug that is used for the treatment of metastatic colorectal cancer and was formerly known as TAS-102. It is a combination of two active pharmaceutical compounds, trifluridine, an antineoplastic thymidine-based nucleoside analog, and tipiracil, which enhances the bioavailability of trifluridine in vivo. TFTD is used for the treatment of patients with unresectable advanced or recurrent colorectal cancer that is resistant to standard therapies. In the present study, the anticancer effects of trifluridine in combination with nintedanib, an oral triple angiokinase inhibitor, on human colorectal cancer cell lines were investigated. The cytotoxicity against DLD-1, HT-29, and HCT116 cell lines was determined by the crystal violet staining method. The combination of trifluridine and nintedanib exerted an additive effect on the growth inhibition of DLD-1 and HT-29 cells and a sub-additive effect on HCT116 cells, as determined by isobologram analyses. Subsequently, the human colorectal cancer cell lines were implanted subcutaneously into nude mice to allow the evaluation of the in vivo tumor growth inhibitory effects of TFTD and nintedanib combination therapy. TFTD (150 mg/kg/day) and/or nintedanib (40 mg/kg/day) were orally administered to the mice twice daily from day 1 to day 14. The tumor growth inhibition with combination therapy was 61.5, 72.8, 67.6 and 67.5% for the DLD-1, DLD-1/5-FU, HT-29, and HCT116 xenografts, respectively. This was significantly (P<0.05) higher than the effects of monotherapy with either TFTD or nintedanib. These results demonstrated the effectiveness of the combination of TFTD and nintedanib in the treatment of colorectal cancer xenografts. The concentration of trifluridine incorporated into DNA in the HT-29 and HCT116 tumors was determined by liquid chromatography-tandem mass spectrometry. The incorporation levels following treatment with TFTD and nintedanib for 14 consecutive days were higher than

  11. The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4

    PubMed Central

    Li, Yan; Adamek, Pavel; Zhang, Haijun; Tatsui, Claudio Esteves; Rhines, Laurence D.; Mrozkova, Petra; Li, Qin; Kosturakis, Alyssa K.; Cassidy, Ryan M.; Harrison, Daniel S.; Cata, Juan P.; Sapire, Kenneth; Zhang, Hongmei; Kennamer-Chapman, Ross M.; Jawad, Abdul Basit; Ghetti, Andre; Yan, Jiusheng; Palecek, Jiri

    2015-01-01

    Peripheral neuropathy is dose limiting in paclitaxel cancer chemotherapy and can result in both acute pain during treatment and chronic persistent pain in cancer survivors. The hypothesis tested was that paclitaxel produces these adverse effects at least in part by sensitizing transient receptor potential vanilloid subtype 1 (TRPV1) through Toll-like receptor 4 (TLR4) signaling. The data show that paclitaxel-induced behavioral hypersensitivity is prevented and reversed by spinal administration of a TRPV1 antagonist. The number of TRPV1+ neurons is increased in the dorsal root ganglia (DRG) in paclitaxel-treated rats and is colocalized with TLR4 in rat and human DRG neurons. Cotreatment of rats with lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides (LPS-RS), a TLR4 inhibitor, prevents the increase in numbers of TRPV1+ neurons by paclitaxel treatment. Perfusion of paclitaxel or the archetypal TLR4 agonist LPS activated both rat DRG and spinal neurons directly and produced acute sensitization of TRPV1 in both groups of cells via a TLR4-mediated mechanism. Paclitaxel and LPS sensitize TRPV1 in HEK293 cells stably expressing human TLR4 and transiently expressing human TRPV1. These physiological effects also are prevented by LPS-RS. Finally, paclitaxel activates and sensitizes TRPV1 responses directly in dissociated human DRG neurons. In summary, TLR4 was activated by paclitaxel and led to sensitization of TRPV1. This mechanism could contribute to paclitaxel-induced acute pain and chronic painful neuropathy. SIGNIFICANCE STATEMENT In this original work, it is shown for the first time that paclitaxel activates peripheral sensory and spinal neurons directly and sensitizes these cells to transient receptor potential vanilloid subtype 1 (TRPV1)-mediated capsaicin responses via Toll-like receptor 4 (TLR4) in multiple species. A direct functional interaction between TLR4 and TRPV1 is shown in rat and human dorsal root ganglion neurons, TLR4/TRPV1

  12. (Coordinated research of chemotherapeutic agents and radiopharmaceuticals)

    SciTech Connect

    Srivastava, P.C.

    1991-01-14

    The traveler received a United Nations Development Program (UNDP) Award for Distinguished Scientists to visit Indian Research Institutions including Central Drug Research Institute (CDRI), Lucknow, the host institution, in cooperation with the Council of Scientific and Industrial Research (CSIR) of India. At CDRI, the traveler had meetings to discuss progress and future directions of on-going collaborative research work on nucleosides and had the opportunity to initiate new projects with the divisions of pharmacology, biopolymers, and membrane biology. As a part of this program, the traveler also visited Sanjay Gandhi Post Graduate Institute (SGPI) of Medical Sciences, Lucknow; Board of Radiation and Isotope Technology (BRIT) and Bhabha Atomic Research Center (BARC), Bombay; Variable Energy Cyclotron Center (VECC) and Indian Institute of Chemical Biology, Calcutta. He also attended the Indo-American Society of Nuclear Medicine Meeting held in Calcutta. The traveler delivered five seminars describing various aspects of radiopharmaceutical development at the Oak Ridge National Laboratory (ORNL) and discussed the opportunities for exchange visits to ORNL by Indian scientists.

  13. The influence of active hexose correlated compound (AHCC) on cisplatin-evoked chemotherapeutic and side effects in tumor-bearing mice

    SciTech Connect

    Hirose, Aya; Sato, Eri; Fujii, Hajime; Sun Buxiang; Nishioka, Hiroshi . E-mail: nishioka@aminoup.co.jp; Aruoma, Okezie I. . E-mail: okezie.aruoma@touro.edu

    2007-07-15

    Cisplatin (cis-diaminedichloroplatinum (II) or CDDP) (a widely used platinum-containing anticancer drug) is nephrotoxic and has a low percentage of tolerance in patients during chemotherapy. The active hexose correlated compound (AHCC) is an extract of Basidiomycotina marketed as a supplement for cancer patients due to its nutrients and fibre content and its ability to strengthen and optimize the capacity of the immune system. The possibility that AHCC could reduce the side effects of cisplatin was assessed in the tumor-bearing BALB/cA mice on the basis of the ability to ameliorate the cisplatin-induced body weight loss, anorexia, nephrotoxicity and hematopoietic toxicity. Although cisplatin (8 mg/kg body weight) reduced the size and weight of the solid tumors, supplementation with AHCC significantly enhanced cisplatin-induced antitumor effect in both the size (p < 0.05) and weight (p < 0.05). Food intake in the cisplatin-treated mice were decreased following commencement of treatment and this remained low compared with the cisplatin-untreated group (control) throughout the experiment period. Supplementation with AHCC increased the food intake in the cisplatin-treated mice. The blood urea nitrogen and serum creatinine concentrations, and the ratio of blood urea nitrogen to serum creatinine were significantly increased in the cisplatin alone treated group compared to the control group. Their increased levels were mitigated by supplementation with AHCC (100 mg/kg body weight) in the cisplatin-treated group. AHCC was also able to modulate the suppression of bone marrow due to cisplatin and the improvement was statistically significant. The histopathological examination of the kidney revealed the presence of cisplatin-induced damage and this was modulated by AHCC treatment. The potential for AHCC to ameliorate the cisplatin-evoked toxicity as well as the chemotherapeutic effect could have beneficial economic implications for patients undergoing chemotherapy with

  14. Antiendotoxin activity of cationic peptide antimicrobial agents.

    PubMed

    Gough, M; Hancock, R E; Kelly, N M

    1996-12-01

    The endotoxin from gram-negative bacteria consists of a molecule lipopolysaccharide (LPS) which can be shed by bacteria during antimicrobial therapy. A resulting syndrome, endotoxic shock, is a leading cause of death in the developed world. Thus, there is great interest in the development of antimicrobial agents which can reverse rather than promote sepsis, especially given the recent disappointing clinical performance of antiendotoxin therapies. We describe here two small cationic peptides, MBI-27 and MBI-28, which have both antiendotoxic and antibacterial activities in vitro and in vivo in animal models. We had previously demonstrated that these peptides bind to LPS with an affinity equivalent to that of polymyxin B. Consistent with this, the peptides blocked the ability of LPS and intact cells to induce the endotoxic shock mediator, tumor necrosis factor (TNF), upon incubation with the RAW 264.7 murine macrophage cell line. MBI-28 was equivalent to polymyxin B in its ability to block LPS induction of TNF by this cell line, even when added 60 min after the TNF stimulus. Furthermore, MBI-28 offered significant protection in a galactosamine-sensitized mouse model of lethal endotoxic shock. This protection correlated with the ability of MBI-28 to reduce LPS-induced circulating TNF by nearly 90% in this mouse model. Both MBI-27 and MBI-28 demonstrated antibacterial activity against gram-negative bacteria in vitro and in vivo against Pseudomonas aeruginosa infections in neutropenic mice.

  15. Antiendotoxin activity of cationic peptide antimicrobial agents.

    PubMed Central

    Gough, M; Hancock, R E; Kelly, N M

    1996-01-01

    The endotoxin from gram-negative bacteria consists of a molecule lipopolysaccharide (LPS) which can be shed by bacteria during antimicrobial therapy. A resulting syndrome, endotoxic shock, is a leading cause of death in the developed world. Thus, there is great interest in the development of antimicrobial agents which can reverse rather than promote sepsis, especially given the recent disappointing clinical performance of antiendotoxin therapies. We describe here two small cationic peptides, MBI-27 and MBI-28, which have both antiendotoxic and antibacterial activities in vitro and in vivo in animal models. We had previously demonstrated that these peptides bind to LPS with an affinity equivalent to that of polymyxin B. Consistent with this, the peptides blocked the ability of LPS and intact cells to induce the endotoxic shock mediator, tumor necrosis factor (TNF), upon incubation with the RAW 264.7 murine macrophage cell line. MBI-28 was equivalent to polymyxin B in its ability to block LPS induction of TNF by this cell line, even when added 60 min after the TNF stimulus. Furthermore, MBI-28 offered significant protection in a galactosamine-sensitized mouse model of lethal endotoxic shock. This protection correlated with the ability of MBI-28 to reduce LPS-induced circulating TNF by nearly 90% in this mouse model. Both MBI-27 and MBI-28 demonstrated antibacterial activity against gram-negative bacteria in vitro and in vivo against Pseudomonas aeruginosa infections in neutropenic mice. PMID:8945527

  16. Melanoma targeting with the loco-regional chemotherapeutic, Melphalan: From cell death to immunotherapeutic efficacy.

    PubMed

    Dudek-Perić, Aleksandra Maria; Gołąb, Jakub; Garg, Abhishek D; Agostinis, Patrizia

    2015-12-01

    All immunoregulatory chemotherapeutics are chiefly applied in a systemic setting for anticancer therapy. However, immune responses following loco-regional application of chemotherapy may differ from those after systemic application. We recently found that Melphalan, a prototypical loco-regionally applied chemotherapeutic agent, exhibits the ability to increase the immunogenicity of dying melanoma cells.

  17. The adsorption of sympathomimetic agents by activated carbon hemoperfusion.

    PubMed

    Horres, C R; Hill, J B; Ellis, F W

    1976-01-01

    Sympathomimetic agents with mixed and pure alpha and beta adrenergic activity are adsorbed by coconut shell activated carbon from blood, sufficiently rapidly to markedly reduce the activity of these agents. The results of this study suggest that the site of injection of sympathomimetic agents being considered for correcting hypotension during activated carbon hemoperfusion be selected to permit systemic mixing before circulation into the adsorption device.

  18. Lipid biosynthesis pathways as chemotherapeutic targets in kinetoplastid parasites.

    PubMed

    Urbina, J A

    1997-01-01

    Inhibitors of sterol and phospholipid biosynthesis in kinetoplastid parasites such as Trypanosoma cruzi, the causative agent of Chagas' disease, and different species of Leishmania have potent and selective activity as chemotherapeutic agents in vitro and in vivo. Recent work with the sterol C14 alpha-demethylase inhibitor D0870, a bis triazole derivative, showed that this compound is capable of inducing radical parasitological cure in murine models of both acute and chronic Chagas' disease. Other inhibitors of this type, such as SCH 56592, have also shown curative, rather than suppressive, activity against T. cruzi in these models. Leishmania species have different susceptibilities to sterol biosynthesis inhibitors, both in vitro and in vivo. Leishmania braziliensis promastigotes, naturally resistant to C14 alpha-demethylase inhibitors such as ketoconazole and D0870, were susceptible to these drugs when used in combination with the squalene epoxidase inhibitor terbinafine. Inhibitors of delta 24(25) sterol methyl transferase have been shown to act as potent antiproliferative agents against Trypanosoma cruzi, both in vitro and in vivo. New inhibitors of this type which show enhanced activity and novel mechanisms of action have been synthesized. Recent work has also demonstrated that this type of enzyme inhibitors can block sterol biosynthesis and cell proliferation in Pneumocystis carinii, a fungal pathogen which had previously been found resistant to other sterol biosynthesis inhibitors. Ajoene, an antiplatelet compound derived from garlic, was shown to have potent antiproliferative activity against epimastigotes and amastigotes of Trypanosoma cruzi in vitro; this activity was associated with a significant alteration of the phospholipid composition of the cells with no significant effects on the sterol content. In addition, alkyllsophospholipids such as ilmofosine, miltefosine and edelfosine have been shown to block the proliferation of T. cruzi and Leishmania and

  19. An Active Learning Exercise for Introducing Agent-Based Modeling

    ERIC Educational Resources Information Center

    Pinder, Jonathan P.

    2013-01-01

    Recent developments in agent-based modeling as a method of systems analysis and optimization indicate that students in business analytics need an introduction to the terminology, concepts, and framework of agent-based modeling. This article presents an active learning exercise for MBA students in business analytics that demonstrates agent-based…

  20. Dietary phytochemicals as potent chemotherapeutic agents against breast cancer: Inhibition of NF-κB pathway via molecular interactions in rel homology domain of its precursor protein p105

    PubMed Central

    Khan, Mohammad K. A.; Ansari, Irfan A.; Khan, M. Salman; Arif, Jamal M.

    2013-01-01

    Background: Dietary phytochemicals consist of a wide variety of biologically active compounds that are ubiquitous in plants, many of which have been reported to have anti-tumor as well as anti-inflammatory properties. Objective: In the present study, we aimed to validate these findings by using docking protocols and explicate the possible mechanism of action for a dataset of nine phytochemicals namely boswellic acid, 1-caffeoylquinic acid, ellagic acid, emodin, genistein, guggulsterone, quercetin, resveratrol, and sylibinin from different plants against the nuclear factor- kappaB (NF-κB) precursor protein p105, an important transcription factor reported to be overexpressed in breast cancer. Materials and Methods: 2-D structures of all phytochemicals were retrieved from PubChem Compound database and their subsequent conversion into 3-D structures was performed by using online software system CORINA. The X-ray crystallographic structure of the NF-κB precursor p105 was extracted from Brookhaven Protein Data Bank. Molecular docking simulation study was carried out by using AutoDock Tools 4.0. Results: Our results showed significant binding affinity of different phytochemicals with the Rel homology domain of the NF-κB precursor protein p105. Quercetin and 1-caffeoylquinic acid were found to be very effective inhibitors against target molecule as they showed binding energy of −12.11 and −11.50 Kcal/mol, respectively. The order of affinity of other ligands with p105 was found as follows: guggulsterone > sylibinin > emodin > resveratrol > genistein > boswellic acid > ellagic acid. Conclusion: Our in silico study has explored the possible chemopreventive mechanism of these phytochemicals against the NF-κB precursor protein p105 and deciphered that quercetin, 1-caffeoylquinic acid and guggulsterone were the potent inhibitors against target molecule. In addition, large scale preclinical and clinical trials are needed to explore the role of these chemotherapeutic

  1. Coordinating Learning Agents for Active Information Collection

    DTIC Science & Technology

    2011-06-30

    ranging from robocup soccer [26, 27], to rover coordination [19], to trading agents [25, 43], to air traffic management [32]. What makes this problem...Bazzan, A. and Ossowski, S. (eds.), Applications of Agent Technology in Traffic and Transportation ( Springer , 2005). [19] Mataric, M. J., Coordination...of Complex Systems ( Springer , 2004). September 16, 2009 16:40 WSPC/169-ACS 00230 472 K. Tumer and N. Khani [24] Pynadath, D. and Tambe, M., The

  2. Novel 3,4-Methylenedioxybenzene Scaffold Incorporated 1,3,5-Trisubstituted-2-pyrazolines: Synthesis, Characterization and Evaluation for Chemotherapeutic Activity

    PubMed Central

    Deshpande, S. R.; Nagrale, S. N.; Patil, M. V.; Chavan, P. S.

    2015-01-01

    A series of novel 3, 4-methylenedioxybenzene scaffold incorporated 1,3,5-trisubstituted-2-pyrazoline derivatives was synthesised as potent antitubercular agents via chalcone intermediates by reaction with hydrazines. The structures of the compounds were confirmed by IR, 1HNMR, 13CNMR and mass spectral data. The novel pyrazolines were screened for in vitro antitubercular activity by almar blue dye method against M. tuberculosis H37Rv. All the compounds exhibited excellent activity that could be due to the presence of 3,4-methylenedioxybenzene frame work in the molecules. Some of the compounds also showed in vitro cytotoxicity on EAC cell lines in tryphan blue exclusion assay suggesting their safety. PMID:25767315

  3. Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer: The role of inflammation

    PubMed Central

    Lee, Chun Seng; Ryan, Elizabeth J; Doherty, Glen A

    2014-01-01

    Chemotherapy-induced diarrhea (CID) is a common and often severe side effect experienced by colorectal cancer (CRC) patients during their treatment. As chemotherapy regimens evolve to include more efficacious agents, CID is increasingly becoming a major cause of dose limiting toxicity and merits further investigation. Inflammation is a key factor behind gastrointestinal (GI) toxicity of chemotherapy. Different chemotherapeutic agents activate a diverse range of pro-inflammatory pathways culminating in distinct histopathological changes in the small intestine and colonic mucosa. Here we review the current understanding of the mechanisms behind GI toxicity and the mucositis associated with systemic treatment of CRC. Insights into the inflammatory response activated during this process gained from various models of GI toxicity are discussed. The inflammatory processes contributing to the GI toxicity of chemotherapeutic agents are increasingly being recognised as having an important role in the development of anti-tumor immunity, thus conferring added benefit against tumor recurrence and improving patient survival. We review the basic mechanisms involved in the promotion of immunogenic cell death and its relevance in the treatment of colorectal cancer. Finally, the impact of CID on patient outcomes and therapeutic strategies to prevent or minimise the effect of GI toxicity and mucositis are discussed. PMID:24744571

  4. Erythropoiesis stimulating agents: approaches to modulate activity

    PubMed Central

    Sinclair, Angus M

    2013-01-01

    Recombinant human erythropoietin (rHuEPO), such as the approved agents epoetin alfa and epoetin beta, has been used successfully for over 20 years to treat anemia in millions of patients. However, due to the relatively short half-life of the molecule (approximately 8 hours), frequent dosing may be required to achieve required hemoglobin levels. Therefore, a need was identified in some anemic patient populations for erythropoiesis stimulating agents with longer half-lives that required less frequent dosing. This need led to the development of second generation molecules which are modified versions of rHuEPO with improved pharma-cokinetic and pharmacodynamic properties such as darbepoetin alfa, a hyperglycosylated analog of rHuEPO, and pegzyrepoetin, a pegylated rHuEPO. Third generation molecules, such as peginesatide, which are peptide mimetics that have no sequence homology to rHuEPO have also recently been developed. The various molecular, pharmacokinetic, and pharmacodynamic properties of these and other erythropoiesis stimulating agents will be discussed in this review. PMID:23847411

  5. Development of a novel, physiologically relevant cytotoxicity model: Application to the study of chemotherapeutic damage to mesenchymal stromal cells

    SciTech Connect

    May, Jennifer E. Morse, H. Ruth Xu, Jinsheng Donaldson, Craig

    2012-09-15

    There is an increasing need for development of physiologically relevant in-vitro models for testing toxicity, however determining toxic effects of agents which undergo extensive hepatic metabolism can be particularly challenging. If a source of such metabolic enzymes is inadequate within a model system, toxicity from prodrugs may be grossly underestimated. Conversely, the vast majority of agents are detoxified by the liver, consequently toxicity from such agents may be overestimated. In this study we describe the development of a novel in-vitro model, which could be adapted for any toxicology setting. The model utilises HepG2 liver spheroids as a source of metabolic enzymes, which have been shown to more closely resemble human liver than traditional monolayer cultures. A co-culture model has been developed enabling the effect of any metabolised agent on another cell type to be assessed. This has been optimised to enable the study of damaging effects of chemotherapy on mesenchymal stem cells (MSC), the supportive stem cells of the bone marrow. Several optimisation steps were undertaken, including determining optimal culture conditions, confirmation of hepatic P450 enzyme activity and ensuring physiologically relevant doses of chemotherapeutic agents were appropriate for use within the model. The developed model was subsequently validated using several chemotherapeutic agents, both prodrugs and active drugs, with resulting MSC damage closely resembling effects seen in patients following chemotherapy. Minimal modifications would enable this novel co-culture model to be utilised as a general toxicity model, contributing to the drive to reduce animal safety testing and enabling physiologically relevant in-vitro study. -- Highlights: ► An in vitro model was developed for study of drugs requiring hepatic metabolism ► HepG2 spheroids were utilised as a physiologically relevant source of liver enzymes ► The model was optimised to enable study of chemotherapeutic

  6. Grapefruit-Derived Nanovectors Use an Activated Leukocyte Trafficking Pathway to Deliver Therapeutic Agents to Inflammatory Tumor Sites.

    PubMed

    Wang, Qilong; Ren, Yi; Mu, Jingyao; Egilmez, Nejat K; Zhuang, Xiaoyin; Deng, Zhongbin; Zhang, Lifeng; Yan, Jun; Miller, Donald; Zhang, Huang-Ge

    2015-06-15

    Inflammation is a hallmark of cancer. Activated immune cells are intrinsically capable of homing to inflammatory sites. Using three inflammatory-driven disease mouse models, we show that grapefruit-derived nanovectors (GNV) coated with inflammatory-related receptor enriched membranes of activated leukocytes (IGNVs) are enhanced for homing to inflammatory tumor tissues. Blocking LFA-1 or CXCR1 and CXCR2 on the IGNVs significantly inhibits IGNV homing to the inflammatory tissue. The therapeutic potential of IGNVs was further demonstrated by enhancing the chemotherapeutic effect as shown by inhibition of tumor growth in two tumor models and inhibiting the inflammatory effects of dextran sulfate sodium-induced mouse colitis. The fact that IGNVs are capable of homing to inflammatory tissue and that chemokines are overexpressed in diseased human tissue provides the rationale for using IGNVs to more directly deliver therapeutic agents to inflammatory tumor sites and the rationale for the use of IGNVs as treatment for certain cancers in personalized medicine.

  7. Grapefruit-derived nanovectors use an activated leukocyte trafficking pathway to deliver therapeutic agents to inflammatory tumor sites

    PubMed Central

    Wang, Qilong; Ren, Yi; Mu, Jingyao; Egilmez, Nejat; Zhuang, Xiaoyin; Deng, Zhongbin; Zhang, Lifeng; Yan, Jun; Miller, Donald; Zhang, Huang-Ge

    2015-01-01

    Inflammation is a hallmark of cancer. Activated immune cells are intrinsically capable of homing to inflammatory sites. Using three inflammatory driven disease mouse models, we show that grapefruit-derived nanovectors (GNVs) coated with inflammatory related receptor enriched membranes of activated leukocytes (IGNVs) are enhanced for homing to inflammatory tumor tissues. Blocking LFA-1 or CXCR1 and CXCR2 on the IGNVs significantly inhibits IGNV homing to the inflammatory tissue. The therapeutic potential of IGNVs was further demonstrated by enhancing the chemotherapeutic effect as shown by inhibition of tumor growth in two tumor models and inhibiting the inflammatory effects of DSS induced mouse colitis. The fact that IGNVs are capable of homing to inflammatory tissue and that there is an overexpression of chemokines in diseased human tissue provides the rationale for using IGNVs to more directed delivery of therapeutic agents to inflammatory tumor sites and the use of IGNVs as personalized medicine for treatment of certain cancers. PMID:25883092

  8. Akt activation suppresses Chk2-mediated, methylating agent-induced G2 arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence.

    PubMed

    Hirose, Yuchi; Katayama, Makoto; Mirzoeva, Olga K; Berger, Mitchel S; Pieper, Russell O

    2005-06-01

    Pharmacologic inhibition of the DNA signal transducers Chk1 and p38 blocks G2 arrest and sensitizes glioblastoma cells to chemotherapeutic methylating agent-induced cytotoxicity. Because Akt pathway activation has been suggested to also block G2 arrest induced by DNA-damaging agents and because glioma cells frequently have high levels of Akt activation, we examined the contribution of the Akt pathway to methylating agent-induced G2 arrest and toxicity. U87MG human glioma cells containing an inducible Akt expression construct were incubated with inducing agent or vehicle, after which the cells were exposed to temozolomide and assayed for activation of the components of the G2 arrest pathway and survival. Temozolomide-treated control cells activated the DNA damage signal transducers Chk1, Chk2, and p38, leading to Cdc25C and Cdc2 inactivation, prolonged G2 arrest, and loss of clonagenicity by a combination of senescence and mitotic catastrophe. Temozolomide-treated cells induced to overexpress Akt, however, exhibited significantly less drug-induced Cdc25C/Cdc2 inactivation and less G2 arrest. Akt-mediated suppression of G2 arrest was associated not with alterations in Chk1 or p38 activation but rather with suppression of Chk2 activation and reduced recruitment of Chk2 to sites of damage in chromatin. Unlike bypass of the G2 checkpoint induced by pharmacologic inhibitors of Chk1 or p38, however, Akt-induced bypass of G2 arrest suppressed, rather than enhanced, temozolomide-induced senescence and mitotic catastrophe. These results show that whereas Akt activation suppresses temozolomide-induced Chk2 activation and G2 arrest, the overriding effect is protection from temozolomide-induced cytotoxicity. The Akt pathway therefore represents a new target for the sensitization of gliomas to chemotherapeutic methylating agents such as temozolomide.

  9. Mechanistic perspectives on cancer chemoprevention/chemotherapeutic effects of thymoquinone.

    PubMed

    Kundu, Juthika; Chun, Kyung-Soo; Aruoma, Okezie I; Kundu, Joydeb Kumar

    2014-10-01

    The bioactive natural products (plant secondary metabolites) are widely known to possess therapeutic value for the prevention and treatment of various chronic diseases including cancer. Thymoquinone (2-methyl-5-isopropyl-1,4-benzoquinone; TQ), a monoterpene present in black cumin seeds, exhibits pleiotropic pharmacological activities including antioxidant, anti-inflammatory, antidiabetic and antitumor effects. TQ inhibits experimental carcinogenesis in a wide range of animal models and has been shown to arrest the growth of various cancer cells in culture as well as xenograft tumors in vivo. The mechanistic basis of anticancer effects of TQ includes the inhibition of carcinogen metabolizing enzyme activity and oxidative damage of cellular macromolecules, attenuation of inflammation, induction of cell cycle arrest and apoptosis in tumor cells, blockade of tumor angiogenesis, and suppression of migration, invasion and metastasis of cancer cells. TQ shows synergistic and/or potentiating anticancer effects when combined with clinically used chemotherapeutic agents. At the molecular level, TQ targets various components of intracellular signaling pathways, particularly a variety of upstream kinases and transcription factors, which are aberrantly activated during the course of tumorigenesis.

  10. Coadministration of the FNIII14 Peptide Synergistically Augments the Anti-Cancer Activity of Chemotherapeutic Drugs by Activating Pro-Apoptotic Bim

    PubMed Central

    Akari, Shougo; Otsuka, Kazuki; Fujita, Motomichi; Itagaki, Keisuke; Takizawa, You-ichi; Orita, Hiroaki; Owaki, Toshiyuki; Taira, Jyunichi; Hayashi, Ryo; Kodama, Hiroaki; Fukai, Fumio

    2016-01-01

    The acquisition of drug resistance mediated by the interaction of tumor cells with the extracellular matrix (ECM), commonly referred to as cell adhesion-mediated drug resistance (CAM-DR), has been observed not only in hematopoietic tumor cells but also in solid tumor cells. We have previously demonstrated that a 22-mer peptide derived from fibronectin, FNIII14, can inhibit cell adhesion through the inactivation of β1 integrin; when coadministered with cytarabine, FNIII14 completely eradicates acute myelogenous leukemia by suppressing CAM-DR. In this study, we show that our FNIII14 peptide also enhances chemotherapy efficacy in solid tumors. Coadministration of FNIII14 synergistically enhances the cytotoxicity of doxorubicin and aclarubicin in mammary tumor and melanoma cells, respectively. The solid tumor cell chemosensitization induced by FNIII14 is dependent upon the upregulation and activation of the pro-apoptotic protein, Bim. Furthermore, the metastasis of tumor cells derived from ventrally transplanted mammary tumor grafts is suppressed by the coadministration of FNIII14 and doxorubicin. These results suggest that the coadministration of our FNIII14 peptide with chemotherapy could achieve efficient solid tumor eradication by increasing chemosensitivity and decreasing metastasis. The major causes of tumor recurrence are the existence of chemotherapy-resistant primary tumor cells and the establishment of secondary metastatic lesions. As such, coadministering FNIII14 with anti-cancer drugs could provide a promising new approach to improve the prognosis of patients with solid tumors. PMID:27622612

  11. In vitro antimicrobial activity of peroxide-based bleaching agents.

    PubMed

    Napimoga, Marcelo Henrique; de Oliveira, Rogério; Reis, André Figueiredo; Gonçalves, Reginaldo Bruno; Giannini, Marcelo

    2007-06-01

    Antibacterial activity of 4 commercial bleaching agents (Day White, Colgate Platinum, Whiteness 10% and 16%) on 6 oral pathogens (Streptococcus mutans, Streptococcus sobrinus, Streptococcus sanguinis, Candida albicans, Lactobacillus casei, and Lactobacillus acidophilus) and Staphylococcus aureus were evaluated. A chlorhexidine solution was used as a positive control, while distilled water was the negative control. Bleaching agents and control materials were inserted in sterilized stainless-steel cylinders that were positioned under inoculated agar plate (n = 4). After incubation according to the appropriate period of time for each microorganism, the inhibition zones were measured. Data were analyzed by 2-way analysis of variance and Tukey test (a = 0.05). All bleaching agents and the chlorhexidine solution produced antibacterial inhibition zones. Antimicrobial activity was dependent on peroxide-based bleaching agents. For most microorganisms evaluated, bleaching agents produced inhibition zones similar to or larger than that observed for chlorhexidine. C albicans, L casei, and L acidophilus were the most resistant microorganisms.

  12. Activities of Antimicrobial Agents against Intracellular Pneumococci

    PubMed Central

    Mandell, Gerald L.; Coleman, Elizabeth J.

    2000-01-01

    Pneumococci can enter and survive inside human lung alveolar carcinoma cells. We examined the activity of azithromycin, gentamicin, levofloxacin, moxifloxacin, penicillin G, rifampin, telithromycin, and trovafloxacin against pneumococci inside and outside cells. We found that moxifloxacin, trovafloxacin, and telithromycin were the most active, but only telithromycin killed all intracellular organisms. PMID:10952618

  13. Synthesis and activities of antitumor agents.

    PubMed

    Suami, T; Machinami, T; Hisamatsu, T

    1979-03-01

    N-(2-Chloroethyl)-N-nitrosocarbamoyl derivatives of glycosylamines have been prepared. Six N-(2-chloroethyl)-N-nitrosoureas, including three disaccharide derivatives, were submitted to a determination of antitumor activity. All the compounds tested exhibited strong antitumor activity against leukemia L1210 in mice.

  14. Novel 2-Aminobenzamides as Potential Orally Active Antithrombotic Agents

    PubMed Central

    2012-01-01

    In an effort to develop potent antithrombotic agents, a series of novel 2-aminobenzamide derivatives were synthesized and screened for their in vivo antithrombotic activity. Among the 23 compounds tested, compound (8g) showed the most promising antithrombotic activity, which was comparable with clinically used aspirin or warfarin, but at variance with these standard drugs, 8g did not exhibit the increased bleeding time, suggesting its potential as a novel antithrombotic agent. PMID:24900559

  15. Garcinia xanthones as orally active antitumor agents.

    PubMed

    Zhang, Xiaojin; Li, Xiang; Sun, Haopeng; Wang, Xiaojian; Zhao, Li; Gao, Yuan; Liu, Xiaorong; Zhang, Shenglie; Wang, Yanyan; Yang, Yingrui; Zeng, Su; Guo, Qinglong; You, Qidong

    2013-01-10

    Using a newly developed strategy whose key step is the regioselective propargylation of hydroxyxanthone substrates, 99 structurally diverse Garcinia natural-product-like xanthones based on gambogic acid were designed and synthesized and their in vitro antitumor activity was evaluated. A set of 40 related compounds was chosen for determination of their physicochemical properties including polar surface area, log D₇.₄, aqueous solubility, and permeability at pH 7.4. In the light of the in vitro antitumor activity and the physicochemical properties, two compounds were advanced into in vivo efficacy experiments. The antitumor activity of compound 112, administered po, showed more potent in vivo oral antitumor activity than gambogic acid.

  16. The Use of Chemotherapeutics for the Treatment of Keloid Scars

    PubMed Central

    Jones, Christopher David; Guiot, Luke; Samy, Mike; Gorman, Mark; Tehrani, Hamid

    2015-01-01

    Keloid scars are pathological scars, which develop as a result of exaggerated dermal tissue proliferation following cutaneous injury and often cause physical, psychological and cosmetic problems. Various theories regarding keloidogenesis exist, however the precise pathophysiological events remain unclear. Many different treatment modalities have been implicated in their management, but currently there is no entirely satisfactory method for treating all keloid lesions. We review a number of different chemotherapeutic agents which have been proposed for the treatment of keloid and hypertrophic scars while giving insight into some of the novel chemotherapeutic drugs which are currently being investigated. Non-randomized trials evaluating the influence of different chemotherapeutic agents, such as 5-fluorouracil (5-FU); mitomycin C; bleomycin and steroid injection, either alone or in combination with other chemotherapeutic agents or alternative treatment modalities, for the treatment of keloids were identified using a predefined PubMed search strategy. Twenty seven papers were identified. Scar improvement ≥50% was found in the majority of cases treated with 5-FU, with similar results found for mitomycin C, bleomycin and steroid injection. Combined intralesional 5-FU and steroid injection produced statistically significant improvements when compared to monotherapy. Monotherapy recurrence rates ranged from 0-47% for 5-FU, 0-15% for bleomycin and 0-50% for steroid injection. However, combined therapy in the form of surgical excision and adjuvant 5-FU or steroid injections demonstrated lower recurrence rates; 19% and 6% respectively. Currently, most of the literature supports the use of combination therapy (usually surgery and adjuvant chemotherapy) as the mainstay treatment of keloids, however further investigation is necessary to determine success rates over longer time frames. Furthermore, there is the potential for novel therapies, but further investigation is

  17. Asphaltenes as a surface active agent

    SciTech Connect

    Sheu, E.Y.; Shields, M.B.; Storm, D.A.

    1995-12-31

    Asphaltene represents the heavy-end materials of the crude oil, conventionally defined via solvent solubility (either heptane or pentane). Chemically, it consists of polynuclear aromatics with the H/C ratio close to unity. Additionally, it contains a great deal of heteroatoms, such as sulfur, nitrogen, nickel, vanadium, etc. Several experiments have revealed the surface activity of asphaltenes in some selected solvents through measurements of their rheology or critical micelle concentrations in these solvents. The asphaltene micelles were found thermodynamically reversible. In a two phase asphaltene/water system, asphaltenes appear to vary their surface activities depending upon the polarity of the aqueous phase. Our recent experiment further showed that asphaltene/water/toluene may form, water-in-oil emulsion under certain conditions.

  18. Agents.

    PubMed

    Chambers, David W

    2002-01-01

    Although health care is inherently an economic activity, it is inadequately described as a market process. An alternative, grounded in organizational economic theory, is to view professionals and many others as agents, contracted to advance the best interests of their principals (patients). This view untangles some of the ethical conflicts in dentistry. It also helps identify major controllable costs in dentistry and suggests that dentists can act as a group to increase or decrease agency costs, primarily by controlling the bad actors who damage the value of all dentists.

  19. Activity of 10 antimicrobial agents against intracellular Rhodococcus equi.

    PubMed

    Giguère, Steeve; Berghaus, Londa J; Lee, Elise A

    2015-08-05

    Studies with facultative intracellular bacterial pathogens have shown that evaluation of the bactericidal activity of antimicrobial agents against intracellular bacteria is more closely associated with in vivo efficacy than traditional in vitro susceptibility testing. The objective of this study was to determine the relative activity of 10 antimicrobial agents against intracellular Rhodococcus equi. Equine monocyte-derived macrophages were infected with virulent R. equi and exposed to erythromycin, clarithromycin, azithromycin, rifampin, ceftiofur, gentamicin, enrofloxacin, vancomycin, imipenem, or doxycycline at concentrations achievable in plasma at clinically recommended dosages in foals. The number of intracellular R. equi was determined 48h after infection by counting colony forming units (CFUs). The number of R. equi CFUs in untreated control wells were significantly higher than those of monolayers treated with antimicrobial agents. Numbers of R. equi were significantly lower in monolayers treated with enrofloxacin followed by those treated with gentamicin, and vancomycin, when compared to monolayers treated with other antimicrobial agents. Numbers of R. equi in monolayers treated with doxycycline were significantly higher than those of monolayers treated with other antimicrobial agents. Differences in R. equi CFUs between monolayers treated with other antimicrobial agents were not statistically significant. Enrofloxacin, gentamicin, and vancomycin are the most active drugs in equine monocyte-derived macrophages infected with R. equi. Additional studies will be needed to determine if these findings correlate with in vivo efficacy.

  20. Efficacy of combined photothermal therapy and chemotherapeutic drugs

    NASA Astrophysics Data System (ADS)

    Madsen, Steen J.; Shih, En-Chung; Hirschberg, Henry

    2015-03-01

    Hyperthermia has been shown to enhance the effects of chemotherapeutic agents in a wide variety of cancers. The purpose of this study was to investigate the combined effects of a number of commonly used chemotherapeutic drugs (bleomycin, doxorubicin and cisplatin) with photothermal therapy (PTT)-induced hyperthermia in an in vitro system consisting of human head and neck squamous carcinoma cells and murine lymphocytic monocytes which were used as delivery vehicles for gold-silica nanoshells (AuNS). PTT was accomplished via near infra-red (NIR) irradiation of AuNS. The results showed that PTT combined with cisplatin resulted in only a mild degree of synergism while additive effects were observed for concurrent treatments of PTT and doxorubicin and PTT and bleomycin.

  1. Mitochondria and redox homoeostasis as chemotherapeutic targets.

    PubMed

    Briehl, Margaret M; Tome, Margaret E; Wilkinson, Sarah T; Jaramillo, Melba C; Lee, Kristy

    2014-08-01

    Characteristics of cancer cells include a more oxidized redox environment, metabolic reprogramming and apoptosis resistance. Our studies with a lymphoma model have explored connections between the cellular redox environment and cancer cell phenotypes. Alterations seen in lymphoma cells made resistant to oxidative stress include: a more oxidized redox environment despite increased expression of antioxidant enzymes, enhanced net tumour growth, metabolic changes involving the mitochondria and resistance to the mitochondrial pathway to apoptosis. Of particular importance, the cells show cross-resistance to multiple chemotherapeutic agents used to treat aggressive lymphomas. Analyses of clinical and tumour data reveal the worst prognosis when patients' lymphomas have gene expression patterns consistent with the most oxidized redox environment. Lymphomas from patients with the worst survival outcomes express increased levels of proteins involved in oxidative phosphorylation, including cytochrome c. This is consistent with these cells functioning as metabolic opportunists. Using lymphoma cell models and primary lymphoma cultures, we observed enhanced killing using genetic and drug approaches which further oxidize the cellular redox environment. These approaches include increased expression of SOD2 (superoxide dismutase 2), treatment with a manganoporphyrin that oxidizes the glutathione redox couple, or treatment with a copper chelator that inhibits SOD1 and leads to peroxynitrite-dependent cell death. The latter approach effectively kills lymphoma cells that overexpress the anti-apoptotic protein Bcl-2. Given the central role of mitochondria in redox homoeostasis, metabolism and the intrinsic pathway to apoptosis, our studies support the development of new anti-cancer drugs to target this organelle.

  2. Chemotherapeutic effect of Berberis integerrima hydroalcoholic extract on colon cancer development in the 1,2-dimethyl hydrazine rat model.

    PubMed

    Malayeri, Mohammad R Mohammadi; Dadkhah, Abolfazl; Fatemi, Faezeh; Dini, Salome; Torabi, Fatemeh; Tavajjoh, Mohammad M; Rabiei, Javad

    The aim of this study was to investigate the efficacy of a Berberis integerrima hydroalcoholic extract as a chemotherapeutic agent in colon carcinogenesis in the rat induced by 1,2-dimethyl hydrazine (DMH). Male Wistar rats were divided into five groups: a negative control group without DMH treatment; a control group injected DMH (20 mg/kg b.w); two groups receiving B. integerrima extract (50 and 100 mg/kg b.w), concomitant with injected DMH, as chemotherapeutic groups; a positive control group receiving 5-fluorouracil (5-FU) along with DMH. The effects of the extracts were determined by assessment of hepatic malondialdehyde (MDA), glutathione (GSH), ferric reducing ability of plasma (FRAP), and the activities of hepatic glutathione S-transferase and cytochrome P450 (GST and CYP450). Additionally, colon tissues were assessed for colonic β-catenin and histopathological analysis. In DMH-treated rats, the extracts partially normalized the levels of FRAP, CYP450, β-catenin, and GST. Likewise, formation of aberrant crypt foci (ACF) in colon tissue of DMH-treated was reduced by the extracts. Thus, the extracts possess chemotherapeutic activity against colon carcinogenesis.

  3. Activation of a photosensitive pharmaceutical agent by a triboluminescent material

    SciTech Connect

    Yuen, Stacey; Schreyer, Magdalena; Finlay, W.H.; Loebenberg, R.; Moussa, W.

    2006-03-20

    Given the recent emphasis on applications of triboluminescent materials, we investigate the ability of a triboluminescent material to activate a photosensitive pharmaceutical agent. Using compressed sucrose doped with wintergreen, which luminesces when fractured, we demonstrate the activation of riboflavin (vitamin B2), a photosensitizer. A product of activation is the highly reactive singlet oxygen. We add ascorbic acid (vitamin C), an antioxidant, and measure the amount of ascorbic acid oxidation to correlate with the amount of riboflavin activation. Up to 17% ascorbic acid oxidation is observed, indicating triboluminescence is worth exploring as a mechanism for activation of photosensitizers in photodynamic therapy.

  4. SEROTONIN AND OTHER VASOACTIVE AGENTS IN EXPERIMENTAL DECOMPRESSION SICKNESS,

    DTIC Science & Technology

    SEROTONIN, DECOMPRESSION SICKNESS), (*VASOACTIVE AGENTS, DECOMPRESSION SICKNESS), RATS, EXERCISE(PHYSIOLOGY), DOSAGE, CHEMOTHERAPEUTIC AGENTS, BLOOD ANALYSIS, TOXICITY, BLOOD CIRCULATION, MORTALITY RATES , CANADA

  5. Keratin sponge/hydrogel II, active agent delivery

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Keratin sponge/hydrogels from oxidation and reduction hydrolysis of fine and coarse wool fibers were formed to behave as cationic hydrogels to swell and release active agents in the specific region of the gastro-intestinal (GI) tract. Their porous, interpenetrating networks (IPN) were effective for...

  6. Trypanothione Reductase: A Viable Chemotherapeutic Target for Antitrypanosomal and Antileishmanial Drug Design

    PubMed Central

    Khan, M. Omar F.

    2007-01-01

    Trypanosomiasis and leishmaniasis are two debilitating disease groups caused by parasites of Trypanosoma and Leishmania spp. and affecting millions of people worldwide. A brief outline of the potential targets for rational drug design against these diseases are presented, with an emphasis placed on the enzyme trypanothione reductase. Trypanothione reductase was identified as unique to parasites and proposed to be an effective target against trypanosomiasis and leishmaniasis. The biochemical basis of selecting this enzyme as a target, with reference to the simile and contrast to human analogous enzyme glutathione reductase, and the structural aspects of its active site are presented. The process of designing selective inhibitors for the enzyme trypanothione reductase has been discussed. An overview of the different chemical classes of inhibitors of trypanothione reductase with their inhibitory activities against the parasites and their prospects as future chemotherapeutic agents are briefly revealed. PMID:21901070

  7. Improving chemotherapeutic efficiency in acute myeloid leukemia treatments by chemically synthesized peptide interfering with CXCR4/CXCL12 axis

    PubMed Central

    Li, Xiaojin; Guo, Hua; Duan, Hongyang; Yang, Yanlian; Meng, Jie; Liu, Jian; Wang, Chen; Xu, Haiyan

    2015-01-01

    Bone marrow stroma can protect acute myeloid leukemia (AML) cells against chemotherapeutic agents and provide anti-apoptosis and chemoresistance signals through secreting chemokine CXCL12 to activate its receptor CXCR4 on AML cells, resulting in minimal residual leukemia and relapse. Therefore disrupting the CXCR4/CXCL12 axis with antagonists is of great significance for improving chemosensitivity and decreasing relapse rate. In a previous study, we reported a novel synthetic peptide E5 with its remarkable effect on inhibiting CXCR4/CXCL12-mediated adhesion and migration of AML cells. Here we presented E5’s capacity of enhancing the therapeutic efficiency of various chemotherapeutics on AML in vitro and in vivo. Results showed that E5 can diminish bone marrow stromal cell-provided protection to leukemia cells, significantly increasing the apoptosis induced by various chemotherapeutics in multiple AML cell lines. In an AML mouse xenograft model, E5 induced 1.84-fold increase of circulating AML cells out of protective stroma niche. Combined with vincristine or cyclophosphamide, E5 inhibited infiltration of AML cells into bone marrow, liver and spleen, as well as prolonged the lifespan of AML mice compared with mice treated with chemotherapy alone. In addition, E5 presented no toxicity in vivo according to the histological analysis and routine clinical parameters of serum analysis. PMID:26538086

  8. Heat Shock Protein translocation induced by membrane fluidization increases tumor-cell sensitivity to chemotherapeutic drugs.

    PubMed

    Dempsey, Nina C; Ireland, H Elyse; Smith, Carly M; Hoyle, Christine F; Williams, John H H

    2010-10-28

    Treatment of chronic lymphocytic leukemia (CLL) remains a challenge due to the frequency of drug resistance amongst patients. Improving the delivery of chemotherapeutic agents while reducing the expression of anti-apoptotic Heat Shock Proteins (HSPs) within the cancer cells may facilitate in overcoming this drug resistance. We demonstrate for the first time that sub-lethal doses of chemotherapeutic agents can be combined with membrane fluidizing treatments to produce a significant increase in drug efficacy and apoptosis in vitro. We show that fluidizers result in a transient decrease in intracellular HSPs, resulting in increased tumor-cell sensitivity and a membrane-associated induction of HSP gene expression.

  9. Halloysite clay nanotubes for controlled delivery of chemically active agents

    NASA Astrophysics Data System (ADS)

    Abdullayev, Elshard

    In this work we explored the capabilities of halloysite nanotubes as capsules for encapsulation and controlled delivery of the chemically and biologically active substances. Halloysite is a two-layered aluminosilicate which has a predominantly hollow tubular structure in the submicron range and is chemically similar to kaolinite [1, 2]. In the first section of this work, we analyzed the structure of the halloysite nanotubes as well as its capability to encapsulate and deliver biologically and chemically active agents, similarities and differences between release characteristics of different agents and how these differences relate with their chemical structure. Models were used to describe the release characteristics of the active agents. Study of the interaction between loaded agents and halloysite nanotubes provides better understanding of the release characteristics of the loaded agents and how halloysite can be implemented for technological and medical applications. The second part of the work deals with self-healing coatings produced on the basis of halloysite nanotubes loaded with corrosion inhibitors. Self-healing coatings are one of the effective methods to protect metals from corrosion and deterioration. The difference between self-healing coatings and the usual coatings is the ability of the first to recover after the formation of the damages due to external or internal stresses. High efficiency of the self- healing coatings produced by halloysite nanotubes were demonstrated on 110 Copper alloys and 2024 aluminum alloys. Controlled delivery of the corrosion inhibitors with additional encapsulation of the halloysite nanotubes by synthesizing stoppers at tube endings was also demonstrated. Additional encapsulation of the halloysite nanotubes may be necessary when slow release of the loaded agents is required or rapid convection of the liquid in the surrounding environment takes place (since this may cause rapid release of the loaded agents without additional

  10. Antibiotic and chemotherapeutic enhanced three-dimensional printer filaments and constructs for biomedical applications.

    PubMed

    Weisman, Jeffery A; Nicholson, James C; Tappa, Karthik; Jammalamadaka, UdayaBhanu; Wilson, Chester G; Mills, David K

    2015-01-01

    Three-dimensional (3D) printing and additive manufacturing holds potential for highly personalized medicine, and its introduction into clinical medicine will have many implications for patient care. This paper demonstrates the first application of 3D printing as a method for the potential sustained delivery of antibiotic and chemotherapeutic drugs from constructs for patient treatment. Our design is focused on the on-demand production of anti-infective and chemotherapeutic filaments that can be used to create discs, beads, catheters, or any medical construct using a 3D printing system. The design parameters for this project were to create a system that could be modularly loaded with bioactive agents. All 3D-printed constructs were loaded with either gentamicin or methotrexate and were optimized for efficient and extended antibacterial and cancer growth-inhibiting cytostatic activity. Preliminary results demonstrate that combining gentamicin and methotrexate with polylactic acid forms a composite possessing a superior combination of strength, versatility, and enhanced drug delivery. Antibacterial effects and a reduction in proliferation of osteosarcoma cells were observed with all constructs, attesting to the technical and clinical viability of our composites. In this study, 3D constructs were loaded with gentamicin and methotrexate, but the method can be extended to many other drugs. This method could permit clinicians to provide customized and tailored treatment that allows patient-specific treatment of disease and has significant potential for use as a tunable drug delivery system with sustained-release capacity for an array of biomedical applications.

  11. Hypoglycemic agents and potential anti-inflammatory activity

    PubMed Central

    Kothari, Vishal; Galdo, John A; Mathews, Suresh T

    2016-01-01

    Current literature shows an association of diabetes and secondary complications with chronic inflammation. Evidence of these immunological changes include altered levels of cytokines and chemokines, changes in the numbers and activation states of various leukocyte populations, apoptosis, and fibrosis during diabetes. Therefore, treatment of diabetes and its complications may include pharmacological strategies to reduce inflammation. Apart from anti-inflammatory drugs, various hypoglycemic agents have also been found to reduce inflammation that could contribute to improved outcomes. Extensive studies have been carried out with thiazolidinediones (peroxisome proliferator-activated receptor-γ agonist), dipeptidyl peptidase-4 inhibitors, and metformin (AMP-activated protein kinase activator) with each of these classes of compounds showing moderate-to-strong anti-inflammatory action. Sulfonylureas and alpha glucosidase inhibitors appeared to exert modest effects, while the injectable agents, insulin and glucagon-like peptide-1 receptor agonists, may improve secondary complications due to their anti-inflammatory potential. Currently, there is a lack of clinical data on anti-inflammatory effects of sodium–glucose cotransporter type 2 inhibitors. Nevertheless, for all these glucose-lowering agents, it is essential to distinguish between anti-inflammatory effects resulting from better glucose control and effects related to intrinsic anti-inflammatory actions of the pharmacological class of compounds. PMID:27114714

  12. Activity of quinone alkylating agents in quinone-resistant cells.

    PubMed

    Begleiter, A; Leith, M K

    1990-05-15

    The role of the quinone group in the antitumor activity of quinone alkylating agents, such as mitomycin C and 2,5-diaziridinyl-3,5-bis(carboethoxyamino)-1,4-benzoquinone, is still uncertain. The quinone group may contribute to antitumor activity by inducing DNA strand breaks through the formation of free radicals and/or by influencing the alkylating activity of the quinone alkylators. The cytotoxic activity and DNA damage produced by the model quinone alkylating agents, benzoquinone mustard and benzoquinone dimustard, were compared in L5178Y murine lymphoblasts sensitive and resistant to the model quinone antitumor agent, hydrolyzed benzoquinone mustard. The resistant cell lines, L5178Y/HBM2 and L5178Y/HBM10, have increased concentrations of glutathione and elevated catalase, superoxide dismutase, glutathione S-transferase, and DT-diaphorase activity. L5178Y/HBM2 and L5178Y/HBM10 cells were 7.4- and 8.5-fold less sensitive to benzoquinone mustard and 1.7- and 4.3-fold less sensitive to benzoquinone dimustard, respectively, compared with sensitive cells, but showed no resistance to the non-quinone alkylating agent, aniline mustard. The formation of DNA double strand breaks by benzoquinone mustard was reduced by 2- and 8-fold in L5178Y/HBM2 and L5178Y/HBM10 cells, respectively, while double strand break formation by benzoquinone dimustard was reduced only in the L5178Y/HBM10 cells. The number of DNA-DNA cross-links produced by benzoquinone mustard was 3- and 6-fold lower, and the number produced by benzoquinone dimustard was 35% and 2-fold lower in L5178Y/HBM2 and L5178Y/HBM10 cells, respectively, compared with L5178Y parental cells. In contrast, cross-linking by aniline mustard was unchanged in sensitive and resistant cells. Dicoumarol, an inhibitor of DT-diaphorase, increased the cytotoxic activity of both benzoquinone mustard and benzoquinone dimustard in L5178Y/HBM10 cells. This study provides evidence that elevated DT-diaphorase activity in the resistant cells

  13. Synthesis, characterization and biological activities of some Ru(II) complexes with substituted chalcones and their applications as chemotherapeutics against breast cancer

    NASA Astrophysics Data System (ADS)

    Singh, Ashok K.; Saxena, Gunjan; Dixit, Shivani; Hamidullah; Singh, Sachin K.; Singh, Sudheer K.; Arshad, M.; Konwar, Rituraj

    2016-05-01

    Four new Ru(II) DMSO complexes with substituted chalcone ligands viz. (E)-1-(2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (HL1), (E)-1-(2-hydroxyphenyl)-3-(4-nitrophenyl)prop-2-en-1-one (HL2), (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (HL3) and (E)-1-(2-hydroxyphenyl)-3-(4-Chlorophenyl)prop-2-en-1-one (HL4) have been synthesized, and characterized by micro-analyses, IR, 1H NMR, UV-Vis and ESI-MS and screened for anti-cancer activity against breast cancer cell lines (MCF-7 and MDA MB-231). Compounds HL4 and [Ru(HL1) (O-DMSO)3(S-DMSO)]Cl (M1R) showed significant anti-breast cancer activity as evident from cytotoxicity, morphological and nuclear changes, DNA fragmentation and cell cycle arrest in breast cancer cells. UV-Vis and CD-spectra analysis showed HL4 and M1R interfered with DNA absorption spectra possibly due to DNA binding whereas these compounds were devoid of DNA topoisomerase inhibiting activity. Thus, these Ru(II) compounds have been established as new leads for future optimization by improving anti-cancer potency and safety.

  14. Predictive value of serum bradykinin and desArg9-bradykinin levels for chemotherapeutic responses in active tuberculosis patients: A retrospective case series

    PubMed Central

    Qian, Xu; Nguyen, Duc T.M.; Li, Yaojun; Lyu, Jianxin; Graviss, Edward A.; Hu, Tony Y.

    2016-01-01

    Background There is an urgent need for methods that can rapidly and accurately assess therapeutic responses in patients with active tuberculosis (TB) in order to predict treatment outcomes. Exposure to bacterial pathogens can rapidly activate the plasma contact system, triggering the release of bradykinin (BK) and its metabolite desArg9-bradykinin (DABK) to induce inflammation and innate immune responses. We hypothesized that serum BK and DABK levels might act as sensitive immune response signatures for changes in Mycobacterium tuberculosis (Mtb) burden, and therefore examined how serum levels of these markers corresponded with anti-TB therapy in a small cohort of active TB cases. Methods Nanotrap Mass-Spectrometry (MS) was used to analyze serial blood specimens from 13 HIV-negative adults with microbiologically confirmed active TB who were treated with first-line anti-TB chemotherapy. MS signal for BK (m/z 1060.5) and DABK (m/z 904.5) serum peptides were evaluated at multiple time-points (before, during, and after treatment) to evaluate how BK and DABK levels corresponded with disease status. Results Serum BK levels declined from pretreatment baseline levels during the early stage anti-TB therapy (induction phase) and tended to remain below baseline levels during extended treatment (consolidation phase) and after therapy completion. BK levels were consistent with induction phase sputum culture conversions indicative of decreased Mtb burden reflecting good treatment responses. Serum DABK levels tended to increase during the induction phase and decrease at consolidation and post-therapy time points, which may indicate a shift from active disease to chronic inflammation to a disease free state. Elevated BK and DABK levels after treatment completion in one patient may be related to the subsequent recurrent TB disease. Conclusions Our pilot data suggests that changes in the circulating BK and DABK levels in adult TB patients can be used as potential surrogate markers

  15. Activities of Therapeutic Agents and Myristamidopropyl Dimethylamine against Acanthamoeba Isolates

    PubMed Central

    Kilvington, Simon; Hughes, Reanne; Byas, James; Dart, John

    2002-01-01

    The activities of therapeutic agents and myristamidopropyl dimethylamine (MAPD) against Acanthamoeba strains recalcitrant to medical therapy were studied. MAPD minimum cysticidal concentrations were 6.25 to 25 μg/ml; 10 to 30 μg/ml gave at least a 3-log cyst kill after 6 h, and 50 and 100 μg/ml gave at least a 3-log cyst kill within 2 and 1 h, respectively. PMID:12019127

  16. Activities of therapeutic agents and myristamidopropyl dimethylamine against Acanthamoeba isolates.

    PubMed

    Kilvington, Simon; Hughes, Reanne; Byas, James; Dart, John

    2002-06-01

    The activities of therapeutic agents and myristamidopropyl dimethylamine (MAPD) against Acanthamoeba strains recalcitrant to medical therapy were studied. MAPD minimum cysticidal concentrations were 6.25 to 25 microg/ml; 10 to 30 microg/ml gave at least a 3-log cyst kill after 6 h, and 50 and 100 microg/ml gave at least a 3-log cyst kill within 2 and 1 h, respectively.

  17. γ-Tocotrienol but not γ-tocopherol blocks STAT3 cell signaling pathway through induction of protein-tyrosine phosphatase SHP-1 and sensitizes tumor cells to chemotherapeutic agents.

    PubMed

    Kannappan, Ramaswamy; Yadav, Vivek R; Aggarwal, Bharat B

    2010-10-22

    Although γ-tocotrienol (T3), a vitamin E isolated primarily from palm and rice bran oil, has been linked with anticancer activities, the mechanism of this action is poorly understood. In this study, we investigated whether γ-T3 can modulate the STAT3 cell signaling pathway, closely linked to inflammation and tumorigenesis. We found that γ-T3 but not γ-tocopherol, the most common saturated form of vitamin E, inhibited constitutive activation of STAT3 in a dose- and time-dependent manner, and this inhibition was not cell type-specific. γ-T3 also inhibited STAT3 DNA binding. This correlated with inhibition of Src kinase and JAK1 and JAK2 kinases. Pervanadate reversed the γ-T3-induced down-regulation of STAT3 activation, suggesting the involvement of a protein-tyrosine phosphatase. When examined further, we found that γ-T3 induced the expression of the tyrosine phosphatase SHP-1, and gene silencing of the SHP-1 by small interfering RNA abolished the ability of γ-T3 to inhibit STAT3 activation, suggesting a vital role for SHP-1 in the action of γ-T3. Also γ-T3 down-modulated activation of STAT3 and induced SHP-1 in vivo. Eventually, γ-T3 down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) gene products; and this correlated with suppression of proliferation, the accumulation of cells in sub-G(1) phase of the cell cycle, and induction of apoptosis. This vitamin also sensitized the tumor cells to the apoptotic effects of thalidomide and bortezomib. Overall, our results suggest that γ-T3 is a novel blocker of STAT3 activation pathway both in vitro and in vivo and thus may have potential in prevention and treatment of cancers.

  18. Coordinating the activities of a planner and an execution agent

    NASA Technical Reports Server (NTRS)

    Tate, Austin

    1989-01-01

    A research program was defined that will explore the link between planning and execution systems. A simple scenario was defined in which a very capable off-line planning system interacts with the user and a smaller, less capable, on-line real-time system executing plans and reacting to faults. However, the on-line execution system may have a more flexible representation of the plans it is executing. This imbalance in the capabilities of the two agents involved should clarify some of the research objectives and give an experimental framework for the work. The task is to investigate the knowledge representations and communication protocols needed to link a user stating some requirements for a task to be carried out through a planning system to the (remote) execution agent that can carry out the user's wishes. The notion that a single representation can encapsulate the expression of the user's requirements, the capabilities for action, the communication to the execution agent, the successful or faulty response from the execution agent and the means of keeping the user informed, is examined. Methods of creating plan patches to update the plans separately held by each of the parties involved to keep them in step as they each react to changing circumstances in real-time is investigated. This involves the specification of plan patch attachment points that can be understood by the recipient. Transaction based methods are also investigated for coordinating the activities of the planner with those of the execution agent and user. The trial application area for the research is in the command and control of an advanced Earth Observation Space Platform.

  19. Synthesis and structure-activity relationship of amidine derivatives of 3,4-ethylenedioxythiophene as novel antibacterial agents.

    PubMed

    Stolić, Ivana; Čipčić Paljetak, Hana; Perić, Mihaela; Matijašić, Mario; Stepanić, Višnja; Verbanac, Donatella; Bajić, Miroslav

    2015-01-27

    Current antibacterial chemotherapeutics are facing an alarming increase in bacterial resistance pressuring the search for novel agents that would expand the available therapeutic arsenal against resistant bacterial pathogens. In line with these efforts, a series of 9 amidine derivatives of 3,4-ethylenedioxythiophene were synthesized and, together with 18 previously synthesized analogs, evaluated for their relative DNA binding affinity, in vitro antibacterial activities and preliminary in vitro safety profile. Encouraging antibacterial activity of several subclasses of tested amidine derivatives against Gram-positive (including resistant MRSA, MRSE, VRE strains) and Gram-negative bacterial strains was observed. The bis-phenyl derivatives were the most antibacterially active, while compound 19 from bis-benzimidazole class exhibited the widest spectrum of activity (with MIC of 4, 2, 0.5 and ≤0.25 μg/ml against laboratory strains of Staphyloccocus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, respectively and 4-32 μg/ml against clinical isolates of sensitive and resistant S. aureus, Staphylococcus epidermidis and Enterococcus faecium) and also demonstrated the strongest DNA binding affinity (ΔTm of 15.4 °C). Asymmetrically designed compounds and carboxamide-amidines were, in general, less active. Molecular docking indicated that the shape of the 3,4-ethylenedioxythiophene derivatives and their ability to form multiple electrostatic and hydrogen bonds with DNA, corresponds to the binding modes of other minor-groove binders. Herein reported results encourage further investigation of this class of compounds as novel antibacterial DNA binding agents.

  20. Pharmacological activity of metal binding agents that alter copper bioavailability

    PubMed Central

    Helsel, Marian E.

    2015-01-01

    Iron, copper and zinc are required nutrients for many organisms but also potent toxins if misappropriated. An overload of any of these metals can be cytotoxic and ultimately lead to organ failure, whereas deficiencies can result in anemia, weakened immune system function, and other medical conditions. Cellular metal imbalances have been implicated in neurodegenerative diseases, cancer and infection. It is therefore critical for living organisms to maintain careful control of both the total levels and subcellular distributions of these metals to maintain healthy function. This perspective explores several strategies envisioned to alter the bioavailability of metal ions by using synthetic metal-binding agents targeted for diseases where misappropriated metal ions are suspected of exacerbating cellular damage. Specifically, we discuss chemical properties that influence the pharmacological outcome of a subset of metal-binding agents known as ionophores, and review several examples that have shown multiple pharmacological activities in metal-related diseases, with a specific focus on copper. PMID:25797044

  1. Spectroscopic detection of chemotherapeutics and antioxidants

    NASA Astrophysics Data System (ADS)

    Latka, Ines; Grüner, Roman; Matthäus, Christian; Dietzek, Benjamin; Werncke, W.; Lademann, Jürgen; Popp, Jürgen

    2012-06-01

    The hand-foot-syndrome presents a severe dermal side-effect of chemotherapeutic cancer treatment. The cause of this side-effect is the elimination of systemically administered chemotherapeutics with the sweat. Transported to the skin surface, the drugs subsequently penetrate into the skin in the manner of topically applied substances. Upon accumulation of the chemotherapeutics in the skin the drugs destroy cells and tissue - in the same way as they are supposed to act in cancer cells. Aiming at the development of strategies to illuminate the molecular mechanism underlying the handfoot- syndrome (and, in a second step, strategies to prevent this severe side-effect), it might be important to evaluate the concentration and distribution of chemotherapeutics and antioxidants in the human skin. The latter can be estimated by the carotenoid concentration, as carotenoids serve as marker substances for the dermal antioxidative status.Following the objectives outlined above, this contribution presents a spectroscopic study aiming at the detection and quantification of carotenoids and selected chemotherapeutics in human skin. To this end, spontaneous Raman scattering and coherent anti-Stokes Raman scattering (CARS) microspectroscopy are combined with two-photon excited fluorescence. While the latter technique is Please verify that (1) all pages are present, (2) all figures are correct, (3) all fonts and special characters are correct, and (4) all text and figures fit within the red margin lines shown on this review document. Complete formatting information is available at http://SPIE.org/manuscripts Return to your MySPIE To Do List at http://myspie.org and approve or disapprove this submission. Your manuscript will not be published without this approval.restricted to the detection of fluorescent chemotherapeutics, e.g., doxorubicin, the vibrational spectroscopic techniques can - in principle - be applied to any type of analyte molecules. Furthermore, we will present the

  2. Effect of Paullinia cupana on MCF-7 breast cancer cell response to chemotherapeutic drugs.

    PubMed

    Hertz, Everaldo; Cadoná, Francine Carla; Machado, Alencar Kolinski; Azzolin, Verônica; Holmrich, Sabrina; Assmann, Charles; Ledur, Pauline; Ribeiro, Euler Esteves; DE Souza Filho, Olmiro Cezimbra; Mânica-Cattani, Maria Fernanda; DA Cruz, Ivana Beatrice Mânica

    2015-01-01

    Previous studies suggested that certain plants, such as guarana (Paullinia cupana), exert a protective effect against cancer-related fatigue in breast cancer patients undergoing chemotherapy. However, guarana possesses bioactive molecules, such as caffeine and catechin, which may affect the pharmacological properties of antitumor drugs. Therefore, the aim of this study was to evaluate the effects of guarana on breast cancer cell response to 7 chemotherapeutic agents currently used in the treatment of breast cancer. To perform this study, MCF-7 breast cancer cells were cultured under controlled conditions and exposed to 1, 5 and 10 µg/ml guarana concentrations, with and without chemotherapeutics (gemcitabine, vinorelbine, methotrexate, 5-fluorouracil, paclitaxel, doxorubicin and cyclophosphamide). The effect of these treatments on MCF-7 cell viability and proliferation was spectrophotometrically analyzed with the MTT assay. The main results demonstrated an antiproliferative effect of guarana at concentrations of 5 and 10 µg/ml and a significant effect on chemotherapeutic drug action. In general, guarana improved the antiproliferative effect of chemotherapeutic agents, causing a decrease of >40% in cell growth after 72 h of exposure. The results suggested an interaction of guarana with the chemotherapeutic drugs, which requires confirmation by in vivo complementary studies.

  3. Synthesis and crystal structure elucidation of new copper(II)-based chemotherapeutic agent coupled with 1,2-DACH and orthovanillin: Validated by in vitro DNA/HSA binding profile and pBR322 cleavage pathway.

    PubMed

    Zaki, Mehvash; Afzal, Mohd; Ahmad, Musheer; Tabassum, Sartaj

    2016-08-01

    New copper(II)-based complex (1) was synthesized and characterized by analytical, spectroscopic and single crystal X-ray diffraction. The in vitro binding studies of complex 1 with CT DNA and HSA have been investigated by employing biophysical techniques to examine the binding propensity of 1 towards DNA and HSA. The results showed that 1 avidly binds to CT DNA via electrostatic mode along with the hydrogen bonding interaction of NH2 and CN groups of Schiff base ligand with the base pairs of DNA helix, leads to partial unwinding and destabilization of the DNA double helix. Moreover, the CD spectral studies revealed that complex 1 binds through groove binding interaction that stabilizes the right-handed B-form of DNA. Complex 1 showed an impressive photoinduced nuclease activity generating single-strand breaks in comparison with the DNA cleavage activity in presence of visible light. The mechanistic investigation revealed the efficiency of 1 to cleave DNA strands by involving the generation of reactive oxygen species. Furthermore, the time dependent DNA cleavage activity showed that there was gradual increase in the amount of NC DNA on increasing the photoexposure time. However, the interaction of 1 and HSA showed that the change of intrinsic fluorescence intensity of HSA was induced by the microenvironment of Trp residue.

  4. Mechanistic investigation of beta-galactosidase-activated MR contrast agents.

    PubMed

    Urbanczyk-Pearson, Lauren M; Femia, Frank J; Smith, Jeffrey; Parigi, Giacomo; Duimstra, Joseph A; Eckermann, Amanda L; Luchinat, Claudio; Meade, Thomas J

    2008-01-07

    We report a mechanistic investigation of an isomeric series of beta-galactosidase-activated magnetic resonance contrast agents. Our strategy focuses on the synthesis of macrocyclic caged-complexes that coordinatively saturate a chelated lanthanide. Enzyme cleavage of the complex results in an open coordination site available for water that creates a detectable MR contrast agent. The complexes consist of a DO3A Gd(III) chelator modified with a galactopyranose at the N-10 position of the macrocycle. We observed significant differences in relaxometric properties and coordination geometry that can be correlated to subtle variations of the linker between the macrocycle and the galactopyranose. After synthesis and purification of the R, S, and racemic mixtures of complexes 1 and 3 and measurement of the hydration number, water residence lifetime, and longitudinal relaxation rates, we propose mechanisms for water exclusion from the lanthanide in the precleavage state. While the stereochemistry of the linker does not influence the agents' properties, the mechanism of water exclusion for each isomer is significantly influenced by the position of modification. Data for one series with a methyl group substituted on the sugar-macrocycle linker at the alpha-position suggests a steric mechanism where the galactopyranose sugar blocks water from the Gd(III) center. In contrast, our observations for a second series with methyl substitution at the beta position of the sugar-macrocycle linker are consistent with a mechanism in which a bidentate anion occupies two available coordination sites of Gd(III) in the precleavage state.

  5. Pyridazinopsoralens of wide chemotherapeutic interest.

    PubMed

    Dalla Via, Lisa; Gia, Ornella; Marciani Magno, Sebastiano; Braga, Alessandra; González-Gómez, José Carlos; Pérez-Montoto, Lázaro Guillermo; Uriarte, Eugenio

    2010-08-01

    The synthesis of new 6,10-dimethylpyridazino[4,5-h]psoralens, carrying no (4), one (5), or two (6-9) dialkylaminoalkylcarboxamide side chains on the pyridazine ring is reported. All compounds exert a significant photoantiproliferative activity. Moreover, the derivatives characterised by the protonable side chains show a notable cytotoxicity in the dark. The investigation on the mechanism of action demonstrated the capacity to intercalate into DNA base pairs and to inhibit the relaxation activity of topoisomerase II.

  6. The myosin activator omecamtiv mecarbil: a promising new inotropic agent.

    PubMed

    Nánási, Péter; Váczi, Krisztina; Papp, Zoltán

    2016-10-01

    Heart failure became a leading cause of mortality in the past few decades with a progressively increasing prevalence. Its current therapy is restricted largely to the suppression of the sympathetic activity and the renin-angiotensin system in combination with diuretics. This restrictive strategy is due to the potential long-term adverse effects of inotropic agents despite their effective influence on cardiac function when employed for short durations. Positive inotropes include inhibitors of the Na(+)/K(+) pump, β-receptor agonists, and phosphodiesterase inhibitors. Theoretically, Ca(2+) sensitizers may also increase cardiac contractility without resulting in Ca(2+) overload; nevertheless, their mechanism of action is frequently complicated by other pleiotropic effects. Recently, a new positive inotropic agent, the myosin activator omecamtiv mecarbil, has been developed. Omecamtiv mecarbil binds directly to β-myosin heavy chain and enhances cardiac contractility by increasing the number of the active force-generating cross-bridges, presumably without major off-target effects. This review focuses on recent in vivo and in vitro results obtained with omecamtiv mecarbil, and discusses its mechanism of action at a molecular level. Based on clinical data, omecamtiv mecarbil is a promising new tool in the treatment of systolic heart failure.

  7. Perspective of surface active agents in baking industry: an overview.

    PubMed

    Ahmad, Asif; Arshad, Nazish; Ahmed, Zaheer; Bhatti, Muhammad Shahbaz; Zahoor, Tahir; Anjum, Nomana; Ahmad, Hajra; Afreen, Asma

    2014-01-01

    Different researchers have previously used surfactants for improving bread qualities and revealed that these compounds result in improving the quality of dough and bread by influencing dough strength, tolerance, uniform crumb cell size, and improve slicing characteristics and gas retention. The objective of this review is to highlight the areas where surfactants are most widely used particularly in the bread industries, their role and mechanism of interaction and their contribution to the quality characteristics of the dough and bread. This review reveals some aspects of surface-active agents regarding its role physiochemical properties of dough that in turn affect the bread characteristics by improving its sensory quality and storage stability.

  8. Molluscicidal properties and selective toxicity of surface-active agents

    PubMed Central

    Visser, S. A.

    1965-01-01

    Of over 100 commercially produced surface-active agents tested against the bilharziasis vector snail Biomphalaria sudanica, 13 were found to possess considerable and highly selective molluscicidal properties at concentrations of less than 1 ppm for exposures of 48 hours. Against crustacea, fish, water plants, mosquito larvae, mice, and the eggs of B. sudanica, the toxicities of the 13 surfactants were slight. The chemicals did not appear to be absorbed by organic matter to any appreciable extent. It is thought that the toxicity to B. sudanica is of both a chemical and a physical nature. PMID:5294185

  9. Enhancing the Efficacy of Chemotherapeutic Breast Cancer Treatment with Nonanticoagulant Heparins

    DTIC Science & Technology

    2008-05-01

    intervals throughout the course of treatment. LMWH compounds (Enoxaparin or non- anticoagulant heparin NACH) given together with chemotherapeutic agent ... Anticoagulants , Antiplatelets , and Thrombolytics. 2004. SA Mousa (Ed). Humana Press Inc., 133-155, 2004. 11. Mousa SA, Mohamed S. Anti-angiogenic mechanisms...doxorubicin decreased tumor growth rate and prolong survival in animals bearing MCF7 wild-type tumors. These agents appeared to be less effective in

  10. Wet deposition of the seeding agent after weather modification activities.

    PubMed

    Curić, Mladjen; Janc, Dejan

    2013-09-01

    Weather modification activities are performed mostly by cloud seeding. Some operational projects have been conducted for more than a half century and cover planetary scales. These activities have led to large amounts of seeding agents being deposited on the ground in precipitation. The main intent of this paper is to identify the spatial pattern of silver iodide deposits after hail suppression. The spatial pattern of silver iodide deposits is determined using the weather modification project measurements from seeding agent reports, two weather radars and 316 launching sites during a 5-year period. The estimated spatial distribution of the deposits is not uniform, with the maximum silver iodide amount located in the southern part of the study area (up to 140 μg m(-2)). Our results are comparable with the measurements performed by chemical analyses during other cloud seeding experiments. The maximum location coincides well with that of the maximum seeded hailstorm precipitation frequency. A new method for identifying the spatial pattern of wet-deposited material has been established. The location with the maximum amount is found. This method would be important as a means of placing samplers and monitoring at the representative sites because those are where most weather modification projects would be performed in the future.

  11. Reactive oxygen species-activated nanomaterials as theranostic agents

    PubMed Central

    Kim, Kye S; Lee, Dongwon; Song, Chul Gyu; Kang, Peter M

    2015-01-01

    Reactive oxygen species (ROS) are generated from the endogenous oxidative metabolism or from exogenous pro-oxidant exposure. Oxidative stress occurs when there is excessive production of ROS, outweighing the antioxidant defense mechanisms which may lead to disease states. Hydrogen peroxide (H2O2) is one of the most abundant and stable forms of ROS, implicated in inflammation, cellular dysfunction and apoptosis, which ultimately lead to tissue and organ damage. This review is an overview of the role of ROS in different diseases. We will also examine ROS-activated nanomaterials with emphasis on hydrogen peroxide, and their potential medical implications. Further development of the biocompatible, stimuli-activated agent responding to disease causing oxidative stress, may lead to a promising clinical use. PMID:26328770

  12. Dissociative electron attachment to the radiosensitizing chemotherapeutic agent hydroxyurea

    NASA Astrophysics Data System (ADS)

    Huber, S. E.; Śmiałek, M. A.; Tanzer, K.; Denifl, S.

    2016-06-01

    Dissociative electron attachment to hydroxyurea was studied in the gas phase for electron energies ranging from zero to 9 eV in order to probe its radiosensitizing capabilities. The experiments were carried out using a hemispherical electron monochromator coupled with a quadrupole mass spectrometer. Diversified fragmentation of hydroxyurea was observed upon low energy electron attachment and here we highlight the major dissociation channels. Moreover, thermodynamic thresholds for various fragmentation reactions are reported to support the discussion of the experimental findings. The dominant dissociation channel, which was observed over a broad range of energies, is associated with formation of NCO-, water, and the amidogen (NH2) radical. The second and third most dominant dissociation channels are associated with formation of NCNH- and NHCONH2-, respectively, which are both directly related to formation of the highly reactive hydroxyl radical. Other ions observed with significant abundance in the mass spectra were NH2-/O-, OH-, CN-, HNOH-, NCONH2-, and ONHCONH2-.

  13. Synthesis of Taxol-Like Prostate Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2006-11-01

    opening reaction of sulfolene 1 where the corresponding chiral epoxide 19 was readily available from L-tartaric acid.5) The resulting secondary alcohol...toluene, reflux OH OTBS 41% over 2 steps MOMBr DIPEA, DMAP DCMSO2 + OMOM OTBS 64% 1) TBAF 2) SO3- pyridine OMOM O 20191 21 22 40% over 2 steps

  14. Design and Sythesis of New Breast Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2000-08-01

    Point, PA) Smith, Kline and Beckmann Invited Lecturer, Symposium on Organic Synthesis , Great Lakes Regional ACS Meeting, Dekalb, Illinois Invited...Ann Arbor, Michigan Invited Lecturer, Symposium on Organic Synthesis , Middle Atlantic Regional ACS Meeting, Baltimore, Maryland Technion-Israel...Photochemical Key Steps in Organic Synthesis 1994, J. Mattay and A. Griesbeck, Eds., VCH, Weinheim, 109-111. 40. K. Davis, T. Berrodin, T., J. Stelmach

  15. Mechanisms of tumour resistance against chemotherapeutic agents in veterinary oncology.

    PubMed

    Klopfleisch, R; Kohn, B; Gruber, A D

    2016-01-01

    Several classes of chemotherapy drugs are used as first line or adjuvant treatment of the majority of tumour types in veterinary oncology. However, some types of tumour are intrinsically resistant to several anti-cancer drugs, and others, while initially sensitive, acquire resistance during treatment. Chemotherapy often significantly prolongs survival or disease free interval, but is not curative. The exact mechanisms behind intrinsic and acquired chemotherapy resistance are unknown for most animal tumours, but there is increasing knowledge on the mechanisms of drug resistance in humans and a few reports on molecular changes in resistant canine tumours have emerged. In addition, approaches to overcome or prevent chemotherapy resistance are becoming available in humans and, given the overlaps in molecular alterations between human and animal tumours, these may also be relevant in veterinary oncology. This review provides an overview of the current state of research on general chemotherapy resistance mechanisms, including drug efflux, DNA repair, apoptosis evasion and tumour stem cells. The known resistance mechanisms in animal tumours and the potential of these findings for improving treatment efficacy in veterinary oncology are also explored.

  16. The Effect of Chemotherapeutic Agents on Immune Reactions.

    DTIC Science & Technology

    1982-08-01

    Tween - 80 in saline. The drugs were first . ... p. p-𔃾 dissolved in methylcellulose- Tween - 80 mixture and then diluted to the exact concentration with...Control mice received 0.4 ml solvent (methyl- cellulose- Tween - 80 in saline). Drugs were injected one day before or one day after the antigei for the

  17. Quantitative structure-activity relationship studies on nitrofuranyl antitubercular agents

    PubMed Central

    Hevener, Kirk E.; Ball, David M.; Buolamwini, John K.

    2008-01-01

    A series of nitrofuranylamide and related aromatic compounds displaying potent activity against M. tuberculosis has been investigated utilizing 3-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) techniques. Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods were used to produce 3D-QSAR models that correlated the Minimum Inhibitory Concentration (MIC) values against M. tuberculosis with the molecular structures of the active compounds. A training set of 95 active compounds was used to develop the models, which were then evaluated by a series of internal and external cross-validation techniques. A test set of 15 compounds was used for the external validation. Different alignment and ionization rules were investigated as well as the effect of global molecular descriptors including lipophilicity (cLogP, LogD), Polar Surface Area (PSA), and steric bulk (CMR), on model predictivity. Models with greater than 70% predictive ability, as determined by external validation, and high internal validity (cross validated r2 > .5) have been developed. Incorporation of lipophilicity descriptors into the models had negligible effects on model predictivity. The models developed will be used to predict the activity of proposed new structures and advance the development of next generation nitrofuranyl and related nitroaromatic anti-tuberculosis agents. PMID:18701298

  18. ActivitySim: large-scale agent based activity generation for infrastructure simulation

    SciTech Connect

    Gali, Emmanuel; Eidenbenz, Stephan; Mniszewski, Sue; Cuellar, Leticia; Teuscher, Christof

    2008-01-01

    The United States' Department of Homeland Security aims to model, simulate, and analyze critical infrastructure and their interdependencies across multiple sectors such as electric power, telecommunications, water distribution, transportation, etc. We introduce ActivitySim, an activity simulator for a population of millions of individual agents each characterized by a set of demographic attributes that is based on US census data. ActivitySim generates daily schedules for each agent that consists of a sequence of activities, such as sleeping, shopping, working etc., each being scheduled at a geographic location, such as businesses or private residences that is appropriate for the activity type and for the personal situation of the agent. ActivitySim has been developed as part of a larger effort to understand the interdependencies among national infrastructure networks and their demand profiles that emerge from the different activities of individuals in baseline scenarios as well as emergency scenarios, such as hurricane evacuations. We present the scalable software engineering principles underlying ActivitySim, the socia-technical modeling paradigms that drive the activity generation, and proof-of-principle results for a scenario in the Twin Cities, MN area of 2.6 M agents.

  19. Activity of catalytic silver nanoparticles modulated by capping agent hydrophobicity.

    PubMed

    Janani, Seralathan; Stevenson, Priscilla; Veerappan, Anbazhagan

    2014-05-01

    In this paper, a facile in situ method is reported for the preparation of catalytic silver nanoparticles (AgNPs) using N-acyl tyramine (NATA) with variable hydrophobic acyl length. Scanning electron microscopic analysis shows that NATA exists initially as larger aggregates in alkaline aqueous solution. The addition of AgNO3 dissociates these larger aggregate and subsequently promotes the formation of self-assembled NATA and AgNPs. Characterization of AgNPs using UV-vis spectroscopy, scanning electron microscope and transmission electron microscope revealed that the hydrophobic acyl chain length of NATA does not influence the particle size, shape and morphology. All NATA-AgNPs yielded relatively identical values in full width at half-maximum (FWHM) analysis, indicating that the AgNPs prepared with NATA are relatively polydispersed at all tested acyl chain lengths. These nanoparticles are able to efficiently catalyze the reduction of 4-nitro phenol to 4-amino phenol, 2-nitro aniline to 1,2-diamino benzene, 2,4,6-trinitro phenol to 2,4,6-triamino phenol by NaBH4 in an aqueous environment. The reduction reaction rate is determined to be pseudo-first order and the apparent rate constant is linearly dependent on the hydrophobic acyl chain length of the NATA. All reaction kinetics presented an induction period, which is dependent on the N-acyl chain length, indicating that the hydrophobic effects play a critical role in bringing the substrate to the metal nanoparticle surface to induce the catalytic reaction. In this study, however, the five catalytic systems have similar size and polydispersity, differing only in terms of capping agent hydrophobicity, and shows different catalytic activity with respect to the alkyl chain length of the capping agent. As discussed, the ability to modulate the metal nanoparticles catalytic property, by modifying the capping agent hydrophobicity represents a promising future for developing an efficient nanocatalyst without altering the size

  20. Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Several benzoic acid analogs showed antifungal activity against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis. Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids increased by addition of a methyl, methoxyl...

  1. 2-(4-Aminophenyl)benzothiazoles: novel agents with selective profiles of in vitro anti-tumour activity.

    PubMed Central

    Bradshaw, T. D.; Wrigley, S.; Shi, D. F.; Schultz, R. J.; Paull, K. D.; Stevens, M. F.

    1998-01-01

    2-(4-Aminophenyl)benzothiazole (CJM 126) elicits biphasic growth-inhibitory effects against a panel of oestrogen receptor-positive (ER+) and oestrogen receptor-negative (ER-) human mammary carcinoma cell lines in vitro, yielding IC50 values in the nM range. Substitutions adjacent to the amino group in the 2-phenyl ring with a halogen atom or methyl group enhance potency in sensitive breast lines (pM IC50 values). Transient biphasic dose responses were induced but rapidly eradicated after specific drug exposure periods. Two human prostate carcinoma cell lines were refractory to the growth-inhibitory properties of 2-(4-aminophenyl)benzothiazoles; IC50 values > 30 microM were obtained. Potency and selectivity were confirmed when compounds were examined in the National Cancer Institute's Developmental Therapeutics screen; the spectrum of activity included specific ovarian, renal, colon as well as breast carcinoma cell lines. Moreover, comparing 6-day and 48-h incubations, the exposure time-dependent nature of the biphasic response was corroborated. Differential perturbation of cell cycle distribution followed treatment of MCF-7 and MDA 468 cells with substituted 2-(4-aminophenyl)benzothiazoles. In MDA 468 populations only, accumulation of events in G2/M phase was observed. Two MCF-7 cell lines were established with acquired resistance to CJM 126 (IC50 values > 20 microM), which exhibit cross-resistance to substituted benzothiazoles, but equal sensitivity to tamoxifen and doxorubicin. Compared with standard anti-tumour agents evaluated in the National Cancer Institute in vitro cell panel, benzothiazoles revealed unique profiles of growth inhibition, suggesting a mode(s) of action shared with no known clinically active class of chemotherapeutic agents. PMID:9514053

  2. SEQUESTERING AGENTS FOR ACTIVE CAPS - REMEDIATION OF METALS AND ORGANICS

    SciTech Connect

    Knox, A; Michael Paller, M; Danny D. Reible, D; Xingmao Ma, X; Ioana G. Petrisor, I

    2007-05-10

    This research evaluated organoclays, zeolites, phosphates, and a biopolymer as sequestering agents for inorganic and organic contaminants. Batch experiments were conducted to identify amendments and mixtures of amendments for metal and organic contaminants removal and retention. Contaminant removal was evaluated by calculating partitioning coefficients. Metal retention was evaluated by desorption studies in which residue from the removal studies was extracted with 1 M MgCl{sub 2} solution. The results indicated that phosphate amendments, some organoclays, and the biopolymer, chitosan, were very effective sequestering agents for metals in fresh and salt water. Organoclays were very effective sorbents for phenanthrene, pyrene, and benzo(a)pyrene. Partitioning coefficients for the organoclays were 3000-3500 ml g{sup -1} for benzo(a)pyrene, 400-450 ml g{sup -1} for pyrene, and 50-70 ml g{sup -1} for phenanthrene. Remediation of sites with a mixture of contaminants is more difficult than sites with a single contaminant because metals and organic contaminants have different fate and transport mechanisms in sediment and water. Mixtures of amendments (e.g., organoclay and rock phosphate) have high potential for remediating both organic and inorganic contaminants under a broad range of environmental conditions, and have promise as components in active caps for sediment remediation.

  3. Biological Activity of Coumarin Derivatives as Anti-Leishmanial Agents

    PubMed Central

    Mandlik, Vineetha; Patil, Sohan; Bopanna, Ramanamurthy; Basu, Sudipta; Singh, Shailza

    2016-01-01

    Cutaneous leishmaniasis affects nearly 0.7 to 1.3 million people annually. Treatment of this disease is difficult due to lack of appropriate medication and the growing problem of drug resistance. Natural compounds such as coumarins serve as complementary therapeutic agents in addition to the current treatment modalities. In this study, we have performed an in-silico screening of the coumarin derivatives and their anti-leishmanial properties has been explored both in-vitro and in-vivo. One of the compounds (compound 2) exhibited leishmanicidal activity and to further study its properties, nanoliposomal formulation of the compound was developed. Treatment of cutaneous lesions in BALB/c mice with compound 2 showed significantly reduced lesion size as compared to the untreated mice (p<0.05) suggesting that compound 2 may possess anti-leishmanial properties. PMID:27768694

  4. Laboratory activities involving transmissible spongiform encephalopathy causing agents

    PubMed Central

    Leunda, Amaya; Van Vaerenbergh, Bernadette; Baldo, Aline; Roels, Stefan; Herman, Philippe

    2013-01-01

    Since the appearance in 1986 of epidemic of bovine spongiform encephalopathy (BSE), a new form of neurological disease in cattle which also affected human beings, many diagnostic and research activities have been performed to develop detection and therapeutic tools. A lot of progress was made in better identifying, understanding and controlling the spread of the disease by appropriate monitoring and control programs in European countries. This paper reviews the recent knowledge on pathogenesis, transmission and persistence outside the host of prion, the causative agent of transmissible spongiform encephalopathies (TSE) in mammals with a particular focus on risk (re)assessment and management of biosafety measures to be implemented in diagnostic and research laboratories in Belgium. Also, in response to the need of an increasing number of European diagnostic laboratories stopping TSE diagnosis due to a decreasing number of TSE cases reported in the last years, decontamination procedures and a protocol for decommissioning TSE diagnostic laboratories is proposed. PMID:24055928

  5. Multiphysics and Multiscale Analysis for Chemotherapeutic Drug

    PubMed Central

    Zhang, Linan; Kim, Sung Youb; Kim, Dongchoul

    2015-01-01

    This paper presents a three-dimensional dynamic model for the chemotherapy design based on a multiphysics and multiscale approach. The model incorporates cancer cells, matrix degrading enzymes (MDEs) secreted by cancer cells, degrading extracellular matrix (ECM), and chemotherapeutic drug. Multiple mechanisms related to each component possible in chemotherapy are systematically integrated for high reliability of computational analysis of chemotherapy. Moreover, the fidelity of the estimated efficacy of chemotherapy is enhanced by atomic information associated with the diffusion characteristics of chemotherapeutic drug, which is obtained from atomic simulations. With the developed model, the invasion process of cancer cells in chemotherapy treatment is quantitatively investigated. The performed simulations suggest a substantial potential of the presented model for a reliable design technology of chemotherapy treatment. PMID:26491672

  6. Antitumour activity of novel taxanes that act at the same time as cytotoxic agents and P-glycoprotein inhibitors

    PubMed Central

    Ferlini, C; Distefano, M; Pignatelli, F; Lin, S; Riva, A; Bombardelli, E; Mancuso, S; Ojima, I; Scambia, G

    2000-01-01

    Taxanes antitumour agents such as paclitaxel and docetaxel represent a successful family of chemotherapeutic drugs. Unfortunately, acquired and innate resistance represents a clinical problem for these drugs. We investigated, on a panel of 7 human cancer cell lines, the growth inhibition effect of 3 newly developed taxanes (SB-T-1213, SB-T-1250 and SB-T-101187) with modification at the C10 and C3′ positions of the taxane framework. These positions have been previously characterized as critical to make taxanes highly active against cells overexpressing the efflux pump P-glycoprotein (P-gp). Paclitaxel and docetaxel were used as reference compounds. Results unambiguously indicate the exceptional activity of the novel taxanes toward P-gp positive cells (up to >400 fold higher potency than that of paclitaxel). SB-T-1213 and SB-T-1250 are also substantially more active than the reference compounds against P-gp negative cells. To better understand the mechanisms underlying the enhanced activity of the newly developed taxanes, we performed cell cycle and apoptosis analysis. This study demonstrates that the striking growth inhibition effect exhibited by the novel taxanes is ascribed to their increased ability in inducing apoptosis and G 2/M cell cycle block. SB-T-1213 and SB-T-1250 are also more active than reference compounds in inducing intracellular accumulation of the beta-tubulin subunits. Finally, it is revealed that these novel taxanes have ability to inhibit the function of the P-gp efflux pump on the basis of the Rhodamine 123 assay. These findings strongly suggest that SB-T-1213, SB-T-1250 and SB-T-101187 represent a new tool to overcome innate or acquired P-gp mediated taxane-resistance. © 2000 Cancer Research Campaign http://www.bjcancer.com PMID:11104578

  7. Local bacteria affect the efficacy of chemotherapeutic drugs

    PubMed Central

    Lehouritis, Panos; Cummins, Joanne; Stanton, Michael; Murphy, Carola T.; McCarthy, Florence O.; Reid, Gregor; Urbaniak, Camilla; Byrne, William L.; Tangney, Mark

    2015-01-01

    In this study, the potential effects of bacteria on the efficacy of frequently used chemotherapies was examined. Bacteria and cancer cell lines were examined in vitro and in vivo for changes in the efficacy of cancer cell killing mediated by chemotherapeutic agents. Of 30 drugs examined in vitro, the efficacy of 10 was found to be significantly inhibited by certain bacteria, while the same bacteria improved the efficacy of six others. HPLC and mass spectrometry analyses of sample drugs (gemcitabine, fludarabine, cladribine, CB1954) demonstrated modification of drug chemical structure. The chemoresistance or increased cytotoxicity observed in vitro with sample drugs (gemcitabine and CB1954) was replicated in in vivo murine subcutaneous tumour models. These findings suggest that bacterial presence in the body due to systemic or local infection may influence tumour responses or off-target toxicity during chemotherapy. PMID:26416623

  8. Potentiation of chemotherapeutics by bromelain and N-acetylcysteine: sequential and combination therapy of gastrointestinal cancer cells

    PubMed Central

    Amini, Afshin; Masoumi-Moghaddam, Samar; Ehteda, Anahid; Liauw, Winston; Morris, David Lawson

    2016-01-01

    Intraperitoneal chemotherapy together with cytoreductive surgery is the standard of care for a number of peritoneal surface malignancies. However, this approach fails to maintain the complete response and disease recurs due to microscopic residual disease. Although safer than systemic chemotherapy regimens, locoregional treatment with chemotherapeutics can induce toxicity which is a major concern affecting the patient’s treatment protocol and outcome. For an enhanced treatment efficacy, efforts should be made to maximize cytotoxic effects of chemotherapeutic agents on tumor cells while minimizing their toxic effects on host cells. Bromelain and N-acetylcysteine are two natural agents with good safety profiles shown to have anti-cancer effects. However, their interaction with chemotherapeutics is unknown. In this study, we investigated if these agents have the potential to sensitize in vitro gastrointestinal cancer models to cisplatin, paclitaxel, 5-fluorouracil, and vincristine. The drug-drug interaction was also analyzed. Our findings suggest that combination of bromelain and N-acetylcysteine with chemotherapeutic agents could give rise to an improved chemotherapeutic index in therapeutic approaches to peritoneal surface malignancies of gastrointestinal origin so that maximum benefits could result from less toxic and more patient-friendly doses. This represents a potentially efficacious strategy for the enhancement of microscopic cytoreduction and is a promising area for future research. PMID:27186409

  9. Synthesis, antifungal activities and qualitative structure activity relationship of carabrone hydrazone derivatives as potential antifungal agents.

    PubMed

    Wang, Hao; Ren, Shuang-Xi; He, Ze-Yu; Wang, De-Long; Yan, Xiao-Nan; Feng, Jun-Tao; Zhang, Xing

    2014-03-11

    Aimed at developing novel fungicides for relieving the ever-increasing pressure of agricultural production caused by phytopathogenic fungi, 28 new hydrazone derivatives of carabrone, a natural bioactive sesquisterpene, in three types were designed, synthesized and their antifungal activities against Botrytis cinerea and Colletotrichum lagenarium were evaluated. The result revealed that all the derivatives synthesized exhibited considerable antifungal activities in vitro and in vivo, which led to the improved activities for carabrone and its analogues and further confirmed their potential as antifungal agents.

  10. Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids were increased against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis, by addition of a methyl, methoxyl or a chloro group at position 4 of the aromatic ri...

  11. Occurrence of Surface Active Agents in the Environment

    PubMed Central

    Olkowska, Ewa; Ruman, Marek; Polkowska, Żaneta

    2014-01-01

    Due to the specific structure of surfactants molecules they are applied in different areas of human activity (industry, household). After using and discharging from wastewater treatment plants as effluent stream, surface active agents (SAAs) are emitted to various elements of the environment (atmosphere, waters, and solid phases), where they can undergo numerous physic-chemical processes (e.g., sorption, degradation) and freely migrate. Additionally, SAAs present in the environment can be accumulated in living organisms (bioaccumulation), what can have a negative effect on biotic elements of ecosystems (e.g., toxicity, disturbance of endocrine equilibrium). They also cause increaseing solubility of organic pollutants in aqueous phase, their migration, and accumulation in different environmental compartments. Moreover, surfactants found in aerosols can affect formation and development of clouds, which is associated with cooling effect in the atmosphere and climate changes. The environmental fate of SAAs is still unknown and recognition of this problem will contribute to protection of living organisms as well as preservation of quality and balance of various ecosystems. This work contains basic information about surfactants and overview of pollution of different ecosystems caused by them (their classification and properties, areas of use, their presence, and behavior in the environment). PMID:24527257

  12. Rapid test for distinguishing membrane-active antibacterial agents.

    PubMed

    Prakash Singh, Maya

    2006-10-01

    In the search for antibacterial agents with a novel mode-of-action (MOA) many targeted cellular and cell-free assays are developed and used to screen chemical and natural product libraries. Frequently, hits identified by the primary screens include compounds with nonspecific activities that can affect the integrity and function of bacterial membrane. For a rapid dereplication of membrane-active compounds, a simple method was established using a commercially available Live/Dead(R) Bacterial Viability Kit. This method utilized two fluorescent nucleic acid stains, SYTO9 (stains all cells green) and propidium iodide (stains cells with damaged membrane red) for the drug-treated bacterial cells. The cells were then either examined visually by fluorescence microscopy or their fluorescence emissions were recorded using a multi-label plate reader set to measure emissions at two different wavelengths. The ratio of green versus red was compared to a standard curve indicating the percentage of live versus dead bacteria. Nine known antibiotics and 14 lead compounds from various antibacterial screens were tested with results consistent with their MOA.

  13. Large-scale field trials of active immunizing agents

    PubMed Central

    Cockburn, W. Charles

    1955-01-01

    In this discussion of the methods to be used in large-scale field trials of active immunizing agents and of the results to be expected from such trials, special emphasis is laid on pertussis vaccine trials in Great Britain. After a review of the criteria for strictly controlled field studies and of the investigation of typhoid vaccines conducted in 1904-08 by the Antityphoid Committee of the British Army, the author describes the pertussis vaccine studies which have been and are now being carried by the Whooping-Cough Immunization Committee of the Medical Research Council of Great Britain. The original strictly controlled trials have been completed and the results published. Studies are now being made of vaccines prepared by different methods and evaluated both in the field and in the laboratory. Each vaccine is given to some 2000-3000 children of 4-6 months to 4 years of age. By the end of the studies 30 000-40 000 children will have been followed up for a period of two years. Since in the current studies all the children are vaccinated and none are left as unvaccinated controls, the relative and not the absolute protective value of the vaccines will be measured. PMID:13270079

  14. pH-Sensitive Microparticles with Matrix-Dispersed Active Agent

    NASA Technical Reports Server (NTRS)

    Li, Wenyan (Inventor); Buhrow, Jerry W. (Inventor); Jolley, Scott T. (Inventor); Calle, Luz M. (Inventor)

    2014-01-01

    Methods to produce pH-sensitive microparticles that have an active agent dispersed in a polymer matrix have certain advantages over microcapsules with an active agent encapsulated in an interior compartment/core inside of a polymer wall. The current invention relates to pH-sensitive microparticles that have a corrosion-detecting or corrosion-inhibiting active agent or active agents dispersed within a polymer matrix of the microparticles. The pH-sensitive microparticles can be used in various coating compositions on metal objects for corrosion detecting and/or inhibiting.

  15. Role of pregnane X receptor in chemotherapeutic treatment

    PubMed Central

    Zhuo, Wei; Hu, Lei; Lv, Jinfeng; Wang, Hongbing; Zhou, Honghao; Fan, Lan

    2015-01-01

    Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that differently expresses not only in human normal tissues but also in numerous types of human cancers. PXR can be activated by many endogenous substances and exogenous chemicals, and thus affects chemotherapeutic effects and intervenes drug–drug interactions by regulating its target genes involving drug metabolism and transportation, cell proliferation and apoptosis, and modulating endobiotic homeostasis. Tissue and context-specific regulation of PXR contributes to diverse effects in the treatment for numerous cancers. Genetic variants of PXR lead to intra- and inter-individual differences in the expression and inducibility of PXR, resulting in different responses to chemotherapy in PXR-positive cancers. The purpose of this review is to summarize and discuss the role of PXR in the metabolism and clearance of anticancer drugs. It is also expected that this review will provide insights into PXR-mediated enhancement for chemotherapeutic treatment, prediction of drug–drug interactions and personalized medicine. PMID:24889719

  16. The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines

    NASA Astrophysics Data System (ADS)

    Beaufils, Damien; Jepaul, Sandra; Liu, Ziwei; Boiteau, Laurent; Pascal, Robert

    2016-03-01

    The activation of dipeptides was studied in the perspective of the abiotic formation of oligopeptides of significant length as a requirement for secondary structure formation. The formation of piperazin-2,5-diones (DKP), previously considered as a dead end when activating free dipeptides, was shown in this work to be efficiently suppressed when using strong activating agents (e.g., carbodiimides). This behaviour was explained by the fast formation of a 5(4 H)-oxazolone intermediate at a rate that exceeds the time scale of the rotation of the peptide bond from the predominant trans-conformation into the cis-isomer required for DKP formation. No DKP was observed when using strong activating agents whereas phosphate mixed anhydrides or moderately activated esters were observed to predominantly yield DKP. The DKP side-reaction no longer constitutes a drawback for the C-terminus elongation of peptides. These results are considered as additional evidence that pathways involving strong activation are required to drive the emergence of living entities rather than close to equilibrium processes.

  17. The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines.

    PubMed

    Beaufils, Damien; Jepaul, Sandra; Liu, Ziwei; Boiteau, Laurent; Pascal, Robert

    2016-03-01

    The activation of dipeptides was studied in the perspective of the abiotic formation of oligopeptides of significant length as a requirement for secondary structure formation. The formation of piperazin-2,5-diones (DKP), previously considered as a dead end when activating free dipeptides, was shown in this work to be efficiently suppressed when using strong activating agents (e.g., carbodiimides). This behaviour was explained by the fast formation of a 5(4H)-oxazolone intermediate at a rate that exceeds the time scale of the rotation of the peptide bond from the predominant trans-conformation into the cis-isomer required for DKP formation. No DKP was observed when using strong activating agents whereas phosphate mixed anhydrides or moderately activated esters were observed to predominantly yield DKP. The DKP side-reaction no longer constitutes a drawback for the C-terminus elongation of peptides. These results are considered as additional evidence that pathways involving strong activation are required to drive the emergence of living entities rather than close to equilibrium processes.

  18. Chemotherapeutic trial to control enterobiasis in schoolchildren.

    PubMed

    Yang, Y S; Kim, S W; Jung, S H; Huh, S; Lee, J H

    1997-12-01

    To assess several chemotherapeutic schemes for control of enterobiasis, 738 children in five primary schools in Chunchon, Korea, were studied from May 1994 to June 1995. They were divided into 6 groups by the schemes: treatment of once or twice a year; treatment of positive cases or of whole class students; treatment with or without family members. The overall egg positive rate before intervention was 17.5% out of 789 children. Treating all individuals in a class together with family members of positive cases brought better control efficacy than other schemes (p = 0.000). However, when egg positive rate is less than 30%, treating only egg positive cases also can reduce egg positive rate. The confounding factors for the enterobiasis control in primary schoolchildren were new-comer to a class and familial infection.

  19. Efficacy of oncolytic herpesvirus NV1020 can be enhanced by combination with chemotherapeutics in colon carcinoma cells.

    PubMed

    Gutermann, Anja; Mayer, Elfriede; von Dehn-Rothfelser, Karin; Breidenstein, Claudia; Weber, Mihaela; Muench, Martina; Gungor, Denis; Suehnel, Juergen; Moebius, Ulrich; Lechmann, Martin

    2006-12-01

    NV1020, an oncolytic herpes simplex virus type 1, can destroy colon cancer cells by selectively replicating within these cells, while sparing normal cells. NV1020 is currently under investigation in a clinical phase I/II trial as an agent for the treatment of colon cancer liver metastases, in combination with conventional chemotherapeutic agents such as 5-fluorouracil (5-FU), SN38 (the active metabolite of irinotecan), and oxaliplatin. To study the synergy of NV1020 and chemotherapy, cytotoxicity and viral replication were evaluated in vitro by treating various human and murine colon carcinoma cell lines, using a colorimetric viability assay, a clonogenic assay, and a plaque-forming assay. In vivo experiments, using a subcutaneous syngeneic CT-26 tumor model in BALB/c mice, were performed to determine the efficacy of combination therapy. In vitro studies showed that the efficacy of NV1020 on human colon carcinoma cell lines HT-29, WiDr, and HCT-116 was additively or synergistically enhanced in combination with 5-FU, SN38, or oxaliplatin. The sequence of application was not important and effects were still apparent after a 21-day incubation period. Three intra-tumoral treatments with NV1020 (1 x 10(7) plaque-forming units), followed by three subcutaneous treatments with 5-FU (50 mg/kg), resulted in substantially higher inhibition of tumor growth and prolongation of survival compared with monotherapies (NV1020/5-FU vs. NV1020, p = 0.027). On WiDr cells, reduced replication of NV1020, in combination with 5-FU, indicated that additive and synergistic effects of combination therapy must be independent from viral replication. These results suggest that NV1020, in combination with chemotherapy, is a promising therapy for treating patients with metastatic colorectal cancer of the liver. We hypothesize that infection of cells with NV1020 sensitizes the infected cells for the cytotoxic effect of the chemotherapeutics.

  20. Mechanisms of resistance to chemotherapeutic and anti-angiogenic drugs as novel targets for pancreatic cancer therapy

    PubMed Central

    Tamburrino, Anna; Piro, Geny; Carbone, Carmine; Tortora, Giampaolo; Melisi, Davide

    2013-01-01

    Pancreatic cancer remains one of the most lethal and poorly understood human malignancies and will continue to be a major unsolved health problem in the 21st century. Despite efforts over the past three decades to improve diagnosis and treatment, the prognosis for patients with pancreatic cancer is extremely poor with or without treatment, and incidence rates are virtually identical to mortality rates. Although advances have been made through the identification of relevant molecular pathways in pancreatic cancer, there is still a critical, unmet need for the translation of these findings into effective therapeutic strategies that could reduce the intrinsic drug resistance of this disease and for the integration of these molecularly targeted agents into established combination chemotherapy and radiotherapy regimens in order to improve patients’ survival. Tumors are heterogeneous cellular entities whose growth and progression depend on reciprocal interactions between genetically altered neoplastic cells and a non-neoplastic microenvironment. To date, most of the mechanisms of resistance studied have been related to tumor cell-autonomous signaling pathways. However, recent data suggest a putative important role of tumor microenvironment in the development and maintenance of resistance to classic chemotherapeutic and targeted therapies. This present review is meant to describe and discuss some of the most important advances in the comprehension of the tumor cell-autonomous and tumor microenvironment-related molecular mechanisms responsible for the resistance of pancreatic cancer to the proapoptotic activity of the classic chemotherapeutic agents and to the most novel anti-angiogenic drugs. We present some of the emerging therapeutic targets for the modulation of this resistant phenotype. PMID:23641216

  1. Potential antitumor agents. 29. Quantitative structure-activity relationships for the antileukemic bisquaternary ammonium heterocycles.

    PubMed

    Denny, W A; Atwell, G J; Baguley, B C; Cain, B F

    1979-02-01

    Quantitative relationships between physicochemical drug properties and antileukemic (L1210) efficacy have been examined for a series of bisquaternary ammonium heterocycles employing multiple variable regression analysis. Three measures of biologic response were examined: ILSmax, the percentage increase in mean life span of leukemic animals at the LD10 dose; D40, the drug dose necessary to provide 40% increase in life span; and CI (=LD 10/D40), the chemotherapeutic index. A cross correlation matrix between these three measures and the LD10 values demonstrates ILSmax and CI to be independent of toxicity. D40 is highly inversely correlated with LD10 and positively correlated with ILSmax, suggesting that this parameter measures a composite of both drug selectivity and toxicity. Superior regression equations resulted at all stages employing ILSmax as a measure of antitumor selectivity. Acceptable equations modeling LD10 could not be obtained. There was a parabolic relationship between agent lipophilic-hydrophilic balance, measured as chromatographic Rm values, and ILSmax. To reduce residual variance in the L1210 screening data, not accepted by this parabolic equation, measures of agent-DNA interaction were investigated as possible indices of site fit. Relative levels of drug-DNA interaction were obtained by spectrofluorimetric quantitation of drug displacement of DNA-bound ethidium. Addition to regression equations of agent C50 values for calf thymus DNA, those micromolar drug concentrations necessary to displace 50% of the ethidium bound to that DNA, provided a significant reduction in the screening data variance. C50 values for drug interactions with poly[d(A-T)] and poly[d(G-C)] were also investigated as possible indicators of drug selectivity towards different DNA sites. Marked differences were observed in the C50 values for the two synthetic nucleic acids, with those for calf thymus DNA and poly[d(G-C)] proving highly covariant. A regression equation containing a

  2. Methods for improved selectivity in photo-activation and detection of molecular diagnostic agents

    DOEpatents

    Wachter, Eric A.; Fisher, Walter G.; Dees, H. Craig

    2008-03-18

    A method for the imaging of a particular volume of plant or animal tissue, wherein the plant or animal tissue contains at least one photo-active molecular agent. The method comprises the steps of treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of the photo-active molecular agent contained in the particular volume of the plant or animal tissue, photo-activating at least one of the at least one photo-active molecular agent in the particular volume of the plant or animal tissue, thereby producing at least one photo-activated molecular agent, wherein the at least one photo-activated molecular agent emits energy, detecting the energy emitted by the at least one photo-activated molecular agent, and producing a detected energy signal which is characteristic of the particular volume of plant or animal tissue. The present invention also provides a method for the imaging of a particular volume of material, wherein the material contains at least one photo-active molecular agent.

  3. Method for improved selectivity in photo-activation and detection of molecular diagnostic agents

    DOEpatents

    Wachter, E.A.; Fisher, W.G.; Dees, H.C.

    1998-11-10

    A method for the imaging of a particular volume of plant or animal tissue, wherein the plant or animal tissue contains at least one photo-active molecular agent. The method includes the steps of treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of the photo-active molecular agent contained in the particular volume of the plant or animal tissue, photo-activating at least one of the at least one photo-active molecular agent in the particular volume of the plant or animal tissue, thereby producing at least one photo-activated molecular agent, wherein the at least one photo-activated molecular agent emits energy, detecting the energy emitted by the at least one photo-activated molecular agent, and producing a detected energy signal which is characteristic of the particular volume of plant or animal tissue. The present invention is also a method for the imaging of a particular volume of material, wherein the material contains at least one photo-active molecular agent. 13 figs.

  4. Method for improved selectivity in photo-activation and detection of molecular diagnostic agents

    DOEpatents

    Wachter, Eric A.; Fisher, Walter G.; Dees, H. Craig

    1998-01-01

    A method for the imaging of a particular volume of plant or animal tissue, wherein the plant or animal tissue contains at least one photo-active molecular agent. The method includes the steps of treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of the photo-active molecular agent contained in the particular volume of the plant or animal tissue, photo-activating at least one of the at least one photo-active molecular agent in the particular volume of the plant or animal tissue, thereby producing at least one photo-activated molecular agent, wherein the at least one photo-activated molecular agent emits energy, detecting the energy emitted by the at least one photo-activated molecular agent, and producing a detected energy signal which is characteristic of the particular volume of plant or animal tissue. The present invention is also a method for the imaging of a particular volume of material, wherein the material contains at least one photo-active molecular agent.

  5. [Preparation and optimum process of walnut peel activated carbon by zinc chloride as activating agent].

    PubMed

    Liu, Xiao-hong; Wang, Xing-wei; Zhao, Bo; Lü, Jun-fang; Kang, Ni-na; Zhang, Yao-jun

    2014-12-01

    Walnut peel as raw material, zinc chloride was used as activating agent for preparation walnut peel activated carbon in the muffle furnace in this experiment, using orthogonal design. Yield, the specific surface area and iodine number of walnut peel activated carbon were determined at all designed experimental conditions and the optimum technological condition of preparation was obtained. By analysis of aperture, infrared spectra and the content of acidic group in surface with Boehm, walnut peel activated carbon of prepared at the optimum condition was characterized. The results showed the optimum technological parameters of preparation: activation temperature (600 °C), activation time (1 h), the concentration of zinc chloride (50%), the particle size (60 mesh). The specific surface area of walnut peel activated carbon obtained at optimum condition was mounting to 1258.05 m2 · g(-1), the ratio of medium porous 32.18%. Therefore, walnut peel can be used in the preparation of the high-quality activated carbon of large surface area. Agricultural wastes, as walnut peel, not only were implemented recycle, but also didn't make any pollution. Meanwhile, a cheap adsorbent was provided and it was of great significance to open a new source of activated carbon.

  6. Bis(acridine-9-carboxylate)-nitro-europium(III) dihydrate complex a new apoptotic agent through Flk-1 down regulation, caspase-3 activation and oligonucleosomes DNA fragmentation.

    PubMed

    Azab, Hassan A; Hussein, Belal H M; El-Azab, Mona F; Gomaa, Mohamed; El-Falouji, Abdullah I

    2013-01-01

    New bis(acridine-9-carboxylate)-nitro-europium(III) dihydrate complex was synthesized and characterized. In vivo anti-angiogenic activities of bis(acridine-9-carboxylate)-nitro-europium(III) dihydrate complex against Ehrlich ascites carcinoma (EAC) cells are described. The newly synthesized complex resulted in inhibition of proliferation of EAC cells and ascites formation. The anti-tumor effect was found to be through anti-angiogenic activity as evident by the reduction of microvessel density in EAC solid tumors. The anti-angiogenic effect is mediated through down-regulation of VEGF receptor type-2 (Flk-1). The complex was also found to significantly increase the level of caspase-3 in laboratory animals compared to the acridine ligand and to the control group. This was also consistent with the DNA fragmentation detected by capillary electrophoresis that proved the apoptotic effect of the new complex. Our complex exhibited anti-angiogenic and apoptotic activity in vivo, a thing that makes it a potential effective chemotherapeutic agent. The interaction of calf thymus DNA (ct-DNA) with bis(acridine-9-carboxylate)-nitro-europium(III) dihydrate complex has been investigated using fluorescence technique. A competitive experiment of the europium(III)-acridine complex with ethidium bromide (EB) to bind DNA revealed that interaction between the europium(III)-acridine and DNA was via intercalation. The interaction of the synthesized complex with tyrosine kinases was also studied using molecular docking simulation to further substantiate its mode of action.

  7. Signaling via the anti-CD30 mAb SGN-30 sensitizes Hodgkin's disease cells to conventional chemotherapeutics.

    PubMed

    Cerveny, C G; Law, C-L; McCormick, R S; Lenox, J S; Hamblett, K J; Westendorf, L E; Yamane, A K; Petroziello, J M; Francisco, J A; Wahl, A F

    2005-09-01

    SGN-30, a monoclonal antibody with activity against CD30+ malignancies, is currently in phase II clinical evaluation for treatment of Hodgkin's disease (HD) and anaplastic large cell lymphoma. The mechanisms underlying SGN-30's antitumor activity were investigated using cDNA array of L540 cells. SGN-30 treatment activated NF-kappaB and modulation of several messages including the growth regulator p21WAF1/CIP1 (p21) and cellular adhesion marker ICAM-1. p21 protein levels increased coincident with growth arrest and Annexin V/PI staining in treated HD cells. To determine if SGN-30-induced growth arrest would sensitize tumor cells to chemotherapeutics used against HD, L540cy and L428 cells were exposed to SGN-30 in combination with a panel of cytotoxic agents and resultant interactions quantified by the Combination Effects Method. Interactions between SGN-30 and all cytotoxic agents examined were additive or better. These in vitro data translated to increased efficacy of SGN-30 and bleomycin against L540cy tumor xenografts. In addition to direct cell killing, SGN-30 affects growth arrest and drug sensitization through growth regulating and proapoptotic machinery. Importantly, these data suggest that SGN-30 can enhance the efficacy of standard chemotherapies used to treat patients with CD30+ malignancies.

  8. Combination of metformin with chemotherapeutic drugs via different molecular mechanisms.

    PubMed

    Peng, Mei; Darko, Kwame Oteng; Tao, Ting; Huang, Yanjun; Su, Qiongli; He, Caimei; Yin, Tao; Liu, Zhaoqian; Yang, Xiaoping

    2017-03-01

    Metformin, a widely prescribed drug for treating type II diabetes, is one of the most extensively recognized metabolic modulators which has shown an important anti-cancer property. However, fairly amount of clinical trials on its single administration have not demonstrated a convincing efficiency yet. Thus, recent studies tend to combine metformin with clinical commonly used chemotherapeutic drugs to decrease their toxicity and attenuate their tumor resistance. These strategies have displayed promising clinical benefits. Interestingly, metformin experiences a diversity of molecular mechanisms when it combines different chemotherapeutic drugs. For example, AMPK/mTOR signaling pathway activation plays a major role when it combines with hormone modulating drugs. In contrast, suppression of HIF-1, p-gp and MRP1 protein expression is its main mechanism when metformin combines with anti-metabolites. Furthermore, when combining of metformin with antibiotics, inhibition of oxidative stress and inflammatory signaling pathway becomes a novel pharmaceutical mechanism for its cardio-protective effect. Induction of apoptotic mitochondria and nucleus could be the major player for the synergistic effect of its combination with cisplatin. In contrast, down-regulation of lipoprotein or cholesterol synthesis might be the undefined molecular base when metformin combines with taxane. Thus, deep exploration of molecular mechanisms of metformin with these different drugs is critical to understand its synergistic effect and help for personalized administration. In this mini-review, detailed molecular mechanisms of these combinations are discussed and summarized. This work will promote better understanding of molecular mechanisms of metformin and provide precise targets to identify specific patient groups to achieve satisfactory treatment efficacy.

  9. Chronic chemotherapeutic stress promotes evolution of stemness and WNT/beta-catenin signaling in colorectal cancer cells: implications for clinical use of WNT-signaling inhibitors

    PubMed Central

    Ayadi, Meriam; Bouygues, Anaïs; Ouaret, Djamila; Ferrand, Nathalie; Chouaib, Salem; Thiery, Jean-Paul; Muchardt, Christian; Sabbah, Michèle; Larsen, Annette K

    2015-01-01

    Most solid tumors contain a subfraction of cells with stem/progenitor cell features. Stem cells are naturally chemoresistant suggesting that chronic chemotherapeutic stress may select for cells with increased “stemness”. We carried out a comprehensive molecular and functional analysis of six independently selected colorectal cancer (CRC) cell lines with acquired resistance to three different chemotherapeutic agents derived from two distinct parental cell lines. Chronic drug exposure resulted in complex alterations of stem cell markers that could be classified into three categories: 1) one cell line, HT-29/5-FU, showed increased “stemness” and WNT-signaling, 2) three cell lines showed decreased expression of stem cell markers, decreased aldehyde dehydrogenase activity, attenuated WNT-signaling and lost the capacity to form colonospheres and 3) two cell lines displayed prominent expression of ABC transporters with a heterogeneous response for stem cell markers. While WNT-signaling could be attenuated in the HT-29/5-FU cells by the WNT-signaling inhibitors ICG-001 and PKF-118, this was not accompanied by any selective growth inhibitory effect suggesting that the cytotoxic activity of these compounds is not directly linked to WNT-signaling inhibition. We conclude that classical WNT-signaling inhibitors have toxic off-target activities that need to be addressed for clinical development. PMID:26041882

  10. Methods, microfluidic devices, and systems for detection of an active enzymatic agent

    DOEpatents

    Sommer, Gregory J; Hatch, Anson V; Singh, Anup K; Wang, Ying-Chih

    2014-10-28

    Embodiments of the present invention provide methods, microfluidic devices, and systems for the detection of an active target agent in a fluid sample. A substrate molecule is used that contains a sequence which may cleave in the presence of an active target agent. A SNAP25 sequence is described, for example, that may be cleaved in the presence of Botulinum Neurotoxin. The substrate molecule includes a reporter moiety. The substrate molecule is exposed to the sample, and resulting reaction products separated using electrophoretic separation. The elution time of the reporter moiety may be utilized to identify the presence or absence of the active target agent.

  11. Method for improved selectivity in photo-activation of molecular agents

    DOEpatents

    Fisher, Walter G.; Wachter, Eric A.; Dees, H. Craig

    2000-01-01

    An apparatus for the treatment of a particular volume of plant or animal tissue by treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue.

  12. Structure-activity relationship for the reactivators of acetylcholinesterase inhibited by nerve agent VX.

    PubMed

    Kuca, Kamil; Musilek, Kamil; Jun, Daniel; Karasova, Jana; Soukup, Ondrej; Pejchal, Jaroslav; Hrabinova, Martina

    2013-08-01

    Nerve agents such as sarin, VX and tabun are organophosphorus compounds able to inhibit an enzyme acetylcholinesterase (AChE). AChE reactivators and anticholinergics are generally used as antidotes in the case of intoxication with these agents. None from the known AChE reactivators is able to reactivate AChE inhibited by all kinds of nerve agents. In this work, reactivation potency of seventeen structurally different AChE reactivators was tested in vitro and subsequently, relationship between their chemical structure and biological activity was outlined. VX was chosen as appropriate member of the nerve agent family.

  13. Ubiquitin E3 ligase CRL4(CDT2/DCAF2) as a potential chemotherapeutic target for ovarian surface epithelial cancer.

    PubMed

    Pan, Wei-Wei; Zhou, Jian-Jie; Yu, Chao; Xu, Ying; Guo, Lian-Jun; Zhang, Hai-Yi; Zhou, Dawang; Song, Fang-Zhou; Fan, Heng-Yu

    2013-10-11

    Cullin-RING ubiquitin ligases (CRLs) are the largest family of E3 ligases and require cullin neddylation for their activation. The NEDD8-activating enzyme inhibitor MLN4924 reportedly blocked cullin neddylation and inactivated CRLs, which resulted in apoptosis induction and tumor suppression. However, CRL roles in ovarian cancer cell survival and the ovarian tumor repressing effects of MLN4924 are unknown. We show here that CRL4 components are highly expressed in human epithelial ovarian cancer tissues. MLN4924-induced DNA damage, cell cycle arrest, and apoptosis in ovarian cancer cells in a time- and dose-dependent manner. In addition, MLN4924 sensitized ovarian cancer cells to other chemotherapeutic drug treatments. Depletion of CRL4 components Roc1/2, Cul4a, and DDB1 had inhibitory effects on ovarian cancer cells similar to MLN4924 treatment, which suggested that CRL4 inhibition contributed to the chemotherapeutic effect of MLN4924 in ovarian cancers. We also investigated for key CRL4 substrate adaptors required for ovarian cancer cells. Depleting Vprbp/Dcaf1 did not significantly affect ovarian cancer cell growth, even though it was expressed by ovarian cancer tissues. However, depleting Cdt2/Dcaf2 mimicked the pharmacological effects of MLN4924 and caused the accumulation of its substrate, CDT1, both in vitro and in vivo. MLN4924-induced DNA damage and apoptosis were partially rescued by Cdt1 depletion, suggesting that CRL4(CDT2) repression and CDT1 accumulation were key biochemical events contributing to the genotoxic effects of MLN4924 in ovarian cancer cells. Taken together, these results indicate that CRL4(CDT2) is a potential drug target in ovarian cancers and that MLN4924 may be an effective anticancer agent for targeted ovarian cancer therapy.

  14. Cellular Delivery and Photochemical Activation of Antisense Agents through a Nucleobase Caging Strategy

    PubMed Central

    Govan, Jeane M.; Uprety, Rajendra; Thomas, Meryl; Lusic, Hrvoje; Lively, Mark O.; Deiters, Alexander

    2013-01-01

    Antisense oligonucleotides are powerful tools to regulate gene expression in cells and model organisms. However, a transfection or microinjection is needed for efficient delivery of the antisense agent. We report the conjugation of multiple HIV TAT peptides to a hairpin-protected antisense agent through a light-cleavable nucleobase caging group. This conjugation allows for the facile delivery of the antisense agent without a transfection reagent and photochemical activation offers precise control over gene expression. The developed approach is highly modular, as demonstrated by the conjugation of folic acid to the caged antisense agent. This enabled targeted cell delivery through cell-surface folate receptors followed by photochemical triggering of antisense activity. Importantly, the presented strategy delivers native oligonucleotides after light-activation, devoid of any delivery functionalities or modifications that could otherwise impair their antisense activity. PMID:23915424

  15. Depletion of mammalian O6-alkylguanine-DNA alkyltransferase activity by O6-benzylguanine provides a means to evaluate the role of this protein in protection against carcinogenic and therapeutic alkylating agents.

    PubMed Central

    Dolan, M E; Moschel, R C; Pegg, A E

    1990-01-01

    O6-Alkylguanine-DNA alkyltransferase was rapidly and irreversibly inactivated by exposure to O6-benzylguanine or the p-chlorobenzyl and p-methylbenzyl analogues. This inactivation was much more rapid than with O6-methylguanine: incubation with 2.5 microM O6-benzylguanine led to more than a 90% loss of activity within 10 min, whereas 0.2 mM O6-methylguanine for 60 min was required for the same reduction. O6-Benzylguanine was highly effective in depleting the alkyltransferase activity of cultured human colon tumor (HT29) cells. Complete loss of activity was produced within 15 min after addition of O6-benzylguanine to the culture medium and a maximal effect was obtained with 5 microM. In contrast, at least 100 microM O6-methylguanine for 4 hr was needed to get a maximal effect, and this reduced the alkyltransferase by only 80%. Pretreatment of HT29 cells with 10 microM O6-benzylguanine for 2 hr led to a dramatic increase in the cytotoxicity produced by the chemotherapeutic agents 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) or 2-chloroethyl(methysulfonyl)methanesulfonate (Clomesone). Administration of O6-benzylguanine to mice at a dose of 10 mg/kg reduced alkyltransferase levels by more than 95% in both liver and kidney. These results indicate that depletion of the alkyltransferase by O6-benzylguanine may be used to investigate the role of the DNA repair protein in carcinogenesis and mutagenesis and that this treatment may be valuable to increase the chemotherapeutic effectiveness of chloroethylating agents. PMID:2164681

  16. Effects of surface active agents on DNAPL migration and distribution in saturated porous media.

    PubMed

    Cheng, Zhou; Gao, Bin; Xu, Hongxia; Sun, Yuanyuan; Shi, Xiaoqing; Wu, Jichun

    2016-11-15

    Dissolved surface active agents such as surfactant and natural organic matter can affect the distribution and fate of dense nonaqueous liquids (DNAPLs) in soil and groundwater systems. This work investigated how two common groundwater surface active agents, humic acid (HA) and Tween 80, affected tetrachloroethylene (PCE) migration and source zone architecture in saturated porous media under environmentally relevant conditions. Batch experiments were first conducted to measure the contact angles and interfacial tensions (IFT) between PCE and quartz surface in water containing different amount of surface active agents. Results showed that the contact angle increased and IFT decreased with concentration of surface active agent increasing, and Tween 80 was much more effective than HA. Five 2-D flow cell experiments were then conducted. Correspondingly, Tween 80 showed strong effects on the migration and distribution of PCE in the porous media due to its ability to change the medium wettability from water-wet into intermediate/NAPL-wet. The downward migration velocities of the PCE in three Tween 80 cells were slower than those in the other two cells. In addition, the final saturation of the PCE in the cells containing surface active agents was higher than that in the water-only cell. Results from this work indicate that the presence of surface active agents in groundwater may strongly affect the fate and distribution of DNAPL through altering porous medium wettability.

  17. C60(Nd) nanoparticles enhance chemotherapeutic susceptibility of cancer cells by modulation of autophagy

    NASA Astrophysics Data System (ADS)

    Wei, Pengfei; Zhang, Li; Lu, Yang; Man, Na; Wen, Longping

    2010-12-01

    Autophagy, an evolutionally conserved intracellular process degrading cytoplasmic proteins and organelles for recycling, has become one of the most remarkable strategies applied in cancer research. The fullerene C60 nanoparticle (nC60) has been shown to induce autophagy and sensitize chemotherapeutic killing of cancer cells, but the details still remain unknown. Here we show that a water-dispersed nanoparticle solution of derivatized fullerene C60, C60(Nd) nanoparticles (nC60(Nd)), has greater potential in inducing autophagy and sensitizing chemotherapeutic killing of both normal and drug-resistant cancer cells than nC60 does in an autophagy-dependent fashion. Additionally we further demonstrated that autophagy induced by nC60/C60(Nd) and Rapamycin had completely different roles in cancer chemotherapy. Our results, for the first time, revealed a novel and more potent derivative of the C60 nanoparticle in enhancing the cytotoxicity of chemotherapeutic agents and reducing drug resistance through autophagy modulation, which may ultimately lead to novel therapeutic strategies in cancer therapy.

  18. PSMA-Activated Imaging Agents for Prostate Cancer

    DTIC Science & Technology

    2009-07-01

    media and the cell extract were run on the LCMS . Figure 3. MTT assay evaluating varying concentrations of I-PD...Society 62, 2422-2423. 7. Fujii, A., Tanaka, K., Tsuchiya, Y., Cook, E.S., 1971. Antistaphylococcal and Antifibrinolytic Activities of Omega- Amino ... Acids and Their L-Histidine Dipeptides. Journal of Medicinal Chemistry 14, 354-&.

  19. Chemotherapeutic effects of bioassay-guided extracts of the American cockroach, Periplaneta americana.

    PubMed

    Wang, Xiao-Yu; He, Zheng Chun; Song, Li-Yan; Spencer, Shawn; Yang, Lei Xiang; Peng, Fang; Liu, Guang-Ming; Hu, Ming-Hui; Li, Hai Bo; Wu, Xiu-Mei; Zeng, Su; Hilgenfeld, Rolf; Stöckigt, Joachim; Zhao, Yu; Qian, Jin Fu

    2011-09-01

    The organic extract of Periplaneta americana L. (Dictyoptera; Blattidae) has been traditionally used in southwestern China as an alternative medicine against disorders such as hepatitis, trauma, gastric ulcers, burns, and heart disease. The present study describes bioassay-guided purification and chemotherapeutic evaluation of the 60% ethanolic fraction of P americana organic extracts (PAE60). The most effective cytotoxic fraction was determined by way of repeated in vitro screenings against 12 distinct cultured human carcinoma cell lines: Eca 109, BGC823, HO8910, LS174T, CNE, HeLa, K562, PC-3, A549, BEL 7404, HL-60, and KB, followed by in vivo antitumor assays of the lead fraction (PAE60). The complexity of enriched active fraction was qualitatively evaluated using thin layer chromatography. Reconstituted PAE60 was effective at inhibiting HL-60, KB, CNE, and BGC823 cell growth with IC(50) values <20 µg mL-(1). PAE60 reduced tumor growth in S180-bearing immunocompetent mice by 72.62% after 10 days following oral doses of 500 mg kg d-(1) compared with 78.75% inhibition following 40 mg kg d-(1) of cyclophosphamide (CTX). Thymus and spleen indices of S180-bearing mice treated with PAE60 were significantly greater (P < .05) than CTX treatment groups, suggesting potential immunomodulation of antitumor host defenses by PAE60. Antiviral activity was also investigated and PAE60 inhibited herpes simplex type-2 replication (IC(50) = 4.11 ± 0.64 µg mL-(1)) with a selectivity index (CC(50) to IC(50) ratio) of 64.84 in Vero cells but was less effective on type-1 virus (IC(50) of 25.6 ± 3.16 µg mL-(1)). These results support future clinical trials on P. americana as an alternative or complementary medicinal agent.

  20. Rostral anterior cingulate activity generates posterior versus anterior theta activity linked to agentic extraversion.

    PubMed

    Chavanon, Mira-Lynn; Wacker, Jan; Stemmler, Gerhard

    2011-06-01

    Recent research using the resting electroencephalogram (EEG) showed that posterior versus anterior theta activity (around 4-8 Hz) is consistently associated with agency, reflecting the dopaminergic core of extraversion (i.e., incentive motivation, positive emotion). Neuroimaging studies using various methodologies and experimental paradigms have converged on the anterior cingulate cortex (ACC) as a neurophysiological correlate of extraversion. The aim of the present study is integrate these lines of research by testing the hypothesis that posterior versus anterior EEG theta is at least partly based on ACC theta activity. Resting EEG data were analyzed in N = 78 healthy, male participants extremely high or low in agentic extraversion (aE). Using the low-resolution electromagnetic tomography algorithm, we localized the sources of aE-dependent intracerebral theta activity within rostral subdivisions of the ACC. The posterior versus anterior index and theta current density within the rostral ACC were significantly correlated (r = -.52), and both displayed high retest stability across 5 hr and were associated with traits from the aE spectrum. These neurophysiological correlates of aE and their possible functional significance are discussed.

  1. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.

    PubMed

    Wang, Hui; Liu, Xiufei; Long, Min; Huang, Yi; Zhang, Linlin; Zhang, Rui; Zheng, Yi; Liao, Xiaoyu; Wang, Yuren; Liao, Qian; Li, Wenjie; Tang, Zili; Tong, Qiang; Wang, Xiaocui; Fang, Fang; Rojo de la Vega, Montserrat; Ouyang, Qin; Zhang, Donna D; Yu, Shicang; Zheng, Hongting

    2016-04-13

    Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that antidiabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic α-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant response through inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis.

  2. Mitigating the antimicrobial activities of selected organic acids and commercial sanitizers with various neutralizing agents.

    PubMed

    Park, Yoen Ju; Chen, Jinru

    2011-05-01

    This study was conducted to evaluate the abilities of five neutralizing agents, Dey-Engley (DE) neutralizing broth (single or double strength), morpholinepropanesulfonic acid (MOPS) buffer, phosphate-buffered saline (PBS), and sodium thiosulfate buffer, in mitigating the activities of acetic or lactic acid (2%) and an alkaline or acidic sanitizer (a manufacturer-recommended concentration) againt the cells of Shiga toxin-producing Escherichia coli (STEC; n = 9). To evaluate the possible toxicity of the neutralizing agents to the STEC cells, each STEC strain was exposed to each of the neutralizing agents at room temperature for 10 min. Neutralizing efficacy was evaluated by placing each STEC strain in a mixture of sanitizer and neutralizer under the same conditions. The neutralizing agents had no detectable toxic effect on the STEC strains. PBS was least effective for neutralizing the activity of selected organic acids and sanitizers. Single-strength DE and sodium thiosulfate neutralized the activity of both acetic and lactic acids. MOPS buffer neutralized the activity of acetic acid and lactic acid against six and five STEC strains, respectively. All neutralizing agents, except double-strength DE broth, had a limited neutralizing effect on the activity of the commercial sanitizers used in the study. The double-strength DE broth effectively neutralized the activity of the two commercial sanitizers with no detectable toxic effects on STEC cells.

  3. Method for improved selectivity in photo-activation of molecular agents

    DOEpatents

    Fisher, W.G.; Wachter, E.A.; Dees, H.C.

    1998-11-03

    A method for the treatment of a particular volume of plant or animal tissue comprising the steps of treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue. There is also disclosed a method for the treatment of cancer in plant or animal tissue and a method for producing at least one photo-activated molecular agent in a particular volume of a material. 23 figs.

  4. Method for improved selectivity in photo-activation of molecular agents

    DOEpatents

    Fisher, Walter G.; Wachter, Eric A.; Dees, H. Craig

    1999-01-01

    A method for the treatment of a particular volume of plant or animal tissue comprising the steps of treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue. There is also disclosed a method for the treatment of cancer in plant or animal tissue and a method for producing at least one photo-activated molecular agent in a particular volume of a material.

  5. Method for improved selectivity in photo-activation of molecular agents

    DOEpatents

    Fisher, Walter G.; Wachter, Eric A.; Dees, H. Craig

    1998-01-01

    A method for the treatment of a particular volume of plant or animal tissue comprising the steps of treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue. There is also disclosed a method for the treatment of cancer in plant or animal tissue and a method for producing at least one photo-activated molecular agent in a particular volume of a material.

  6. Antimicrobial agents from plants: antibacterial activity of plant volatile oils.

    PubMed

    Dorman, H J; Deans, S G

    2000-02-01

    The volatile oils of black pepper [Piper nigrum L. (Piperaceae)], clove [Syzygium aromaticum (L.) Merr. & Perry (Myrtaceae)], geranium [Pelargonium graveolens L'Herit (Geraniaceae)], nutmeg [Myristica fragrans Houtt. (Myristicaceae), oregano [Origanum vulgare ssp. hirtum (Link) Letsw. (Lamiaceae)] and thyme [Thymus vulgaris L. (Lamiaceae)] were assessed for antibacterial activity against 25 different genera of bacteria. These included animal and plant pathogens, food poisoning and spoilage bacteria. The volatile oils exhibited considerable inhibitory effects against all the organisms under test while their major components demonstrated various degrees of growth inhibition.

  7. Antianaerobic activity of sulopenem compared to six other agents.

    PubMed

    Ednie, Lois M; Appelbaum, Peter C

    2009-05-01

    Agar dilution MIC methodology was used to compare the activity of sulopenem with those of amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 431 anaerobes. Overall, MIC(50)/(90) values were as follows: sulopenem, 0.25/1.0 microg/ml; amoxicillin/clavulanate, 0.5/2.0 microg/ml; ampicillin/sulbactam, 0.5/4.0 microg/ml; piperacillin/tazobactam, 0.25/8.0 microg/ml; imipenem, 0.06/1.0 microg/ml; clindamycin, 0.25/16.0 microg/ml; and metronidazole, 1.0/4.0 microg/ml.

  8. Antibody–drug conjugates as novel anti-cancer chemotherapeutics

    PubMed Central

    Peters, Christina; Brown, Stuart

    2015-01-01

    Over the past couple of decades, antibody–drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and deliver a highly potent cytotoxic agent. The synergistic combination of mAbs conjugated to small-molecule chemotherapeutics, via a stable linker, has given rise to an extremely efficacious class of anti-cancer drugs with an already large and rapidly growing clinical pipeline. The primary objective of this paper is to review current knowledge and latest developments in the field of ADCs. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. In addition to these, the choice of clinically relevant targets and the position and number of linkages have also been the key determinants of ADC efficacy. The only marketed ADCs, brentuximab vedotin and trastuzumab emtansine (T-DM1), have demonstrated their use against both haematological and solid malignancies respectively. The success of future ADCs relies on improving target selection, increasing cytotoxin potency, developing innovative linkers and overcoming drug resistance. As more research is conducted to tackle these issues, ADCs are likely to become part of the future of targeted cancer therapeutics. PMID:26182432

  9. The Synthesis and Study of Azole Carboxamide Nucleosides as Agents Active Against RNA Viruses.

    DTIC Science & Technology

    1986-09-15

    5012 62770A 62770A8,1. AH 355 11. TITLE (Include Security Classification) The Synthesis and Study of Azole Carboxamide Nucleosides as Agents Active...broad-spectrum antiviral agent has stimulated a great deal of effort toward the chemical synthesis of nucleosides of other azole heterocycles. During the...4 II. Chemistry and Discussion . . .. .. . 6 1. Synthesis of Certain 5’-Substituted Derivatives of Ribavirin and Tiazofurin . . .. . 6 2

  10. Novel Oxidatively Activated Agents Modify DNA and are Enhanced by Ercc1 Silencing

    PubMed Central

    Jones, Amy R.; Bell-Horwath, Tiffany R.; Li, Guorui; Rollmann, Stephanie M.; Merino, Edward J.

    2012-01-01

    Agents that chemically modify DNA form a backbone of many cancer treatments. A key problem for DNA modifying agents is lack of specificity. To address this issue, we designed novel molecular scaffolds, termed An-Hq and An-Hq2, which are activated by a hallmark of some cancers: elevated concentrations of reactive oxygen species. Elevated reactive oxygen species are linked to oncogenesis and is found to increase in several aggressive cancers. The agents are quinones that, upon oxidation, form highly electrophilic species. In vitro studies identified the mode of addition to DNA. The aniline portion of An-Hq serves to enhance nucleophilic addition to the ethyl phenyl ether instead of forming common Michael additions. Structural characterization showed the agents add to 2′-deoxyguanosine at the N2,N3-positions. The product formed is a bulky hydroxy-N2,3-benzetheno-2′-deoxyguanosine adduct. In addition, the oxidatively activated agents added to 2′-deoxyadenosine and 2′-deoxycytidine, but not thymidine or 2′-deoxyinosine. These findings are confirmed by primer extension analysis of a 392 base pair DNA. The full-length primer extension product was reduced by 69.0 ± 0.6% upon oxidative activation of An-Hq2 compared to controls. Little sequence dependence was observed with 76% of guanine, adenine, and cytosine residues showing an increase in extension stops between two and four fold above controls. Benzetheno-nucleobase addition to double stranded DNA was confirmed by LC/MS of a self-complementary oligonucletide. Experiments were carried out to confirm in vivo DNA damage. Because of the lesion identified in vitro, we reasoned that nucleotide excision repair should be involved in reversing the effects of these oxidatively activated agents and enhance toxicity in Drosophila melanogaster. Using an RNAi based approach, Ercc1 was silenced and survival monitored after injection of an agent. As expected, bulky cross-linking DNA modifying agents, cisplatin and

  11. Antianaerobic Activity of Sulopenem Compared to Six Other Agents

    PubMed Central

    Ednie, Lois M.; Appelbaum, Peter C.

    2009-01-01

    Agar dilution MIC methodology was used to compare the activity of sulopenem with those of amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 431 anaerobes. Overall, MIC50/90 values were as follows: sulopenem, 0.25/1.0 μg/ml; amoxicillin/clavulanate, 0.5/2.0 μg/ml; ampicillin/sulbactam, 0.5/4.0 μg/ml; piperacillin/tazobactam, 0.25/8.0 μg/ml; imipenem, 0.06/1.0 μg/ml; clindamycin, 0.25/16.0 μg/ml; and metronidazole, 1.0/4.0 μg/ml. PMID:19223615

  12. [Cytotoxic and genotoxic activity of certain preservative agents in cosmetics].

    PubMed

    Jantová, S; Hojerová, J; Hanusová, B; Mikulásová, M

    2001-09-01

    Cytotoxic effects of the preservative compounds for cosmetics JMAC TD, Bronopol, CA 24, and Euxyl K100 were studied. Bronopol demonstrated the highest cytotoxic effect on the proliferation of V79 and VH10 fibroblast cell lines--the IC100 values being 10 mg/l during the whole experiment. The preservatives CA 24 and Euxyl K100 showed 4-times and 5-times smaller cytotoxic activity than Bronopol IC100 = 42 or 50.3 mg/l). The preservative compounds on silver chloride ions JMAC TD manifested the lowest cytotoxicity of the preservatives tested (IC100 = 150 mg/l); 15-times smaller than Bronopol, 3.5-times smaller than CA 24 and 3-times smaller than Euxyl K100. The biocide JMAC TD did not exhibit mutagenic effects on the bacteria Salmonella typhimurium TA 98 and TA 100.

  13. Chelating agents inhibit activity and prevent expression of streptococcal glucan-binding lectins.

    PubMed Central

    Lü-Lü; Singh, J S; Galperin, M Y; Drake, D; Taylor, K G; Doyle, R J

    1992-01-01

    Several of the cariogenic mutans streptococci produce cell wall-associated glucan-binding lectins (GBLs). The lectins bind alpha-1,6-linked glucans and have no affinity for other polysaccharides or anomeric linkages. When citrate or lactate was included in the growth medium, expression of the activities of the GBLs of Streptococcus cricetus and S. sobrinus was prevented. Furthermore, chelating agents, including citrate, lactate, EDTA, and acetylacetone, were able to reversibly inhibit glucan-induced aggregation of GBL+ streptococci. In addition, the chelating agents prevented sucrose-dependent streptococcal adhesion to glass surfaces and dispersed preformed adherent masses of the streptococci. Neither citrate nor other chelating agents modified the activities of glucosyltransferases. Expression of the lectin could only be achieved by the addition of manganous ion to the growth medium. Chloramphenicol and other metabolic inhibitors prevented synthesis of GBL in cells obtained from manganese-deficient medium and shifted to manganous ion-sufficient medium. The GBL may be a manganoprotein, the manganese of which may be perturbed, but not removed, by chelating agents. During synthesis of the GBL, manganous ion may be required in order for the protein to achieve an active conformation. Citrate or other chelating agents may have promise as anticaries agents. Images PMID:1500189

  14. Pharmacological activity and toxicity of some neurotropic agents under conditions of experimental hypodynamia

    NASA Technical Reports Server (NTRS)

    Kirichek, L. T.

    1980-01-01

    The indices of pharmacological range, risk coefficients, ED50, LD50, the size of the area of toxic activity, and maximal tolerated and absolute lethal doses were compared in hypodynamic mice. The pharmacological activity of the test neurotropic agents exhibiting a central action underwent change, but their toxicity remained unchanged.

  15. Development of anticancer agents: wizardry with osmium.

    PubMed

    Hanif, Muhammad; Babak, Maria V; Hartinger, Christian G

    2014-10-01

    Platinum compounds are one of the pillars of modern cancer chemotherapy. The apparent disadvantages of existing chemotherapeutics have led to the development of novel anticancer agents with alternative modes of action. Many complexes of the heavy metal osmium (Os) are potent growth inhibitors of human cancer cells and are active in vivo, often superior or comparable to cisplatin, as the benchmark metal-based anticancer agent, or clinically tested ruthenium (Ru) drug candidates. Depending on the choice of ligand system, osmium compounds exhibit diverse modes of action, including redox activation, DNA targeting or inhibition of protein kinases. In this review, we highlight recent advances in the development of osmium anticancer drug candidates and discuss their cellular mechanisms of action.

  16. Antifungal activities of azole agents against the Malassezia species.

    PubMed

    Miranda, Karla Carvalho; de Araujo, Crystiane Rodrigues; Costa, Carolina Rodrigues; Passos, Xisto Sena; de Fátima Lisboa Fernandes, Orionalda; do Rosário Rodrigues Silva, Maria

    2007-03-01

    In this paper, we identified 95 Malassezia isolates by morphological and biochemical criteria and assessed the in vitro activity of fluconazole, itraconazole, ketoconazole and voriconazole by broth microdilution against these species using slightly modified Leeming-Notman medium. The Malassezia isolates were identified as M. furfur (74), M. sympodialis (11), M. obtusa (8) and M. globosa (2). The modified Leeming-Notman medium used for susceptibility testing allowed good growth of Malassezia spp. Visual reading of the minimal inhibitory concentration (MIC) was readily achieved until Day 5 of incubation at 32 degrees C. Although high MIC values of 16 microg/mL for fluconazole were observed in 9.5% of Malassezia isolates, in general these microorganisms were susceptible to all drugs studied. Interestingly, one M. globosa isolate showed high MIC values for voriconazole, itraconazole and fluconazole. For the 95 strains, the MIC ranges were <0.03-4 microg/mL for ketoconazole, <0.03 to >16 microg/mL for voriconazole, <0.125 to >64 microg/mL for fluconazole and <0.03-16 microg/mL for itraconazole. In summary, the good reproducibility and visual readings obtained using modified Leeming-Notman medium suggest that this medium should be proposed for antifungal testing of drugs against Malassezia spp.

  17. Molecular Cloning and Characterization of Taurocyamine Kinase from Clonorchis sinensis: A Candidate Chemotherapeutic Target

    PubMed Central

    Tokuhiro, Shinji; Nagataki, Mitsuru; Jarilla, Blanca R.; Nomura, Haruka; Kim, Tae Im; Hong, Sung-Jong; Agatsuma, Takeshi

    2013-01-01

    Background Adult Clonorchis sinensis lives in the bile duct and causes endemic clonorchiasis in East Asian countries. Phosphagen kinases (PK) constitute a highly conserved family of enzymes, which play a role in ATP buffering in cells, and are potential targets for chemotherapeutic agents, since variants of PK are found only in invertebrate animals, including helminthic parasites. This work is conducted to characterize a PK from C. sinensis and to address further investigation for future drug development. Methology/Principal findings A cDNA clone encoding a putative polypeptide of 717 amino acids was retrieved from a C. sinensis transcriptome. This polypeptide was homologous to taurocyamine kinase (TK) of the invertebrate animals and consisted of two contiguous domains. C. sinensis TK (CsTK) gene was reported and found consist of 13 exons intercalated with 12 introns. This suggested an evolutionary pathway originating from an arginine kinase gene group, and distinguished annelid TK from the general CK phylogenetic group. CsTK was found not to have a homologous counterpart in sequences analysis of its mammalian hosts from public databases. Individual domains of CsTK, as well as the whole two-domain enzyme, showed enzymatic activity and specificity toward taurocyamine substrate. Of the CsTK residues, R58, I60 and Y84 of domain 1, and H60, I63 and Y87 of domain 2 were found to participate in binding taurocyamine. CsTK expression was distributed in locomotive and reproductive organs of adult C. sinensis. Developmentally, CsTK was stably expressed in both the adult and metacercariae stages. Recombinant CsTK protein was found to have low sensitivity and specificity toward C. sinensis and platyhelminth-infected human sera on ELISA. Conclusion CsTK is a promising anti-C. sinensis drug target since the enzyme is found only in the C. sinensis and has a substrate specificity for taurocyamine, which is different from its mammalian counterpart, creatine. PMID:24278491

  18. The influence of active vision on the exoskeleton of intelligent agents

    NASA Astrophysics Data System (ADS)

    Smith, Patrice; Terry, Theodore B.

    2016-04-01

    Chameleonization occurs when a self-learning autonomous mobile system's (SLAMR) active vision scans the surface of which it is perched causing the exoskeleton to changes colors exhibiting a chameleon effect. Intelligent agents having the ability to adapt to their environment and exhibit key survivability characteristics of its environments would largely be due in part to the use of active vision. Active vision would allow the intelligent agent to scan its environment and adapt as needed in order to avoid detection. The SLAMR system would have an exoskeleton, which would change, based on the surface it was perched on; this is known as the "chameleon effect." Not in the common sense of the term, but from the techno-bio inspired meaning as addressed in our previous paper. Active vision, utilizing stereoscopic color sensing functionality would enable the intelligent agent to scan an object within its close proximity, determine the color scheme, and match it; allowing the agent to blend with its environment. Through the use of its' optical capabilities, the SLAMR system would be able to further determine its position, taking into account spatial and temporal correlation and spatial frequency content of neighboring structures further ensuring successful background blending. The complex visual tasks of identifying objects, using edge detection, image filtering, and feature extraction are essential for an intelligent agent to gain additional knowledge about its environmental surroundings.

  19. Effect of an Ice-Nucleating Activity Agent on Subzero Survival of Nematode Juveniles

    PubMed Central

    Wergin, William P.; Yaklich, Robert W.; Carta, Lynn K.; Erbe, Eric F.; Murphy, Charles A.

    2000-01-01

    Juveniles of five species of nematodes, Caenorhabditis elegans, Panagrellus redivivus, Pratylenchus agilis, Pristionchus pacificus, and Distolabrellus veechi, were added to solutions with (treatment) and without (control) a commercial ice-nucleating activity (INA) agent. Ten-microliter droplets of the solutions containing the juveniles were placed on glass microscope slides and transferred to a temperaturecontrolled freeze plate where the temperature was reduced to -6 to -8 °C. At this temperature, the droplets containing the INA agent froze while those without the agent remained liquid. After 2 minutes, the temperature of the plate was raised to 24 °C, and the slides were examined with a light microscope to determine the viability of the juveniles. The results showed that usually most juveniles (43% to 88%, depending on species) in solutions that did not contain the INA agent (controls) were active, indicating that the juveniles were capable of supercooling and were thereby protected from the subzero temperatures. Alternatively, less than 10% of the juveniles that had frozen for 2 minutes in solutions containing the INA agent remained viable, indicating that inoculative freezing of the solution was lethal to the supercooled juveniles. Our results suggest that, in geographical areas where winter temperatures may not be sufficiently low or sustained to freeze soil, the addition of an INA agent may help induce ice nucleation and thereby reduce the populations of nematode species that are unable to survive when the soil solution is frozen. PMID:19270966

  20. Activation of Aluminum as an Effective Reducing Agent by Pitting Corrosion for Wet-chemical Synthesis

    PubMed Central

    Li, Wei; Cochell, Thomas; Manthiram, Arumugam

    2013-01-01

    Metallic aluminum (Al) is of interest as a reducing agent because of its low standard reduction potential. However, its surface is invariably covered with a dense aluminum oxide film, which prevents its effective use as a reducing agent in wet-chemical synthesis. Pitting corrosion, known as an undesired reaction destroying Al and is enhanced by anions such as F−, Cl−, and Br− in aqueous solutions, is applied here for the first time to activate Al as a reducing agent for wet-chemical synthesis of a diverse array of metals and alloys. Specifically, we demonstrate the synthesis of highly dispersed palladium nanoparticles on carbon black with stabilizers and the intermetallic Cu2Sb/C, which are promising candidates, respectively, for fuel cell catalysts and lithium-ion battery anodes. Atomic hydrogen, an intermediate during the pitting corrosion of Al in protonic solvents (e.g., water and ethylene glycol), is validated as the actual reducing agent. PMID:23390579

  1. Innovative agents in cancer prevention.

    PubMed

    Manson, Margaret M; Farmer, Peter B; Gescher, Andreas; Steward, William P

    2005-01-01

    There are many facets to cancer prevention: a good diet, weight control and physical activity, a healthy environment, avoidance of carcinogens such as those in tobacco smoke, and screening of populations at risk to allow early detection. But there is also the possibility of using drugs or naturally occurring compounds to prevent initiation of, or to suppress, tumour growth. Only a few such agents have been used to date in the clinic with any success, and these include non-steroidal anti-inflammatory drugs for colon, finasteride for prostate and tamoxifen or raloxifene for breast tumours. An ideal chemopreventive agent would restore normal growth control to a preneoplastic or cancerous cell population by modifying aberrant signalling pathways or inducing apoptosis (or both) in cells beyond repair. Characteristics for such an agent include selectivity for damaged or transformed cells, good bioavailability and more than one mechanism of action to foil redundancy or crosstalk in signalling pathways. As more research effort is being targeted towards this area, the distinction between chemotherapeutic and chemopreventive agents is blurring. Chemotherapeutic drugs are now being designed to target over- or under-active signalling molecules within cancer cells, a philosophy which is just as relevant in chemoprevention. Development of dietary agents is particularly attractive because of our long-standing exposure to them, their relative lack of toxicity, and encouraging indications from epidemiology. The carcinogenic process relies on the cell's ability to proliferate abnormally, evade apoptosis, induce angiogenesis and metastasise to distant sites. In vitro studies with a number of different diet-derived compounds suggest that there are molecules capable of modulating each of these aspects of tumour growth. However, on the negative side many of them have rather poor bioavailability. The challenge is to uncover their multiple mechanisms of action in order to predict their

  2. Active extravasation of gadolinium-based contrast agent into the subdural space following lumbar puncture.

    PubMed

    Kothari, Pranay D; Hanser, Evelyn M; Wang, Harrison; Farid, Nikdokht

    2016-01-01

    A 38year-old male presented with cauda equina syndrome following multiple lumbar puncture attempts. Lumbar spine magnetic resonance imaging (MRI) showed a subdural hematoma and an area of apparent contrast enhancement in the spinal canal on sagittal post-contrast images. Axial post-contrast images obtained seven minutes later demonstrated an increase in size and change in shape of the region of apparent contrast enhancement, indicating active extravasation of the contrast agent. This is the first reported case of active extravasation of gadolinium-based contrast agent in the spine.

  3. Attenuation of nonsense-mediated mRNA decay facilitates the response to chemotherapeutics

    PubMed Central

    Popp, Maximilian W.; Maquat, Lynne E.

    2015-01-01

    Nonsense-mediated mRNA decay (NMD) limits the production of aberrant mRNAs containing a premature termination codon and also controls the levels of endogenous transcripts. Here we show that when human cells are treated with clinically used chemotherapeutic compounds, NMD activity declines partly as a result of the proteolytic production of a dominant-interfering form of the key NMD factor UPF1. Production of cleaved UPF1 functions to upregulate genes involved in the response to apoptotic stresses. The biological consequence is the promotion of cell death. Combined exposure of cells to a small molecule inhibitor of NMD, NMDI-1, and the chemotherapeutic doxorubicin leads to enhanced cell death, while inhibiting UPF1 cleavage protects cells from doxorubicin challenge. We propose a model to explain why the expression levels of genes producing mRNAs of diverse structure that encode proteins of diverse function are under the purview of NMD. PMID:25808464

  4. The Cell’s Nucleolus: an Emerging Target for Chemotherapeutic Intervention

    PubMed Central

    Pickard, Amanda J.

    2013-01-01

    The transient nucleolus plays a central role in the upregulated synthesis of ribosomal RNA (rRNA) to sustain ribosome biogenesis, a hallmark of aberrant cell growth. This function, in conjunction with its unique pathohistological features in malignant cells and its ability to mediate apoptosis, renders this subnuclear structure a potential target for chemotherapeutic agents. In this Minireview, structurally and functionally diverse small molecules are discussed that have been reported to either interact with the nucleolus directly or perturb its function indirectly by acting on its dynamic components. These molecules include all major classes of nucleic acid-targeted agents, antimetabolites, kinase inhibitors, anti-inflammatory drugs, natural product antibiotics, oligopeptides, as well asnano-sized particles. Together, these molecules are invaluable probes of structure and function of the nucleolus. They also provide a unique opportunity to develop novel strategies for more selective and therefore better tolerated chemotherapeutic intervention. In this regard, inhibition of RNA polymerase I-mediated rRNA synthesis appears to be a promising mechanism of cancer cell kill. The recent development of molecules targeted at G-quadruplex forming rRNA gene sequences, which are currently undergoing clinical trials, seems to attest to the success of this approach. PMID:23881648

  5. Cell Membrane Capsules for Encapsulation of Chemotherapeutic and Cancer Cell Targeting in Vivo.

    PubMed

    Peng, Li-Hua; Zhang, Yuan-Hong; Han, Li-Jie; Zhang, Chen-Zhen; Wu, Jia-He; Wang, Xia-Rong; Gao, Jian-Qing; Mao, Zheng-Wei

    2015-08-26

    Systemic administration of chemotherapeutic agents can cause indiscriminate drug distribution and severe toxicity. Until now, encapsulation and targeting of drugs have typically relied on synthetic vehicles, which cannot minimize the clearance by the renal system and may also increase the risk of chemical side effects. Cell membrane capsules (CMCs) provide a generic and far more natural approach to the challenges of drug encapsulation and delivery in vivo. Here aptamer AS1411, which can recognize and bind overexpressed nucleolin on a cancer cell membrane, was chemically conjugated onto CMCs. As a result, AS1411 modified CMCs showed enhanced ingestion in certain cancer cells in vitro and accumulation in mouse cancer xenografts in vivo. Chemotherapeutics and contrast agents with therapeutically significant concentrations can be packaged into CMCs by reversible permeating their plasma membranes. The systematic administration of cancer targeting CMCs loaded with doxorubicin hydrochloride can significantly inhibit tumor growth in mouse xenografts, with significantly reduced toxicity compared to free drug. These findings suggest that cancer targeting CMCs may have considerable benefits in drug delivery and cancer treatment.

  6. Multi-Agent System for Managing Human Activities in Space Operations

    NASA Technical Reports Server (NTRS)

    Schrenkenghost, Debra; Bonasso, R. Peter

    2006-01-01

    In manned space operations today, the astronauts' activity schedules are preplanned and adjusted daily on Earth. We have developed the Distributed Collaboration and Interaction (DCI) multi-agent system to investigate automating aspects of human activity management. The DCI System assists (1) plan generation, (2) human activity tracking, (3) plan revision, and (4) mixed initiative interaction with the plan. We have deployed and evaluated the DCI system at JSC to assist control engineers in managing anomaly handling activities for automated life support systems. DCI operated round the clock for 20 months in the Water Research Facility at JSC. Using this software, we reduced anomaly response time by engineers from up to 10 hours in previous tests to under an hour. Based on this evaluation, we conclude that agent assistance for schedule management has potential to improve astronaut activity awareness and reduce response time in situations where crew are interrupted to handle anomalies.

  7. Ethanol Extract of Oldenlandia diffusa – an Effective Chemotherapeutic for the Treatment of Colorectal Cancer in Humans

    PubMed Central

    Lee, Soojin; Shim, Ji Hwan; Gim, Huijin; Park, Hyun Soo

    2016-01-01

    Objectives: Oldenlandia diffusa is traditionally used to relieve the symptoms of and to treat various diseases, but its anti-cancer activity has not been well studied. In the present study, the authors investigated the anti-cancer effects of an ethanol extract of Oldenlandia diffusa (EOD) on HT-29 human adenocarcinoma cells. Methods: Cells were treated with different concentrations of an EOD, and cell death was assessed by using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Analyses of the sub G1 peak, the caspase-3 and -9 activities, and the mitochondrial membrane depolarizations were conducted to confirm cell death by apoptosis. Also, intracellular reactive oxygen species (ROS) generation was determined using carboxy-H2DCFDA (5-(and-6)-carboxy-20,70-dichlorodihydrofluorescein diacetate). Results: EOD inhibited the proliferation of HT-29 cells for 24 hours by 78.6% ± 8.1% at 50 μg/mL, 74.4% ± 4.6% at 100 μg/mL, 65.9% ± 5.2% at 200 μg/mL, 51.4% ± 6.2% at 300 μg/mL, and by 41.7% ± 8.9% at 400 μg/mL, and treatment for 72 hours reduced the proliferation at the corresponding concentrations by 43.3% ± 8.8%, 24.3 ± 5.1 mV, 13.5 ± 3.2 mV, 6.5 ± 2.3 mV, and by 2.6 ± 2.3 mV. EOD increased the number of cells in the sub-G1 peak in a dose-dependent manner. The mitochondrial membrane depolarization was elevated by EOD. Also, caspase activities were dose-dependently elevated in the presence of EOD, and these activities were repressed by a pan-caspase inhibitor (zVAD-fmk). The ROS generation was significantly increased by EOD and N-acetyl-L-cysteine (NAC; a ROS scavenger) remarkably abolished EOD-induced cell death. In addition, a combination of sub-optimal doses of EOD and chemotherapeutic agents noticeably suppressed the growth of HT-29 cancer cells. Conclusion: These results indicate that EOD might be an effective chemotherapeutic for the treatment of human colorectal cancer. PMID:27280050

  8. A novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells

    PubMed Central

    Wang, Si; Placzek, William J.; Stebbins, John L.; Mitra, Sayantan; Noberini, Roberta; Koolpe, Mitchell; Zhang, Ziming; Dahl, Russell; Pasquale, Elena B.; Pellecchia, Maurizio

    2012-01-01

    The efficacy of anti-cancer drugs is often limited by their systemic toxicities and adverse side effects. We report that the EphA2 receptor is over-expressed preferentially in several human cancer cell lines compared to normal tissues and that an EphA2 targeting peptide (YSAYPDSVPMMS) can be effective in delivering anti-cancer agents to such tumors. Hence, we report on the synthesis and characterizations of a novel EphA2-targeting agent conjugated with the chemotherapeutic drug paclitaxel. We found that the peptide-drug conjugate is dramatically more effective than paclitaxel alone at inhibiting tumor growth in a prostate cancer xenograft model, delivering significantly higher levels of drug to the tumor site. We believe these studies open the way to the development of a new class of therapeutic compounds that exploit the EphA2 receptor for drug delivery to cancer cells. PMID:22329578

  9. 21 CFR 178.3400 - Emulsifiers and/or surface-active agents.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Emulsifiers and/or surface-active agents. 178.3400 Section 178.3400 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) INDIRECT FOOD ADDITIVES: ADJUVANTS, PRODUCTION AIDS, AND SANITIZERS Certain Adjuvants...

  10. Identity Agents: Parents as Active and Reflective Participants in their Children's Identity Formation

    ERIC Educational Resources Information Center

    Schachter, Elli P.; Ventura, Jonathan J.

    2008-01-01

    The paper introduces the concept of identity agents. This concept refers to those individuals who actively interact with children and youth with the intention of participating in their identity formation, and who reflectively mediate larger social influences on identity formation. This contrasts with the focus of mainstream research in the…

  11. Multidrug Resistance-Associated Protein 2 Expression Is Upregulated by Adenosine 5’-Triphosphate in Colorectal Cancer Cells and Enhances Their Survival to Chemotherapeutic Drugs

    PubMed Central

    Vinette, Valérie; Placet, Morgane; Arguin, Guillaume; Gendron, Fernand-Pierre

    2015-01-01

    Extracellular adenosine 5’-triphosphate (ATP) is a signaling molecule that induces a plethora of effects ranging from the regulation of cell proliferation to modulation of cancerous cell behavior. In colorectal cancer, ATP was reported to stimulate epithelial cell proliferation and possibly promote resistance to anti-cancer treatments. However, the exact role of this danger-signaling molecule on cancerous intestinal epithelial cells (IECs) in response to chemotherapeutic agents remains unknown. To address how ATP may influence the response of cancerous IECs to chemotherapeutic agents, we used Caco-2 cells, which display enterocyte-like features, to determine the effect of ATP on the expression of multidrug resistance-associated protein 2 (MRP2). Gene and protein expression were determined by quantitative real-time PCR (qRT-PCR) and Western blotting. Resistance to etoposide, cisplatin and doxorubicin was determined by MTT assays in response to ATP stimulation of Caco-2 cells and in cells for which MRP2 expression was down-regulated by shRNA. ATP increased the expression of MRP2 at both the mRNA and protein levels. MRP2 expression involved an ATP-dependent stimulation of the MEK/ERK signaling pathway that was associated with an increase in relative resistance of Caco-2 cells to etoposide. Abolition of MRP2 expression using shRNA significantly reduced the protective effect of MRP2 toward etoposide as well as to cisplatin and doxorubicin. This study describes the mechanism by which ATP may contribute to the chemoresistance of cancerous IECs in colorectal cancer. Given the heterogeneity of colorectal adenocarcinoma responses to anti-cancer drugs, these findings call for further study to understand the role of P2 receptors in cancer drug therapy and to develop novel therapies aimed at regulating P2 receptor activity. PMID:26295158

  12. Engineering novel targeted nanoparticle formulations to increase the therapeutic efficacy of conventional chemotherapeutics against multiple myeloma

    NASA Astrophysics Data System (ADS)

    Ashley, Jonathan D.

    Multiple myeloma (MM) is a hematological malignancy which results from the uncontrolled clonal expansion of plasma cells within the body. Despite recent medical advances, this disease remains largely incurable, with a median survival of ˜7 years, owing to the development of drug resistance. This dissertation will explore new advances in nanotechnology that will combine the cytotoxic effects of small molecule chemotherapeutics with the tumor targeting capabilities of nanoparticles to create novel nanoparticle formulations that exhibit enhanced therapeutic indices in the treatment of MM. First, doxorubicin was surfaced conjugated onto micellar nanoparticles via an acid labile hydrazone bond to increase the drug accumulation at the tumor. The cell surface receptor Very Late Antigen-4 (VLA-4; alpha4beta1) is expressed on cancers of hematopoietic origin and plays a vital role in the cell adhesion mediated drug resistance (CAM-DR) in MM. Therefore, VLA-4 antagonist peptides were conjugated onto the nanoparticles via a multifaceted procedure to actively target MM cells and simultaneously inhibit CAM-DR. The micellar doxorubicin nanoparticles were able to overcome CAM-DR and demonstrated improved therapeutic index relative to free doxorubicin. In addition to doxorubicin, other classes of therapeutic agents, such as proteasome inhibitors, can be incorporated in nanoparticles for improved therapeutic outcomes. Utilizing boronic acid chemistry, bortezomib prodrugs were synthesized using a reversible boronic ester bond and then incorporated into liposomes. The different boronic ester bonds that could be potentially used in the synthesis of bortezomib prodrugs were screened based on stability using isobutylboronic acid. The liposomal bortezomib nanoparticles demonstrated significant proteasome inhibition and cytotoxicity in MM cells in vitro, and dramatically reduced the non-specific toxicities associated with free bortezomib while maintaining significant tumor growth

  13. Effect of Activating Agent on the Preparation of Bamboo-Based High Surface Area Activated Carbon by Microwave Heating

    NASA Astrophysics Data System (ADS)

    Xia, Hongying; Wu, Jian; Srinivasakannan, Chandrasekar; Peng, Jinhui; Zhang, Libo

    2016-06-01

    The present work attempts to convert bamboo into a high surface area activated carbon via microwave heating. Different chemical activating agents such as KOH, NaOH, K2CO3 and Na2CO3 were utilized to identify a most suitable activating agent. Among the activating agents tested KOH was found to generate carbon with the highest porosity and surface area. The effect of KOH/C ratio on the porous nature of the activated carbon has been assessed. An optimal KOH/C ratio of 4 was identified, beyond which the surface area as well as the pore volume were found to decrease. At the optimized KOH/C ratio the surface area and the pore volume were estimated to be 3,441 m2/g and 2.093 ml/g, respectively, with the significant proportion of which being microporous (62.3%). Activated carbon prepared under the optimum conditions was further characterized using Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM). Activated carbons with so high surface area and pore volume are very rarely reported, which could be owed to the nature of the precursor and the optimal conditions of mixture ratio adopted in the present work.

  14. Discovery of novel dual-action antidiabetic agents that inhibit glycogen phosphorylase and activate glucokinase.

    PubMed

    Zhang, Lei; Chen, Xiaojie; Liu, Jun; Zhu, Qingzhang; Leng, Ying; Luo, Xiaomin; Jiang, Hualiang; Liu, Hong

    2012-12-01

    Dual-target-directed agents simultaneously inhibiting glycogen phosphorylase (GP) and activating glucokinase (GK) could decelerate the inflow of glucose from glycogenolysis and accelerate the outflow of glucose in the liver, therefore allow for a better control over hyperglycaemia in a synergetic manner. A series of hybrid compounds were designed by structure-assisted and ligand-based strategies. In vitro bioassays found two novel compounds (1j, 6g) worthy of further optimization on balance of dual action to GP and GK. In addition, for single-target activity, two compounds exhibited more potent GP inhibitory activity and four compounds showed better GK activation than their corresponding references.

  15. Validation of N-myristoyltransferase as Potential Chemotherapeutic Target in Mammal-Dwelling Stages of Trypanosoma cruzi

    PubMed Central

    Herrera, Linda J.; Brand, Stephen; Santos, Andres; Nohara, Lilian L.; Harrison, Justin; Norcross, Neil R.; Thompson, Stephen; Smith, Victoria; Lema, Carolina; Varela-Ramirez, Armando; Gilbert, Ian H.; Almeida, Igor C.; Maldonado, Rosa A.

    2016-01-01

    Background Trypanosoma cruzi causes Chagas disease, an endemic and debilitating illness in Latin America. Lately, owing to extensive population movements, this neglected tropical disease has become a global health concern. The two clinically available drugs for the chemotherapy of Chagas disease have rather high toxicity and limited efficacy in the chronic phase of the disease, and may induce parasite resistance. The development of new anti-T. cruzi agents is therefore imperative. The enzyme N-myristoyltransferase (NMT) has recently been biochemically characterized, shown to be essential in Leishmania major, Trypanosoma brucei, and T. cruzi¸ and proposed as promising chemotherapeutic target in these trypanosomatids. Methodology/Principal Findings Here, using high-content imaging we assayed eight known trypanosomatid NMT inhibitors, against mammal-dwelling intracellular amastigote and trypomastigote stages and demonstrated that three of them (compounds 1, 5, and 8) have potent anti-proliferative effect at submicromolar concentrations against T. cruzi, with very low toxicity against human epithelial cells. Moreover, metabolic labeling using myristic acid, azide showed a considerable decrease in the myristoylation of proteins in parasites treated with NMT inhibitors, providing evidence of the on-target activity of the inhibitors. Conclusions/Significance Taken together, our data point out to the potential use of NMT inhibitors as anti-T. cruzi chemotherapy. PMID:27128971

  16. Synthesis and alkylation activity of a nitrogen mustard agent to penetrate the blood-brain barrier.

    PubMed

    Bartzatt, Ronald L

    2004-01-01

    Nitrogen mustard agents are widely used for the clinical treatment of cancers. A nitrogen mustard (N-mustard) agent was synthesized utilizing nicotinic acid as the carrier of the alkylating substituent (-OCH2CH2N(CH2CH2Cl)2) that forms an ester group (R-C(O)-OR) on a heterocyclic ring. The N-mustard agent is a solid at room temperature and is stable for more than 6 weeks when stored at -10 degrees C. To determine the kinetics of alkylation activity a nucleophilic primary amine compound (4-chloroaniline) was placed in aqueous solution with the mustard agent at physiological pH 7.4 (pH of blood) and 37 degrees C. The alkylation reaction was found to be second-order with rate equation: rate = k2[N-mustard][Nu], where Nu = nucleophile and k2 = 0.0415 L/(mol x min). Pharmacological descriptors calculated showed values indicating a strong potential of penetrating the blood-brain barrier. The partition coefficient (Log P) of the mustard agent is 1.95 compared with 0.58 for nicotinic acid. Values of descriptors such as dipole, polar surface area, Log BB, molar refractivity, parachor, and violations of Rule of 5 were found to be 5.057 Debye, 42.44 A2, 0.662, 72.7 cm3, 607.7 cm3, and 0.0 for the N-mustard agent. Value of polar surface area for the mustard agent (42.44 A2) predicts that >90% of any amount present in the intestinal tract will be absorbed.

  17. In vitro activities of antimicrobial agents, alone and in combination, against Acinetobacter baumannii isolated from blood.

    PubMed

    Chang, S C; Chen, Y C; Luh, K T; Hsieh, W C

    1995-11-01

    In vitro activities of 15 antimicrobial agents against 90 strains of Acinetobacter baumannii isolated from blood cultures from hospitalized patients were determined using the agar dilution method. Imipenem, ofloxacin, and ciprofloxacin had the best antimicrobial activity with minimum inhibitory concentrations (MIC50s) of 0.25 mu g/ml and MIC90s of 0.5-1 mu g/ml. beta-lactam antibiotics other than imipenem had poor activity, with MIC50s ranging from 8 to 64 mu g/ml and MIC90s from 32 to > or = 256 mu g/ml. The checkerboard titration method was used to study the effects of combination of two antimicrobial agents. Combinations of ceftazidime, aztreonam, imipenem, or ciprofloxacin with amikacin showed either synergistic effects or partial synergistic effects for 40.9%-86.4% of 22 tested strains. The best in vitro activity was observed with the combination of imipenem and amikacin. No antagonistic effects were observed with the combination of imipenem and amikacin. Synergistic effects were confirmed by time-kill curve studies. In conclusion, imipenem, ofloxacin, and ciprofloxacin were the three most active agents against human blood isolates of A. baumannii. The combination of a beta-lactam or ciprofloxacin with amikacin was synergistic for some of the isolates.

  18. Balancing the stability and the catalytic specificities of OP hydrolases with enhanced V-agent activities.

    PubMed

    Reeves, T E; Wales, M E; Grimsley, J K; Li, P; Cerasoli, D M; Wild, J R

    2008-06-01

    Rational site-directed mutagenesis and biophysical analyses have been used to explore the thermodynamic stability and catalytic capabilities of organophosphorus hydrolase (OPH) and its genetically modified variants. There are clear trade-offs in the stability of modifications that enhance catalytic activities. For example, the H254R/H257L variant has higher turnover numbers for the chemical warfare agents VX (144 versus 14 s(-1) for the native enzyme (wild type) and VR (Russian VX, 465 versus 12 s(-1) for wild type). These increases are accompanied by a loss in stability in which the total Gibb's free energy for unfolding is 19.6 kcal/mol, which is 5.7 kcal/mol less than that of the wild-type enzyme. X-ray crystallographic studies support biophysical data that suggest amino acid residues near the active site contribute to the chemical and thermal stability through hydrophobic and cation-pi interactions. The cation-pi interactions appear to contribute an additional 7 kcal/mol to the overall global stability of the enzyme. Using rational design, it has been possible to make amino acid changes in this region that restored the stability, yet maintained effective V-agent activities, with turnover numbers of 68 and 36 s(-1) for VX and VR, respectively. This study describes the first rationally designed, stability/activity balance for an OPH enzyme with a legitimate V-agent activity, and its crystal structure.

  19. Evaluation of Colloids and Activation Agents for Determination of Melamine Using UV-SERS

    PubMed Central

    2012-01-01

    UV-SERS measurements offer a great potential for environmental or food (detection of food contaminats) analytics. Here, the UV-SERS enhancement potential of various kinds of metal colloids, such as Pd, Pt, Au, Ag, Au–Ag core–shell, and Ag–Au core–shell with different shapes and sizes, were studied using melamine as a test molecule. The influence of different activation (KF, KCl, KBr, K2SO4) agents onto the SERS activity of the nanomaterials was investigated, showing that the combination of a particular nanoparticle with a special activation agent is extremely crucial for the observed SERS enhancement. In particular, the size dependence of spherical nanoparticles of one particular metal on the activator has been exploited. By doing so, it could be shown that the SERS enhancement increases or decreases for increasing or decreasing size of a nanoparticle, respectively. Overall, the presented results demonstrate the necessity to adjust the nanoparticle size and the activation agent for different experiments in order to achieve the best possible UV-SERS results. PMID:22428076

  20. Agent-based power sharing scheme for active hybrid power sources

    NASA Astrophysics Data System (ADS)

    Jiang, Zhenhua

    The active hybridization technique provides an effective approach to combining the best properties of a heterogeneous set of power sources to achieve higher energy density, power density and fuel efficiency. Active hybrid power sources can be used to power hybrid electric vehicles with selected combinations of internal combustion engines, fuel cells, batteries, and/or supercapacitors. They can be deployed in all-electric ships to build a distributed electric power system. They can also be used in a bulk power system to construct an autonomous distributed energy system. An important aspect in designing an active hybrid power source is to find a suitable control strategy that can manage the active power sharing and take advantage of the inherent scalability and robustness benefits of the hybrid system. This paper presents an agent-based power sharing scheme for active hybrid power sources. To demonstrate the effectiveness of the proposed agent-based power sharing scheme, simulation studies are performed for a hybrid power source that can be used in a solar car as the main propulsion power module. Simulation results clearly indicate that the agent-based control framework is effective to coordinate the various energy sources and manage the power/voltage profiles.

  1. Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors

    DTIC Science & Technology

    2005-04-01

    chemotherapeutic agents including cyclophosphamide, methotrexate, anthracycline, cytarabine , paclitaxel, and corticosteroids (28). To determine whether the...cyclophosphamide, methotrexate, anthracycline, cytarabine , paclitaxel, and corticosteroids (28). Sasaki et al reported that the level of Bcl-2 in cancer cells

  2. A new macromolecular paramagnetic MR contrast agent binds to activated human platelets.

    PubMed

    Chaubet, Frédéric; Bertholon, Isabelle; Serfaty, Jean-Michel; Bazeli, Ramin; Alsaid, Hasan; Jandrot-Perrus, Martine; Zahir, Charaf; Even, Pascale; Bachelet, Laure; Touat, Ziad; Lancelot, Eric; Corot, Claire; Canet-Soulas, Emmanuelle; Letourneur, Didier

    2007-07-01

    A new functionalized macromolecular magnetic resonance (MR) contrast agent has been developed from a carboxymethyldextran-Gd(DOTA) devoid of biospecificity. The functionalized contrast agent was synthesized in order to mimic PSGL-1, the main ligand of P-selectin, a glycoprotein mainly expressed on the surface of activated platelets. The starting compound, CM1, was first carboxymethylated by monochloroacetic acid leading to a series of 10 derivatives varying in their carboxymethyl content. CM8 derivative, with a degree of substitution in carboxymethyl of 0.84, was chosen for subsequent fluorolabeling and sulfation to give CM8FS. CM8FS has an average number molecular weight of 27 000 +/- 500 g/mol, a hydrodynamic radius of 5.7 +/- 0.2 nm and a high relaxivity (r(1) = 11.2/mM (Gd)/s at 60 MHz). Flow cytometry experiments on whole human blood or on isolated platelets evidenced in vitro a preferential binding of CM8FS on TRAP-activated human platelets. Interestingly, CM8FS did not bind to other blood cells or to resting platelets. Pellets of TRAP-activated human platelets have also been imaged in tubes with a 1.5 T MR imager. A MR signal was observed for activated platelets incubated with CM8FS. Altogether, these in vitro results evidenced the recognition of activated human platelets by a fluorescent paramagnetic contrast agent grafted with carboxyl and sulfate groups. This biomimetic approach associated with the versatile macromolecular platform appears promising for the development of new contrast agents for molecular imaging of activated platelets in cardiovascular diseases such as atherosclerosis and aneurysms.

  3. Bacteriostatic and bactericidal activities of 24 antimicrobial agents against Campylobacter fetus subsp. jejuni.

    PubMed

    Vanhoof, R; Gordts, B; Dierickx, R; Coignau, H; Butzler, J P

    1980-07-01

    The bacteriostatic and bactericidal activities of 24 antimicrobial agents were tested with the Dynatech MIC 2000 system against 86 strains of Campylobacter fetus subsp. jejuni from human sources. The penicillins (penicillin G, ampicillin, amoxycillin, carbenicillin) had poor activity. Ampicillin and amoxycillin were equally active. Cefotaxime revealed a rather good activity. Erythromycin, gentamicin, tobramycin, amikacin, and furazolidone were the most active compounds. Two strains (2.3%) were resistant to erythromycin. One strain (1.2%) was completely resistant to tobramycin. The tetracyclines (tetracyline, doxycycline, minocycline) were generally effective, but 8% of the strains were totally resistant to them. Minocycline was the most active. Chloramphenicol, thiamphenicol, and clindamycin had good activity. The bacteriostatic and bactericidal distributions for colistin, nalidixic acid, and metronidazole were broad.

  4. Chemotherapeutic potential of cow urine: A review

    PubMed Central

    Randhawa, Gurpreet Kaur; Sharma, Rajiv

    2015-01-01

    In the grim scenario where presently about 70% of pathogenic bacteria are resistant to at least one of the drugs for the treatment, cue is to be taken from traditional/indigenous medicine to tackle it urgently. The Indian traditional knowledge emanates from ayurveda, where Bos indicus is placed at a high pedestal for numerous uses of its various products. Urine is one of the products of a cow with many benefits and without toxicity. Various studies have found good antimicrobial activity of cow’s urine (CU) comparable with standard drugs such as ofloxacin, cefpodoxime, and gentamycin, against a vast number of pathogenic bacteria, more so against Gram-positive than negative bacteria. Interestingly antimicrobial activity has also been found against some resistant strains such as multidrug-resistant (MDR) Escherichia coli and Klebsiella pneumoniae. Antimicrobial action is enhanced still further by it being an immune-enhancer and bioenhancer of some antibiotic drugs. Antifungal activity was comparable to amphotericin B. CU also has anthelmintic and antineoplastic action. CU has, in addition, antioxidant properties, and it can prevent the damage to DNA caused by the environmental stress. In the management of infectious diseases, CU can be used alone or as an adjunctive to prevent the development of resistance and enhance the effect of standard antibiotics. PMID:26401404

  5. Activity-Based Protein Profiling Reveals Broad Reactivity of the Nerve Agent Sarin.

    PubMed

    Tuin, Adriaan W; Mol, Marijke A E; van den Berg, Roland M; Fidder, A; van der Marel, Gijs A; Overkleeft, Herman S; Noort, Daan

    2009-04-01

    Elucidation of noncholinesterase protein targets of organophosphates, and nerve agents in particular, may reveal additional mechanisms for their high toxicity as well as clues for novel therapeutic approaches toward intoxications with these agents. Within this framework, we here describe the synthesis of the activity-based probe 3, which contains a phosphonofluoridate moiety, a P-Me moiety, and a biotinylated O-alkyl group, and its use in activity-based protein profiling with two relevant biological samples, that is, rhesus monkey liver and cultured human A549 lung cells. In this way, we have unearthed eight serine hydrolases (fatty acid synthase, acylpeptide hydrolase, dipeptidyl peptidase 9, prolyl oligopeptidase, carboxylesterase, long-chain acyl coenzyme A thioesterase, PAF acetylhydrolase 1b, and esterase D/S-formyl glutathione hydrolase) as targets that are modified by the nerve agent sarin. It is also shown that the newly developed probe 3 might find its way into the development of alternative, less laborious purification protocols for human butyrylcholinesterase, a potent bioscavenger currently under clinical investigation as a prophylactic/therapeutic for nerve agent intoxications.

  6. Blockade of the phosphatidylinositol-3-kinase-Akt signaling pathway enhances the induction of apoptosis by microtubule-destabilizing agents in tumor cells in which the pathway is constitutively activated.

    PubMed

    Fujiwara, Yusuke; Hosokawa, Yoshihisa; Watanabe, Kazushi; Tanimura, Susumu; Ozaki, Kei-ichi; Kohno, Michiaki

    2007-03-01

    Constitutive activation of the phosphatidylinositol-3-kinase (PI3K)-Akt signaling pathway is associated with the neoplastic phenotype in many human tumor cell types. Given the antiapoptotic role of this pathway, we examined whether its specific blockade might sensitize human tumor cells to the induction of apoptosis by various anticancer drugs. Although specific blockade of the PI3K-Akt pathway alone with inhibitors such as LY294002 did not induce cell death, it resulted in marked and selective enhancement of the induction of apoptosis by microtubule-destabilizing agents such as vincristine. This effect was apparent only in tumor cells in which the PI3K-Akt pathway is constitutively activated. Blockade of the PI3K-Akt pathway induced the activation of glycogen synthase kinase-3beta, which phosphorylates microtubule-associated proteins such as tau and thereby reduces their ability to bind and stabilize microtubules. The consequent destabilization of microtubules induced by the inhibition of PI3K-Akt signaling appeared to increase their sensitivity to low concentrations of microtubule-destabilizing agents that alone do not lead to the disruption of cytoplasmic microtubules in tumor cells. Such a synergistic effect on microtubule integrity was not apparent for stable microtubules in the neurites of neuronal cells. These results suggest that the administration of a combination of a PI3K-Akt pathway inhibitor and a microtubule-destabilizing agent is a potential chemotherapeutic strategy for the treatment of tumor cells in which this signaling pathway is constitutively activated.

  7. A novel bifunctional mitochondria-targeted anticancer agent with high selectivity for cancer cells

    PubMed Central

    He, Huan; Li, Dong-Wei; Yang, Li-Yun; Fu, Li; Zhu, Xun-Jin; Wong, Wai-Kwok; Jiang, Feng-Lei; Liu, Yi

    2015-01-01

    Mitochondria have recently emerged as novel targets for cancer therapy due to its important roles in fundamental cellular function. Discovery of new chemotherapeutic agents that allow for simultaneous treatment and visualization of cancer is urgent. Herein, we demonstrate a novel bifunctional mitochondria-targeted anticancer agent (FPB), exhibiting both imaging capability and anticancer activity. It can selectively accumulate in mitochondria and induce cell apoptosis. Notably, it results in much higher toxicity toward cancer cells owing to much higher uptake by cancer cells. These features make it highly attractive in cancer imaging and treatment. PMID:26337336

  8. Using an agent-based model to simulate children’s active travel to school

    PubMed Central

    2013-01-01

    Background Despite the multiple advantages of active travel to school, only a small percentage of US children and adolescents walk or bicycle to school. Intervention studies are in a relatively early stage and evidence of their effectiveness over long periods is limited. The purpose of this study was to illustrate the utility of agent-based models in exploring how various policies may influence children’s active travel to school. Methods An agent-based model was developed to simulate children’s school travel behavior within a hypothetical city. The model was used to explore the plausible implications of policies targeting two established barriers to active school travel: long distance to school and traffic safety. The percent of children who walk to school was compared for various scenarios. Results To maximize the percent of children who walk to school the school locations should be evenly distributed over space and children should be assigned to the closest school. In the case of interventions to improve traffic safety, targeting a smaller area around the school with greater intensity may be more effective than targeting a larger area with less intensity. Conclusions Despite the challenges they present, agent based models are a useful complement to other analytical strategies in studying the plausible impact of various policies on active travel to school. PMID:23705953

  9. Thiazole: a promising heterocycle for the development of potent CNS active agents.

    PubMed

    Mishra, Chandra Bhushan; Kumari, Shikha; Tiwari, Manisha

    2015-03-06

    Thiazole is a valuable scaffold in the field of medicinal chemistry and has accounted to display a variety of biological activities. Thiazole and its derivatives have attracted continuing interest to design various novel CNS active agents. In the past few decades, thiazoles have been widely used to develop a variety of therapeutic agents against numerous CNS targets. Thiazole containing drug molecules are currently being used in treatment of various CNS disorders and a number of thiazole derivatives are also presently in clinical trials. A lot of research has been carried out on thiazole and their analogues, which has proved their efficacy to overcome several CNS disorders in rodent as well as primate models. The aim of present review is to highlights diverse CNS activities displayed by thiazole and their derivatives. SAR of this nucleus has also been well discussed. This review covers the recent updates present in literature and will surely provide a greater insight for the designing and development of potent thiazole based CNS active agents in future.

  10. Characterizing biological variability in livestock blood cholinesterase activity for biomonitoring organophosphate nerve agent exposure

    SciTech Connect

    Halbrook, R.S.; Shugart, L.R.; Watson, A.P.; Munro, N.B.; Linnabary, R.D. )

    1992-09-01

    A biomonitoring protocol, using blood cholinesterase (ChE) activity in livestock as a monitor of potential organophosphate nerve agent exposure during the planned destruction of US unitary chemical warfare agent stockpiles, is described. The experimental design included analysis of blood ChE activity in individual healthy sheep, horses, and dairy and beef cattle during a 10- to 12-month period. Castrated and sexually intact males, pregnant and lactating females, and adult and immature animals were examined through at least one reproductive cycle. The same animals were used throughout the period of observation and were not exposed to ChE-inhibiting organophosphate or carbamate compounds. A framework for an effective biomonitoring protocol within a monitoring area includes establishing individual baseline blood ChE activity for a sentinel group of 6 animals on the bases of blood samples collected over a 6-month period, monthly collection of blood samples for ChE-activity determination during monitoring, and selection of adult animals as sentinels. Exposure to ChE-inhibiting compounds would be suspected when all blood ChE activity of all animals within the sentinel group are decreased greater than 20% from their own baseline value. Sentinel species selection is primarily a logistical and operational concern; however, sheep appear to be the species of choice because within-individual baseline ChE activity and among age and gender group ChE activity in sheep had the least variability, compared with data from other species. This protocol provides an effective and efficient means for detecting abnormal depressions in blood ChE activity in livestock and can serve as a valuable indicator of the extent of actual plume movement and/or deposition in the event of organophosphate nerve agent release.

  11. Effect of various capping agents on photocatalytic, antibacterial and antibiofilm activities of ZnO nanoparticles.

    PubMed

    Akhil, K; Jayakumar, J; Gayathri, G; Khan, S Sudheer

    2016-07-01

    Zinc oxide nanoparticles (ZnO NPs) are extensively used in a wide variety of commercial products including sunscreens, textiles and paints It is a known fact that ZnO NPs are not stable when dispersed in water, therefore manufacturers use several surface modifying agents to increase the stability of ZnO NPs. In the present study, ZnO NPs were synthesized via chemical co-precipitation with and without the use of surface modifying agents including ethylene glycol (EG), gelatin, polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP). Preliminary characterization was done by UV-Visible spectroscopy. Electron microscopic analysis showed that the particles were hexagonal in shape. The hydrodynamic size distribution was analyzed by using dynamic light scattering method and crystalline nature was determined by X-ray diffraction method. The study evaluated the photocatalytic, antibacterial and antibiofilm activities of the particles with and without the addition of surface modifying agents. The capping of the particle was confirmed by FT-IR spectroscopy. The photocatalytic activity was checked against methylene blue. Capping of the particles reduced the photocatalytic activity of the particles. The antibacterial and antibiofilm activities were checked against Staphylococcus aureus (MTCC 3160) and Pseudomonas aeruginosa (MTCC 1688). Antibacterial activity was analyzed by simple plate count method both under dark as well as light condition. Antibiofilm activity was checked in both pre- and post-biofilm formation period under both dark as well as light condition. The activity was evaluated via crystal violet staining method. All the particles showed good antibacterial and antibiofilm activities.

  12. [Design and study of new agents having antitubercular activity: the original compound perchlosone as a potent agent of etiotropic therapy for tuberculosis].

    PubMed

    Vinogradova, T I; Aleksandrova, A E; Antonenkova, E V; Elokhina, V N; Nakhmanovich, A S

    1999-01-01

    Studies dealing with the design of new antituberculous agents based on goal-oriented synthesis have provided the agent Perchlosone which is similar to isoniazid and rifampicin, produces in tuberculostatic activity against sensitive laboratory cultured mycobacteria, produces an inhibitory action on polyresistant clinical strains. Experiments on animals (mice, rabbits) with experimental tuberculosis have established that Perchlosone and isoniazid have equal therapeutical properties, and the former shows a synergist interaction with rifampicin, has neither mutagenic activity nor negative effects on immunity and the surfactant system of the lung.

  13. Vulnerable families as active agents of their own change process: a bidirectional perspective.

    PubMed

    Goh, Esther C L

    2015-04-01

    The literature on successful practice with vulnerable families reports social workers' efforts in forging therapeutic bonds with clients, their ability to both recognize clients' strengths and pain and support them as they work through adversity. Vulnerable families' own contribu- tions to their change process, however, have remained largely opaque. This article offers concrete conceptual tools to consider both social workers and clients from vulnerable families as active agents in the change process. Empirical evidence collected by practitioner-researchers through in-depth discussions with 10 vulnerable families illustrates clients' agentic capacities for autonomy, construction, and action as well as joint construction and maintenance of the helping relationships with social workers, thereby illustrating their active contribution to the process of change.

  14. Salinomycin: a novel anti-cancer agent with known anti-coccidial activities.

    PubMed

    Zhou, Shuang; Wang, Fengfei; Wong, Eric T; Fonkem, Ekokobe; Hsieh, Tze-Chen; Wu, Joseph M; Wu, Erxi

    2013-01-01

    Salinomycin, traditionally used as an anti-coccidial drug, has recently been shown to possess anti-cancer and anti-cancer stem cell (CSC) effects, as well as activities to overcome multi-drug resistance based on studies using human cancer cell lines, xenograft mice, and in case reports involving cancer patients in pilot clinical trials. Therefore, salinomycin may be considered as a promising novel anti-cancer agent despite its largely unknown mechanism of action. This review summarizes the pharmacologic effects of salinomycin and presents possible mechanisms by which salinomycin exerts its anti-tumorigenic activities. Recent advances and potential complications that might limit the utilization of salinomycin as an anti-cancer and anti-CSC agent are also presented and discussed.

  15. Decontamination of adsorbed chemical warfare agents on activated carbon using hydrogen peroxide solutions.

    PubMed

    Osovsky, Ruth; Kaplan, Doron; Nir, Ido; Rotter, Hadar; Elisha, Shmuel; Columbus, Ishay

    2014-09-16

    Mild treatment with hydrogen peroxide solutions (3-30%) efficiently decomposes adsorbed chemical warfare agents (CWAs) on microporous activated carbons used in protective garments and air filters. Better than 95% decomposition of adsorbed sulfur mustard (HD), sarin, and VX was achieved at ambient temperatures within 1-24 h, depending on the H2O2 concentration. HD was oxidized to the nontoxic HD-sulfoxide. The nerve agents were perhydrolyzed to the respective nontoxic methylphosphonic acids. The relative rapidity of the oxidation and perhydrolysis under these conditions is attributed to the microenvironment of the micropores. Apparently, the reactions are favored due to basic sites on the carbon surface. Our findings suggest a potential environmentally friendly route for decontamination of adsorbed CWAs, using H2O2 without the need of cosolvents or activators.

  16. Network Interventions on Physical Activity in an Afterschool Program: An Agent-Based Social Network Study

    PubMed Central

    Zhang, Jun; Shoham, David A.; Tesdahl, Eric

    2015-01-01

    Objectives. We studied simulated interventions that leveraged social networks to increase physical activity in children. Methods. We studied a real-world social network of 81 children (average age = 7.96 years) who lived in low socioeconomic status neighborhoods, and attended public schools and 1 of 2 structured afterschool programs. The sample was ethnically diverse, and 44% were overweight or obese. We used social network analysis and agent-based modeling simulations to test whether implementing a network intervention would increase children’s physical activity. We tested 3 intervention strategies. Results. The intervention that targeted opinion leaders was effective in increasing the average level of physical activity across the entire network. However, the intervention that targeted the most sedentary children was the best at increasing their physical activity levels. Conclusions. Which network intervention to implement depends on whether the goal is to shift the entire distribution of physical activity or to influence those most adversely affected by low physical activity. Agent-based modeling could be an important complement to traditional project planning tools, analogous to sample size and power analyses, to help researchers design more effective interventions for increasing children’s physical activity. PMID:25689202

  17. Synthesis and biological evaluation of diarylthiazole derivatives as antimitotic and antivascular agents with potent antitumor activity.

    PubMed

    Wang, Fang; Yang, Zhuang; Liu, Yibin; Ma, Liang; Wu, Yuzhe; He, Lin; Shao, Mingfeng; Yu, Kun; Wu, Wenshuang; Pu, Yuzhi; Nie, Chunlai; Chen, Lijuan

    2015-07-01

    By switching position of the N and S atom in the thiazole ring which were similar to the previously reported agent 5-(4-ethoxyphenyl)-4-(3',4',5'-trimethoxyphenyl)thiazol-2-amine, a series of 4,5-diarylthiazole derivatives were synthesized using Friedel-Crafts reaction based on chemical modification of Combrestatatin A-4 (CA-4). Their antiproliferative activities were evaluated and identified as new microtubule destabilizing agents. Structure-activity relationship study indicated that compound 8a with 3,4,5-trimethoxyphenyl group at the C-4 position and 4-ethoxyphenyl group at the C-5 position of 2-amino substituted thiazole was of the most potent inhibitory activity in this series. 8a was found to exhibit the IC50 values of 8.4-26.4nM in five human cancer cell lines, with comparable inhibition effects to CA-4. Moreover, 8a showed potency as a tubulin polymerization inhibitor, with colchicine site binding ability and comparable extent of inhibition against the growth of P-glycoprotein over-expressing multidrug resistant cell lines. Mechanism studies revealed that 8a could block the progression of cell cycle in the G2/M phase and result in cellular apoptosis in cancer cells. As a new tubulin destabilizing agent, 8a was also found high antivascular activity as it concentration-dependently reduced the cell migration and disrupted capillary like tube formation of HUVEC cells. Furthermore, 8a significantly suppressed the tumor growth in HCT116 and SK-OV-3 xenograft models with tumor growth inhibitory rate of 55.12% and 72.7%, respectively. Our studies highlighted that 8a was a promising microtubule targeting antitumor agent.

  18. Novel Bis-Indole Agents Active Against Multidrug-Resistant Acinetobacter baumannii

    PubMed Central

    Jacobs, Michael R.; Bajaksouzian, Saralee; Good, Caryn E.; Butler, Michelle M.; Williams, John D.; Peet, Norton P.; Bowlin, Terry L.; Endimiani, Andrea; Bonomo, Robert A

    2013-01-01

    The in vitro activity of five novel Microbiotix bis-indole agents (MBXs) against 30 multidrug-resistant (MDR) A. baumannii (including 18 resistant to carbapenems) was evaluated. Overall, MIC90s ranged from 1-8 μg/ml, whereas those for imipenem were > 64 μg/ml. MBX 1196 was the most potent (MIC90 1 μg/ml). MBXs are compounds that are highly effective against MDR A. baumannii. PMID:21146724

  19. A minimum core outcome dataset for the reporting of preclinical chemotherapeutic drug studies: Lessons learned from multiple discordant methodologies in the setting of colorectal cancer.

    PubMed

    West, M A; Roman, A; Sayan, E; Primrose, J N; Wedge, S R; Underwood, T J; Mirnezami, A H

    2017-04-01

    In vivo studies in animal models are critical tools necessary to study the fundamental complexity of carcinogenesis. A constant strive to improve animal models in cancer exists, especially those investigating the use of chemotherapeutic effectiveness. In the present systematic review, colorectal cancer (CRC) is used as an example to highlight and critically evaluate the range of reporting strategies used when investigating chemotherapeutic agents in the preclinical setting. A systematic review examining the methodology and reporting of preclinical chemotherapeutic drug studies using CRC murine models was conducted. A total of 45 studies were included in this systematic review. The literature was found to be highly heterogeneous with various cell lines, animal strains, animal ages and chemotherapeutic compounds/regimens tested, proving difficult to compare outcomes between similar studies or indeed gain any significant insight into which chemotherapeutic regimen caused adverse events. From this analysis we propose a minimum core outcome dataset that could be regarded as a standardised way of reporting results from in vivo experimentation.

  20. Synthesis and biological activity of thiazolyl-acetic acid derivatives as possible antimicrobial agents.

    PubMed

    Shirai, Akihiro; Fumoto, Yasuko; Shouno, Tomoaki; Maseda, Hideaki; Omasa, Takeshi

    2013-01-01

    5a-h, a series of (5-substituted-2-methyl-1,3-thiazole-4-yl) acetic acids as heterocyclic acetic acid derivatives, was designed and synthesized from ethyl acetoacetate. The synthesized compounds were screened for their antimicrobial activities against bacterial and fungal strains, and their characteristics were investigated by assays under various temperature and pH conditions. Cytotoxicity was evaluated with the use of sheep erythrocytes and human neonate dermal fibroblasts. Similarly, agents such as lauric acid 6 and parabens 7a-b, which are used as preservative agents for commercial cosmetics and detergents, were assayed for comparison. Although the structure of 5a is simple, comprising a thiazole attached with an octyl group and acetic acid moiety, the compound showed stronger and broader antibacterial and antifungal activities among the 5 series against the tested microbes other than gram-negative bacteria. Interestingly, 5a overcame the weak antifungal activity of parabens 7a-b. Also, the cytotoxicity of 5a was less than that of parabens 7a-b, especially to human dermal fibroblasts. These results suggest that thiazolyl-acetic acid 5a is a potentially effective biocide, and that it could be used as a preservative agent in commercially sold cosmetics and detergents, facilitated by the hydrophilic and charge properties of its carboxylic acid moiety.

  1. Sensitive detection of chemical agents and toxic industrial chemicals using active open-path FTIRs

    NASA Astrophysics Data System (ADS)

    Walter, William T.

    2004-03-01

    Active open-path FTIR sensors provide more sensitive detection of chemical agents than passive FTIRs, such as the M21 RSCAAL and JSLSCAD, and at the same time identify and quantify toxic industrial chemicals (TIC). Passive FTIRs are bistatic sensors relying on infrared sources of opportunity. Utilization of earth-based sources of opportunity limits the source temperatures available for passive chemical-agent FTIR sensors to 300° K. Active FTIR chemical-agent sensors utilize silicon carbide sources, which can be operated at 1500° K. The higher source temperature provides more than an 80-times increase in the infrared radiant flux emitted per unit area in the 7 to 14 micron spectral fingerprint region. Minimum detection limits are better than 5 μgm/m3 for GA, GB, GD, GF and VX. Active FTIR sensors can (1) assist first responders and emergency response teams in their assessment of and reaction to a terrorist threat, (2) provide information on the identification of the TIC present and their concentrations and (3) contribute to the understanding and prevention of debilitating disorders analogous to the Gulf War Syndrome for military and civilian personnel.

  2. New investigational drugs with single-agent activity in multiple myeloma

    PubMed Central

    Rajan, A M; Kumar, S

    2016-01-01

    The treatment of multiple myeloma (MM) is rapidly evolving. In the United States, four drugs (panobinostat, ixazomib, daratumumab and elotuzumab) were approved for the treatment of MM in 2015. As a result of improved diagnosis and therapy, there has been a dramatic improvement in the outcome of MM in the last decade, probably more than any other malignancy. Numerous agents continue to be studied in preclinical models and in clinical trials, with many demonstrating clinical efficacy that appears promising enough to have a trajectory for regulatory approval. The purpose of this article is to summarize the current data and provide perspective on new investigational agents with promising single-agent activity in MM. The agents reviewed include Isatuximab, an anti-CD38 monoclonal antibody; marizomib, a new proteasome inhibitor; oprozomib, an oral proteasome inhibitor; filanesib (ARRY-520), a kinesin spindle protein inhibitor; dinaciclib, a cyclin-dependent kinase inhibitor; venetoclax (ABT-199), a selective BCL-2 inhibitor; and LGH-447, pan PIM kinase inhibitor. PMID:27471867

  3. Insect-gene-activity detection system for chemical and biological warfare agents and toxic industrial chemicals

    NASA Astrophysics Data System (ADS)

    Mackie, Ryan S.; Schilling, Amanda S.; Lopez, Arturo M.; Rayms-Keller, Alfredo

    2002-02-01

    Detection of multiple chemical and biological weapons (CBW) agents and/or complex mixtures of toxic industrial chemicals (TIC) is imperative for both the commercial and military sectors. In a military scenario, a multi-CBW attack would create confusion, thereby delaying decontamination and therapeutic efforts. In the commercial sector, polluted sites invariably contain a mixture of TIC. Novel detection systems capable of detecting CBW and TIC are sorely needed. While it may be impossible to build a detector capable of discriminating all the possible combinations of CBW, a detection system capable of statistically predicting the most likely composition of a given mixture is within the reach of current emerging technologies. Aquatic insect-gene activity may prove to be a sensitive, discriminating, and elegant paradigm for the detection of CBW and TIC. We propose to systematically establish the expression patterns of selected protein markers in insects exposed to specific mixtures of chemical and biological warfare agents to generate a library of biosignatures of exposure. The predicting capabilities of an operational library of biosignatures of exposures will allow the detection of emerging novel or genetically engineered agents, as well as complex mixtures of chemical and biological weapons agents. CBW and TIC are discussed in the context of war, terrorism, and pollution.

  4. In Vitro and In Vivo Antidermatophyte Activities of NND-502, a Novel Optically Active Imidazole Antimycotic Agent

    PubMed Central

    Niwano, Yoshimi; Kuzuhara, Naoki; Kodama, Hiroki; Yoshida, Masanori; Miyazaki, Tsuneo; Yamaguchi, Hideyo

    1998-01-01

    In vitro and in vivo antidermatophyte activities of NND-502, a new imidazole antimycotic agent, were compared with those of two existing antifungal agents, lanoconazole and terbinafine. NND-502 exhibited strong in vitro antifungal activity against Trichophyton spp.; its MIC was 1 to 4 times lower than that of lanoconazole or terbinafine. In an in vivo study with a guinea pig model of tinea pedis, 7-day topical treatment with a 0.5% solution of NND-502 (dissolved in polyethylene glycol 400) was more effective than that with a 0.5% solution of either lanoconazole or terbinafine for eradicating fungi from the infected feet. When the duration of treatment was shortened to 3 days, a topical 1% solution of NND-502 achieved a complete mycological cure, while topical 1% solutions of lanoconazole and terbinafine did not. PMID:9559824

  5. The incorporation of activities to control dengue by community health agents

    PubMed Central

    Cazola, Luiza Helena de Oliveira; Tamaki, Edson Mamoru; Pontes, Elenir Rose Jardim Cury; de Andrade, Sonia Maria Oliveira

    2014-01-01

    OBJECTIVE To evaluate the performance of Community Health Agents when dengue control activities were added to their tasks. METHODS Performance was measured comparing the evolution of selected indicators from the Brazilian National Dengue Control Program and the Family Health Strategy for 2002 to 2008 in the municipality of Sao Gabriel do Oeste, MS, Central Western Brazil, with those of Rio Verde de Mato Grosso, neighboring municipality with demographic, socioeconomic and health services similarities. Data were collected from municipal databases of the Information System for Yellow Fever and Dengue and the Information System for Primary Healthcare of the Mato Grosso do Sul State Health Office. The variables selected for the family health strategy activities were: monthly home visits, pregnant women whose antenatal care began in the first trimester, children under one with up-to-date vaccinations and hypertensive patients. Those selected for the Brazilian National Dengue Control Program were: properties inspected with Aedes aegypti and properties not inspected. RESULTS The two municipalities maintained a similar trend in dengue control indicators in the period studied. With regard to the Family Health Strategy, in 2002 Sao Gabriel do Oeste was better off in three of the four indicators studied, however, this situation was reversed at the end of the period when the county was overtaken by Rio Verde de Mato Grosso in three of the four indicators analyzed, including, the monthly average community health worker visits per registered family, the main activity of a Family Health Strategy agent. CONCLUSIONS: Incorporating the National Dengue Control Program into the Family Health Strategy is viable and developed without prejudice to dengue control activities, however, the same did not occur with the activities of family health in Sao Gabriel do Oeste. The additional workload of the community health workers is the most likely hypothesis for the declining performance of these

  6. Strategies for improving chemotherapeutic delivery to solid tumors mediated by vascular permeability modulation

    NASA Astrophysics Data System (ADS)

    Roy Chaudhuri, Tista

    An essential mode of distribution of blood-borne chemotherapeutic agents within a solid tumor is via the micro-circulation. Poor tumor perfusion, because of a lack of functional vasculature or a lack of microvessels, as well as low tumor vascular permeability, can prevent adequate deposition of even low molecular-weight agents into the tumor. The modulation of tumor vascular function and density can provides numerous strategies for improving intratumor deposition of chemotherapeutic agents. Here we investigated strategies to improve drug delivery to two tumor types that share in common poor drug delivery, but differ in the underlying cause. First, in an angiogenesis-driven brain tumor model of Glioblastoma, the vascular permeability barrier, along with poorly-functional vasculature, hinders drug delivery. A strategy of nanoparticle-based tumor 'priming' to attack the vascular permeability barrier, employing sterically stabilized liposomal doxorubicin (SSL-DXR), was investigated. Functional and histological evaluation of tumor vasculature revealed that after an initial period of depressed vascular permeability and vascular pruning 3--4 days after SSL-DXR administration, vascular permeability and perfusion were restored and then elevated after 5--7 days. As a result of tumor priming, deposition of subsequently-administered nanoparticles was enhanced, and the efficacy of temozolomide (TMZ), if administered during the window of elevated permeability, was increased. The sequenced regimen resulted in a persistent reduction of the tumor proliferative index and a 40% suppression of tumor volume, compared to animals that received both agents simultaneously. Second, in a hypovascular, pancreatic ductal adenocarcinoma model, disruption of tumor-stromal communication via sonic hedgehog (sHH) signaling pathway inhibition mediated an indirect vascular proliferation and a more than 2-fold increase in intratumor nanoparticle deposition. Enhanced delivery of SSL-DXR in tumors pre

  7. Activation of the chemosensing transient receptor potential channel A1 (TRPA1) by alkylating agents.

    PubMed

    Stenger, Bernhard; Zehfuss, Franziska; Mückter, Harald; Schmidt, Annette; Balszuweit, Frank; Schäfer, Eva; Büch, Thomas; Gudermann, Thomas; Thiermann, Horst; Steinritz, Dirk

    2015-09-01

    The transient receptor potential ankyrin 1 (TRPA1) cation channel is expressed in different tissues including skin, lung and neuronal tissue. Recent reports identified TRPA1 as a sensor for noxious substances, implicating a functional role in the molecular toxicology. TRPA1 is activated by various potentially harmful electrophilic substances. The chemical warfare agent sulfur mustard (SM) is a highly reactive alkylating agent that binds to numerous biological targets. Although SM is known for almost 200 years, detailed knowledge about the pathophysiology resulting from exposure is lacking. A specific therapy is not available. In this study, we investigated whether the alkylating agent 2-chloroethyl-ethylsulfide (CEES, a model substance for SM-promoted effects) and SM are able to activate TRPA1 channels. CEES induced a marked increase in the intracellular calcium concentration ([Ca(2+)]i) in TRPA1-expressing but not in TRPA1-negative cells. The TRP-channel blocker AP18 diminished the CEES-induced calcium influx. HEK293 cells permanently expressing TRPA1 were more sensitive toward cytotoxic effects of CEES compared with wild-type cells. At low CEES concentrations, CEES-induced cytotoxicity was prevented by AP18. Proof-of-concept experiments using SM resulted in a pronounced increase in [Ca(2+)]i in HEK293-A1-E cells. Human A549 lung epithelial cells, which express TRPA1 endogenously, reacted with a transient calcium influx in response to CEES exposure. The CEES-dependent calcium response was diminished by AP18. In summary, our results demonstrate that alkylating agents are able to activate TRPA1. Inhibition of TRPA1 counteracted cellular toxicity and could thus represent a feasible approach to mitigate SM-induced cell damage.

  8. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer

    PubMed Central

    Shree, Tanaya; Olson, Oakley C.; Elie, Benelita T.; Kester, Jemila C.; Garfall, Alfred L.; Simpson, Kenishana; Bell-McGuinn, Katherine M.; Zabor, Emily C.; Brogi, Edi; Joyce, Johanna A.

    2011-01-01

    The microenvironment is known to critically modulate tumor progression, yet its role in regulating treatment response is poorly understood. Here we found increased macrophage infiltration and cathepsin protease levels in mammary tumors following paclitaxel (Taxol) chemotherapy. Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in coculture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin. Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect. Additionally incorporating continuous low-dose cyclophosphamide dramatically impaired tumor growth and metastasis and improved survival. This study highlights the importance of integrated targeting of the tumor and its microenvironment and implicates macrophages and cathepsins in blunting chemotherapeutic response. PMID:22156207

  9. Chemotherapeutics challenges in developing effective treatments for the endemic malarias

    PubMed Central

    Kevin Baird, J.

    2012-01-01

    The endemic malarias threaten the several billion people residing where transmission occurs. Chemotherapeutic strategy pitted against these threats hinges upon species- and stage-specific treatments guided by diagnosis and screening against sometime dangerous contraindications. This approach suits malaria as it occurs among travelers in the developed, non-endemic world. However, limiting treatment to that which diagnosis affirms may not be rational in endemic zones. Most of the endemic malarias remain out of diagnostic reach, either by inaccessibility of the parasite stage, insensitivity of the technology, or unavailability of diagnostic services. The partial and fragmented chemotherapeutic attack of malaria guided by confirmed diagnostics leaves most of the endemic malarias unchallenged. Development of elimination therapy, a single course of treatment aimed at all species and stages, would significantly advance progress against the major killers known collectively as malaria. PMID:24533286

  10. Chicken cathelicidin-2-derived peptides with enhanced immunomodulatory and antibacterial activities against biological warfare agents.

    PubMed

    Molhoek, E Margo; van Dijk, Albert; Veldhuizen, Edwin J A; Dijk-Knijnenburg, Helma; Mars-Groenendijk, Roos H; Boele, Linda C L; Kaman-van Zanten, Wendy E; Haagsman, Henk P; Bikker, Floris J

    2010-09-01

    Host defence peptides (HDPs) are considered to be excellent candidates for the development of novel therapeutic agents. Recently, it was demonstrated that the peptide C1-15, an N-terminal segment of chicken HDP cathelicidin-2, exhibits potent antibacterial activity while lacking cytotoxicity towards eukaryotic cells. In the present study, we report that C1-15 is active against bacteria such as Bacillus anthracis and Yersinia pestis that may potentially be used by bioterrorists. Substitution of single and multiple phenylalanine (Phe) residues to tryptophan (Trp) in C1-15 resulted in variants with improved antibacterial activity against B. anthracis and Y. pestis as well as decreased salt sensitivity. In addition, these peptides exhibited enhanced neutralisation of lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs). The antibacterial and LPS-neutralising activities of these C1-15-derived peptides are exerted at concentrations far below the concentrations that are toxic to human PBMCs. Taken together, we show that Phe-->Trp substitutions in C1-15 variants enhances the antibacterial and LPS-neutralising activities against pathogenic bacteria, including those that may potentially be used as biological warfare agents.

  11. A structure-activity analysis of the variation in oxime efficacy against nerve agents

    SciTech Connect

    Maxwell, Donald M. Koplovitz, Irwin; Worek, Franz; Sweeney, Richard E.

    2008-09-01

    A structure-activity analysis was used to evaluate the variation in oxime efficacy of 2-PAM, obidoxime, HI-6 and ICD585 against nerve agents. In vivo oxime protection and in vitro oxime reactivation were used as indicators of oxime efficacy against VX, sarin, VR and cyclosarin. Analysis of in vivo oxime protection was conducted with oxime protective ratios (PR) from guinea pigs receiving oxime and atropine therapy after sc administration of nerve agent. Analysis of in vitro reactivation was conducted with second-order rate contants (k{sub r2}) for oxime reactivation of agent-inhibited acetylcholinesterase (AChE) from guinea pig erythrocytes. In vivo oxime PR and in vitro k{sub r2} decreased as the volume of the alkylmethylphosphonate moiety of nerve agents increased from VX to cyclosarin. This effect was greater with 2-PAM and obidoxime (> 14-fold decrease in PR) than with HI-6 and ICD585 (< 3.7-fold decrease in PR). The decrease in oxime PR and k{sub r2} as the volume of the agent moiety conjugated to AChE increased was consistent with a steric hindrance mechanism. Linear regression of log (PR-1) against log (k{sub r2} {center_dot} [oxime dose]) produced two offset parallel regression lines that delineated a significant difference between the coupling of oxime reactivation and oxime protection for HI-6 and ICD585 compared to 2-PAM and obidoxime. HI-6 and ICD585 appeared to be 6.8-fold more effective than 2-PAM and obidoxime at coupling oxime reactivation to oxime protection, which suggested that the isonicotinamide group that is common to both of these oximes, but absent from 2-PAM and obidoxime, is important for oxime efficacy.

  12. NIR-activated iron oxides as a new multi-functional contrast agent of photoacoustic imaging

    NASA Astrophysics Data System (ADS)

    Ting, Pei-Hsien; Huang, Chih-Chia; Li, Meng-Lin

    2014-03-01

    Iron oxide nanoparticles are commonly used contrast agents for theranostic nanomedicines because of their advantages of good biocompatibility, high stability in physiological conditions, low cytotoxicity and excellent safety record in clinical settings for human use. In this study, we developed a NIR-activated iron oxide (NIR-Fe3O4) nanoparticle as a new multi-functional contrast agent of photoacoustic (PA) imaging. Unlike traditional iron oxides, the developed NIR-Fe3O4 owns biocompatibility and optical tunability capable of providing strong optical absorption in the NIR range for PA signal generation. Its intrinsic magnetic property enables the active magnetic tumor targeting. Phantom experiments were performed to confirm the tunability of NIR-Fe3O4's optical absorption in NIR and demonstrate its magnetic targeting capability. The PA signal response of NIR-Fe3O4 as a function of concentration was also investigated. The results showed that the PA signal of NIR-Fe3O4 with OD=1.25 was comparable to that of blood at 715 nm - the wavelength of peak absorption of the used NIR-Fe3O4. Moreover, the PA signal from NIR-Fe3O4 could be further improved by magnetic targeting. Overall, we proved that the potential of the developed NIR-Fe3O4 as a good tumor targeting contrast agent of PA imaging.

  13. Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth.

    PubMed

    Yoon, Sorah; Huang, Kai-Wen; Reebye, Vikash; Spalding, Duncan; Przytycka, Teresa M; Wang, Yijie; Swiderski, Piotr; Li, Lin; Armstrong, Brian; Reccia, Isabella; Zacharoulis, Dimitris; Dimas, Konstantinos; Kusano, Tomokazu; Shively, John; Habib, Nagy; Rossi, John J

    2017-03-17

    Aptamer-drug conjugates (ApDCs) have the potential to improve the therapeutic index of traditional chemotherapeutic agents due to their ability to deliver cytotoxic drugs specifically to cancer cells while sparing normal cells. This study reports on the conjugation of cytotoxic drugs to an aptamer previously described by our group, the pancreatic cancer RNA aptamer P19. To this end, P19 was incorporated with gemcitabine and 5-fluorouracil (5-FU), or conjugated to monomethyl auristatin E (MMAE) and derivative of maytansine 1 (DM1). The ApDCs P19-dFdCMP and P19-5FdUMP were shown to induce the phosphorylation of histone H2AX on Ser139 (γ-H2AX) and significantly inhibited cell proliferation by 51%-53% in PANC-1 and by 54%-34% in the gemcitabine-resistant pancreatic cancer cell line AsPC-1 (p ≤ 0.0001). P19-MMAE and P19-DM1 caused mitotic G2/M phase arrest and inhibited cell proliferation by up to 56% in a dose-dependent manner when compared to the control group (p ≤ 0.001). In addition, the cytotoxicity of P19-MMAE and P19-DM1 in normal cells and the control human breast cancer cell line MCF7 was minimal. These results suggest that this approach may be useful in decreasing cytotoxic side effects in non-tumoral tissue.

  14. Environmental factors affect the activity of biocontrol agents against ochratoxigenic Aspergillus carbonarius on wine grape.

    PubMed

    De Curtis, F; de Felice, D V; Ianiri, G; De Cicco, V; Castoria, R

    2012-09-17

    The influence of temperature and relative humidity (RH) on the activity of three biocontrol agents-the yeast Metschnikowia pulcherrima LS16 and two strains of the yeast-like fungus Aureobasidium pullulans LS30 and AU34-2-against infection by A. carbonarius and ochratoxin A (OTA) accumulation in wine grape berries was investigated in lab-scale experiments. The presence of wounds on grape skin dramatically favored infection of berries by A. carbonarius strain A1102, since unwounded berries showed very low levels of infection at all conditions of RH and temperature tested. Artificially wounded berries pre-treated with the biocontrol agents were inoculated with the ochratoxigenic A. carbonarius strain A1102 and were incubated for 5 days at two levels of RH (60% and 100%) and three different temperatures (20, 25 and 30 °C). The three biocontrol agents were able to prevent infections at 60% RH and 20 °C. At 60% RH and 25 °C only strain AU34-2 achieved some protection on day 5, whereas at 30 °C a limited biocontrol efficacy was evident only up to day 2. At 100% RH, LS16, LS30 and AU34-2 showed effective protection of grape berries at 20 °C until the 5th day of incubation. The three biocontrol agents achieved significant protection at higher temperatures only until the 2nd day after the beginning of the experiment: all three strains at 25 °C, and only strain LS16 at 30 °C. After 5 days, the three biocontrol agents were able to significantly reduce the level of OTA in berries at all the conditions tested. This occurred even when protection from infection was not significant, except at 30 °C and 100% of RH for all the three strains, and at 25 °C and 100% of RH for strain LS16. The biocontrol agents displayed a higher rate of colonization on grape berries at 20 and 25 °C than at 30 °C. The higher value of RH (100%) appeared to increase the rate of colonization, in particular at 20 and 25 °C. Taken together, our results emphasize the significant influence of

  15. Antibacterial activity and ion release of bonding agent containing amorphous calcium phosphate nanoparticles

    PubMed Central

    Chen, Chen; Weir, Michael D.; Cheng, Lei; Lin, Nancy; Lin-Gibson, Sheng; Chow, Laurence C.; Zhou, Xuedong; Xu, Hockin H. K.

    2015-01-01

    Objectives Recurrent caries at the margins is a primary reason for restoration failure. The objectives of this study were to develop bonding agent with the double benefits of antibacterial and remineralizing capabilities, to investigate the effects of NACP filler level and solution pH on Ca and P ion release from adhesive, and to examine the antibacterial and dentin bond properties. Methods Nanoparticles of amorphous calcium phosphate (NACP) and a quaternary ammonium monomer (dimethylaminododecyl methacrylate, DMADDM) were synthesized. Scotchbond Multi-Purpose (SBMP) primer and adhesive served as control. DMADDM was incorporated into primer and adhesive at 5% by mass. NACP was incorporated into adhesive at filler mass fractions of 10%, 20%, 30% and 40%. A dental plaque microcosm biofilm model was used to test the antibacterial bonding agents. Calcium (Ca) and phosphate (P) ion releases from the cured adhesive samples were measured vs. filler level and solution pH of 7, 5.5 and 4. Results Adding 5% DMADDM and 10–40% NACP into bonding agent, and water-aging for 28 days, did not affect dentin bond strength, compared to SBMP control at 1 day (p > 0.1). Adding DMADDM into bonding agent substantially decreased the biofilm metabolic activity and lactic acid production. Total microorganisms, total streptococci, and mutans streptococci were greatly reduced for bonding agents containing DMADDM. Increasing NACP filler level from 10% to 40% in adhesive increased the Ca and P ion release by an order of magnitude. Decreasing solution pH from 7 to 4 increased the ion release from adhesive by 6–10 folds. Significance Bonding agents containing antibacterial DMADDM and remineralizer NACP were formulated to have Ca and P ion release, which increased with NACP filler level from 10% to 40% in adhesive. NACP adhesive was “smart” and dramatically increased the ion release at cariogenic pH 4, when these ions would be most-needed to inhibit caries. Therefore, bonding agent

  16. Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance.

    PubMed

    Perez, Edith A

    2009-08-01

    Microtubules are important cellular targets for anticancer therapy because of their key role in mitosis. Microtubule inhibitors (MTI) such as taxanes, vinca alkaloids, and epothilones stabilize or destabilize microtubules, thereby suppressing microtubule dynamics required for proper mitotic function, effectively blocking cell cycle progression and resulting in apoptosis. In spite of their antitumor activity, innate or acquired drug resistance to MTIs such as the taxanes is common, limiting their overall clinical efficacy. Further insight into the mechanisms of action of microtubule-targeting drugs has lead to the discovery of novel agents that may provide higher efficacy with limited toxicity and help overcome resistance to conventional MTIs. This review will focus on the different mechanisms of action of MTIs, potential factors related to resistance and tolerability, and will discuss the recent approval as well as the development of new antineoplastic agents.

  17. The application of click chemistry in the synthesis of agents with anticancer activity

    PubMed Central

    Ma, Nan; Wang, Ying; Zhao, Bing-Xin; Ye, Wen-Cai; Jiang, Sheng

    2015-01-01

    The copper(I)-catalyzed 1,3-dipolar cycloaddition between alkynes and azides (click chemistry) to form 1,2,3-triazoles is the most popular reaction due to its reliability, specificity, and biocompatibility. This reaction has the potential to shorten procedures, and render more efficient lead identification and optimization procedures in medicinal chemistry, which is a powerful modular synthetic approach toward the assembly of new molecular entities and has been applied in anticancer drugs discovery increasingly. The present review focuses mainly on the applications of this reaction in the field of synthesis of agents with anticancer activity, which are divided into four groups: topoisomerase II inhibitors, histone deacetylase inhibitors, protein tyrosine kinase inhibitors, and antimicrotubule agents. PMID:25792812

  18. The application of click chemistry in the synthesis of agents with anticancer activity.

    PubMed

    Ma, Nan; Wang, Ying; Zhao, Bing-Xin; Ye, Wen-Cai; Jiang, Sheng

    2015-01-01

    The copper(I)-catalyzed 1,3-dipolar cycloaddition between alkynes and azides (click chemistry) to form 1,2,3-triazoles is the most popular reaction due to its reliability, specificity, and biocompatibility. This reaction has the potential to shorten procedures, and render more efficient lead identification and optimization procedures in medicinal chemistry, which is a powerful modular synthetic approach toward the assembly of new molecular entities and has been applied in anticancer drugs discovery increasingly. The present review focuses mainly on the applications of this reaction in the field of synthesis of agents with anticancer activity, which are divided into four groups: topoisomerase II inhibitors, histone deacetylase inhibitors, protein tyrosine kinase inhibitors, and antimicrotubule agents.

  19. Biomarker-Guided Repurposing of Chemotherapeutic Drugs for Cancer Therapy: A Novel Strategy in Drug Development

    PubMed Central

    Stenvang, Jan; Kümler, Iben; Nygård, Sune Boris; Smith, David Hersi; Nielsen, Dorte; Brünner, Nils; Moreira, José M. A.

    2013-01-01

    Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early diagnosis, optimized surgery, development of novel drugs, and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non-cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I (Top1) inhibitors and Top1 as a potential predictive biomarker as case in point. PMID:24400218

  20. HURON (HUman and Robotic Optimization Network) Multi-Agent Temporal Activity Planner/Scheduler

    NASA Technical Reports Server (NTRS)

    Hua, Hook; Mrozinski, Joseph J.; Elfes, Alberto; Adumitroaie, Virgil; Shelton, Kacie E.; Smith, Jeffrey H.; Lincoln, William P.; Weisbin, Charles R.

    2012-01-01

    HURON solves the problem of how to optimize a plan and schedule for assigning multiple agents to a temporal sequence of actions (e.g., science tasks). Developed as a generic planning and scheduling tool, HURON has been used to optimize space mission surface operations. The tool has also been used to analyze lunar architectures for a variety of surface operational scenarios in order to maximize return on investment and productivity. These scenarios include numerous science activities performed by a diverse set of agents: humans, teleoperated rovers, and autonomous rovers. Once given a set of agents, activities, resources, resource constraints, temporal constraints, and de pendencies, HURON computes an optimal schedule that meets a specified goal (e.g., maximum productivity or minimum time), subject to the constraints. HURON performs planning and scheduling optimization as a graph search in state-space with forward progression. Each node in the graph contains a state instance. Starting with the initial node, a graph is automatically constructed with new successive nodes of each new state to explore. The optimization uses a set of pre-conditions and post-conditions to create the children states. The Python language was adopted to not only enable more agile development, but to also allow the domain experts to easily define their optimization models. A graphical user interface was also developed to facilitate real-time search information feedback and interaction by the operator in the search optimization process. The HURON package has many potential uses in the fields of Operations Research and Management Science where this technology applies to many commercial domains requiring optimization to reduce costs. For example, optimizing a fleet of transportation truck routes, aircraft flight scheduling, and other route-planning scenarios involving multiple agent task optimization would all benefit by using HURON.

  1. Structure-activity relationship study of novel iminothiadiazolo-pyrimidinone antimicrobial agents.

    PubMed

    Paudel, Atmika; Kaneko, Keiichi; Watanabe, Ayako; Matsunaga, Shigeki; Shigeki, Matsunaga; Kanai, Motomu; Motomu, Kanai; Hamamoto, Hiroshi; Sekimizu, Kazuhisa

    2013-11-01

    An iminothiadiazolo-pyrimidinone derivative, 0002-04-KK, harboring a furan moiety, acts as an antimicrobial agent with a minimum inhibitory concentration (MIC) against Staphylococcus aureus of 25 μg ml(-1). Several derivatives of 0002-04-KK were synthesized and among them 0026-59-KK, harboring a nitrofuran moiety, had the most potent antimicrobial activity with an MIC of 6 μg ml(-1). Both 0002-04-KK and 0026-59-KK inhibited the biosynthesis of DNA, RNA and proteins. Peptidoglycan biosynthesis was inhibited by 0026-59-KK, and slightly inhibited by 0002-04-KK. Derivative 0002-04-KK showed bactericidal activity in contrast to the bacteriostatic activity of 0002-04-KK. Derivative 0002-04-KK had less toxicity in silkworms (lethal dose fifty (LD50): >230 μg g(-1)) than 0002-04-KK (LD50: 100 μg g(-1)). The bactericidal activity against S. aureus was because of the nitrofuran moiety. These findings suggest that iminothiadiazolo-pyrimidinone compounds could be used as lead molecules to develop antimicrobial agents.

  2. [Effects of nootropic agents on visual functions and lacrimal antioxidative activity in patients with primary open-angle glaucoma].

    PubMed

    Davydova, N G; Kuznetsova, T P; Borisova, S A; Abdulkadyrova, M Zh

    2006-01-01

    The paper presents the results of an investigation of the effect of the nootropic agents pantogam and nooclerine on visual functions in patients with primary open-angle glaucoma. These agents have been found to have a beneficial effect on the functional activity of the retina and optic nerve, light sensitivity, hemo- and hydrodynamics of the eye.

  3. Alkylating agents and immunotoxins exert synergistic cytotoxic activity against ovarian cancer cells. Mechanism of action.

    PubMed Central

    Lidor, Y J; O'Briant, K C; Xu, F J; Hamilton, T C; Ozols, R F; Bast, R C

    1993-01-01

    Alkylating agents can be administered in high dosage to patients with ovarian cancer using autologous bone marrow support, but drug-resistant tumor cells can still persist. Immunotoxins provide reagents that might eliminate drug resistant cells. In the present study, concurrent treatment with alkylators and immunotoxins proved superior to treatment with each agent alone. Toxin immunoconjugates prepared from different monoclonal antibodies and recombinant ricin A chain (rRTA) inhibited clonogenic growth of ovarian cancer cell lines in limiting dilution assays. When alkylating agents and toxin conjugates were used in combination, the addition of the immunotoxins to cisplatin, or to cisplatin and thiotepa, produced synergistic cytotoxic activity against the OVCA 432 and OVCAR III cell lines. Studies performed to clarify the mechanism of action showed that cisplatin and thiotepa had no influence on internalization and binding of the 317G5-rRTA immunotoxin. Intracellular uptake of [195m]Pt-cisplatin was not affected by the immunoconjugate and thiotepa. The combination of the 317G5-rRTA and thiotepa, as well as 317G5-rRTA alone, increased [195m]Pt cisplatin-DNA adduct levels. The immunotoxin alone and in combination with the alkylators decreased intracellular glutathione levels and reduced glutathione-S-transferase activity. Repair of DNA damage induced by the combination of alkylators and 317G5-rRTA was significantly reduced when compared to repair after damage with alkylators alone. These findings suggest that immunotoxins affect levels and activity of enzymes required for the prevention and repair of alkylator damage. Images PMID:8227359

  4. Agents that activate the High Osmolarity Glycerol pathway as a means to combat pathogenic molds.

    PubMed

    Wiedemann, Annegret; Spadinger, Anja; Löwe, Axel; Seeger, Allison; Ebel, Frank

    2016-12-01

    Treatment of invasive fungal infections often fails due to the limited number of therapeutic options. In this study, we have analyzed the impact of agents activating the High Osmolarity Glycerol (HOG) pathway on molds that cause infections in humans and livestock. We found that agents like fludioxonil and iprodione, have a clear anti-fungal activity against pathogenic Aspergillus, Lichtheimia, Rhizopus and Scedosporium species. Only A. terreus turned out to be resistant to fludioxonil, even though it is sensitive to iprodione and able to adapt to hyperosmotic conditions. Moreover, the A. terreus tcsC gene can fully complement an A. fumigatus ΔtcsC mutant, thereby also restoring its sensitivity to fludioxonil. The particular phenotype of A. terreus is therefore likely to be independent of its TcsC kinase. In a second part of this study, we further explored the impact of fludioxonil using A. fumigatus as a model organism. When applied in concentrations of 1-2μg/ml, fludioxonil causes an immediate growth arrest and, after longer exposure, a quantitative killing. Hyphae respond to fludioxonil by the formation of new septa and closure of nearly all septal pores. Mitosis occurs in all compartments and is accompanied by a re-localization of the NimA kinase to the cytoplasm. In the swollen compartments, the massive extension of the cell wall triggers a substantial reorganization resulting in an enhanced incorporation of chitin and, most strikingly, a massive loss of galactomannan. Hence, HOG-activating agents have dramatic cell biological consequences and may represent a valuable, future element in the armory that can be used to combat mold infections.

  5. In vitro activities of 47 antimicrobial agents against three Campylobacter spp. from pigs.

    PubMed Central

    Gebhart, C J; Ward, G E; Kurtz, H J

    1985-01-01

    The in vitro activities of 47 antimicrobial agents against 30 isolates of Campylobacter species from pigs were determined by the agar dilution technique. The isolates were obtained from pigs with proliferative enteritis and included 10 strains each of Campylobacter coli, Campylobacter sputorum subsp. mucosalis, and "Campylobacter hyointestinalis Gebhart et al." (this name is not on the Approved Lists). Carbadox, furazolidone, nitrofurantoin, gentamicin, and dimetridazole were the most active drugs, inhibiting all three Campylobacter species with a MIC for 50% of the isolates of 2 micrograms/ml or less. Trimethoprim-sulfamethoxazole, cefazolin, sulfachloropyridazine, novobiocin, vancomycin, sulfathiazole, cyclohexamide, bacitracin, p-arsanilic acid, and colistin were the least active, with MICs for 50% of the isolates ranging from 16 to greater than or equal to 128 micrograms/ml. PMID:3985597

  6. Inhibition of Helicobacter pylori glycosulfatase activity towards human gastric sulfomucin by a gastroprotective agent, sulglycotide.

    PubMed

    Murty, V L; Piotrowski, J; Czajkowski, A; Slomiany, A; Slomiany, B L

    1993-11-01

    1. A glycosulfatase activity towards human gastric sulfomucin was identified in the extracellular material elaborated by Helicobacter pylori, a pathogen implicated in the etiology of gastric disease. 2. The purified enzyme displayed an apparent molecular weight of 30 kDa, and exhibited maximum activity at pH 5.7 in the presence of 0.3% Triton X-100 and 100 mM CaCl2. 3. The H. pylori glycosulfatase activity towards human gastric sulfomucin was inhibited by a gastroprotective agent, sulglycotide. The inhibitory effect was proportional to the concentration of sulglycotide up to 20 micrograms/ml, at which a 98% decrease in mucin desulfation occurred. However, the drug lost the inhibitory effect following its chemical desulfation. 4. The results demonstrate that sulglycotide is a potent inhibitor of H. pylori glycosulfatase and, hence, may be of value in the treatment of gastric disease associated with this bacterial infection.

  7. Anti-angiogenic activity of a novel synthetic agent, 9alpha-fluoromedroxyprogesterone acetate.

    PubMed

    Yamaji, T; Tsuboi, H; Murata, N; Uchida, M; Kohno, T; Sugino, E; Hibino, S; Shimamura, M; Oikawa, T

    1999-10-18

    9Alpha-fluoromedroxyprogesterone acetate (FMPA) is a novel synthetic analog of medroxyprogesterone acetate (MPA), widely used as therapeutic agent for breast and endometrium cancers. FMPA showed almost the same binding affinities to the progesterone and glucocorticoid receptors as MPA. In the rabbit corneal assay, FMPA, MPA and fumagillin significantly inhibited the angiogenic response induced by rat mammary tumor at doses of 0. 1, 1 and 50 microg/pellet, respectively, so FMPA showed greater anti-angiogenic activity than MPA and fumagillin. In the mouse dorsal air sac method, FMPA inhibited the mouse sarcoma 180 cell-induced angiogenesis by oral administration at a dose of 200 mg/kg. FMPA inhibited the activity of plasminogen activator (PA) in bovine endothelial cells. These results suggest that FMPA may be useful for diseases associated with angiogenesis by oral administration.

  8. Organometallic Titanocene–Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties

    PubMed Central

    2015-01-01

    Early–late transition metal TiAu2 compounds [(η-C5H5)2Ti{OC(O)CH2PPh2AuCl}2] (3) and new [(η-C5H5)2Ti{OC(O)-4-C6H4PPh2AuCl}2] (5) were evaluated as potential anticancer agents in vitro against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold(I) [{HOC(O)RPPh2}AuCl] (R = −CH2– 6, −4-C6H4– 7) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for 5 in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y. Initial mechanistic studies in Caki-1 cells in vitro coupled with studies of their inhibitory properties on a panel of 35 kinases of oncological interest indicate that these compounds inhibit protein kinases of the AKT and MAPKAPK families with a higher selectivity toward MAPKAPK3 (IC503 = 91 nM, IC505 = 117 nM). The selectivity of the compounds in vitro against renal cancer cell lines when compared to a nontumorigenic human embryonic kidney cell line (HEK-293T) and the favorable preliminary toxicity profile on C57black6 mice indicate that these compounds (especially 5) are excellent candidates for further development as potential renal cancer chemotherapeutics. PMID:25435644

  9. In vitro antifungal activity of dihydroxyacetone against causative agents of dermatomycosis.

    PubMed

    Stopiglia, Cheila Denise Ottonelli; Vieira, Fabiane Jamono; Mondadori, Andressa Grazziotin; Oppe, Tércio Paschke; Scroferneker, Maria Lúcia

    2011-04-01

    Dihydroxyacetone (DHA), a three-carbon sugar, is the browning ingredient in commercial sunless tanning formulations. DHA preparations have been used for more than 50 years and are currently highly popular for producing temporary pigmentation resembling an ultraviolet-induced tan. In this work, the in vitro antifungal activity of dihydroxyacetone was tested against causative agents of dermatomycosis, more specifically against dermatophytes and Candida spp. The antifungal activity was determined by the broth microdilution method according to the Clinical and Laboratory Standards Institute guidelines for yeasts and filamentous fungi. The data obtained show that the fungicidal activity varied from 1.6 to 50 mg ml(-1). DHA seems to be a promising substance for the treatment of dermatomycosis because it has antifungal properties at the same concentration used in artificial suntan lotions. Therefore, it is a potential low-toxicity antifungal agent that may be used topically because of its penetration into the corneal layers of the skin.

  10. Removal of gadolinium-based contrast agents: adsorption on activated carbon.

    PubMed

    Elizalde-González, María P; García-Díaz, Esmeralda; González-Perea, Mario; Mattusch, Jürgen

    2017-01-31

    Three carbon samples were employed in this work, including commercial (1690 m(2) g(-1)), activated carbon prepared from guava seeds (637 m(2) g(-1)), and activated carbon prepared from avocado kernel (1068 m(2) g(-1)), to study the adsorption of the following gadolinium-based contrast agents (GBCAs): gadoterate meglumine Dotarem®, gadopentetate dimeglumine Magnevist®, and gadoxetate disodium Primovist®. The activation conditions with H3PO4 were optimized using a Taguchi methodology to obtain mesoporous materials. The best removal efficiency by square meter in a batch system in aqueous solution and model urine was achieved by avocado kernel carbon, in which mesoporosity prevails over microporosity. The kinetic adsorption curves were described by a pseudo-second-order equation, and the adsorption isotherms in the concentration range 0.5-6 mM fit the Freundlich equation. The chemical characterization of the surfaces shows that materials with a greater amount of phenolic functional groups adsorb the GBCA better. Adsorption strongly depends on the pH due to the combination of the following factors: contrast agent protonated forms and carbon surface charge. The tested carbon samples were able to adsorb 70-90% of GBCA in aqueous solution and less in model urine. This research proposes a method for the elimination of GBCA from patient urine before its discharge into wastewater.

  11. Disposal of chemical agents and munitions stored at Umatilla Depot Activity, Hermiston, Oregon

    SciTech Connect

    Zimmerman, G.P.; Hillsman, E.L.; Johnson, R.O.; Miller, R.L.; Patton, T.G.; Schoepfle, G.M.; Tolbert, V.R.; Feldman, D.L.; Hunsaker, D.B. Jr.; Kroodsma, R.L.; Morrissey, J.; Rickert, L.W.; Staub, W.P.; West, D.C.

    1993-02-01

    The Umatilla Depot Activity (UMDA) near Hermiston, Oregon, is one of eight US Army installations in the continental United States where lethal unitary chemical agents and munitions are stored, and where destruction of agents and munitions is proposed under the Chemical Stockpile Disposal Program (CSDP). The chemical agent inventory at UMDA consists of 11.6%, by weight, of the total US stockpile. The destruction of the stockpile is necessary to eliminate the risk to the public from continued storage and to dispose of obsolete and leaking munitions. In 1988 the US Army issued a Final Programmatic Environmental Impact Statement (FPEIS) for the CSDP that identified on-site disposal of agents and munitions as the environmentally preferred alternative (i.e., the alternative with the least potential to cause significant adverse impacts), using a method based on five measures of risk for potential human health and ecosystem/environmental effects; the effectiveness and adequacy of emergency preparedness capabilities also played a key role in the FPEIS selection methodology. In some instances, the FPEIS included generic data and assumptions that were developed to allow a consistent comparison of potential impacts among programmatic alternatives and did not include detailed conditions at each of the eight installations. The purpose of this Phase 1 report is to examine the proposed implementation of on-site disposal at UMDA in light of more recent and more detailed data than those included in the FPEIS. Specifically, this Phase 1 report is intended to either confirm or reject the validity of on-site disposal for the UMDA stockpile. Using the same computation methods as in the FPEIS, new population data were used to compute potential fatalities from hypothetical disposal accidents. Results indicate that onsite disposal is clearly preferable to either continued storage at UMDA or transportation of the UMDA stockpile to another depot for disposal.

  12. A Comprehensive Review on Cyclodextrin-Based Carriers for Delivery of Chemotherapeutic Cytotoxic Anticancer Drugs

    PubMed Central

    Gidwani, Bina; Vyas, Amber

    2015-01-01

    Most of the cytotoxic chemotherapeutic agents have poor aqueous solubility. These molecules are associated with poor physicochemical and biopharmaceutical properties, which makes the formulation difficult. An important approach in this regard is the use of combination of cyclodextrin and nanotechnology in delivery system. This paper provides an overview of limitations associated with anticancer drugs, their complexation with cyclodextrins, loading/encapsulating the complexed drugs into carriers, and various approaches used for the delivery. The present review article aims to assess the utility of cyclodextrin-based carriers like liposomes, niosomes, nanoparticles, micelles, millirods, and siRNA for delivery of antineoplastic agents. These systems based on cyclodextrin complexation and nanotechnology will camouflage the undesirable properties of drug and lead to synergistic or additive effect. Cyclodextrin-based nanotechnology seems to provide better therapeutic effect and sustain long life of healthy and recovered cells. Still, considerable study on delivery system and administration routes of cyclodextrin-based carriers is necessary with respect to their pharmacokinetics and toxicology to substantiate their safety and efficiency. In future, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents. PMID:26582104

  13. Silver nanoparticles-loaded activated carbon fibers using chitosan as binding agent: Preparation, mechanism, and their antibacterial activity

    NASA Astrophysics Data System (ADS)

    Tang, Chengli; Hu, Dongmei; Cao, Qianqian; Yan, Wei; Xing, Bo

    2017-02-01

    The effective and strong adherence of silver nanoparticles (AgNPs) to the substrate surface is pivotal to the practical application of those AgNPs-modified materials. In this work, AgNPs were synthesized through a green and facile hydrothermal method. Chitosan was introduced as the binding agent for the effective loading of AgNPs on activated carbon fibers (ACF) surface to fabricate the antibacterial material. Apart from conventional instrumental characterizations, i. e., scanning electron microscope (SEM), X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FT-IR), zeta potential and Brunauer-Emmett-Teller (BET) surface area measurement, molecular dynamics simulation method was also applied to explore the loading mechanism of AgNPs on the ACF surface. The AgNPs-loaded ACF material showed outstanding antibacterial activity for S. aureus and E. coli. The combination of experimental and theoretical calculation results proved chitosan to be a promising binding agent for the fabrication of AgNPs-loaded ACF material with excellent antibacterial activity.

  14. Effects of Slime Produced by Clinical Isolates of Coagulase-Negative Staphylococci on Activities of Various Antimicrobial Agents

    PubMed Central

    Souli, Maria; Giamarellou, Helen

    1998-01-01

    A novel in vitro semiquantitative method was developed to investigate the influence of staphylococcal slime on the activities of 22 antimicrobial agents. Pefloxacin, teicoplanin, and vancomycin demonstrated remarkable decreases in efficacy: 30, 52, and 63%, respectively. The activity of rifampin was not significantly reduced (0.99%), whereas all other agents tested were modestly affected (<15% decrease). These data could be influential in the treatment of implant-associated infections caused by slime-producing staphylococci. PMID:9559814

  15. Study on the influence of the decoking agent on the activity of limestone in wet flue gas desulfurization

    NASA Astrophysics Data System (ADS)

    Li, Qianjun; Xu, Dongyang; Wu, Yunxia; Yu, Jin

    2017-01-01

    Influence of the main components of decoking agent (magnesium nitrate, aluminum nitrate, copper nitrate, ammonium nitrate and actual decoking agent) on the activity of limestone is studied in laboratory by MET method. Results show that magnesium nitrate, ammonium nitrate and copper nitrate almost has no effect on the activity of limestone. With the concentration increasing, aluminum nitrate has an increasing inhibition on the dissolution of limestone. Fly ash has inhibition on dissolution of limestone due to the blockage of limestone pore by fly ash. The actual decoking agent has almost no effect on the limestone.

  16. Ciprofloxacin-Induced Antibacterial Activity Is Atteneuated by Pretreatment with Antioxidant Agents

    PubMed Central

    Masadeh, Majed M.; Alzoubi, Karem H.; Al-azzam, Sayer I.; Khabour, Omar F.; Al-buhairan, Ahlam M.

    2016-01-01

    Ciprofloxacin works through interfering with replication and transcription of bacterial DNA, which leads to increased oxidative stress, and death of bacterial cells. Drugs with strong antioxidant such as tempol, melatonin and pentoxifylline might interfere with the antibacterial activity of ciprofloxacin. In the current study, the effect of these drugs on the cytotoxicity of ciprofloxacin was investigated against several reference bacteria. Standard bacterial strains included Escherichia coli ATCC 35218, Staphylococcus aureus ATCC29213, Pseudomonas aeruginosa ATCC 9027, Staphylococcus epidermidis ATCC 12228, Acinetobacter baumannii ATCC 17978, Proteus mirabilis ATCC 12459, Klebsiella pneumoniae ATCC 13883, methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300), and Streptococcus pneumoniae (ATCC 25923). The antibacterial activity of ciprofloxacin with or without treatment of bacterial cells by tempol, melatonin or pentoxifylline was assessed using the disc diffusion method and by measuring the minimum inhibitory concentration (MIC) and zones of inhibition of bacterial growth. All of the tested bacterial strains were sensitive to ciprofloxacin. When treated with tempol, melatonin or pentoxifylline, all bacterial strains showed significantly smaller zones of inhibition and larger MIC values compared ciprofloxacin alone. In correlation, reactive oxygen species (ROS) generation induced by ciprofloxacin antibacterial action was diminished by treatment of bacterial cells with tempol, melatonin or pentoxifylline. In conclusion, results indicate the possible antagonistic properties for agents with antioxidant properties such as tempol, melatonin and pentoxifylline when they are used concurrently with flouroquinolones. This could be related to the ability of these agents to inhibit oxidative stress in bacterial cells. PMID:27005666

  17. Ciprofloxacin-Induced Antibacterial Activity Is Atteneuated by Pretreatment with Antioxidant Agents.

    PubMed

    Masadeh, Majed M; Alzoubi, Karem H; Al-Azzam, Sayer I; Khabour, Omar F; Al-Buhairan, Ahlam M

    2016-03-09

    Ciprofloxacin works through interfering with replication and transcription of bacterial DNA, which leads to increased oxidative stress, and death of bacterial cells. Drugs with strong antioxidant such as tempol, melatonin and pentoxifylline might interfere with the antibacterial activity of ciprofloxacin. In the current study, the effect of these drugs on the cytotoxicity of ciprofloxacin was investigated against several reference bacteria. Standard bacterial strains included Escherichia coli ATCC 35218, Staphylococcus aureus ATCC29213, Pseudomonas aeruginosa ATCC 9027, Staphylococcus epidermidis ATCC 12228, Acinetobacter baumannii ATCC 17978, Proteus mirabilis ATCC 12459, Klebsiella pneumoniae ATCC 13883, methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300), and Streptococcus pneumoniae (ATCC 25923). The antibacterial activity of ciprofloxacin with or without treatment of bacterial cells by tempol, melatonin or pentoxifylline was assessed using the disc diffusion method and by measuring the minimum inhibitory concentration (MIC) and zones of inhibition of bacterial growth. All of the tested bacterial strains were sensitive to ciprofloxacin. When treated with tempol, melatonin or pentoxifylline, all bacterial strains showed significantly smaller zones of inhibition and larger MIC values compared ciprofloxacin alone. In correlation, reactive oxygen species (ROS) generation induced by ciprofloxacin antibacterial action was diminished by treatment of bacterial cells with tempol, melatonin or pentoxifylline. In conclusion, results indicate the possible antagonistic properties for agents with antioxidant properties such as tempol, melatonin and pentoxifylline when they are used concurrently with flouroquinolones. This could be related to the ability of these agents to inhibit oxidative stress in bacterial cells.

  18. An Artemisinin Derivative of Praziquantel as an Orally Active Antischistosomal Agent

    PubMed Central

    Chen, Jinglei; Sun, Huan; Qiao, Chunhua; Xia, Chao-ming

    2014-01-01

    Background Schistosomiasis is a major health problem in tropical and sub-tropical areas caused by species of trematode belonging to the genus Schistosoma. The treatment and control of this disease has been relying on the use of a single drug praziquantel. However, the drug resistance concern urged the development of new drugs against schistosoma. Here, we report our systematic biological evaluation of DW-3-15, a new lead compound developed based on our conjugation design rationale as an effective anti-schistosomal agent. Methodology/Principal Findings The antischistosomal activity of DW-3-15 was systematically evaluated in S. japonicum infected mouse model for its stage-sensitivity and dose response. The results revealed that DW-3-15 exhibited 60–85% worm reduction rate against different development stage of worm. Scanning electron microscopy (SEM) observation indicated that DW-3-15 may damage to the tegument of male schistosomes. Conclusions/Significance Our results demonstrated that DW-3-15 showed potent anti-schistosomal activities in vivo. The results strongly support our conjugation design strategy of artemisinin analogs and further development of DW-3-15 as a new lead compound as anti-schistosomal agent. PMID:25386745

  19. Induction of megakaryocytic colony-stimulating activity in mouse skin by inflammatory agents and tumor promoters

    SciTech Connect

    Clark, D.A.; Dessypris, E.N.; Koury, M.J.

    1987-03-01

    The production of megakaryocytic colony-stimulating activity (MEG-CSA) was assayed in acetic acid extracts of skin from mice topically treated with inflammatory and tumor-promoting agents. A rapid induction of MEG-CSA was found in skin treated both with phorbol 12-myristate 13-acetate (PMA), a strong tumor promoter, and with mezerein, a weak tumor promoter, but no induction was found in untreated skin. The time course of induction of MEG-CSA following treatment of skin with PMA or mezerein was very similar to that previously demonstrated for the induction of granulocyte-macrophage colony-stimulating activity in mouse skin by these agents. The induced MEG-CSA was found in both the epidermis and the dermis. Pretreatment of the skin with US -methasone abrogated the MEG-CSA induction. The cell number response curve suggests that the MEG-CSA acts directly on the progenitor cells of the megakaryocyte colonies. That topical administration of diterpene esters results in the rapid, local induction of MEG-CSA which can be blocked by US -methasone pretreatment suggests a mechanism for the thrombocytosis associated with some inflammatory states. The indirect action in which diterpene esters induce in certain cells the production or release of growth regulatory factors for other cell types may also aid in understanding their carcinogenic properties.

  20. Use of activated sludge biomass as an agent for advanced primary separation.

    PubMed

    Araneda, Michael; Pavez, Javier; Luza, Benjamín; Jeison, David

    2017-05-01

    Conventional primary settling is a physical process of solid-liquid separation, normally presenting low removal efficiencies. Improvement of this separation process would result in energetic advantages: lower aeration requirements and higher biogas production form primary and secondary sludges. Secondary sludge has been proposed as a potential agent promoting an increase in primary separation efficiency. Few processes have been proposed, based on the cultivation of sludge under special conditions. However, one can speculate that regular sludge may have a similar effect. The aim of this research was to study that possibility. Sludges from different activated sludge reactors were tested. Results showed that COD removals were up to 55%, 2 times higher than that for simple settling. Under that condition, COD balances showed that aeration requirements would reduce 40%, and biogas production from primary and secondary sludges would increase 50%. It is inferred then that the application of activated sludge as an external agent represents an interesting alternative that have the potential to significantly improve energetic efficiency of sewage treatment plants.

  1. From Docking False-Positive to Active Anti-HIV Agent

    PubMed Central

    Barreiro, Gabriela; Kim, Joseph T.; Guimarães, Cristiano R. W.; Bailey, Christopher M.; Domaoal, Robert A.; Wang, Ligong; Anderson, Karen S.

    2008-01-01

    Virtual screening of the Maybridge library of ca. 70,000 compounds was performed using a similarity filter, docking, and MM-GB/SA post-processing to seek potential non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Though known NNRTIs were retrieved well, purchase and assaying of representative, top-scoring compounds from the library failed to yield any active anti-HIV agents. However, the highest-ranked library compound, oxadiazole 1, was pursued as a potential “near-miss” with the BOMB program to seek constructive modifications. Subsequent synthesis and assaying of several polychloro-analogs did yield anti-HIV agents with EC50 values as low as 310 nM. The study demonstrates that it is possible to learn from a formally unsuccessful virtual-screening exercise and, with the aid of computational analyses, to evolve efficiently a false positive into a true active. In addition, the need for adequate structure validation was confirmed by the apparent misrepresentation of a purchased compound elsewhere as the present oxadiazole core compound, 16. PMID:17918923

  2. Effects of antifungal agents in sap activity of Candida albicans isolates.

    PubMed

    Costa, Carolina Rodrigues; Jesuíno, Rosália Santos Amorim; de Aquino Lemos, Janine; de Fátima Lisboa Fernandes, Orionalda; Hasimoto e Souza, Lúcia Kioko; Passos, Xisto Sena; do Rosário Rodrigues Silva, Maria

    2010-02-01

    Some antifungal agents have shown to exert effects on expression of virulent factors of Candida as the production of secretory aspartyl proteinase (Sap). In this study, we sought to determine and to compare the influence of fluconazole and voriconazole in proteinase activity of this microorganism. Thirty-one isolates obtained from oral mucosa of human immunodeficiency virus positive (HIV) patients were used in this study. The minimal inhibitory concentrations (MIC) of fluconazole and voriconazole were determined using the broth microdilution method with RPMI 1640 medium and with yeast carbon base-bovine serum albumin (YCB-BSA) medium. The Sap activity following by digestion of BSA as substrate was determined for four Candida albicans strains arbitrarily chosen according to susceptibility (susceptible or resistant) to fluconazole or voriconazole. Besides, the SAP1 to SAP7 genes were screened by PCR for the same isolates that were determined by the Sap activity. In vitro susceptibility testing using the two media presented similar MIC values. Increased Sap activity was observed in resistant isolates on presence of drugs, but the Sap activity by susceptible isolates to azoles showed different behavior on the presence of drug. We detected the presence of SAP1 to SAP7 genes from all susceptible or resistant C. albicans isolates. The present study provides important data about the proteinase activity and the presence of genes of SAP family in fluconazole and voriconazole susceptible or resistant C. albicans isolates.

  3. Design, modeling, synthesis and biological activity evaluation of camptothecin-linked platinum anticancer agents.

    PubMed

    Cincinelli, Raffaella; Musso, Loana; Dallavalle, Sabrina; Artali, Roberto; Tinelli, Stella; Colangelo, Donato; Zunino, Franco; De Cesare, Michelandrea; Beretta, Giovanni Luca; Zaffaroni, Nadia

    2013-05-01

    The design, modeling, synthesis and biological activity evaluation of two hybrid agents formed by 7-oxyiminomethylcamptothecin derivatives and diaminedichloro-platinum (II) complex are reported. The compounds showed growth inhibitory activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. The derivatives were active in all the tested cell lines, and compound 1b, the most active one, was able to overcome cisplatin resistance in the osteosarcoma U2OS/Pt cell line. Platinum-containing camptothecins produced platinum-DNA adducts and topoisomerase I-mediated DNA damage with cleavage pattern and persistence similar to SN38, the active principle of irinotecan. Compound 1b exhibited an appreciable antitumor activity in vivo against human H460 tumor xenograft, comparable to that of irinotecan at lower well-tolerated dose levels and superior to cisplatin. The results support the interpretation that the diaminedichloro-platinum (II) complex conjugated via an oxyiminomethyl linker at the 7-position of the camptothecin resulted in a new class of effective antitumor compounds.

  4. Sparfloxacin-metal complexes as antifungal agents - Their synthesis, characterization and antimicrobial activities

    NASA Astrophysics Data System (ADS)

    Sultana, Najma; Arayne, M. Saeed; Gul, Somia; Shamim, Sana

    2010-06-01

    Metal complexes with the third-generation quinolone antibacterial agent sparfloxacin (SPFX) or 5-amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8,di-fluoro-1-4-dihydro-4-oxo-3-quinocarboxylic acid have been synthesized and characterized with physicochemical and spectroscopic techniques such as TLC, IR, NMR and elemental analyses. In these complexes, sparfloxacin acts as bidentate deprotonated ligands bound to the metal through the pyridone oxygen and one carboxylate oxygen. The antimicrobial activity of these complexes has been evaluated against four Gram-positive and seven Gram-negative bacteria. Antifungal activity against five different fungi has been evaluated and compared with reference drug sparfloxacin. Fe 2+-SPFX and Cd 2+-SPFX complexes showed remarkable potency as compared to the parent drug.

  5. Quaternized Chitosan as an Antimicrobial Agent: Antimicrobial Activity, Mechanism of Action and Biomedical Applications in Orthopedics

    PubMed Central

    Tan, Honglue; Ma, Rui; Lin, Chucheng; Liu, Ziwei; Tang, Tingting

    2013-01-01

    Chitosan (CS) is a linear polysaccharide with good biodegradability, biocompatibility and antimicrobial activity, which makes it potentially useful for biomedical applications, including an antimicrobial agent either alone or blended with other polymers. However, the poor solubility of CS in most solvents at neutral or high pH substantially limits its use. Quaternary ammonium CS, which was prepared by introducing a quaternary ammonium group on a dissociative hydroxyl group or amino group of the CS, exhibited improved water solubility and stronger antibacterial activity relative to CS over an entire range of pH values; thus, this quaternary modification increases the potential biomedical applications of CS in the field of anti-infection. This review discusses the current findings on the antimicrobial properties of quaternized CS synthesized using different methods and the mechanisms of its antimicrobial actions. The potential antimicrobial applications in the orthopedic field and perspectives regarding future studies in this field are also considered. PMID:23325051

  6. Structure-activity analysis of 2'-modified cinnamaldehyde analogues as potential anticancer agents.

    PubMed

    Gan, Fei Fei; Chua, Yee Shin; Scarmagnani, Silvia; Palaniappan, Puvithira; Franks, Mark; Poobalasingam, Thurka; Bradshaw, Tracey D; Westwell, Andrew D; Hagen, Thilo

    2009-10-02

    The natural product 2'-hydroxycinnamaldehyde (HCA) and its analogue, 2'-benzoyloxycinnamaldehyde (BCA), have been previously shown to have antiproliferative and proapoptotic effects in vitro and inhibit tumor growth in vivo. In this study, we use structure-activity analysis to define structural features that are important for the activity of cinnamaldehyde analogues. Our results emphasize an important role for both the propenal group as well as the modification at the 2'-position. Further studies were aimed to characterize the mechanism of action of BCA. Exposure to BCA induced cell death via caspase-dependent and -independent pathways. Cell death was not due to autophagy or necrosis as a result of energy depletion or induction of reactive oxygen species. Our findings have important implications for future drug design and highlight the importance of defining molecular drug targets for this promising class of potential anticancer agents.

  7. Synthesis of Arylpiperazine Derivatives As Protease Activated Receptor 1 Antagonists And Their Evaluation As Antiproliferative Agents.

    PubMed

    Zotti, Andrea Ilaria; Di Gennaro, Elena; Corvino, Angela; Frecentese, Francesco; Magli, Elisa; Perissutti, Elisa; Cirino, Giuseppe; Roviezzo, Fiorentina; Terranova-Barberio, Manuela; Iannelli, Federica; Caliendo, Giuseppe; Santagada, Vincenzo; Fiorino, Ferdinando; Budillon, Alfredo; Severino, Beatrice

    2016-09-26

    Protease activated receptor-1 (PAR1) is a G-coupled receptor activated by α-thrombin and other proteases. Several reports demonstrate PAR1 involvement in tumorigenesis and tumor progression. In order to investigate on potential use of PAR1 antagonists as antiproliferative agents, we have identified a series of arylpiperazine derivatives acting as PAR1 antagonists; the selected molecules have been evaluated for their antiproliferative properties. All the compounds inhibited the growth of a panel of cell lines expressing PAR1; two of them, compounds 13 and 15, were able to inhibit, in a dose dependent manner, the growth of the selected cell lines with the lowest IC50 values, and were further characterized to define the mechanism responsible for the observed antiproliferative effect. This study directed us to the identification of two interesting leads that may help to further validate PAR1 as an important therapeutic target for cancer treatment.

  8. Formulation of microemulsion propolis fluoride (PF) as varnish topical agent to stop activity of teeth caries

    NASA Astrophysics Data System (ADS)

    Sahlan, Muhamad; Prakoso, Chandra Dwi; Darwita, Risqa Rina; Hermansyah, Heri

    2017-02-01

    Topical fluoride is proven to have higher efficacy in preventing dental caries with low production cost and easy to apply. The objective of this research is to formulate alternative agent topical fluoride NH4F 5% mixed with extract ethanol propolis (EEP) in the micro-emulsion system that has high stability, antimicrobial activity, and remineralization capability to arrest teeth caries activity. By using total plate count (TPC) analysis, formulation 2.7% EEP; 6,3% surfactant; and 90,9% NH4F shows good perform to inhibit cariogenic bacteria development around 78-80%. Scanning Electron Microscopy (SEM) and Energy Dispersive X-Ray (EDX) result also showed that sample successfully remineralized enamel surface. In addition, sample showed good pH, flavonoid, and polyphenol stability for 40 days.

  9. Agents that activate protein kinase C reduce acetylcholine sensitivity in cultured myotubes

    PubMed Central

    1985-01-01

    We have examined acetylcholine (ACh)-elicited potentials or currents in current- or voltage-clamped cultured myotubes exposed to 12-O- tetradecanoyl-phorbol-13-acetate (TPA), a potent tumor promoter that activates protein kinase C. Although this agent had little action on either membrane resting potential or electrical resistance, a reversible decrease in ACh sensitivity was induced on 3-4-d-old chick myotubes. Depression of transmitter action by TPA was extended to 7-8-d mouse myotubes only when they were treated with phosphatidylserine. Glyceryl dioleate had effects on myotubes similar to those of TPA but with a reduced efficacy. We conclude that the activation of protein kinase C might be involved with the capacity of ACh receptors to respond to transmitter stimulation. PMID:3156868

  10. Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-kB, Calcium Signaling, and Calcineurin

    PubMed Central

    Jin, Shunqian; Orabi, Abrahim I.; Le, Tianming; Javed, Tanveer A.; Sah, Swati; Eisses, John F.; Bottino, Rita; Molkentin, Jeffery D.; Husain, Sohail Z.

    2015-01-01

    Background & Aims Radiocontrast agents are required for radiographic procedures, but these agents can injure tissues by unknown mechanisms. We investigated whether exposure of pancreatic tissues to radiocontrast agents during endoscopic retrograde cholangiopancreatography (ERCP) causes pancreatic inflammation, and studied the effects of these agents on human cell lines and in mice. Methods We exposed mouse and human acinar cells to the radiocontrast agent iohexol (Omnipaque) and measured intracellular release of Ca2+, calcineurin activation (using a luciferase reporter), activation of nuclear factor-κB (NF-κB, using a luciferase reporter), and cell necrosis (via propidium iodide uptake). We infused the radiocontrast agent into the pancreatic ducts of wild type mice (C57BL/6) to create a mouse model of post-ERCP pancreatitis; some mice were given intraperitoneal injections of the calcineurin inhibitor FK506 before and after infusion of the radiocontrast agent. CnAβ−/− mice were also used. This experiment was also performed in mice given infusions of AAV6-NF-κB-luciferase, to assess activation of this transcription factor in vivo. Results Incubation of mouse and human acinar cells, but not HEK293 or COS7 cells, with iohexol led to a peak and then plateau in Ca2+ signaling, along with activation of the transcription factors NF-κB and NFAT. Suppressing Ca2+ signaling or calcineurin with BAPTA, cyclosporine A, or FK506 prevented activation of NF-κB and acinar cell injury. Calcineurin Aβ-deficient mice were protected against induction of pancreatic inflammation by iohexol. The calcineurin inhibitor FK506 prevented contrast-induced activation of NF-κB in pancreata of mice; this was observed by live imaging of mice given infusions of AAV6- NF-kB-luciferase. Conclusions Radiocontrast agents cause pancreatic inflammation in mice, via activation of NF-κB, Ca2+ signaling, and calcineurin. Calcineurin inhibitors might be developed to prevent post-ERCP pancreatitis

  11. Interfacial Activity of Gold Nanoparticles Coated with a Polymeric Patchy Shell and the Role of Spreading Agents

    PubMed Central

    2016-01-01

    Gold patchy nanoparticles (PPs) were prepared under surfactant-free conditions by functionalization with a binary ligand mixture of polystyrene and poly(ethylene glycol) (PEG) as hydrophobic and hydrophilic ligands, respectively. The interfacial activity of PPs was compared to that of homogeneous hydrophilic nanoparticles (HPs), fully functionalized with PEG, by means of pendant drop tensiometry at water/air and water/decane interfaces. We compared interfacial activities in three different spreading agents: water, water/chloroform, and pure chloroform. We found that the interfacial activity of PPs was close to zero (∼2 mN/m) when the spreading agent was water and increased to ∼14 mN/m when the spreading agent was water/chloroform. When the nanoparticles were deposited with pure chloroform, the interfacial activity reached up to 60 mN/m by compression. In all cases, PPs exhibited higher interfacial activity than HPs, which were not interfacially active, regardless of the spreading agent. The interfacial activity at the water/decane interface was found to be significantly lower than that at the water/air interface because PPs aggregate in decane. Interfacial dilatational rheology showed that PPs form a stronger elastic shell at the pendant drop interface, compared to HPs. The significantly high interfacial activity obtained with PPs in this study highlights the importance of the polymeric patchy shell and the spreading agent. PMID:27656691

  12. Nrf2 activity as a potential biomarker for the pan-epigenetic anticancer agent, RRx-001

    PubMed Central

    Ning, Shoucheng; Sekar, Thillai Veerapazham; Scicinski, Jan; Oronsky, Bryan; Peehl, Donna M.; Knox, Susan J.; Paulmurugan, Ramasamy

    2015-01-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulatory transcription factor that plays an important role in the antioxidant response pathway against anticancer drug-induced cytotoxic effects. RRx-001 is a new anticancer agent that generates reactive oxygen and nitrogen species, and leads to epigenetic alterations in cancer cells. Here we report the RRx-001 mediated nuclear translocation of Nrf2 and the activation of expression of its downstream enzymes HO-1 and NQO1 in tumor cells. Inhibition of intrinsic Nrf2 expression by Nrf2-specific siRNA increased cell sensitivity to RRx-001. Molecular imaging of tumor cells co-expressing pARE-Firefly luciferase and pCMV-Renilla luciferase-mRFP in vitro and in vivo in mice revealed that RRx-001 significantly increased ARE-FLUC signal in cells in a dose- and time-dependent manner, suggesting that RRx-001 is an effective activator of the Nrf2-ARE signaling pathway. The pre-treatment level of ARE-FLUC signal in cells, reflecting basal activity of Nrf2, negatively correlated with the tumor response to RRx-001. The results support the concept that RRx-001 activates Nrf2-ARE antioxidant signaling pathways in tumor cells. Hence measurement of Nrf2-mediated activation of downstream target genes through ARE signaling may constitute a useful molecular biomarker for the early prediction of response to RRx-001 treatment, and thereby guide therapeutic decision-making. PMID:26280276

  13. Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma.

    PubMed

    Tsen, Andrew R; Long, Patrick M; Driscoll, Heather E; Davies, Matthew T; Teasdale, Benjamin A; Penar, Paul L; Pendlebury, William W; Spees, Jeffrey L; Lawler, Sean E; Viapiano, Mariano S; Jaworski, Diane M

    2014-03-15

    Cancer is associated with epigenetic (i.e., histone hypoacetylation) and metabolic (i.e., aerobic glycolysis) alterations. Levels of N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate, are reduced in glioma; yet, few studies have investigated acetate as a potential therapeutic agent. This preclinical study sought to test the efficacy of the food additive Triacetin (glyceryl triacetate, GTA) as a novel therapy to increase acetate bioavailability in glioma cells. The growth-inhibitory effects of GTA, compared to the histone deacetylase inhibitor Vorinostat (SAHA), were assessed in established human glioma cell lines (HOG and Hs683 oligodendroglioma, U87 and U251 glioblastoma) and primary tumor-derived glioma stem-like cells (GSCs), relative to an oligodendrocyte progenitor line (Oli-Neu), normal astrocytes, and neural stem cells (NSCs) in vitro. GTA was also tested as a chemotherapeutic adjuvant with temozolomide (TMZ) in orthotopically grafted GSCs. GTA-induced cytostatic growth arrest in vitro comparable to Vorinostat, but, unlike Vorinostat, GTA did not alter astrocyte growth and promoted NSC expansion. GTA alone increased survival of mice engrafted with glioblastoma GSCs and potentiated TMZ to extend survival longer than TMZ alone. GTA was most effective on GSCs with a mesenchymal cell phenotype. Given that GTA has been chronically administered safely to infants with Canavan disease, a leukodystrophy due to ASPA mutation, GTA-mediated acetate supplementation may provide a novel, safe chemotherapeutic adjuvant to reduce the growth of glioma tumors, most notably the more rapidly proliferating, glycolytic and hypoacetylated mesenchymal glioma tumors.

  14. Activation of tissue plasminogen activator gene transcription by Neovastat, a multifunctional antiangiogenic agent.

    PubMed

    Gingras, Denis; Nyalendo, Carine; Di Tomasso, Geneviève; Annabi, Borhane; Béliveau, Richard

    2004-07-16

    We recently reported that Neovastat, an antiangiogenic drug that is currently undergoing Phase III clinical trials for the treatment of non-small cell lung cancer, may inhibit angiogenesis through an increase in tPA activity. Here, we show that Neovastat also stimulates tPA gene transcription in endothelial cells, in a TNFalpha-like manner. RT-PCR analysis and gene reporter assays using the human tPA promoter indicated that upregulation of the tPA gene transcription by both Neovastat and TNFalpha was correlated with the phosphorylation of JNK1/2 and of IkappaB and that SP600125 and BAY11-7082, inhibitors of JNK and IkappaK, respectively, inhibit the increase of tPA gene transcription induced by Neovastat and TNFalpha. These results suggest that Neovastat induces tPA gene transcription through activation of the JNK and NFkappaB signaling pathways, leading to an increase of tPA secretion by endothelial cells. This may lead to the localized destruction of the fibrin provisional matrix that is necessary for neovessel formation and thus contribute to the reported antiangiogenic properties of this compound.

  15. Screening of Pharmacologically Active Small Molecule Compounds Identifies Antifungal Agents Against Candida Biofilms

    PubMed Central

    Watamoto, Takao; Egusa, Hiroshi; Sawase, Takashi; Yatani, Hirofumi

    2015-01-01

    Candida species have emerged as important and common opportunistic human pathogens, particularly in immunocompromised individuals. The current antifungal therapies either have toxic side effects or are insufficiently effect. The aim of this study is develop new small-molecule antifungal compounds by library screening methods using Candida albicans, and to evaluate their antifungal effects on Candida biofilms and cytotoxic effects on human cells. Wild-type C. albicans strain SC5314 was used in library screening. To identify antifungal compounds, we screened a small-molecule library of 1,280 pharmacologically active compounds (LOPAC1280TM) using an antifungal susceptibility test (AST). To investigate the antifungal effects of the hit compounds, ASTs were conducted using Candida strains in various growth modes, including biofilms. We tested the cytotoxicity of the hit compounds using human gingival fibroblast (hGF) cells to evaluate their clinical safety. Only 35 compounds were identified by screening, which inhibited the metabolic activity of C. albicans by >50%. Of these, 26 compounds had fungistatic effects and nine compounds had fungicidal effects on C. albicans. Five compounds, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate, ellipticine and CV-3988, had strong fungicidal effects and could inhibit the metabolic activity of Candida biofilms. However, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate and ellipticine were cytotoxic to hGF cells at low concentrations. CV-3988 showed no cytotoxicity at a fungicidal concentration. Four of the compounds identified, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate and ellipticine, had toxic effects on Candida strains and hGF cells. In contrast, CV-3988 had fungicidal effects on Candida strains, but low cytotoxic effects on hGF cells. Therefore, this screening reveals agent, CV-3988 that was previously unknown to be antifungal agent, which could be a novel therapies for superficial mucosal candidiasis. PMID

  16. Antimicrobial activity of biodegradable polysaccharide and protein-based films containing active agents.

    PubMed

    Kuorwel, Kuorwel K; Cran, Marlene J; Sonneveld, Kees; Miltz, Joseph; Bigger, Stephen W

    2011-04-01

    Significant interest has emerged in the introduction of food packaging materials manufactured from biodegradable polymers that have the potential to reduce the environmental impacts associated with conventional packaging materials. Current technologies in active packaging enable effective antimicrobial (AM) packaging films to be prepared from biodegradable materials that have been modified and/or blended with different compatible materials and/or plasticisers. A wide range of AM films prepared from modified biodegradable materials have the potential to be used for packaging of various food products. This review examines biodegradable polymers derived from polysaccharides and protein-based materials for their potential use in packaging systems designed for the protection of food products from microbial contamination. A comprehensive table that systematically analyses and categorizes much of the current literature in this area is included in the review.

  17. Highly effective bacterial agents against Cimbex quadrimaculatus (Hymenoptera: Cimbicidae): isolation of bacteria and their insecticidal activities.

    PubMed

    Cakici, Filiz Ozkan; Ozgen, İnanc; Bolu, Halil; Erbas, Zeynep; Demirbağ, Zihni; Demir, İsmail

    2015-01-01

    Cimbex quadrimaculatus (Hymenoptera: Cimbicidae) is one of the serious pests of almonds in Turkey and worldwide. Since there is no effective control application against this pest, it has been a serious problem up to now. Therefore, we aimed to find an effective bacterium that can be utilized as a biocontrol agent against C. quadrimaculatus in pest management. We isolated seven bacteria from dead and live C. quadrimaculatus larvae, and evaluated the larvicidal potency of all isolates on the respective pest. Based on the morphological, physiological, biochemical and molecular properties (partial sequence of 16S rRNA gene), the isolates were identified to be Bacillus safensis (CQ1), Bacillus subtilis (CQ2), Bacillus tequilensis (CQ3), Enterobacter sp. (CQ4), Kurthia gibsonii (CQ5), Staphylococcus sp. (CQ6) and Staphylococcus sciuri (CQ7). The results of the larvicidal activities of these isolates indicated that the mortality value obtained from all treatments changed from 58 to 100 %, and reached 100 % with B. safensis (CQ1) and B. subtilis (CQ2) on the 3rd instar larvae within 10 days of application of 1.89 × 10(9) cfu/mL bacterial concentration at 25 °C under laboratory conditions. Findings from this study indicate that these isolates appear to be a promising biocontrol agent for C. quadrimaculatus.

  18. Light-activated nanotube-porphyrin conjugates as effective antiviral agents

    NASA Astrophysics Data System (ADS)

    Banerjee, Indrani; Douaisi, Marc P.; Mondal, Dhananjoy; Kane, Ravi S.

    2012-03-01

    Porphyrins have been used for photodynamic therapy (PDT) against a wide range of targets like bacteria, viruses and tumor cells. In this work, we report porphyrin-conjugated multi-walled carbon nanotubes (NT-P) as potent antiviral agents. Specifically, we used Protoporphyrin IX (PPIX), which we attached to acid-functionalized multi-walled carbon nanotubes (MWNTs). We decided to use carbon nanotubes as scaffolds because of their ease of recovery from a solution through filtration. In the presence of visible light, NT-P was found to significantly reduce the ability of Influenza A virus to infect mammalian cells. NT-P may be used effectively against influenza viruses with little or no chance of them developing resistance to the treatment. Furthermore, NT-P can be easily recovered through filtration which offers a facile strategy to reuse the active porphyrin moiety to its fullest extent. Thus NT-P conjugates represent a new approach for preparing ex vivo reusable antiviral agents.

  19. Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells.

    PubMed

    Gray, Lachlan R; On, Hung; Roberts, Emma; Lu, Hao K; Moso, Michael A; Raison, Jacqueline A; Papaioannou, Catherine; Cheng, Wan-Jung; Ellett, Anne M; Jacobson, Jonathan C; Purcell, Damian F J; Wesselingh, Steve L; Gorry, Paul R; Lewin, Sharon R; Churchill, Melissa J

    2016-08-01

    Despite the success of combination antiretroviral therapy (cART), HIV persists in long lived latently infected cells in the blood and tissue, and treatment is required lifelong. Recent clinical studies have trialed latency-reversing agents (LRA) as a method to eliminate latently infected cells; however, the effects of LRA on the central nervous system (CNS), a well-known site of virus persistence on cART, are unknown. In this study, we evaluated the toxicity and potency of a panel of commonly used and well-known LRA (panobinostat, romidepsin, vorinostat, chaetocin, disulfiram, hexamethylene bisacetamide [HMBA], and JQ-1) in primary fetal astrocytes (PFA) as well as monocyte-derived macrophages as a cellular model for brain perivascular macrophages. We show that most LRA are non-toxic in these cells at therapeutic concentrations. Additionally, romidepsin, JQ-1, and panobinostat were the most potent at inducing viral transcription, with greater magnitude observed in PFA. In contrast, vorinostat, chaetocin, disulfiram, and HMBA all demonstrated little or no induction of viral transcription. Together, these data suggest that some LRA could potentially activate transcription in latently infected cells in the CNS. We recommend that future trials of LRA also examine the effects of these agents on the CNS via examination of cerebrospinal fluid.

  20. Novel Pharmacological Activity of Artesunate and Artemisinin: Their Potential as Anti-Tubercular Agents

    PubMed Central

    Choi, Won Hyung

    2017-01-01

    Tuberculosis is a major infectious disease that globally causes the highest human mortality. From this aspect, this study was carried out to evaluate novel pharmacological activities/effects of artesunate and artemisinin causing anti-tubercular activity/effects against Mycobacterium tuberculosis (Mtb). The anti-Mtb activities/effects of artesunate and artemisinin were evaluated using different anti-Mtb indicator assays, such as the resazurin microtiter assay, the Mycobacteria Growth Indicator Tube (MGIT) 960 system assay, and the Ogawa slant medium assay, as well as in vivo tests. Artesunate showed selective anti-Mtb effects by strongly inhibiting the growth of Mtb compared to artemisinin, and consistently induced anti-Mtb activity/effects by effectively inhibiting Mtb in the MGIT 960 system and in Ogawa slant medium for 21 days with a single dose; its minimum inhibitory concentration was 300 µg/mL in in vitro testing. Furthermore, artesunate demonstrated an anti-tubercular effect/action with a daily dose of 3.5 mg/kg in an in vivo test for four weeks, which did not indicate or induce toxicity and side effects. These results demonstrate that artesunate effectively inhibits the growth and/or proliferation of Mtb through novel pharmacological activities/actions, as well as induces anti-Mtb activity. This study shows its potential as a potent candidate agent for developing new anti-tuberculosis drugs of an effective/safe next generation, and suggests novel insights into its effective use by repurposing existing drugs through new pharmacological activity/effects as one of the substantive alternatives for inhibiting tuberculosis. PMID:28287416

  1. [Removal of fluorescent whitening agent by hydrogen peroxide oxidation catalyzed by activated carbon].

    PubMed

    Liu, Hai-Long; Zhang, Zhong-Min; Zhao, Xia; Jiao, Ru-Yuan

    2014-06-01

    Degradation of fluorescent whitening agent VBL in the processes of activated carbon (AC) and activated carbon modified (ACM) adsorptions, hydrogen peroxide (H2O2) oxidation, and hydrogen peroxide oxidation catalyzed by activated carbon were studied. Mechanism of the above catalytic oxidation was also investigated by adding tert-Butyl alcohol (TBA), the free radical scavenger, and detecting the released gases. The results showed that: the activated carbon modified by Fe (NO3)3 (ACM)exhibited better adsorption removal than AC. Catalytic oxidation showed efficient removal of VBL, and the catalytic removal of AC (up to 95%) was significantly higher than that of ACM (58% only). Catalytic oxidation was inhibited by TBA, which indicates that the above reaction involved *OH radicals and atom oxygen generated by hydrogen peroxide with the presence of AC. The results of H2O2 decomposition and released gases detection involved in the process showed that activated carbon enhanced the decomposition of H2O2 which released oxygen and heat. More O2 was produced and higher temperature of the reactor was achieved, which indicated that H2O2 decomposition catalyzed by ACM was significantly faster than that of AC. Combining the results of VBL removal, it could be concluded that the rate of active intermediates (*OH radicals and atom oxygen) production by ACM catalytic reaction was faster than that of AC. These intermediates consumed themselves and produced O2 instead of degrading VBL. It seemed that the improper mutual matching of the forming rate of activating intermediates and the supply rate of reactants was an important reason for the lower efficiency of ACM catalytic reaction comparing with AC.

  2. N-Substituted piperazinyl quinolones as potential cytotoxic agents: structure-activity relationships study.

    PubMed

    Foroumadi, Alireza; Emami, Saeed; Rajabalian, Saeed; Badinloo, Marziyeh; Mohammadhosseini, Negar; Shafiee, Abbas

    2009-03-01

    As part of a continuing search for new potential anticancer candidates in the piperazinyl quinolone series, the cytotoxicity evaluation of new N-substituted piperazinyl quinolones was of our interest. The growth inhibitory activities of 12 new compounds, namely N-[2-(5-chlorothiophen-2-yl)-2-oxoethyl] and N-[2-(5-chlorothiophen-2-yl)-2-oxyiminoethyl] piperazinyl quinolones 1-12 were determined against six cancer cell lines using MTT colorimetric assay. Preliminary screening showed that most of the new N-[2-(5-chlorothiophen-2-yl)ethyl]piperazinyl quinolones 4-12 containing (un)substituted oxime moiety showed significant cytotoxic activity and the modification of functionality on ethyl spacer produced a relatively minor change of activity. Thus, in the piperazinyl quinolone series, cytotoxic activity can be positively modulated through the introduction of 2-(5-chlorothiophen-2-yl)ethyl residue on the piperazine ring. The results revealed that the introduction of 2-(5-chlorothiophen-2-yl)ethyl moiety on the piperazine ring of quinolone antibacterials (ciprofloxacin, norfloxacin and enoxacin) changes the biological profile of piperazinyl quinolones from antibacterials to cytotoxic agents.

  3. The antidiabetic agent sodium tungstate activates glycogen synthesis through an insulin receptor-independent pathway.

    PubMed

    Domínguez, Jorge E; Muñoz, M Carmen; Zafra, Delia; Sanchez-Perez, Isabel; Baqué, Susanna; Caron, Martine; Mercurio, Ciro; Barberà, Albert; Perona, Rosario; Gomis, Ramon; Guinovart, Joan J

    2003-10-31

    Sodium tungstate is a powerful antidiabetic agent when administered orally. In primary cultured hepatocytes, tungstate showed insulin-like actions, which led to an increase in glycogen synthesis and accumulation. However, this compound did not significantly alter the insulin receptor activation state or dephosphorylation rate in cultured cells (CHO-R) or in primary hepatocytes, in either short or long term treatments. In contrast, at low concentrations, tungstate induced a transient strong activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) after 5-10 min of treatment, in a similar way to insulin. Moreover, this compound did not significantly delay or inhibit the dephosphorylation of ERK1/2. ERK1/2 activation triggered a cascade of downstream events, which included the phosphorylation of p90rsk and glycogen synthase-kinase 3beta. Experiments with a specific inhibitor of ERK1/2 activation and kinase assays indicate that these proteins were directly involved in the stimulation of glycogen synthase and glycogen synthesis induced by tungstate without a direct involvement of protein kinase B (PKB/Akt). These results show a direct involvement of ERK1/2 in the mechanism of action of tungstate at the hepatic level.

  4. The Structure Activity Relationship of Urea Derivatives as Anti-Tuberculosis Agents

    PubMed Central

    Brown, Joshua R.; North, Elton J.; Hurdle, Julian G.; Morisseau, Christophe; Scarborough, Jerrod S.; Sun, Dianqing; Korduláková, Jana; Scherman, Michael S.; Jones, Victoria; Grzegorzewicz, Anna; Crew, Rebecca M.; Jackson, Mary; McNeil, Michael R.; Lee, Richard E.

    2011-01-01

    The treatment of tuberculosis is becoming more difficult due to the ever increasing prevalence of drug resistance. Thus, it is imperative that novel anti-tuberculosis agents, with unique mechanisms of action, be discovered and developed. The direct anti-tubercular testing of a small compound library led to discovery of adamantyl urea hit compound 1. In this study, the hit was followed up through the synthesis of an optimization library. This library was generated by systematically replacing each section of the molecule with a similar moiety until a clear structure activity relationship was obtained with respect to anti-tubercular activity. The best compounds in this series contained a 1-adamantyl-3-phenyl urea core and had potent activity against Mycobacterium tuberculosis plus an acceptable therapeutic index. It was noted that the compounds identified and the pharmacophore developed is consistent with inhibitors of epoxide hydrolase family of enzymes. Consequently, the compounds were tested for inhibition of representative epoxide hydrolases: M. tuberculosis EphB and EphE; and human soluble epoxide hydrolase. Many of the optimized inhibitors showed both potent EphB and EphE inhibition suggesting the antitubercular activity is through inhibition of multiple epoxide hydrolyase enzymes. The inhibitors also showed potent inhibition of humans soluble expoxide hydrolyase, but limited cytotoxicity suggesting that future studies must be towards increasing the selectivity of epoxide hydrolyase inhibition towards the M. tuberculosis enzymes. PMID:21840723

  5. Coumarin derivatives as potential antitumor agents: Growth inhibition, apoptosis induction and multidrug resistance reverting activity.

    PubMed

    Bisi, Alessandra; Cappadone, Concettina; Rampa, Angela; Farruggia, Giovanna; Sargenti, Azzurra; Belluti, Federica; Di Martino, Rita M C; Malucelli, Emil; Meluzzi, Alessia; Iotti, Stefano; Gobbi, Silvia

    2017-02-15

    A small library of coumarins, carrying butynyl-amino chains, was synthesized continuing our studies in the field of MDR reverting ageEnts and in order to obtain multipotent agents to combat malignancies. In particular, the reported anticancer and chemopreventive natural product 7-isopentenyloxycoumarin was linked to different terminal amines, selected on the basis of our previously reported results. The anticancer behaviour and the MDR reverting ability of the new compounds were evaluated on human colon cancer cells, particularly prone to develop the MDR phenotype. Some of the new derivatives showed promising effects, directly acting as cytotoxic compounds and/or counteracting MDR phenomenon. Compound 1e emerged as the most interesting of this series, showing a multipotent biological profile and suggesting that conjugation of an appropriate coumarin core with a properly selected butynyl-amino chain allows to obtain novel hybrid molecules endowed with improved in vitro antitumor activity.

  6. Novel anticancer agent, SQAP, binds to focal adhesion kinase and modulates its activity

    PubMed Central

    Izaguirre-Carbonell, Jesus; Kawakubo, Hirofumi; Murata, Hiroshi; Tanabe, Atsushi; Takeuchi, Toshifumi; Kusayanagi, Tomoe; Tsukuda, Senko; Hirakawa, Takeshi; Iwabata, Kazuki; Kanai, Yoshihiro; Ohta, Keisuke; Miura, Masahiko; Sakaguchi, Kengo; Matsunaga, Sachihiro; Sahara, Hiroeki; Kamisuki, Shinji; Sugawara, Fumio

    2015-01-01

    SQAP is a novel and promising anticancer agent that was obtained by structural modifications from a natural compound. SQAP inhibits angiogenesis in vivo resulting in increased hypoxia and reduced tumor volume. In this study, the mechanism by which SQAP modifies the tumor microenvironment was revealed through the application of a T7 phage display screening. This approach identified five SQAP-binding proteins including sterol carrier protein 2, multifunctional enzyme type 2, proteasomal ubiquitin receptor, UV excision repair protein and focal adhesion kinase (FAK). All the interactions were confirmed by surface plasmon resonance analysis. Since FAK plays an important role in cell turnover and angiogenesis, the influence of SQAP on FAK was the principal goal of this study. SQAP decreased FAK phosphorylation and cell migration in human umbilical vein endothelial cells and A549 cancer cells. These findings suggest that inhibition of FAK phosphorylation works as the mechanism for the anti-angiogenesis activity of SQAP. PMID:26456697

  7. Laboratory activities involving transmissible spongiform encephalopathy causing agents: risk assessment and biosafety recommendations in Belgium.

    PubMed

    Leunda, Amaya; Van Vaerenbergh, Bernadette; Baldo, Aline; Roels, Stefan; Herman, Philippe

    2013-01-01

    Since the appearance in 1986 of epidemic of bovine spongiform encephalopathy (BSE), a new form of neurological disease in cattle which also affected human beings, many diagnostic and research activities have been performed to develop detection and therapeutic tools. A lot of progress was made in better identifying, understanding and controlling the spread of the disease by appropriate monitoring and control programs in European countries. This paper reviews the recent knowledge on pathogenesis, transmission and persistence outside the host of prion, the causative agent of transmissible spongiform encephalopathies (TSE) in mammals with a particular focus on risk (re)assessment and management of biosafety measures to be implemented in diagnostic and research laboratories in Belgium. Also, in response to the need of an increasing number of European diagnostic laboratories stopping TSE diagnosis due to a decreasing number of TSE cases reported in the last years, decontamination procedures and a protocol for decommissioning TSE diagnostic laboratories is proposed.

  8. Determination of anionic surface active agents using silica coated magnetite nanoparticles modified with cationic surfactant aggregates.

    PubMed

    Pena-Pereira, Francisco; Duarte, Regina M B O; Trindade, Tito; Duarte, Armando C

    2013-07-19

    The development of a novel methodology for extraction and preconcentration of the most commonly used anionic surface active agents (SAAs), linear alkylbenzene sulfonates (LAS), is presented herein. The present method, based on the use of silica-magnetite nanoparticles modified with cationic surfactant aggregates, was developed for determination of C10-C13 LAS homologues. The proposed methodology allowed quantitative recoveries of C10-C13 LAS homologues by using a reduced amount of magnetic nanoparticles. Limits of detection were in the range 0.8-1.9μgL(-1) for C10-C13 LAS homologues, while the repeatability, expressed as relative standard deviation (RSD), ranged from 2.0 to 3.9% (N=6). Finally, the proposed method was successfully applied to the analysis of a variety of natural water samples.

  9. Synthesis and structural studies of indolylazaindoles and their potency as anticancer chemotherapeutics

    NASA Astrophysics Data System (ADS)

    Maciejewska, Dorota; Niemyjska, Maria; Wolska, Irena; Młynarczuk-Biały, Izabela; Kędziora, Anna

    2015-11-01

    Novel indolylazaindoles were synthesized and characterized by elemental analysis and IR, 1H, 13C, NMR techniques. The single crystal X-ray diffraction data for two new compounds: 3-(3-indolylmethyl)-7-azaindole (2) and 1-(1-benzenesulfonyl-3-indolylmethyl)-7-azaindole (3) were included together with the intermolecular interactions analysis in the solid state. To establish the possible relationship between structure and activity, the set of indole derivatives was extended to include the previously synthesized bisindoles. The cytotoxic/cytostatic activities were evaluated against human leukemia (HL-60) and human prostate (DU145) cancer cells, whilst NHI3T3 fibroblasts were used as non-tumor control cells. Two lead structures 3-(3-Indolylmethyl)-7-azaindole (2) and di-5-iodoindol-3-yl disulfide (6) were discovered as promising compounds in search for new anticancer chemotherapeutics.

  10. Identification of small molecule Hes1 modulators as potential anticancer chemotherapeutics.

    PubMed

    Sail, Vibhavari; Hadden, M Kyle

    2013-03-01

    Hes1 is a key transcriptional regulator primarily controlled by the Notch signaling pathway, and recent studies have demonstrated both an oncogenic and tumor suppressor role for Hes1, depending on the cell type. Small molecules that activate and inhibit Hes1 activity hold promise as future anticancer chemotherapeutics. We have utilized a cell-based dual luciferase assay to identify modulators of Hes1 expression in a medium-throughput format. A modest screen was performed in HCT-116 colon cancer cell lines, and two small molecules were identified and characterized as Hes1 regulators. Compound 3 induced Hes1 expression and exhibited anticancer effects in pulmonary carcinoid tumor cells, a cell type in which the upregulated Notch/Hes1 signaling plays a tumor suppressive role. Treatment of HCT-116 cells with compound 12 resulted in Hes1 downregulation and antitumor effects.

  11. Is matching ruthenium with dithiocarbamato ligands a potent chemotherapeutic weapon in oncology?

    PubMed

    Nardon, Chiara; Brustolin, Leonardo; Fregona, Dolores

    2016-01-01

    In the last years, several metal-based compounds have been designed and biologically investigated worldwide in order to obtain chemotherapeutics with a better toxicological profile and comparable or higher antiblastic activity than the clinically-established platinum-based drugs. In this context, researchers have addressed their attention to alternative nonplatinum derivatives able to maximize the anticancer activity of the new drugs and to minimize the side effects. Among them, a number of ruthenium complexes have been developed, including the compounds NAMI-A and KP1019, now in clinical trials. Here, we report the results collected so far for a particular class of ruthenium complexes - the ruthenium(II/III)-dithiocarbamates - which proved more potent than cisplatin in vitro, even at nanomolar concentrations, against a wide panel of human tumor cell lines.

  12. L-Serine deaminase activity is induced by exposure of Escherichia coli K-12 to DNA-damaging agents.

    PubMed Central

    Newman, E B; Ahmad, D; Walker, C

    1982-01-01

    The synthesis of L-serine deaminase in Escherichia coli K-12 was induced after exposure of cells to a variety of DNA-damaging agents, including UV irradiation, nalidixic acid, and mitomycin C. Synthesis was also induced during growth at high temperature. A mutant constitutive for SOS functions showed an elevated level of L-serine deaminase activity. The response to DNA-damaging agents thus may be mediated via the SOS system. PMID:6813312

  13. pH and Antimicrobial Activity of Portland Cement Associated with Different Radiopacifying Agents.

    PubMed

    Guerreiro-Tanomaru, Juliane Maria; Cornélio, Ana Lívia G; Andolfatto, Carolina; Salles, Loise P; Tanomaru-Filho, Mário

    2012-01-01

    Objective. The aim of this study was to evaluate the antimicrobial activity and pH changes induced by Portland cement (PC) alone and in association with radiopacifiers. Methods. The materials tested were pure PC, PC + bismuth oxide, PC + zirconium oxide, PC + calcium tungstate, and zinc oxide and eugenol cement (ZOE). Antimicrobial activity was evaluated by agar diffusion test using the following strains: Micrococcus luteus, Streptococcus mutans, Enterococcus faecalis, Pseudomonas aeruginosa, and Candida albicans. After 24 hours of incubation at 37°C, inhibition of bacterial growth was observed and measured. For pH analysis, material samples (n = 10) were placed in polyethylene tubes and immersed in 10 mL of distilled water. After 12, 24, 48, and 72 hours, the pH of the solutions was determined using a pH meter. Results. All microbial species were inhibited by the cements evaluated. All materials composed of PC with radiopacifying agents promoted pH increase similar to pure Portland cement. ZOE had the lowest pH values throughout all experimental periods. Conclusions. All Portland cement-based materials with the addition of different radiopacifiers (bismuth oxide, calcium tungstate, and zirconium oxide) presented antimicrobial activity and pH similar to pure Portland cement.

  14. Broad-spectrum in vivo antiviral activity of 7-thia-8-oxoguanosine, a novel immunopotentiating agent.

    PubMed Central

    Smee, D F; Alaghamandan, H A; Cottam, H B; Sharma, B S; Jolley, W B; Robins, R K

    1989-01-01

    A novel immunopotentiating agent, 5-amino-3-beta-D-ribofuranosylthiazolo [4,5-d]pyrimidine-2,7(3H,6H)-dione (7-thia-8-oxoguanosine), lacks virus-inhibitory properties in vitro but induces interferon and potentiates immune functions, such as natural killer cell activity. It was evaluated in rodent models to determine the spectrum of antiviral activity and effective treatment regimens. At 50 to 200 mg/kg given as single or divided intraperitoneal (i.p.) doses 1 day before virus inoculation, significant protection was afforded to mice infected i.p. with Semliki Forest, San Angelo, banzi, and encephalomyocarditis viruses. Similarly, suckling rats were protected from an intranasal challenge with rat coronavirus. Against San Angelo virus, treatments could be delayed to 1 day post-virus inoculation and still show a beneficial effect. The compound was moderately effective in mice infected i.p. with herpes simplex virus type 2 or intranasally with vesicular stomatitis virus. No activity was seen against influenza B virus in mice when the analog was administered one time pre-virus inoculation or in multiple doses given before and after the virus inoculation. Nor was there a prophylactic effect against herpetic skin lesions on mice. This immune modulator may have promise for the treatment of a variety of virus infections. PMID:2817849

  15. Soft antimicrobial agents: synthesis and activity of labile environmentally friendly long chain quaternary ammonium compounds.

    PubMed

    Thorsteinsson, Thorsteinn; Másson, Már; Kristinsson, Karl G; Hjálmarsdóttir, Martha A; Hilmarsson, Hilmar; Loftsson, Thorsteinn

    2003-09-11

    A series of soft quaternary ammonium antimicrobial agents, which are analogues to currently used quaternary ammonium preservatives such as cetyl pyridinium chloride and benzalkonium chloride, were synthesized. These soft analogues consist of long alkyl chain connected to a polar headgroup via chemically labile spacer group. They are characterized by facile nonenzymatic and enzymatic degradation to form their original nontoxic building blocks. However, their chemical stability has to be adequate in order for them to have antimicrobial effects. Stability studies and antibacterial and antiviral activity measurements revealed relationship between activity, lipophilicity, and stability. Their minimum inhibitory concentration (MIC) was as low as 1 microg/mL, and their viral reduction was in some cases greater than 6.7 log. The structure-activity studies demonstrate that the bioactive compounds (i.e., MIC for Gram-positive bacteria of <10 microg/mL) have an alkyl chain length between 12 and 18 carbon atoms, with a polar headgroup preferably of a small quaternary ammonium group, and their acquired inactivation half-life must be greater than 3 h at 60 degrees C.

  16. Structure-Activity Relationships of Orotidine-5′-Monophosphate Decarboxylase Inhibitors as Anticancer Agents

    SciTech Connect

    Bello, A.; Konforte, D; Poduch, E; Furlonger, C; Wei, L; Liu, Y; Lewis, M; Pai, E; Paige, C; Kotra, L

    2009-01-01

    A series of 6-substituted and 5-fluoro-6-substituted uridine derivatives were synthesized and evaluated for their potential as anticancer agents. The designed molecules were synthesized from either fully protected uridine or the corresponding 5-fluorouridine derivatives. The mononucleotide derivatives were used for enzyme inhibition investigations against ODCase. Anticancer activities of all the synthesized derivatives were evaluated using the nucleoside forms of the inhibitors. 5-Fluoro-UMP was a very weak inhibitor of ODCase. 6-Azido-5-fluoro and 5-fluoro-6-iodo derivatives are covalent inhibitors of ODCase, and the active site Lys145 residue covalently binds to the ligand after the elimination of the 6-substitution. Among the synthesized nucleoside derivatives, 6-azido-5-fluoro, 6-amino-5-fluoro, and 6-carbaldehyde-5-fluoro derivatives showed potent anticancer activities in cell-based assays against various leukemia cell lines. On the basis of the overall profile, 6-azido-5-fluoro and 6-amino-5-fluoro uridine derivatives exhibited potential for further investigations.

  17. Activation of cGAS-dependent antiviral responses by DNA intercalating agents

    PubMed Central

    Pépin, Geneviève; Nejad, Charlotte; Thomas, Belinda J.; Ferrand, Jonathan; McArthur, Kate; Bardin, Philip G.; Williams, Bryan R.G.; Gantier, Michael P.

    2017-01-01

    Acridine dyes, including proflavine and acriflavine, were commonly used as antiseptics before the advent of penicillins in the mid-1940s. While their mode of action on pathogens was originally attributed to their DNA intercalating activity, work in the early 1970s suggested involvement of the host immune responses, characterized by induction of interferon (IFN)-like activities through an unknown mechanism. We demonstrate here that sub-toxic concentrations of a mixture of acriflavine and proflavine instigate a cyclic-GMP-AMP (cGAMP) synthase (cGAS)-dependent type-I IFN antiviral response. This pertains to the capacity of these compounds to induce low level DNA damage and cytoplasmic DNA leakage, resulting in cGAS-dependent cGAMP-like activity. Critically, acriflavine:proflavine pre-treatment of human primary bronchial epithelial cells significantly reduced rhinovirus infection. Collectively, our findings constitute the first evidence that non-toxic DNA binding agents have the capacity to act as indirect agonists of cGAS, to exert potent antiviral effects in mammalian cells. PMID:27694309

  18. Mito-tempol and dexrazoxane exhibit cardioprotective and chemotherapeutic effects through specific protein oxidation and autophagy in a syngeneic breast tumor preclinical model.

    PubMed

    Dickey, Jennifer S; Gonzalez, Yanira; Aryal, Baikuntha; Mog, Steven; Nakamura, Asako J; Redon, Christophe E; Baxa, Ulrich; Rosen, Elliot; Cheng, Gang; Zielonka, Jacek; Parekh, Palak; Mason, Karen P; Joseph, Joy; Kalyanaraman, Balaraman; Bonner, William; Herman, Eugene; Shacter, Emily; Rao, V Ashutosh

    2013-01-01

    Several front-line chemotherapeutics cause mitochondria-derived, oxidative stress-mediated cardiotoxicity. Iron chelators and other antioxidants have not completely succeeded in mitigating this effect. One hindrance to the development of cardioprotectants is the lack of physiologically-relevant animal models to simultaneously study antitumor activity and cardioprotection. Therefore, we optimized a syngeneic rat model and examined the mechanisms by which oxidative stress affects outcome. Immune-competent spontaneously hypertensive rats (SHRs) were implanted with passaged, SHR-derived, breast tumor cell line, SST-2. Tumor growth and cytokine responses (IL-1A, MCP-1, TNF-α) were observed for two weeks post-implantation. To demonstrate the utility of the SHR/SST-2 model for monitoring both anticancer efficacy and cardiotoxicity, we tested cardiotoxic doxorubicin alone and in combination with an established cardioprotectant, dexrazoxane, or a nitroxide conjugated to a triphenylphosphonium cation, Mito-Tempol (4) [Mito-T (4)]. As predicted, tumor reduction and cardiomyopathy were demonstrated by doxorubicin. We confirmed mitochondrial accumulation of Mito-T (4) in tumor and cardiac tissue. Dexrazoxane and Mito-T (4) ameliorated doxorubicin-induced cardiomyopathy without altering the antitumor activity. Both agents increased the pro-survival autophagy marker LC3-II and decreased the apoptosis marker caspase-3 in the heart, independently and in combination with doxorubicin. Histopathology and transmission electron microscopy demonstrated apoptosis, autophagy, and necrosis corresponding to cytotoxicity in the tumor and cardioprotection in the heart. Changes in serum levels of 8-oxo-dG-modified DNA and total protein carbonylation corresponded to cardioprotective activity. Finally, 2D-electrophoresis/mass spectrometry identified specific serum proteins oxidized under cardiotoxic conditions. Our results demonstrate the utility of the SHR/SST-2 model and the potential of

  19. Insulinotropic agent ID-1101 (4-hydroxyisoleucine) activates insulin signaling in rat.

    PubMed

    Broca, Christophe; Breil, Vincent; Cruciani-Guglielmacci, Céline; Manteghetti, Michèle; Rouault, Christine; Derouet, Michel; Rizkalla, Salwa; Pau, Bernard; Petit, Pierre; Ribes, Gérard; Ktorza, Alain; Gross, René; Reach, Gérard; Taouis, Mohammed

    2004-09-01

    ID-1101 (4-hydroxyisoleucine), an amino acid extracted from fenugreek seeds, exhibits an interesting glucose-dependent insulin-stimulating activity. The present study was undertaken to investigate a possible extrapancreatic effect of ID-1101 on insulin signaling and action besides its previously described insulinotropic action. Insulin-sensitizing effects of ID-1101 were investigated in rat in vivo by three different approaches: 1) using euglycemic hyperinsulinemic clamps in two different rat models of insulin resistance, i.e., Zucker fa/fa rats and rats fed a sucrose-lipid diet; 2) measuring liver and muscle phosphatidylinositol (PI) 3-kinase activity after an acute injection of ID-1101 in normal and insulin-resistant diabetic rats; and 3) after chronic treatment in two rat models of insulin resistance. Euglycemic hyperinsulinemic clamp experiments revealed that ID-1101 can improve insulin resistance through an increase of peripheral glucose utilization rate in sucrose-lipid-fed rats and by decreasing hepatic glucose production in Zucker fa/fa rats. Moreover, we demonstrated that a single injection of ID-1101 activates the PI 3-kinase activity in liver and muscle from normal rats but also in muscle from diabetic rats. Finally, chronic ID-1101 treatment significantly reduced insulinemia in type 2 diabetic rats and reduced the progression of hyperinsulinemia in insulin-resistant obese Zucker fa/fa rats. These findings clearly demonstrate that ID-1101 can reduce insulin resistance through activation of the early steps of insulin signaling in peripheral tissues and in liver. In summary, ID-1101, besides its insulinotropic effect, directly improves insulin sensitivity, making it a potentially very valuable therapeutic agent for diabetes treatment.

  20. BW A256C, a chemically novel class 1 antiarrhythmic agent. A comparison of in vitro and in vivo activity with other class 1 antiarrhythmic agents.

    PubMed Central

    Allan, G.; Donoghue, S.; Follenfant, M. J.; Sawyer, D. A.

    1986-01-01

    BW A256C (5(3)-amino-6-(2,3-dichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2 -isopropyl-1,2,4-triazine) is a novel class 1 antiarrhythmic agent designed to combine the features of potency with reduced central nervous system penetration. BW A256C reduced the maximum rate of depolarization of guinea-pig ventricle and dog Purkinje fibres in vitro (EC50, 2.2 X 10(-6) M and 1.8 X 10(-6) M, respectively), being significantly more potent than quinidine, lidocaine, disopyramide and flecainide. BW A256C was also more potent than these agents at inhibiting aconitine-induced arrhythmias in anaesthetized rats; however, unlike these agents, BW A256C was devoid of hypotensive activity at antiarrhythmic doses. In anaesthetized dogs, intravenous administration of BW A256C (0.25-1 mg kg-1) caused a dose-dependent suppression of ventricular arrhythmias that occurred on reperfusion of an occluded coronary artery. In conscious dogs, intravenous infusion (total dose, 1.5 mg kg-1) or oral administration of BW A256C (1.25-5 mg kg-1) caused dose-dependent suppression of the ventricular ectopic activity that occurred following 20-24 h of permanent coronary artery ligation. In the conscious dog, BW A256C was approximately 7 times more potent and was also longer acting than flecainide. Administration of BW A256C was not associated with any evidence of peripheral or CNS toxicity. However, plasma levels 3-4 times greater than the antiarrhythmic levels were associated with a proarrhythmic activity. PMID:3730698

  1. Interaction of standardized mistletoe (Viscum album) extracts with chemotherapeutic drugs regarding cytostatic and cytotoxic effects in vitro

    PubMed Central

    2014-01-01

    Background Given the importance of complementary and alternative medicine (CAM) to cancer patients, there is an increasing need to learn more about possible interactions between CAM and anticancer drugs. Mistletoe (Viscum album L.) belongs to the medicinal herbs that are used as supportive care during chemotherapy. In the in vitro study presented here the effect of standardized mistletoe preparations on the cytostatic and cytotoxic activity of several common conventional chemotherapeutic drugs was investigated using different cancer cell lines. Methods Human breast carcinoma cell lines HCC1937 and HCC1143 were treated with doxorubicin hydrochloride, pancreas adenocarcinoma cell line PA-TU-8902 with gemcitabine hydrochloride, prostate carcinoma cell line DU145 with docetaxel and mitoxantrone hydrochloride and lung carcinoma cell line NCI-H460 was treated with docetaxel and cisplatin. Each dose of the respective chemotherapeutic drug was combined with Viscum album extract (VAE) in clinically relevant concentrations and proliferation and apoptosis were measured. Results VAE did not inhibit chemotherapy induced cytostasis and cytotoxicity in any of our experimental settings. At higher concentrations VAE showed an additive inhibitory effect. Conclusions Our in vitro results suggest that no risk of safety by herb drug interactions has to be expected from the exposition of cancer cells to chemotherapeutic drugs and VAE simultaneously. PMID:24397864

  2. A new agent developed by biotransformation of polyphyllin VII inhibits chemoresistance in breast cancer

    PubMed Central

    Zhang, Liang; Mao, Ai-Qin; Wei, Juan; Liu, De-Quan; Shi, Gui-Yang; Ma, Xin

    2016-01-01

    Biotransformation by the endophytes of certain plants changes various compounds, and this ‘green’ chemistry becomes increasingly important for finding new products with pharmacological activity. In this study, polyphyllin VII (PPL7) was biotransformed by endophytes from the medicinal plant Paris polyphylla Smith, var. yunnanensis. This produced a new compound, ZH-2, with pharmacological activity in vitro and in vivo. ZH-2 was more potent than PPL7 in selectively killing more chemoresistant than chemosensitive breast cancer cells. ZH-2 also re-sensitized chemoresistant breast cancer cells, as evidenced by the improved anti-cancer activity of commonly-used chemotherapeutic agent in vitro, in vivo, and in clinical samples. This anti-chemoresistance effect of ZH-2 was associated with inhibiting the epithelial-mesenchymal transition (EMT) pathway. Taken together, our findings are the first one to link biotransformation with a biomedicine. The results provide insights into developing new pharmacologically-active agents via biotransformation by endophytes. PMID:26701723

  3. DMSO inhibits human platelet activation through cyclooxygenase-1 inhibition. A novel agent for drug eluting stents?

    SciTech Connect

    Asmis, Lars; Tanner, Felix C.; Sudano, Isabella; Luescher, Thomas F.; Camici, Giovanni G.

    2010-01-22

    Background: DMSO is routinely infused together with hematopoietic cells in patients undergoing myeloablative therapy and was recently found to inhibit smooth muscle cells proliferation and arterial thrombus formation in the mouse by preventing tissue factor (TF), a key activator of the coagulation cascade. This study was designed to investigate whether DMSO prevents platelet activation and thus, whether it may represent an interesting agent to be used on drug eluting stents. Methods and results: Human venous blood from healthy volunteers was collected in citrated tubes and platelet activation was studied by cone and platelet analyzer (CPA) and rapid-platelet-function-assay (RPFA). CPA analysis showed that DMSO-treated platelets exhibit a lower adherence in response to shear stress (-15.54 {+-} 0.9427%, n = 5, P < 0.0001 versus control). Additionally, aggregometry studies revealed that DMSO-treated, arachidonate-stimulated platelets had an increased lag phase (18.0% {+-} 4.031, n = 9, P = 0.0004 versus control) as well as a decreased maximal aggregation (-6.388 {+-} 2.212%, n = 6, P = 0.0162 versus control). Inhibitory action of DMSO could be rescued by exogenous thromboxane A2 and was mediated, at least in part, by COX-1 inhibition. Conclusions: Clinically relevant concentrations of DMSO impair platelet activation by a thromboxane A2-dependent, COX-1-mediated effect. This finding may be crucial for the previously reported anti-thrombotic property displayed by DMSO. Our findings support a role for DMSO as a novel drug to prevent not only proliferation, but also thrombotic complications of drug eluting stents.

  4. G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status.

    PubMed

    Agarwal, Pallavi; Jackson, Stephen P

    2016-10-01

    Cancer cells often exhibit altered epigenetic signatures that can misregulate genes involved in processes such as transcription, proliferation, apoptosis and DNA repair. As regulation of chromatin structure is crucial for DNA repair processes, and both DNA repair and epigenetic controls are deregulated in many cancers, we speculated that simultaneously targeting both might provide new opportunities for cancer therapy. Here, we describe a focused screen that profiled small-molecule inhibitors targeting epigenetic regulators in combination with DNA double-strand break (DSB) inducing agents. We identify UNC0638, a catalytic inhibitor of histone lysine N-methyl-transferase G9a, as hypersensitising tumour cells to low doses of DSB-inducing agents without affecting the growth of the non-tumorigenic cells tested. Similar effects are also observed with another, structurally distinct, G9a inhibitor A-366. We also show that small-molecule inhibition of G9a or siRNA-mediated G9a depletion induces tumour cell death under low DNA damage conditions by impairing DSB repair in a p53 independent manner. Furthermore, we establish that G9a promotes DNA non-homologous end-joining in response to DSB-inducing genotoxic stress. This study thus highlights the potential for using G9a inhibitors as anti-cancer therapeutic agents in combination with DSB-inducing chemotherapeutic drugs such as etoposide.

  5. Oral manganese as an MRI contrast agent for the detection of nociceptive activity.

    PubMed

    Jacobs, Kathleen E; Behera, Deepak; Rosenberg, Jarrett; Gold, Garry; Moseley, Michael; Yeomans, David; Biswal, Sandip

    2012-04-01

    The ability of divalent manganese to enter neurons via calcium channels makes manganese an excellent MRI contrast agent for the imaging of nociception, the afferent neuronal encoding of pain perception. There is growing evidence that nociceptive neurons possess increased expression and activity of calcium channels, which would allow for the selective accumulation of manganese at these sites. In this study, we show that oral manganese chloride leads to increased enhancement of peripheral nerves involved in nociception on T(1)-weighted MRI. Oral rather than intravenous administration was chosen for its potentially better safety profile, making it a better candidate for clinical translation with important applications, such as pain diagnosis, therapy and research. The spared nerve injury (SNI) model of neuropathic pain was used for the purposes of this study. SNI rats were given, sequentially, increasing amounts of manganese chloride (lowest, 2.29 mg/100 g weight; highest, 20.6 mg/100 g weight) with alanine and vitamin D(3) by oral gavage. Compared with controls, SNI rats demonstrated increased signal-to-background ratios on T(1)-weighted fast spin echo MRI, which was confirmed by and correlated strongly with spectrometry measurements of nerve manganese concentration. We also found the difference between SNI and control rats to be greater at 48 h than at 24 h after dosing, indicating increased manganese retention in addition to increased manganese uptake in nociceptive nerves. This study demonstrates that oral manganese is a viable method for the imaging of nerves associated with increased nociceptive activity.

  6. Improving the promiscuous nerve agent hydrolase activity of a thermostable archaeal lactonase.

    PubMed

    Merone, Luigia; Mandrich, Luigi; Porzio, Elena; Rossi, Mosé; Müller, Susanne; Reiter, Georg; Worek, Franz; Manco, Giuseppe

    2010-12-01

    The thermostable Phosphotriesterase-Like Lactonase from Sulfolobus solfataricus (SsoPox) hydrolyzes lactones and, at a lower rate, neurotoxic organophosphorus compounds. The persistent demand of detoxification tools in the field of agricultural wastes and restoring of conditions after terrorist acts prompted us to exploit SsoPox as a "starter" to evolve its ancillary nerve agents hydrolytic capability. A directed evolution strategy yielded, among several variants, the single mutant W263F with k(cat) and specificity constant against paraoxon 16- and 6-fold enhanced, respectively, compared to the wild type. Furthermore, a phenomenon of enzyme activation by SDS has been observed, which allowed to increase those values 150- and 28-fold, respectively. The activity of SsoPox against the deadly nerve gas Cyclosarin has been reported for the first time and proved to be substantially unaffected for variant W263F. Finally, outperforming efficiency of W263F was demonstrated, under severe stressing conditions, with respect to the best known phosphotriesterase PTE from Brevundimonas diminuta.

  7. Synthesis, biological evaluation and structure-activity relationship of 2-styrylquinazolones as anti-tubercular agents.

    PubMed

    Jadhavar, Pradeep S; Dhameliya, Tejas M; Vaja, Maulikkumar D; Kumar, Dinesh; Sridevi, Jonnalagadda Padma; Yogeeswari, Perumal; Sriram, Dharmarajan; Chakraborti, Asit K

    2016-06-01

    2-Styrylquinazolones are reported as a novel class of potent anti-mycobacterial agents. Forty-six target compounds have been synthesized using one pot reaction involving isatoic anhydride, amine, and triethyl orthoacetate followed by aldehyde to construct the 2-styrylquinazolone scaffold. The anti-mycobacterial potency of the compounds was determined against H37Rv strain. Twenty-six compounds exhibited anti-Mtb activity in the range of 0.40-6.25μg/mL. Three compounds 8c, 8d and 8ab showed MIC of 0.78μg/mL and were found to be non-toxic (<50% inhibition at 50μg/mL) to HEK 293T cell lines with the therapeutic index >64. The most potent compound 8ar showed MIC of 0.40μg/mL with the therapeutic index >125. An early structure activity relationship for this class of compounds has been established. The computational studies indicate the possibility of these compounds binding to the penicillin binding proteins (PBPs).

  8. Structure-antitussive activity relationships of naltrindole derivatives. Identification of novel and potent antitussive agents.

    PubMed

    Sakami, Satoshi; Maeda, Masayuki; Kawai, Koji; Aoki, Takumi; Kawamura, Kuniaki; Fujii, Hideaki; Hasebe, Ko; Nakajima, Mayumi; Endo, Takashi; Ueno, Shinya; Ito, Tsuyoshi; Kamei, Junzo; Nagase, Hiroshi

    2008-08-14

    We have previously reported antitussive effects of naltrindole (NTI), a typical delta opioid receptor antagonist, in a rat model. The ED50 values of NTI by intraperitoneal and peroral injections were 104 microg/kg and 1840 microg/kg, respectively, comparable to those of codeine. Codeine, one of the most reliable centrally acting antitussive drugs, has micro agonist activity and thus the same side effects as morphine, e.g., constipation, dependency, and respiratory depression. Because NTI is a delta opioid antagonist, its derivatives have potential as highly potent antitussives, free from the mu opioid agonist side effects. We attempted to optimize the NTI derivatives to develop novel antitussive agents. On the basis of the studies of structure-antitussive activity relationships of alkyl substituted NTI derivatives, we designed NTI derivatives with extra ring fused structures. As a clinical candidate, we identified a highly potent new compound, (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol (5b) methanesulfonate (TRK-850) which was effective even by oral administration (ED50 6.40 microg/kg).

  9. 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells

    PubMed Central

    Bauer, Matthias R.; Joerger, Andreas C.; Fersht, Alan R.

    2016-01-01

    The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53’s oncogenic mutants are just destabilized and rapidly aggregate, and are targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity in several cell lines, especially those with mutationally compromised p53. PK11007 acted by two routes: p53 dependent and p53 independent. PK11007 stabilized p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. Unstable p53 was reactivated by PK11007 in some cancer cell lines, leading to up-regulation of p53 target genes such as p21 and PUMA. More generally, there was cell death that was independent of p53 but dependent on glutathione depletion and associated with highly elevated levels of reactive oxygen species and induction of endoplasmic reticulum (ER) stress, as also found for the anticancer agent PRIMA-1MET(APR-246). PK11007 may be a lead for anticancer drugs that target cells with nonfunctional p53 or impaired reactive oxygen species (ROS) detoxification in a wide variety of mutant p53 cells. PMID:27551077

  10. An imaging agent to detect androgen receptor and its active splice variants in prostate cancer

    PubMed Central

    Imamura, Yusuke; Tien, Amy H.; Pan, Jinhe; Leung, Jacky K.; Banuelos, Carmen A.; Jian, Kunzhong; Wang, Jun; Mawji, Nasrin R.; Fernandez, Javier Garcia; Lin, Kuo-Shyan; Andersen, Raymond J.; Sadar, Marianne D.

    2016-01-01

    Constitutively active splice variants of androgen receptor (AR-Vs) lacking ligand-binding domain (LBD) are a mechanism of resistance to androgen receptor LBD–targeted (AR LBD–targeted) therapies for metastatic castration-resistant prostate cancer (CRPC). There is a strong unmet clinical need to identify prostate cancer patients with AR-V–positive lesions to determine whether they will benefit from further AR LBD–targeting therapies or should receive taxanes or investigational drugs like EPI-506 or galeterone. Both EPI-506 (NCT02606123) and galeterone (NCT02438007) are in clinical trials and are proposed to have efficacy against lesions that are positive for AR-Vs. AR activation function-1 (AF-1) is common to the N-terminal domains of full-length AR and AR-Vs. Here, we provide proof of concept for developing imaging compounds that directly bind AR AF-1 to detect both AR-Vs and full-length AR. 123I-EPI-002 had specific binding to AR AF-1, which enabled direct visualization of CRPC xenografts that express full-length AR and AR-Vs. Our findings highlight the potential of 123I-EPI-002 as an imaging agent for the detection of full-length AR and AR-Vs in CRPC. PMID:27525313

  11. Comparative in vitro activity of antimycotic agents against pathogenic vaginal yeast isolates.

    PubMed

    Lynch, M E; Sobel, J D

    1994-01-01

    Although numerous antimycotic agents are available for the treatment of yeast vaginitis there is little comparative data on the in vitro activity of these drugs. In the present two-part study, in vitro macro-broth dilution sensitivity tests were performed on a total of 377 clinical vaginal yeast isolates of nine different species. Antimycotics surveyed included amphotericin B, 5-fluorocytosine and eight azole derivatives. Results show that all vaginal Candida albicans isolates were uniformly sensitive at low concentration to all 10 antimycotics tested. However, non-albicans species, especially Candida glabrata and Saccharomyces cerevisiae, manifested several-fold increases in minimal inhibitory concentrations to all azoles tested except butoconazole. In particular, the in vitro potency of fluconazole and terconazole against species other than C. albicans was relatively poor, whereas the drugs demonstrating the best activity were itraconazole, butoconazole and saperconazole. Susceptibility testing of vaginal C. albicans isolates is not routinely indicated, even in patients with recurrent vaginitis and should be reserved for selected organisms, especially non-albicans species, in patients with clinical failure only.

  12. 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells.

    PubMed

    Bauer, Matthias R; Joerger, Andreas C; Fersht, Alan R

    2016-09-06

    The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53's oncogenic mutants are just destabilized and rapidly aggregate, and are targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity in several cell lines, especially those with mutationally compromised p53. PK11007 acted by two routes: p53 dependent and p53 independent. PK11007 stabilized p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. Unstable p53 was reactivated by PK11007 in some cancer cell lines, leading to up-regulation of p53 target genes such as p21 and PUMA. More generally, there was cell death that was independent of p53 but dependent on glutathione depletion and associated with highly elevated levels of reactive oxygen species and induction of endoplasmic reticulum (ER) stress, as also found for the anticancer agent PRIMA-1(MET)(APR-246). PK11007 may be a lead for anticancer drugs that target cells with nonfunctional p53 or impaired reactive oxygen species (ROS) detoxification in a wide variety of mutant p53 cells.

  13. Comparative in vitro activity of oritavancin and other agents against methicillin-susceptible and methicillin-resistant Staphylococcus aureus.

    PubMed

    Sweeney, Debora; Shinabarger, Dean L; Arhin, Francis F; Belley, Adam; Moeck, Greg; Pillar, Chris M

    2017-02-01

    Methicillin-resistant Staphylococcus aureus (MRSA) infections constitute a threat to the public health due to their prevalence and associated mortality and morbidity. Several agents have been recently approved to treat MRSA skin infections including lipoglycopeptides (dalbavancin, oritavancin, and telavancin), ceftaroline, and tedizolid. This study compared the MIC, minimum bactericidal concentration (MBC), and time-kill of these agents alongside daptomycin, linezolid, and vancomycin against MRSA (n=15); meropenem, cefazolin, and nafcillin were also included against methicillin-susceptible S. aureus (MSSA [n=12]). MIC and MBC testing was conducted in accordance with Clinical and Laboratory Standards Institute guidelines, and time-kills were evaluated at multiples of the MIC and the free-drug maximum plasma concentration (fCmax) at both standard and high inoculum densities for a subset of MRSA (n=2) and MSSA (n=2). MRSA and MSSA were highly susceptible to all agents, with the lipoglycopeptides having the most potent activity by MIC50/90. All agents excluding tedizolid and linezolid were bactericidal by MBC for MRSA and MSSA, though dalbavancin and telavancin exhibited strain-specific bactericidal activity for MRSA. All agents excluding tedizolid and linezolid were bactericidal by time-kill at their respective fCmax against MRSA and MSSA at standard inoculum density, though oritavancin exhibited the most rapid bactericidal activity. Oritavancin and daptomycin at their respective fCmax maintained similar kill curves at high inoculum density. In contrast, the killing observed with other agents was typically reduced or slowed at high inoculum density. These data demonstrate the rapid bactericidal activity of oritavancin and daptomycin against S. aureus relative to other MRSA agents regardless of bacterial burden.

  14. Comparative in vitro activity of 16 antimicrobial agents against Actinobacillus pleuropneumoniae.

    PubMed

    Yoshimura, H; Takagi, M; Ishimura, M; Endoh, Y S

    2002-01-01

    Sixteen antimicrobial agents were tested for their activity against 68 isolates of Actinobacillus pleuropneumoniae by determining the minimum inhibitory concentrations (MICs). Ceftiofur and the fluoroquinolones danofloxacin and enrofloxacin were the most active compounds, with a MIC for 90% of the isolates (MIC90) of (0.05 microg/ml. The MIC90 values of benzylpenicillin, amoxicillin and aspoxicillin were 0.78 units/ml, 0.39 microg/ml and < or = 0.05 microg/ml, respectively. Three isolates (4.4%) were resistant to penicillins, but aspoxicillin was as active as ceftiofur against the susceptible isolates, with MICs of < or = 0.05 microg/ml for all isolates. Resistance to oxytetracycline, chloramphenicol and thiamphenicol occurred in 22 (32.4%), 14 (20.6%) and 15 (22.1%) of the isolates, respectively. Doxycycline was more active than oxytetracycline, with a MIC90 of 1.56 microg/ml as against 25 microg/ml. Florfenicol was not only as active as thiamphenicol, with a MIC for 50% of the isolates (MIC50) of 0.39 microg/ml, but also active against thiamphenicol-resistant isolates. All the isolates were susceptible to florfenicol. All the isolates were also susceptible to gentamicin, spectinomycin, tilmicosin, colistin and tiamulin. Of these, spectinomycin was the least active, with a MIC50 of 25 microg/ml, followed by tiamulin, with a MIC50 of 6.25 microg/ml. Of the 68 isolates tested, 49 (72.0%) were of serotype 2; 14 (20.5%) were of serotype 1; 2 each (3.0%) were of serotypes 5 and 6; and one was of serotype 7. Of the isolates, 23 (33.8%) were resistant to one or more of the major antibiotics. Antibiotic resistance was found only infrequently among serotype 2, with 5 (10.2%) of 49 isolates being resistant to chloramphenicol and/or oxytetracycline, while it occurred in 18 (94.7%) of the 19 isolates of other serotypes.

  15. Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin

    PubMed Central

    Pang, Baoxu; Qiao, Xiaohang; Janssen, Lennert; Velds, Arno; Groothuis, Tom; Kerkhoven, Ron; Nieuwland, Marja; Ovaa, Huib; Rottenberg, Sven; van Tellingen, Olaf; Janssen, Jeroen; Huijgens, Peter; Zwart, Wilbert; Neefjes, Jacques

    2013-01-01

    DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks. Here we identify a novel activity for the anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal areas. We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. The histone variant H2AX, which is a key component of the DNA damage response, is also evicted by anthracyclines, and H2AX eviction is associated with attenuated DNA repair. Histone eviction deregulates the transcriptome in cancer cells and organs such as the heart, and can drive apoptosis of topoisomerase-negative acute myeloid leukaemia blasts in patients. We define a novel mechanism of action of anthracycline anticancer drugs doxorubicin and daunorubicin on chromatin biology, with important consequences for DNA damage responses, epigenetics, transcription, side effects and cancer therapy. PMID:23715267

  16. Effects of different bulking agents on the maturity, enzymatic activity, and microbial community functional diversity of kitchen waste compost.

    PubMed

    Wang, Xiaojuan; Zhang, Wenwei; Gu, Jie; Gao, Hua; Qin, Qingjun

    2016-10-01

    Aerobic composting is an effective method for the disposal and utilization of kitchen waste. However, the addition of a bulking agent is necessary during kitchen waste composting because of its high moisture content and low C/N ratio. In order to select a suitable bulking agent, we investigated the influence of leaf litter (LL), sawdust (SD), and wheat straw (WS) on the enzymatic activity, microbial community functional diversity, and maturity indices during the kitchen waste composting process. The results showed that the addition of WS yielded the highest maturity (the C/N ratio decreased from 25 to 13, T value = 0.5, and germination index (GI) = 114.7%), whereas the compost containing SD as a bulking agent had the lowest maturity (GI = 32.4%). The maximum cellulase and urease activities were observed with the WS treatment on day 8, whereas the SD treatment had the lowest cellulase activity and the LL treatment had the lowest urease activity. The compost temperature and microbial activity (as the average well color development) showed that bulking the composts with SD prolonged the composting process. The diversity index based on the community-level physiological profile showed that the composts bulked with LL and WS had greater microbial community functional diversity compared with those bulked with SD. Thus, the maturity indexes and enzymatic activities suggest that WS is a suitable bulking agent for use in kitchen waste composting systems.

  17. Evaluation of Chemotherapeutic Agents Against Malaria, Drugs, Diet, and Biological Response Modifiers.

    DTIC Science & Technology

    1991-10-29

    In experiment 76 the antioxidant Coenzyme Q10 (ubiquinone 50) was tested to see if it would replace vitamin E as an antioxidant and influence the...low whether started at 3 weeks of age or 4 weeks of age. 49 In experiment 76 the antioxidant coenzyme Q10 (ubiquinone 50) administered PO at 100, 36 or...line has remained stable under drug pressure for this year. Co-enzyme Q10 did not act as an antioxidant like vitamin E during a malarial infection

  18. Monitoring of Breast Tumor Response to Local Chemotherapeutic Agent Delivered by Biodegradable Fibers

    DTIC Science & Technology

    2005-05-01

    16) gives 00 00 ft.[HbO2]0 .(-K)-e-"t .dt 1 J(i().Ie-’ .d(xt) 0" 0=_. (17) f[HbO 2 10. (-K).e-l .dt fe -lt .d(ta) 0 0 Equation (17) indicates that the...Zhao, D., Constantinescu, A., and Mason, R. P., (2004), "Comparison of BOLD contrast and Gd -DTPA dynamic contrast enhanced imaging in rat prostate tumor...I. Chau, and Z. Grossman, "Functional magnetic resonance ( fMR ) imaging of a rat brain tumor model: implications for evaluation of tumor

  19. Effects of St. John’s Wort and Vitamin E on Breast Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2003-05-01

    pharmacokinetics of doxorubicin related to dietary intake of vitamin E or St . John’s wort . Rats ingesting St . John’s wort had similar survival at each...doxorubicin. Our studies indicate that vitamin E and St . John’s wort neither increase nor protect against the toxicity of doxorubicin or docetaxel in rats.

  20. 1-Alpha Hydroxyvitamin D(5) as a Chemotherapeutic and Possibly Chemopreventive Agent

    DTIC Science & Technology

    2007-03-01

    any underlying conditions that would contraindicate therapy with study treatment (or allergies to D5 used in this study). 6.2.5 Patients with prior...D2. Arch Biochem Biophys. 197:119-25. [10] Norman AW. (1998) Sunlight, season , skin pigmentation, vitamin D, and 25-hydroxyvitamin D: integral...cases of breast, colon, and prostate cancer diagnosed in the summer and fall—the seasons when serum levels of vitamin Dj are expected to be the highest

  1. How to Use a Chemotherapeutic Agent When Resistance to It Threatens the Patient.

    PubMed

    Hansen, Elsa; Woods, Robert J; Read, Andrew F

    2017-02-01

    When resistance to anticancer or antimicrobial drugs evolves in a patient, highly effective chemotherapy can fail, threatening patient health and lifespan. Standard practice is to treat aggressively, effectively eliminating drug-sensitive target cells as quickly as possible. This prevents sensitive cells from acquiring resistance de novo but also eliminates populations that can competitively suppress resistant populations. Here we analyse that evolutionary trade-off and consider recent suggestions that treatment regimens aimed at containing rather than eliminating tumours or infections might more effectively delay the emergence of resistance. Our general mathematical analysis shows that there are situations in which regimens aimed at containment will outperform standard practice even if there is no fitness cost of resistance, and, in those cases, the time to treatment failure can be more than doubled. But, there are also situations in which containment will make a bad prognosis worse. Our analysis identifies thresholds that define these situations and thus can guide treatment decisions. The analysis also suggests a variety of interventions that could be used in conjunction with cytotoxic drugs to inhibit the emergence of resistance. Fundamental principles determine, across a wide range of disease settings, the circumstances under which standard practice best delays resistance emergence-and when it can be bettered.

  2. Effects of Saint John’s Wort and Vitamin E on Breast Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2005-05-01

    standard diet and those supplemented with vitamin E (Table 1). None of the treatment means were significantly different from the control means. Table 1...different from the standard diet group (Figure 3). There was no effect of vitamin E supplementation on Hct or Hctfall after docetaxel treatment (data not...E [ High E 5000- •4000- •SEM 8 3000-2000- -1i 1000- 12 15 18 20 Docetaxel Dose (mg/kg) Figure 2. Nadir WBC counts measured 4 days after treatment of

  3. 1 ALPHA-Hydroxyvitamin D5 as a Chemotherapeutic and Possibly Chemopreventive Agent

    DTIC Science & Technology

    2004-09-01

    size 0; Apothecary Products, Inc.) 4. Preparation of 10 jig dosage: a. Weigh 3 gm of cornstarch, NF b. Using a syringe, measure 0.5 mL D5 solution...cornstarch d. Weigh 150 mg of D5/cornstarch mixture to fill each of 52 capsules (size 0; Apothecary Products, Inc.) 5. Preparation of 15 jig dosage: a...capsules (size 0; Apothecary Products, Inc.) lchydroxyvitamin D5 Phase 1/11 Trial Protocol (Version #10 (06/30/04) - Page 32 of 33 6. Preparation of 20

  4. How to Use a Chemotherapeutic Agent When Resistance to It Threatens the Patient

    PubMed Central

    Hansen, Elsa; Woods, Robert J.

    2017-01-01

    When resistance to anticancer or antimicrobial drugs evolves in a patient, highly effective chemotherapy can fail, threatening patient health and lifespan. Standard practice is to treat aggressively, effectively eliminating drug-sensitive target cells as quickly as possible. This prevents sensitive cells from acquiring resistance de novo but also eliminates populations that can competitively suppress resistant populations. Here we analyse that evolutionary trade-off and consider recent suggestions that treatment regimens aimed at containing rather than eliminating tumours or infections might more effectively delay the emergence of resistance. Our general mathematical analysis shows that there are situations in which regimens aimed at containment will outperform standard practice even if there is no fitness cost of resistance, and, in those cases, the time to treatment failure can be more than doubled. But, there are also situations in which containment will make a bad prognosis worse. Our analysis identifies thresholds that define these situations and thus can guide treatment decisions. The analysis also suggests a variety of interventions that could be used in conjunction with cytotoxic drugs to inhibit the emergence of resistance. Fundamental principles determine, across a wide range of disease settings, the circumstances under which standard practice best delays resistance emergence—and when it can be bettered. PMID:28182734

  5. Synergistic Combinations of Multiple Chemotherapeutic Agents in High Capacity Poly(2-oxazoline) Micelles

    PubMed Central

    Han, Yingchao; He, Zhijian; Schulz, Anita; Bronich, Tatiana K.; Jordan, Rainer; Luxenhofer, Robert; Kabanov, Alexander V.

    2012-01-01

    Many effective drugs for cancer treatment are poorly water-soluble. In combination chemotherapy, needed excipients in additive formulations are often toxic and restrict their applications in clinical intervention. Here, we report on amphiphilic poly(2-oxazoline)s (POx) micelles as a promising high capacity delivery platform for multi-drug cancer chemotherapy. A variety of binary and ternary drugs combinations of paclitaxel (PTX), docetaxel (DTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), etoposide (ETO) and bortezomib (BTZ) were solubilized in defined polymeric micelles achieving unprecedented high total loading capacities of up to 50 wt.% drug per final formulation. Multi-drug loaded POx micelles showed enhanced stability in comparison to single-drug loaded micelles. Drug ratio dependent synergistic cytotoxicity of micellar ETO/17-AAG was observed in MCF-7 cancer cells and of micellar BTZ/17-AAG in MCF-7, PC3, MDA-MB-231 and HepG2 cells. PMID:22681126

  6. Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma.

    PubMed

    Veytsman, Irina; Nieman, Lynnette; Fojo, Tito

    2009-09-20

    Adrenal cortical carcinoma (ACC) is a rare malignancy in which patients have poor overall 5-year survival. Patients with ACC can present with symptoms of hormone excess, including Cushing's syndrome, virilization, feminization, or--less frequently--hypertension with hypokalemia. In many patients with ACC, advanced disease at presentation precludes surgery or is followed by local relapse or distant metastatic disease that cannot be managed surgically. In these instances, chemotherapy is often tried, but its limited efficacy all too often leaves the problem of persistent hormonal excess. Physicians who treat patients with ACC and severe hypercortisolism should recognize that uncontrolled hormone production is a malignant disease, which has severe consequences that require aggressive management. Because chemotherapy benefits only a small percentage of patients, steroidogenesis inhibitors, including mitotane, ketoconazole, metyrapone, and etomidate, should be used singly or in combination even as chemotherapy is administered. Diligent management with frequent adjustments is required, especially in patients with chemotherapy-refractory tumors that continue to grow. In the absence of randomized, controlled trials, adjuvant use of mitotane remains controversial, although the authors of a recent case-control study argue for its use. Despite difficulty administering effective doses, most clinicians agree that mitotane should be used if the tumor cannot be removed surgically or should be used as adjuvant therapy if there is a high likelihood of recurrence. The option of long-term monotherapy is restricted to patients who tolerate mitotane and either experience a clinical response or are at high risk for recurrence. Recommendations are provided to help manage patients with this difficult disease and to improve the quality of their lives.

  7. Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents

    PubMed Central

    Chatelut, E; White-Koning, M L; Mathijssen, R HJ; Puisset, F; Baker, S D; Sparreboom, A

    2012-01-01

    Background: Dose banding is a recently suggested dosing method that uses predefined ranges (bands) of body surface area (BSA) to calculate each patient's dose by using a single BSA-value per band. Thus, drugs with sufficient long-term stability can be prepared in advance. The main advantages of dose banding are to reduce patient waiting time and improve pharmacy capacity planning; additional benefits include reduced medication errors, reduced drug wastage, and prospective quality control. This study compares dose banding with individual BSA dosing and fixed dose according to pharmacokinetic criteria. Methods: Three BSA bands were defined: BSA<1.7 m2, 1.7 m2⩽BSA<1.9 m2, BSA⩾1.9 m2 and each patient dose was calculated based on a unique BSA-value per band (1.55, 1.80, and 2.05 m2, respectively). By using individual clearance values of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, and topotecan) from 1012 adult cancer patients in total, the AUCs corresponding to three dosing methods (BSA dosing, dose banding, and fixed dose) were compared with a target AUC for each drug. Results: For all six drugs, the per cent variation in individual dose obtained with dose banding compared with BSA dosing ranged between −14% and +22%, and distribution of AUC values was very similar with both dosing methods. In terms of reaching the target AUC, there was no significant difference in precision between dose banding and BSA dosing, except for paclitaxel (32.0% vs 30.7%, respectively; P<0.05). However, precision was significantly better for BSA dosing compared with fixed dose for four out of six drugs. Conclusion: For the studied drugs, implementation of dose banding should be considered as it entails no significant increase in interindividual plasma exposure. PMID:22929884

  8. Selenium is a Chemotherapeutic Agent for the Treatment of Prostate Cancer

    DTIC Science & Technology

    2007-12-01

    to the AR without decreasing AR levels. Strategic targeting of the AR with ribozymes , antisense oligomers, and small interfering RNAs has been shown... ribozyme . Mol Endrocrinol 1998;12:1558-1566. 20 10. Ko YJ, Devi GR, London CA, et al. Androgen receptor down-regulation in prostate cancer with

  9. Combining chemotherapeutic agents and netrin-1 interference potentiates cancer cell death

    PubMed Central

    Paradisi, Andrea; Creveaux, Marion; Gibert, Benjamin; Devailly, Guillaume; Redoulez, Emeline; Neves, David; Cleyssac, Elsa; Treilleux, Isabelle; Klein, Christian; Niederfellner, Gerhard; Cassier, Philippe A; Bernet, Agnès; Mehlen, Patrick

    2013-01-01

    The secreted factor netrin-1 is upregulated in a fraction of human cancers as a mechanism to block apoptosis induced by netrin-1 dependence receptors DCC and UNC5H. Targeted therapies aiming to trigger tumour cell death via netrin-1/receptors interaction interference are under preclinical evaluation. We show here that Doxorubicin, 5-Fluorouracil, Paclitaxel and Cisplatin treatments trigger, in various human cancer cell lines, an increase of netrin-1 expression which is accompanied by netrin-1 receptors increase. This netrin-1 upregulation which appears to be p53-dependent is a survival mechanism as netrin-1 silencing by siRNA is associated with a potentiation of cancer cell death upon Doxorubicin treatment. We show that candidate drugs interfering with netrin-1/netrin-1 receptors interactions potentiate Doxorubicin, Cisplatin or 5-Fluorouracil-induced cancer cell death in vitro. Moreover, in a model of xenografted nude mice, we show that systemic Doxorubicin treatment triggers netrin-1 upregulation in the tumour but not in normal organs, enhancing and prolonging tumour growth inhibiting effect of a netrin-1 interfering drug. Together these data suggest that combining conventional chemotherapies with netrin-1 interference could be a promising therapeutic approach. PMID:24293316

  10. Monitoring of Breast Tumor Response to Local Chemotherapeutic Agent Delivered by Biodegradable Fibers

    DTIC Science & Technology

    2006-05-01

    Sausalito: University science books) 73-77 (1997) 46. H. Liu, A. H. Hielscher , F. K. Tittel, S. L. Jacques, and B. Chance, “Influence of blood...Reson. Imaging, 15, 41-57 (2004). 92. A. Y. Bluestone, M. Stewart, J. Lasker, G.S. Absoulaev, and A. H. Hielscher , “Three-dimensional optical...during forearm ischemia J. Appl. Physiol. 64 2449–57 [44] Liu H, Hielscher A H, Tittel F K, Jacques S L and Chance B 1995 Influence of blood vessels on

  11. Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention

    PubMed Central

    Grisold, Wolfgang; Cavaletti, Guido; Windebank, Anthony J.

    2012-01-01

    Peripheral neuropathies induced by chemotherapy (CIPN) are an increasingly frequent problem. Contrary to hema­tologic adverse effects, which can be treated with hematopoetic growth factors, neither prophylaxis nor spe­cific treatment is available, and only symptomatic treatment can be offered. Neurotoxic drugs are becoming a major dose-limiting factor. The epidemiology is still unclear. Several drug-dependent pathogenetic mechanisms exist. CIPN are predominately sensory, length-dependent neuropathies that develop after a typical cumulative dose. Usually, the appearance of CIPN is dose dependent, although in at least 2 drugs (oxaliplatin and taxanes), immediate toxic effects occur. The most frequent substances causing CIPN are platin compounds, vinka alkaloids, taxanes, and bortezomib and thalidomide. The role of synergistic neurotoxicity caused by previously given chemo­therapies and concomitant chemotherapies and the role pre-existent neuropathy on the development of a CIPN is not clear. As the number of long-term cancer survivors increases and a new focus on long-term effects of chemotherapy-induced neuropathies emerge, concepts of rehabili­tation need to be implemented to improve the patients’ functions and quality of life. PMID:23095830

  12. Influence of anionic surface-active agents on the uptake of heavy metals by water hyacinth (Eichhornia crassipes)

    SciTech Connect

    Muramoto, S.; Oki, Y.

    1984-10-01

    In a previous paper, the ability of water hyacinth to remove toxic heavy metals, cadmium, lead, and mercury, from a metal-containing solution was reported. However, information on the effects of surface-active agents on the metal uptake from waste water by water hyacinth is insufficient. Surface-active agents including anionic detergents have been found in lake, ponds, and rivers polluted by waste from industry and municipal sewage treatment plants. The present study examines the uptake of cadmium or nickel in the presence of the anionic detergent sodium dedecyl sulfate.

  13. New orally active anticoagulant agents for the prevention and treatment of venous thromboembolism in cancer patients

    PubMed Central

    Gerotziafas, Grigoris T; Mahé, Isabelle; Elalamy, Ismail

    2014-01-01

    Patients with cancer have a 6–7-fold higher risk of venous thromboembolism (VTE) as compared with non-cancer patients. Effective and safe anticoagulation for the prevention and treatment of VTE is the cornerstone of the management of patients with cancer, aiming to decrease morbidity and mortality and to improve quality of life. Unfractionated heparin, low molecular weight heparins, fondaparinux and vitamin K antagonists (VKAs) are used in the prevention and treatment of VTE in cancer patients. Heparins and fondaparinux are administered subcutaneously. VKAs are orally active, but they have a narrow therapeutic window, numerous food and drug interactions, and treatment requires regular laboratory monitoring and dose adjustment. These limitations among others have important negative impact on the quality of life of patients and decrease adherence to the treatment. New orally active anticoagulant (NOAC) agents are specific inhibitors of activated factor Xa (FXa) (rivaroxaban and apixaban) or thrombin (dabigatran). It is expected that NOACs will improve antithrombotic treatment. Cancer patients are a particular group that could benefit from treatment with NOACs. However, NOACs present some significant interactions with drugs frequently used in cancer patients, which might influence their pharmacokinetics, compromising their efficacy and safety. In the present review, we analyzed the available data from the subgroups of patients with active cancer who were included in Phase III clinical trials that assessed the efficacy and safety of NOACs in the prevention and treatment of VTE. The data from the Phase III trials in prophylaxis of VTE by rivaroxaban or apixaban highlight that these two agents, although belonging to the same pharmacological group (direct inhibitors of factor Xa), have substantially different profiles of efficacy and safety, especially in hospitalized acutely ill medical patients with active cancer. A limited number of patients with VTE and active

  14. Antipneumococcal Activity of ABT-773 Compared to Those of 10 Other Agents

    PubMed Central

    Davies, Todd A.; Ednie, Lois M.; Hoellman, Dianne M.; Pankuch, Glenn A.; Jacobs, Michael R.; Appelbaum, Peter C.

    2000-01-01

    MICs, time-kills, and postantibiotic effects (PAEs) of ABT-773 (a new ketolide) and 10 other agents were determined against 226 pneumococci. Against 78 ermB- and 44 mefE-containing strains, ABT-773 MICs at which 50% of the isolates tested were inhibited (MIC50s) and MIC90s were 0.016 to 0.03 and 0.125 μg/ml, respectively. Clindamycin was active only against macrolide-resistant strains containing mefE (MIC50, 0.06 μg/ml; MIC90, 0.125 μg/ml). Activities of pristinamycin (MIC90, 0.5 μg/ml) and vancomycin (MIC90, 0.25 μg/ml) were unaffected by macrolide or penicillin resistance, while β-lactam MICs rose with those of penicillin G. Against 19 strains with L4 ribosomal protein mutations and two strains with mutations in domain V of 23S rRNA, ABT-773 MICs were 0.03 to 0.25 μg/ml, while macrolide and azalide MICs were all ≥16.0 μg/ml. ABT-773 was bactericidal at twice the MIC after 24 h for 8 of 12 strains (including three strains with erythromycin MICs greater than or equal to 64.0 μg/ml). Kill kinetics of erythromycin, azithromycin, clarithromycin, and roxithromycin against macrolide-susceptible strains were slower than those of ABT-773. ABT-773 had longer PAEs than macrolides, azithromycin, clindamycin, or β-lactams, including against ermB-containing strains. ABT-773, therefore, shows promising in vitro activity against macrolide-susceptible as well as -resistant pneumococci. PMID:10858350

  15. In vitro activities of new and conventional antifungal agents against clinical Scedosporium isolates.

    PubMed

    Meletiadis, Joseph; Meis, Jacques F G M; Mouton, Johan W; Rodriquez-Tudela, Juan Luis; Donnelly, J Peter; Verweij, Paul E

    2002-01-01

    The susceptibilities of 13 clinical isolates of Scedosporium apiospermum and 55 clinical isolates of S. prolificans to new and conventional drugs belonging to three different classes of antifungal agents, the azoles (miconazole, itraconazole, voriconazole, UR-9825, posaconazole), the polyenes (amphotericin B, nystatin and liposomal nystatin), and allylamines (terbinafine), were studied by use of proposed standard M38-P of NCCLS. Low growth-inhibitory antifungal activities were found in vitro for most of the drugs tested against S. prolificans isolates, with the MICs at which 90% of isolates are inhibited (MIC(90)s) being >8 microg/ml; the MIC(90)s of voriconazole and UR-9825, however, were 4 microg/ml. S. apiospermum isolates were more susceptible in vitro, with the highest activity exhibited by voriconazole (MIC(90)s, 0.5 microg/ml), followed by miconazole (MIC(90)s, 1 microg/ml), UR-9825 and posaconazole (MIC(90)s, 2 microg/ml), and itraconazole (MIC(90)s, 4 microg/ml). The MICs of terbinafine, amphotericin B, and the two formulations of nystatin (for which no statistically significant differences in antifungal activities were found for the two species) for S. apiospermum isolates were high. Cross-resistance was observed among all the azoles except posaconazole and among all the polyenes except the lipid formulation. A distribution analysis was performed with the MICs of each drug and for each species. Bimodal and skewed MIC distributions were obtained, and cutoffs indicating the borders of different MIC subpopulations of the distributions were determined on the basis of the normal plot technique. These cutoffs were in many cases reproducible between 48 and 72 h.

  16. [Antimycoplasmal activities of ofloxacin and commonly used antimicrobial agents on Mycoplasma gallisepticum].

    PubMed

    Takahashi, I; Yoshida, T

    1989-05-01

    In vitro activities of ofloxacin (OFLX), a new quinolone derivative, against 29 strains of Mycoplasma gallisepticum was compared with those of 4 commonly used antimicrobial agents, doxycycline (DOXY), tylosin (TS), spectinomycin (SPCM) and thiamphenicol (TP). Antimycoplasmal activities of the drugs were evaluated on the MIC (final MIC) and MPC (minimum mycoplasmacidal concentration) values which were determined by a broth dilution procedure. The following results were obtained. 1. The MIC90s of OFLX and DOXY were both 0.20 micrograms/ml. The MICs of TS were distributed through a wide range (less than or equal to 0.006 - 0.78 micrograms/ml), and its MIC90 was 0.78 micrograms/ml. Of 29 M. gallisepticum strains, 27.6% were recognized as TS-resistant. The MIC90 values of SPCM and TP were 1.56 micrograms/ml and 3.13 micrograms/ml, respectively. The MIC90 of OFLX was equal to that of DOXY and 4- to 16-fold smaller than the values of the other 3 antibiotics. 2. The MPC of OFLX was the lowest among the antibiotics tested, its MPC90 value was 0.39 micrograms/ml and was followed by DOXY (1.56 micrograms/ml). The MPCs of TS were distributed in a wide range (0.012 - 3.13 micrograms/ml), and its MPC90 was 3.13 micrograms/ml. The MPC90 values of SPCM and TP were both 6.25 micrograms/ml. Therefore, the mycoplasmacidal activity of OFLX evaluated with MPC90 values was 4- to 16-fold greater than those of the other 4 antibiotics.

  17. Peroxides with antiplasmodial activity inhibit proliferation of Perkinsus olseni, the causative agent of Perkinsosis in bivalves.

    PubMed

    Araujo, N C P; Afonso, R; Bringela, A; Cancela, M L; Cristiano, M L S; Leite, R B

    2013-12-01

    Perkinsus olseni, the causative agent of Perkinsosis, can drastically affect the survival of target marine mollusks, with dramatic economic consequences for aquaculture. P. olseni is a member of the Alveolata group, which also comprises parasites that are highly relevant for medical and veterinary sciences such as Plasmodium falciparum and Toxoplasma. P. olseni shares several unique metabolic pathways with those pathological parasites but is not toxic to humans. In this work, six antimalarially active peroxides, derived from the natural product artemisinin or synthetic trioxolanes, were synthesized and tested on P. olseni proliferation and survival. All peroxides tested revealed an inhibitory effect on P. olseni proliferation at micromolar concentrations. The relevance of the peroxide functionality on toxicity and the effect of Fe(II)-intracellular concentration on activity were also evaluated. Results demonstrated that the peroxide functionality is the toxofore and intracellular iron concentration also proved to be a crucial co-factor on the activation of peroxides in P. olseni. These data points to a mechanism of bioactivation in P. olseni sharing similarities with the one proposed in P. falciparum parasites. Preliminary studies on bioaccumulation were conducted using fluorescent-labeled peroxides. Results show that synthetic trioxolanes tend to accumulate on a vacuole while the labeled artemisinin accumulates in the cytoplasm. Preliminary experiments on differential genes expression associated to Fe(II) transport protein (Nramp) and calcium transport protein (ATP6/SERCA) were also conducted by qPCR. Results point to a fourfold increase in expression of both genes upon exposure to trioxolanes and approximately twofold upon exposure to artemisinin derivatives. Data obtained in this investigation is relevant for better understanding of the biology of Perkinsus and may also be important in the development of new strategies for Perkinsosis prevention and control.

  18. Significant antitumor activity in vivo following treatment with the microtubule agent ENMD-1198.

    PubMed

    LaVallee, Theresa M; Burke, Patricia A; Swartz, Glenn M; Hamel, Ernest; Agoston, Gregory E; Shah, Jamshed; Suwandi, Lita; Hanson, Art D; Fogler, William E; Sidor, Carolyn F; Treston, Anthony M

    2008-06-01

    Clinical studies using the microtubule-targeting agent 2-methoxyestradiol (2ME2; Panzem) in cancer patients show that treatment is associated with clinical benefit, including prolonged stable disease, complete and partial responses, and an excellent safety profile. Studies have shown that 2ME2 is metabolized by conjugation at positions 3 and 17 and oxidation at position 17. To define structure-activity relationships for these positions of 2ME2 and to generate metabolically stable analogues with improved anti-tubulin properties, a series of analogues was generated and three lead analogues were selected, ENMD-1198, ENMD-1200, and ENMD-1237. These molecules showed improved metabolic stability with >65% remaining after 2-h incubation with hepatocytes. Pharmacokinetic studies showed that oral administration of the compounds resulted in increased plasma levels compared with 2ME2. All three analogues bind the colchicine binding site of tubulin, induce G(2)-M cell cycle arrest and apoptosis, and reduce hypoxia-inducible factor-1alpha levels. ENMD-1198 and ENMD-1200 showed improved in vitro antiproliferative activities. Significant reductions in tumor volumes compared with vehicle-treated mice were observed in an orthotopic breast carcinoma (MDA-MB-231) xenograft model following daily oral treatment with all compounds (ANOVA, P < 0.05). Significantly improved median survival time was observed with ENMD-1198 and ENMD-1237 (200 mg/kg/d) in a Lewis lung carcinoma metastatic model (P < 0.05). In both tumor models, the high-dose group of ENMD-1198 showed antitumor activity equivalent to that of cyclophosphamide. ENMD-1198 was selected as the lead molecule in this analogue series and is currently in a phase I clinical trial in patients with refractory solid tumors.

  19. Multidrug resistance: a transport system of antitumor agents and xenobiotics.

    PubMed

    Tsuruo, T

    1990-01-01

    Resistance of tumors to a variety of chemotherapeutic agents presents a major problem in cancer treatment. Resistance to such agents as doxorubicin, Vinca alkaloids, and actinomycin D can be acquired by tumor cells after treatment with a single drug. The gene responsible for multidrug resistance, termed mdr1, encodes a membrane glycoprotein (P-glycoprotein) that acts as a pump to transport various cytotoxic agents including various xenobiotics out of the cell. The amount of P-glycoprotein expression has been measured in tumor samples and was found to be elevated in intrinsically drug-resistant cancers of the colon, kidney, and adrenal as well as in some tumors that acquired drug resistance after chemotherapy. The protein was also found to be elevated in cells treated with xenobiotics. P-glycoprotein has been shown to bind anticancer drugs and several resistance-reversing agents including calcium channel blockers, and to be an ATPase. We recently reconstituted the purified P-glycoprotein into artificial liposomes. Reconstituted P-glycoprotein showed ATPase activity, ATP-dependent drug-transport activity, and calcium channel blocker-binding activity. This model provides many advantages for studies of the biochemical functions of P-glycoprotein. In addition to these basic interests, the protein is of considerable interest as a target for cancer chemotherapy because it appears to be involved in both acquired multidrug resistance and intrinsic drug resistance in human cancer. The selective killing of tumor cells expressing P-glycoprotein could be very important in future cancer therapy.

  20. Porcelain laminate veneer restorations bonded with a three-liquid silane bonding agent and a dual-activated luting composite.

    PubMed

    Matsumura, Hideo; Aida, Yukiko; Ishikawa, Yumi; Tanoue, Naomi

    2006-12-01

    This clinical report describes the fabrication and bonding of porcelain laminate veneer restorations in a patient with anterior open spaces. Laminate veneer restorations made of feldspathic porcelain were etched with 5% hydrofluoric acid, rinsed under tap water, ultrasonically cleaned with methanol, and primed with a chemically activated three-liquid silane bonding agent (Clearfil Porcelain Bond). The enamel surfaces were etched with 40% phosphoric acid, rinsed with water, and primed with a two-liquid bonding agent (Clearfil New Bond) that contained a hydrophobic phosphate (10-methacryloyloxydecyl dihydrogen phosphate; MDP). The restorations were bonded with a dual-activated luting composite (Clapearl DC). The veneers have been functioning satisfactorily for an observation period of one year. Combined use of the Clearfil bonding agents and Clapearl DC luting composite is an alternative to conventional materials for seating porcelain laminate veneer restorations, although the system is inapplicable to dentin bonding.

  1. Review and Analysis of the Role, Activities, and Training of Educational Linking Agents. Final Report.

    ERIC Educational Resources Information Center

    Piele, Philip K.

    A linking agent is a person or team operating at the interface between resources and the school systems for the purpose of facilitating change by producing interaction between the two, thereby reducing the difference between potential and actual educational practice. This discussion of agent roles and training proceeds from a discussion of change…

  2. In-vitro activity of 21 antimicrobial agents against Neisseria gonorrhoeae in Brussels.

    PubMed

    Gordts, B; Vanhoof, R; Hubrechts, J M; Dierickx, R; Coignau, H; Butzler, J P

    1982-02-01

    The minimum inhibitory concentrations (MIC) of 21 antimicrobial agents was measured for 80 strains of Neisseria gonorrhoeae isolated in Brussels in 1978. Bimodal distributions were found for penicillin G, ampicillin, amoxycillin, carbenicillin, and cephalexin. Of the strains, 17.5% were relatively resistant to penicillin G (MIC greater than 0.08 microgram/ml) 27.5% to ampicillin (MIC greater than 0.16 microgram/ml), 23.8% to amoxycillin, and 43.3% to carbenicillin. Cefotaxime was the most active antibiotic, with MICs in the nanogram range; 3.8% and 5% of the strains were relatively resistant to cephaloridine and cephalexin respectively, but no strains were resistant to cefazolin, cefuroxime, or cefotaxime. Resistance to tetracycline, doxycycline, minocycline, erythromycin, and spiramycin (MIC greater than 1 microgram/ml) was found in 6.3%, 2.5%, 5%, and 51.3% of the strains respectively. A very good correlation was present between chloramphenicol and thiamphenicol, with 16.3% and 10% of relatively resistant strains respectively. Only two isolates showed an MIC greater than 1.25 microgram/ml for rifampicin, and 10% of the strains needed greater than or equal to 12 microgram/ml of spectinomycin for complete inhibition of growth. A very high energy was found for the 20 : 1 combination of sulphamethoxazole and trimethoprim, with only one isolate resistant to this combination. None of the strains tested produced beta-lactamase.

  3. [Ajoene the main active compound of garlic (Allium sativum): a new antifungal agent].

    PubMed

    Ledezma, Eliades; Apitz-Castro, Rafael

    2006-06-01

    The curative properties of garlic in medicine have been known for a long time. But, it was only in the last three decades when garlic properties were seriously investigated confirming its potential as therapeutic agent. Allicin, ajoene, thiosulfinates and a wide range of other organosulphurate compounds, are known to be the constituents linked to the garlic properties. Regarding the biochemical properties of these compounds, ajoene [(E,Z)-4,5,9 Trithiadodeca 1,6,11 Triene 9-oxide] is stable in water, and it can be obtained by chemical synthesis. There is evidence that some of the garlic constituents exert a wide variety of effects on different biological systems. However, ajoene is the garlic compound related to more biological activities, as showed in in vitro and in vivo systems. Those studies found that ajoene has antithrombotic, anti-tumoral,antifungal, and antiparasitic effects. This study deals with a recently described antifungal property of ajoene, and its potential use in clinical trails to treat several fungal infections.

  4. Simultaneous two-photon activation of type-I photodynamic therapy agents.

    PubMed

    Fisher, W G; Partridge, W P; Dees, C; Wachter, E A

    1997-08-01

    The excitation and emission properties of several psoralen derivatives are compared using conventional single-photon excitation and simultaneous two-photon excitation (TPE). Two-photon excitation is effected using the output of a mode-locked titanium: sapphire laser, the near infrared output of which is used to promote nonresonant TPE directly. Specifically, the excitation spectra and excited-state properties of 8-methoxypsoralen and 4'-aminomethyl-4,5,8-trimethylpsoralen are shown to be equivalent using both modes of excitation. Further, in vitro feasibility of two-photon photodynamic therapy (PDT) is demonstrated using Salmonella typhimurium. Two-photon excitation may be beneficial in the practice of PDT because it would allow replacement of visible or UV excitation light with highly penetrating, nondamaging near infrared light and could provide a means for improving localization of therapy. Comparison of possible laser excitation sources for PDT reveals the titanium: sapphire laser to be exceptionally well suited for nonlinear excitation of PDT agents in biological systems due to its extremely short pulse width and high repetition rate that together provide efficient PDT activation and greatly reduced potential for biological damage.

  5. Solubilizing properties of new surface-active agents, products of catalytic oxyethylation of cholic acid.

    PubMed

    Kołodziejczyk, Michał Krzysztof; Nachajski, Michal Jakub; Lukosek, Marek; Zgoda, Marian Mikołaj

    2013-01-01

    Solubilizing properties of aqueous solutions of a series of surface-active agents, products of oxyethylation of cholic acid, were examined in the present study. The content of oxyethylated segments determined by means of the 1H NMR method enabled the verification of the molecular mass of surfactants along with the calculation of the structural hydrophilic-lipophilic balance (HLB), the solubility parameter delta1/2, and the required solubility level of balance HLB(R). Viscosimetric measurements enabled the calculation of the limiting viscosity number, the content-average molecular mass, the effective volume, the hydrodynamic radius of the surfactant micelle and their equilibrium adducts with rutin, diclofenac and loratadine (BCS Class II and III). By means of the spectrophotometric method (UV) the amount of the solubilized diclofenac, loratadine and rutin (rutoside) was determined in the equilibrium system (saturated solution) in the environment of aqueous solutions of cholic acid derivatives of n(TE) = 20-70. The obtained results serve as a basis for determining the solubilization mechanism of lipophilic therapeutic products and indirectly for estimating the influence of the above process on pharmaceutical as well as biological availability of a micellar adduct from model drug forms (Lindbladt lithogenolitic index).

  6. Curcumin derivatives as metal-chelating agents with potential multifunctional activity for pharmaceutical applications.

    PubMed

    Ferrari, Erika; Benassi, Rois; Sacchi, Stefania; Pignedoli, Francesca; Asti, Mattia; Saladini, Monica

    2014-10-01

    Curcuminoids represent new perspectives for the development of novel therapeutics for Alzheimer's disease (AD), one probable mechanism of action is related to their metal complexing ability. In this work we examined the metal complexing ability of substituted curcuminoids to propose new chelating molecules with biological properties comparable with curcumin but with improved stability as new potential AD therapeutic agents. The K2T derivatives originate from the insertion of a -CH2COOC(CH3)3 group on the central atom of the diketonic moiety of curcumin. They retain the diketo-ketoenol tautomerism which is solvent dependent. In aqueous solution the prevalent form is the diketo one but the addition of metal ion (Ga(3+), Cu(2+)) causes the dissociation of the enolic proton creating chelate complexes and shifting the tautomeric equilibrium towards the keto-enol form. The formation of metal complexes is followed by both NMR and UV-vis spectroscopy. The density functional theory (DFT) calculations on K2T21 complexes with Ga(3+) and Cu(2+) are performed and compared with those on curcumin complexes. [Ga(K2T21)2(H2O)2](+) was found more stable than curcumin one. Good agreement is detected between calculated and experimental (1)H and (13)C NMR data. The calculated OH bond dissociation energy (BDE) and the OH proton dissociation enthalpy (PDE), allowed to predict the radical scavenging ability of the metal ion complexed with K2T21, while the calculated electronic affinity (EA) and ionization potential (IP) represent yardsticks of antioxidant properties. Eventually theoretical calculations suggest that the proton-transfer-associated superoxide-scavenging activity is enhanced after binding metal ions, and that Ga(3+) complexes display possible superoxide dismutase (SOD)-like activity.

  7. Loss of Cytoplasmic CDK1 Predicts Poor Survival in Human Lung Cancer and Confers Chemotherapeutic Resistance

    PubMed Central

    Zhang, Chunyu; Elkahloun, Abdel G.; Robertson, Matthew; Gills, Joell J.; Tsurutani, Junji; Shih, Joanna H.; Fukuoka, Junya; Hollander, M. Christine; Harris, Curtis C.; Travis, William D.; Jen, Jin; Dennis, Phillip A.

    2011-01-01

    The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early stage patients and individualizing therapeutic choices. We hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery. PMID:21887332

  8. Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma.

    PubMed

    Munson, Jennifer M; Fried, Levi; Rowson, Sydney A; Bonner, Michael Y; Karumbaiah, Lohitash; Diaz, Begoña; Courtneidge, Sara A; Knaus, Ulla G; Brat, Daniel J; Arbiser, Jack L; Bellamkonda, Ravi V

    2012-03-28

    The invasive nature of glioblastoma (GBM) represents a major clinical challenge contributing to poor outcomes. Invasion of GBM into healthy tissue restricts chemotherapeutic access and complicates surgical resection. Here, we test the hypothesis that an effective anti-invasive agent can "contain" GBM and increase the efficacy of chemotherapy. We report a new anti-invasive small molecule, Imipramine Blue (IB), which inhibits invasion of glioma in vitro when tested against several models. IB inhibits NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase-mediated reactive oxygen species generation and alters expression of actin regulatory elements. In vivo, liposomal IB (nano-IB) halts invasion of glioma, leading to a more compact tumor in an aggressively invasive RT2 syngeneic astrocytoma rodent model. When nano-IB therapy was followed by liposomal doxorubicin (nano-DXR) chemotherapy, the combination therapy prolonged survival compared to nano-IB or nano-DXR alone. Our data demonstrate that nano-IB-mediated containment of diffuse glioma enhanced the efficacy of nano-DXR chemotherapy, demonstrating the promise of an anti-invasive compound as an adjuvant treatment for glioma.

  9. Parasite prolyl oligopeptidases and the challenge of designing chemotherapeuticals for Chagas disease, leishmaniasis and African trypanosomiasis.

    PubMed

    Bastos, I M D; Motta, F N; Grellier, P; Santana, J M

    2013-01-01

    The trypanosomatids Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp. cause Chagas disease, leishmaniasis and human African trypanosomiasis, respectively. It is estimated that over 10 million people worldwide suffer from these neglected diseases, posing enormous social and economic problems in endemic areas. There are no vaccines to prevent these infections and chemotherapies are not adequate. This picture indicates that new chemotherapeutic agents must be developed to treat these illnesses. For this purpose, understanding the biology of the pathogenic trypanosomatid- host cell interface is fundamental for molecular and functional characterization of virulence factors that may be used as targets for the development of inhibitors to be used for effective chemotherapy. In this context, it is well known that proteases have crucial functions for both metabolism and infectivity of pathogens and are thus potential drug targets. In this regard, prolyl oligopeptidase and oligopeptidase B, both members of the S9 serine protease family, have been shown to play important roles in the interactions of pathogenic protozoa with their mammalian hosts and may thus be considered targets for drug design. This review aims to discuss structural and functional properties of these intriguing enzymes and their potential as targets for the development of drugs against Chagas disease, leishmaniasis and African trypanosomiasis.

  10. Potent inhibition of DNA unwinding and ATPase activities of pea DNA helicase 45 by DNA-binding agents.

    PubMed

    Pham, Xuan Hoi; Tuteja, Narendra

    2002-06-07

    Pea DNA helicase 45 (PDH45) is an ATP-dependent DNA unwinding enzyme, with intrinsic DNA-dependent ATPase activity [Plant J. 24 (2000) 219]. We have determined the effect of various DNA-binding agents, such as daunorubicin, ethidium bromide, ellipticine, cisplatin, nogalamycin, actinomycin C1, and camptothecin on the DNA unwinding and ATPase activities of the plant nuclear DNA helicase PDH45. The results show that all the agents except actinomycin C1, and camptothecin inhibited the helicase (apparent K(i) values ranging from 1.5 to 7.0 microM) and ATPase (apparent K(i) values ranging from 2.5 to 11.9 microM) activities. This is the first study to show the effect of various DNA-binding agents on the plant nuclear helicase and also first to demonstrate inhibition of any helicase by cisplatin. Another striking finding that the actinomycin C1 and ellipticine act differentially on PDH45 as compared to pea chloroplast helicase suggests that the mechanism of DNA unwinding could be different in nucleus and chloroplast. These results suggest that the intercalation of the inhibitors into duplex DNA generates a complex that impedes translocation of PDH45, resulting in both the inhibitions of unwinding activity and ATP hydrolysis. This study would be useful to obtain a better understanding of the mechanism of plant nuclear DNA helicase unwinding and the mechanism by which these agents can disturb genome integrity.

  11. Hierarchical porous carbon materials prepared using nano-ZnO as a template and activation agent for ultrahigh power supercapacitors.

    PubMed

    Wang, Haoran; Yu, Shukai; Xu, Bin

    2016-09-20

    Hierarchical porous carbon materials with high surface areas and a localized graphitic structure were simply prepared from sucrose using nano-ZnO as a hard template, activation agent and graphitization catalyst simultaneously, which exhibit an outstanding high-rate performance and can endure an ultrafast scan rate of 20 V s(-1) and ultrahigh current density of 1000 A g(-1).

  12. Root Canal Irrigation: Chemical Agents and Plant Extracts Against Enterococcus faecalis

    PubMed Central

    Borzini, Letizia; Condò, Roberta; De Dominicis, Paolo; Casaglia, Adriano; Cerroni, Loredana

    2016-01-01

    Background: There are various microorganisms related to intra and extra-radicular infections and many of these are involved in persistent infections. Bacterial elimination from the root canal is achieved by means of the mechanical action of instruments and irrigation as well as the antibacterial effects of the irrigating solutions. Enterococcus faecalis can frequently be isolated from root canals in cases of failed root canal treatments. Antimicrobial agents have often been developed and optimized for their activity against endodontic bacteria. An ideal root canal irrigant should be biocompatible, because of its close contact with the periodontal tissues during endodontic treatment. Sodium hypoclorite (NaOCl) is one of the most widely recommended and used endodontic irrigants but it is highly toxic to periapical tissues. Objectives: To analyze the literature on the chemotherapeutic agent and plant extracts studied as root canal irrigants. In particularly, the study is focused on their effect on Enterococcus faecalis. Method: Literature search was performed electronically in PubMed (PubMed Central, MEDLINE) for articles published in English from 1982 to April 2015. The searched keywords were “endodontic irrigants” and “Enterococcus faecalis” and “essential oil” and “plant extracts”. Results: Many of the studied chemotherapeutic agents and plant extracts have shown promising results in vitro. Conclusion: Some of the considered phytotherapic substances, could be a potential alternative to NaOCl for the biomechanical treatment of the endodontic space. PMID:28217184

  13. Calcitriol enhances gemcitabine antitumor activity in vitro and in vivo by promoting apoptosis in a human pancreatic carcinoma model system

    PubMed Central

    Yu, Wei-Dong; Ma, Yingyu; Flynn, Geraldine; Muindi, Josephia R; Kong, Rui-Xian; Trump, Donald L

    2010-01-01

    Gemcitabine is the standard care chemotherapeutic agent to treat pancreatic cancer. Previously we demonstrated that calcitriol (1, 25-dihydroxycholecalciferol) has significant anti-proliferative effects in vitro and in vivo in multiple tumor models and enhances the activity of a variety of chemotherapeutic agents. We therefore investigated whether calcitriol could potentiate the cytotoxic activity of gemcitabine in the human pancreatic cancer Capan-1 model system. Isobologram analysis revealed that calcitriol and gemcitabine had synergistic antiproliferative effect over a wide range of drug concentrations. Calcitriol did not reduce the cytidine deaminase activity in Capan-1 tumors nor in the livers of Capan-1 tumor bearing mice. Calcitriol and gemcitabine combination promoted apoptosis in Capan-1 cells compared with either agent alone. The combination treatment also increased the activation of caspases-8, -9, -6 and -3 in Capan-1 cells. This result was confirmed by substrate-based caspase activity assay. Akt phosphorylation was reduced by calcitriol and gemcitabine combination treatment compared to single agent treatment. However, ERK1/2 phosphorylation was not modulated by either agent alone or by the combination. Tumor regrowth delay studies showed that calcitriol in combination with gemcitabine resulted in a significant reduction of Capan-1 tumor volume compared to single agent treatment. Our study suggests that calcitriol and gemcitabine in combination promotes caspase-dependent apoptosis, which may contribute to increased anti-tumor activity compared to either agent alone. PMID:20699664

  14. ['In vitro' activity of different antimicrobial agents on Gram-negative nonfermentative bacilli, excluding Pseudomonas aeruginosa and Acinetobacter spp].

    PubMed

    Vay, C A; Almuzara, M N; Rodríguez, C H; Pugliese, M L; Lorenzo Barba, F; Mattera, J C; Famiglietti, A M R

    2005-01-01

    Gram-negative nonfermentative bacilli (NFB) are widely spread in the environment. Besides of difficulties for identification, they often have a marked multiresistance to antimicrobial agents, including those active against Pseudomonas aeruginosa. The objective of this study was to evaluate the 'in vitro' activity of different antimicrobial agents on 177 gram-negative nonfermentative bacilli isolates (excluding Pseudomonas aeruginosa and Acinetobacter spp.) isolated from clinical specimens. Minimum inhibitory concentrations (MIC) were determined according to the Mueller Hinton agar dilution method against the following antibacterial agents: ampicillin, piperacillin, piperacillin-tazobactam, sulbactam, cefoperazone, cefoperazone-sulbactam, ceftazidime, cefepime, aztreonam, imipenem, meropenem, colistin, gentamicin, amikacin, trimethoprim-sulfamethoxazole, chloramphenicol, erythromycin, rifampin, norfloxacin, ciprofloxacin and minocycline. Seven isolates: Sphingobacterium multivorum (2), Sphingobacteriumspiritivorum (1), Empedobacterbrevis (1), Weeksella virosa (1), Bergeyella zoohelcum (1) and Oligella urethralis (1), were tested for amoxicillin-clavulanic acid and ampicillin-sulbactam susceptibility, and susceptibility to cefoperazone or sulbactam was not determined. Multiresistance was generally found in Stenotrophomonas maltophilia, Burkholderia cepacia, Chryseobacterium spp., Myroides spp., Achromobacter xylosoxidans, and Ochrobactrum anthropi isolates. On the other hand, Pseudomonas stutzeri, Shewanella putrefaciens-algae, Sphingomonas paucimobilis, and Pseudomonas oryzihabitans, Bergeyella zoohelcum, Weeksella virosa and Oligella urethralis were widely susceptible to the antibacterial agents tested. As a result of the wide variation in antimicrobial susceptibility shown by different species, a test on susceptibility to different antibacterial agents is essential in order to select an adequate therapy. The marked multiresistance evidenced by some species

  15. Bis-Acridines as Lead Antiparasitic Agents: Structure-Activity Analysis of a Discrete Compound Library In Vitro▿

    PubMed Central

    Caffrey, Conor R.; Steverding, Dietmar; Swenerton, Ryan K.; Kelly, Ben; Walshe, Deirdre; Debnath, Anjan; Zhou, Yuan-Min; Doyle, Patricia S.; Fafarman, Aaron T.; Zorn, Julie A.; Land, Kirkwood M.; Beauchene, Jessica; Schreiber, Kimberly; Moll, Heidrun; Ponte-Sucre, Alicia; Schirmeister, Tanja; Saravanamuthu, Ahilan; Fairlamb, Alan H.; Cohen, Fred E.; McKerrow, James H.; Weisman, Jennifer L.; May, Barnaby C. H.

    2007-01-01

    Parasitic diseases are of enormous public health significance in developing countries—a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bis-acridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 Å. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC50) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low- to mid-nanomolar EC50 values against Plasmodium falciparum and Trypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent

  16. Identification of novel chemotherapeutic strategies for metastatic uveal melanoma

    PubMed Central

    Fagone, Paolo; Caltabiano, Rosario; Russo, Andrea; Lupo, Gabriella; Anfuso, Carmelina Daniela; Basile, Maria Sofia; Longo, Antonio; Nicoletti, Ferdinando; De Pasquale, Rocco; Libra, Massimo; Reibaldi, Michele

    2017-01-01

    Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS2 web-based utility was used to predict small molecules and drugs targeting the metastatic uveal melanoma gene signature. The most promising drugs were found to be Cinnarizine, an anti-histaminic drug used for motion sickness, Digitoxigenin, a precursor of cardiac glycosides, and Clofazimine, a fat-soluble iminophenazine used in leprosy. In vitro and in vivo validation studies will be needed to confirm the efficacy of these molecules for the prevention and treatment of metastatic uveal melanoma. PMID:28303962

  17. Alterations of chemotherapeutic pharmacokinetic profiles by drug–drug interactions

    PubMed Central

    Ghalib, Mohammed; Chaudhary, Imran; Goel, Sanjay

    2012-01-01

    Background Drug interactions in oncology are common place and largely ignored as we tolerate high thresholds of ‘toxic’ drug responses in these patients. However, in the era of ‘targeted’ or seemingly ‘less toxic’ therapy, these interactions are more commonly flagged and contribute significantly towards poor ‘quality of life’ and medical fatalities. Objective This review and opinion article focuses on alteration of chemotherapeutic pharmacokinetic profiles by drug interactions in the setting of polypharmacy. The assumption is that the drugs, with changes in their pharmacokinetics, will contribute towards changes in their pharmacodynamics. Methods The examples cited for such drug–drug interactions are culled from published literature with an emphasis on those interactions that have been well characterized at the molecular level. Results Although very few drug interaction studies have been performed on approved oncology based drugs, it is clear that drugs whose pharmacokinetics profiles are closely related to their pharmacodynamics will indeed result in clinically important drug interactions. Some newer mechanisms are described that involve interactions at the level of gene transcription, whereby, drug metabolism is significantly altered. However, for any given drug interaction, there does not seem to be a comprehensive model describing interactions. Conclusions Mechanisms based drug interactions are plentiful in oncology; however, there is an absolute lack of a comprehensive model that would predict drug–drug interactions. PMID:19239394

  18. Identification of novel chemotherapeutic strategies for metastatic uveal melanoma.

    PubMed

    Fagone, Paolo; Caltabiano, Rosario; Russo, Andrea; Lupo, Gabriella; Anfuso, Carmelina Daniela; Basile, Maria Sofia; Longo, Antonio; Nicoletti, Ferdinando; De Pasquale, Rocco; Libra, Massimo; Reibaldi, Michele

    2017-03-17

    Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS(2) web-based utility was used to predict small molecules and drugs targeting the metastatic uveal melanoma gene signature. The most promising drugs were found to be Cinnarizine, an anti-histaminic drug used for motion sickness, Digitoxigenin, a precursor of cardiac glycosides, and Clofazimine, a fat-soluble iminophenazine used in leprosy. In vitro and in vivo validation studies will be needed to confirm the efficacy of these molecules for the prevention and treatment of metastatic uveal melanoma.

  19. Activity of human beta-defensin 3 alone or combined with other antimicrobial agents against oral bacteria.

    PubMed

    Maisetta, Giuseppantonio; Batoni, Giovanna; Esin, Semih; Luperini, Filippo; Pardini, Manuela; Bottai, Daria; Florio, Walter; Giuca, Maria Rita; Gabriele, Mario; Campa, Mario

    2003-10-01

    The in vitro activities of human beta-defensin 3 (hBD-3) alone or combined with lysozyme, metronidazole, amoxicillin, and chlorhexidine were investigated with the oral bacteria Streptococcus mutans, Streptococcus sanguinis, Streptococcus sobrinus, Lactobacillus acidophilus, Actinobacillus actinomycetemcomitans, and Porphyromonas gingivalis. hBD-3 showed bactericidal activity against all of the bacterial species tested. The bactericidal effect was enhanced when the peptide was used in combination with the antimicrobial agents mentioned above.

  20. Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure-Activity Relationship Study.

    PubMed

    Rana, Sandeep; Blowers, Elizabeth C; Tebbe, Calvin; Contreras, Jacob I; Radhakrishnan, Prakash; Kizhake, Smitha; Zhou, Tian; Rajule, Rajkumar N; Arnst, Jamie L; Munkarah, Adnan R; Rattan, Ramandeep; Natarajan, Amarnath

    2016-05-26

    Design, synthesis, and evaluation of α-methylene-γ-butyrolactone analogues and their evaluation as anticancer agents is described. SAR identified a spirocyclic analogue 19 that inhibited TNFα-induced NF-κB activity, cancer cell growth and tumor growth in an ovarian cancer model. A second iteration of synthesis and screening identified 29 which inhibited cancer cell growth with low-μM potency. Our data suggest that an isatin-derived spirocyclic α-methylene-γ-butyrolactone is a suitable core for optimization to identify novel anticancer agents.

  1. Antifungal activities of SCY-078 (MK-3118) and standard antifungal agents against clinical non-Aspergillus mold isolates.

    PubMed

    Lamoth, Frédéric; Alexander, Barbara D

    2015-07-01

    The limited armamentarium of active and oral antifungal drugs against emerging non-Aspergillus molds is of particular concern. Current antifungal agents and the new orally available beta-1,3-d-glucan synthase inhibitor SCY-078 were tested in vitro against 135 clinical non-Aspergillus mold isolates. Akin to echinocandins, SCY-078 showed no or poor activity against Mucoromycotina and Fusarium spp. However, SCY-078 was highly active against Paecilomyces variotii and was the only compound displaying some activity against notoriously panresistant Scedosporium prolificans.

  2. New N,N,N',N'-tetradentate Pyrazoly Agents: Synthesis and Evaluation of their Antifungal and Antibacterial Activities.

    PubMed

    Abrigach, Farid; Bouchal, Btissam; Riant, Olivier; Macé, Yohan; Takfaoui, Abdelilah; Radi, Smaail; Oussaid, Abdelouahad; Bellaoui, Mohammed; Touzani, Rachid

    2016-01-01

    A new library of N,N,N',N' -tetradentate pyrazoly compounds containing a pyrazole moiety was synthesized by the condensation of (3,5-dimethyl-1H-pyrazol-1-yl)methanol 2a or (1H-pyrazol-1-yl)methanol 2b with a series of primary diamines in refluxed acetonitrile for 6h. The antifungal activity against the budding yeast Saccharomyces cerevisiae, as well as the antibacterial activity against Escherichia coli of these new tetradentate ligands were studied. We found that these tetradentate ligands act specifically as antifungal agents and lack antibacterial activity. Their biological activities depend on the nature of the structure of the compounds.

  3. Inhibition of Thymidine Kinase Activity and Deoxyribonucleic Acid Synthesis in L Cells Infected with the Meningopneumonitis Agent

    PubMed Central

    Lin, Hsiu-San

    1968-01-01

    The activities of enzymes related to deoxyribonucleic acid (DNA) synthesis were studied in uninfected L cells and in L cells infected with Chlamydia psittaci (strain meningopneumonitis). The meningopneumonitis agent multiplied normally but failed to induce the synthesis of thymidine kinase in LM (TK−) cells which contain no thymidine kinase in the uninfected state. It was concluded that this microorganism has no thymidine kinase of its own and that it does not depend on the functioning of the host enzyme for synthesizing its DNA. Exposure of clone 5b L cells to the meningopneumonitis agent was followed by a decline in their thymidine kinase activity to nearly zero levels, whereas the levels of uridine kinase and thymidylate synthetase remained unchanged. Inhibition of thymidine kinase activity in L cells occurred soon after infection and required new protein synthesis by the meningopneumonitis agent. This inhibition occurred before inhibition of host DNA synthesis, but it was not an essential prelude to the latter inhibition. On the basis of this and previous investigations and in light of present knowledge of the mammalian cell cycle, it was postulated that the meningopneumonitis agent inhibits macromolecular synthesis in L cells by preventing the initiation of a new cell cycle. PMID:5724972

  4. Synthesis and evaluation of some 17-acetamidoandrostane and N,N-dimethyl-7-deoxycholic amide derivatives as cytotoxic agents: structure/activity studies.

    PubMed

    Huang, Yanmin; Cui, Jianguo; Jia, Linyi; Gan, Chunfang; Song, Huacan; Zeng, Chun; Zhou, Aimin

    2013-06-26

    Using pregnenolone and 7-deoxycholic acid as starting materials, some 17-acetamidoandrostane and N,N-dimethyl-7-deoxycholic amide derivatives were synthesized. The cytotoxicity of the synthesized compounds was tested in vitro against two tumor cell lines: SGC 7901 (human gastric carcinoma) and Bel 7404 (human liver carcinoma). The result showed that the blockage of the interaction of the amide group with outside groups might cause a decrease of the cytotoxicity, and an O-benzyloximino group at the 3-position of N,N-dimethyl-7-deoxycholic amide could enhance the cytotoxic activity of the compound. The information obtained from the studies provides the structure-activity relationship for these compounds and may be useful for the design of novel chemotherapeutic drugs.

  5. Methodological optimization of applying neuroactive agents for the study of locomotor-like activity in the mudpuppies (Necturus Maculatus)

    PubMed Central

    Lavrov, Igor; Cheng, Jianguo

    2008-01-01

    We compared the effects of mode of delivery of neuroactive agents and the effects of Dimethyl sulfoxide (DMSO), a vehicle for dissolving neuroactive agents, on locomotor-like activity in vitro. By superfusion, D-glutamate (0.3 – 0.9 mM) produced robust walking-like activity at superfusion rates 10–25 ml/min. In contrast, bolus application of the same or higher doses of glutamate (0.1–1.5 mM) failed to induce any rhythmic activity. Superfusion with AP-5, a NMDA receptor antagonist, produced dose-dependent inhibition of the ongoing walking-like activity induced by D-glutamate and completely blocked the activity at 20 µM. In contrast, bolus application of AP-5 did not block the walking-like activity at concentrations up to 120 µM. Similarly, superfusion of AP-5 inhibited the initiation of walking-like activity and completely blocked the initiation at 20 µM, while bolus application of AP-5 failed to do so at concentrations up to 120 µM. Superfusion of strychnine, a glycine receptor antagonist, blocked the walking-like activity at concentrations of 3–5 µM, while its bolus application altered NMDA-induced, but not glutamate-induced, walking-like activity to a synchronized pattern. DMSO significantly affected the walking-like activity in a dose-dependent manner at concentrations ranging 1–10% (v/v). These results demonstrate that the way by which the neuroactive agents are applied is a significant factor that determines the outcome of experiments on the neural control of locomotion. Also, the dose-dependent effects of DMSO on the activity of neural networks for locomotion should be taken into account in data interpretation. PMID:18692523

  6. Synthesis and investigation of the specific activity of the DNA-doxorubicin conjugates

    NASA Astrophysics Data System (ADS)

    Kokorev, A. V.; Zaborovskiy, A. V.; Kotlyarov, A. A.; Balykova, L. A.; Malkina, M. A.; Kargina, I. V.; Gromova, E. V.; Medvezhonkov, V. Yu; Gurevich, K. G.; Shchukin, S. A.; Pyataev, N. A.

    2017-01-01

    In the present work, the method of obtaining the conjugate of the anticancer chemotherapeutic agent doxorubicin to the exogenous double-stranded DNA of the sturgeons is proposed (the source: commercial drug “Derinat”). The optimal conditions for synthesis of conjugate (pH, temperature and the mass ratio of the components), ensuring the highest degree of binding the chemotherapeutic agent to a carrier, were picked out. Clearing the conjugate from the non-encapsulated chemotherapeutic agent was being made by ultrafiltration method. The investigation of the toxicity and specific antineoplastic activity of the synthesized complex was conducted. The performance of the drug toxicity were established on the intact mice in compliance with the accepted standards. The antineoplastic activity was evaluated upon the Tumor Growth Inhibition Index and Metastasis Inhibition Index on mice with the transplanted Lewis lung carcinoma (LLC). It was demonstrated that the conjugate toxicity is approximately lower that the one of the unconjugated doxorubicin (LD 50 was equal 14.6 mg/kg and 9.9 mg/kg for the conjugate and doxorubicin, respectively). The specific antineoplastic activity was investigated in equitoxic doses of the drug. It was established that the conjugate being administered in equitoxic doses possesses a stronger antineoplastic activity, than the water-soluble drug (maximum 35% more as to the tumor volume and 51% more as to the Tumor Growth Inhibition index).

  7. Redesigning the DNA-Targeted Chromophore in Platinum–Acridine Anticancer Agents: A Structure–Activity Relationship Study

    PubMed Central

    Pickard, Amanda J.; Liu, Fang; Bartenstein, Thomas F.; Haines, Laura G.; Levine, Keith E.; Kucera, Gregory L.; Bierbach, Ulrich

    2014-01-01

    Platinum–acridine hybrid agents show low-nanomolar potency in chemoresistant non-small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build–click–screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7-Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent (P1–B1) that maintained submicromolar activity in several of the DNA-repair proficient and p53-mutant cancer models, while showing improved tolerability in mice by 32-fold compared to the parent platinum–acridine (P1–A1). The distribution and DNA/RNA adduct levels produced by the acridine- and benz[c]acridine-based analogues in NCI-H460 cells (confocal microscopy, ICP-MS), and their ability to bind G-quadruplex forming DNA sequences (CD spectroscopy, HR-ESMS) were studied. P1–B1 emerges as a less genotoxic, more tolerable, and potentially more target-selective hybrid agent than P1–A1. PMID:25302716

  8. Mechanistic Basis of Calmodulin Mediated Estrogen Receptor Alpha Activation and Antiestrogen Resistance

    DTIC Science & Technology

    2009-06-01

    cancers . Calmodulin (CaM) is an obligatory ERa activator. Moreover, antiestrogens (tamoxifen) bind tightly to CaM, and some therapeutic benefits of...antiestrogens for breast cancers are hypothesized to derive from this interaction. The purpose and scope of the research is to define the structural...antiestrogens, including the most widely used chemotherapeutic agent for estrogen-dependent breast cancers , tamoxifen (TAM). The therapeutic effects of

  9. Inhibition of hydrogen sulfide biosynthesis sensitizes lung adenocarcinoma to chemotherapeutic drugs by inhibiting mitochondrial DNA repair and suppressing cellular bioenergetics

    PubMed Central

    Szczesny, Bartosz; Marcatti, Michela; Zatarain, John R.; Druzhyna, Nadiya; Wiktorowicz, John E.; Nagy, Péter; Hellmich, Mark R.; Szabo, Csaba

    2016-01-01

    Therapeutic manipulation of the gasotransmitter hydrogen sulfide (H2S) has recently been proposed as a novel targeted anticancer approach. Here we show that human lung adenocarcinoma tissue expresses high levels of hydrogen sulfide (H2S) producing enzymes, namely, cystathionine beta-synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), in comparison to adjacent lung tissue. In cultured lung adenocarcinoma but not in normal lung epithelial cells elevated H2S stimulates mitochondrial DNA repair through sulfhydration of EXOG, which, in turn, promotes mitochondrial DNA repair complex assembly, thereby enhancing mitochondrial DNA repair capacity. In addition, inhibition of H2S-producing enzymes suppresses critical bioenergetics parameters in lung adenocarcinoma cells. Together, inhibition of H2S-producing enzymes sensitize lung adenocarcinoma cells to chemotherapeutic agents via induction of mitochondrial dysfunction as shown in in vitro and in vivo models, suggesting a novel mechanism to overcome tumor chemoresistance. PMID:27808278

  10. Design of Protease Activated Optical Contrast Agents That Exploit a Latent Lysosomotropic Effect for Use in Fluorescence-Guided Surgery

    PubMed Central

    2015-01-01

    There is a need for new molecular-guided contrast agents to enhance surgical procedures such as tumor resection that require a high degree of precision. Cysteine cathepsins are highly up-regulated in a wide variety of cancers, both in tumor cells and in the tumor-supporting cells of the surrounding stroma. Therefore, tools that can be used to dynamically monitor their activity in vivo could be used as imaging contrast agents for intraoperative fluorescence image guided surgery (FGS). Although multiple classes of cathepsin-targeted substrate probes have been reported, most suffer from overall fast clearance from sites of protease activation, leading to reduced signal intensity and duration in vivo. Here we describe the design and synthesis of a series of near-infrared fluorogenic probes that exploit a latent cationic lysosomotropic effect (LLE) to promote cellular retention upon protease activation. These probes show tumor-specific retention, fast activation kinetics, and rapid systemic distribution. We demonstrate that they are suitable for detection of diverse cancer types including breast, colon and lung tumors. Most importantly, the agents are compatible with the existing, FDA approved, da Vinci surgical system for fluorescence guided tumor resection. Therefore, our data suggest that the probes reported here can be used with existing clinical instrumentation to detect tumors and potentially other types of inflammatory lesions to guide surgical decision making in real time. PMID:26039341

  11. Discovery of new anticancer agents from higher plants

    PubMed Central

    Pan, Li; Chai, Hee-Byung; Kinghorn, A. Douglas

    2012-01-01

    1. ABSTRACT Small organic molecules derived from higher plants have been one of the mainstays of cancer chemotherapy for approximately the past half a century. In the present review, selected single chemical entity natural products of plant origin and their semi-synthetic derivatives currently in clinical trials are featured as examples of new cancer chemotherapeutic drug candidates. Several more recently isolated compounds obtained from plants showing promising in vivo biological activity are also discussed in terms of their potential as anticancer agents, with many of these obtained from species that grow in tropical regions. Since extracts of only a relatively small proportion of the ca. 300,000 higher plants on earth have been screened biologically to date, bioactive compounds from plants should play an important role in future anticancer drug discovery efforts. PMID:22202049

  12. Aminopyrrolic synthetic receptors for monosaccharides: a class of carbohydrate-binding agents endowed with antibiotic activity versus pathogenic yeasts.

    PubMed

    Nativi, Cristina; Francesconi, Oscar; Gabrielli, Gabriele; De Simone, Irene; Turchetti, Benedetta; Mello, Tommaso; Di Cesare Mannelli, Lorenzo; Ghelardini, Carla; Buzzini, Pietro; Roelens, Stefano

    2012-04-16

    The biological activity of a set of structurally related aminopyrrolic synthetic receptors for monosaccharides has been tested versus yeast and yeast-like microorganisms and compared to their binding affinity toward mannosides. Antibiotic activity comparable to that of well-known polyene (amphotericin B) or azole (ketoconazole) drugs has been found for some members of the family, along with a general correlation with binding abilities. A systematic structure-activity-affinity investigation shed light on the structural and functional requirements necessary for antibiotic activity and identified the tripodal compound 1 as the most potent compound of the set. Together with toxicity tests and inhibitor localization experiments performed through fluorescence microscopy, these studies led to the characterization of a new class of carbohydrate binding agents possessing antibiotic activity, in which pyrrolic groups precisely structured on a tripodal architecture appear to be responsible for permeability through the cell wall of pathogens, as well as for antibiotic activity inside the cytoplasm.

  13. Quantifying activation of perfluorocarbon-based phase-change contrast agents using simultaneous acoustic and optical observation.

    PubMed

    Li, Sinan; Lin, Shengtao; Cheng, Yi; Matsunaga, Terry O; Eckersley, Robert J; Tang, Meng-Xing

    2015-05-01

    Phase-change contrast agents in the form of nanoscale droplets can be activated into microbubbles by ultrasound, extending the contrast beyond the vasculature. This article describes simultaneous optical and acoustical measurements for quantifying the ultrasound activation of phase-change contrast agents over a range of concentrations. In experiments, decafluorobutane-based nanodroplets of different dilutions were sonicated with a high-pressure activation pulse and two low-pressure interrogation pulses immediately before and after the activation pulse. The differences between the pre- and post-interrogation signals were calculated to quantify the acoustic power scattered by the microbubbles activated over a range of droplet concentrations. Optical observation occurred simultaneously with the acoustic measurement, and the pre- and post-microscopy images were processed to generate an independent quantitative indicator of the activated microbubble concentration. Both optical and acoustic measurements revealed linear relationships to the droplet concentration at a low concentration range <10(8)/mL when measured at body temperature. Further increases in droplet concentration resulted in saturation of the acoustic interrogation signal. Compared with body temperature, room temperature was found to produce much fewer and larger bubbles after ultrasound droplet activation.

  14. Inhibitory activity of chelating agent against bacteria associated with poultry processing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ethylenediaminetetraacetic acid (EDTA) and ethylenediamine-N, N’-disuccinic acid (EDDS) are chelating agents that can bind minerals that produce water hardness. By sequestering minerals in hard water, chelators reduce water hardness and increase the ability of cleansers to remove dirt and debris dur...

  15. In vitro antioxidant activity of Valeriana officinalis against different neurotoxic agents.

    PubMed

    Sudati, Jéssie Haigert; Fachinetto, Roselei; Pereira, Romaiana Picada; Boligon, Aline Augusti; Athayde, Margareth Linde; Soares, Felix Antunes; de Vargas Barbosa, Nilda Berenice; Rocha, João Batista Teixeira

    2009-08-01

    Valeriana officinalis L. (Valerian) is widely used as a traditional medicine to improve the quality of sleep. Although V. officinalis have been well documented as promising pharmacological agent; the exact mechanisms by which this plant act is still unknown. Limited literature data have indicated that V. officinalis extracts can exhibit antioxidant properties against iron in hippocampal neurons in vitro. However, there is no data available about the possible antioxidant effect of V. officinalis against other pro-oxidants in brain. In the present study, the protective effect of V. officinalis on lipid peroxidation (LPO) induced by different pro-oxidant agents with neuropathological importance was examined. Ethanolic extract of valerian (0-60 microg/ml) was tested against quinolinic acid (QA); 3-nitropropionic acid; sodium nitroprusside; iron sulfate (FeSO4) and Fe2+/EDTA induced LPO in rat brain homogenates. The effect of V. officinalis in deoxyribose degradation and reactive oxygen species (ROS) production was also investigated. In brain homogenates, V. officinalis inhibited thiobarbituric acid reactive substances induced by all pro-oxidants tested in a concentration dependent manner. Similarly, V. officinalis caused a significant decrease on the LPO in cerebral cortex and in deoxyribose degradation. QA-induced ROS production in cortical slices was also significantly reduced by V. officinalis. Our results suggest that V. officinalis extract was effective in modulating LPO induced by different pro-oxidant agents. These data may imply that V. officinalis extract, functioning as antioxidant agent, can be beneficial for reducing insomnia complications linked to oxidative stress.

  16. Production and characterization of vaginal suppositories with propolis wax as active agent to prevent and treat Fluor albus

    NASA Astrophysics Data System (ADS)

    Farida, Siti; Azizah, Nurul; Hermansyah, Heri; Sahlan, Muhamad

    2017-02-01

    Based on the content contained in propolis wax especially antimicrobial function, it can be analyzed that propolis wax had superiority for Fluor albus. This research was conducted on two formulation of vaginal suppositories with base, supplementary and active agent as a fixed variable: 2% propolis wax (% w/w). Evaluation of this research were weight variation, melting time, consistency, irritation effect test and physical and chemical stability test (organoleptic, pH and polyphenol content).

  17. Light illuminated α-Fe2O3/Pt nanoparticles as water activation agent for photoelectrochemical water splitting.

    PubMed

    Li, Xiaodong; Wang, Zhi; Zhang, Zemin; Chen, Lulu; Cheng, Jianli; Ni, Wei; Wang, Bin; Xie, Erqing

    2015-03-16

    The photoelectrochemical (PEC) water splitting is hampered by strong bonds of H2O molecules and low ionic conductivity of pure water. The photocatalysts dispersed in pure water can serve as a water activation agent, which provides an alternative pathway to overcome such limitations. Here we report that the light illuminated α-Fe2O3/Pt nanoparticles may produce a reservoir of reactive intermediates including H2O2, ·OH, OH(-) and H(+) capable of promoting the pure water reduction/oxidation half-reactions at cathode and highly photocatalytic-active TiO2/In2S3/AgInS2 photoanode, respectively. Remarkable photocurrent enhancement has been obtained with α-Fe2O3/Pt as water activation agent. The use of α-Fe2O3/Pt to promote the reactivity of pure water represents a new paradigm for reproducible hydrogen fuel provision by PEC water splitting, allowing efficient splitting of pure water without adding of corrosive chemicals or sacrificial agent.

  18. Activity of 129 Single-Agent Drugs in 228 Phase I and II Clinical Trials in Multiple Myeloma

    PubMed Central

    Kortuem, K. Martin; Zidich, Kaitlyn; Schuster, Steven R.; Khan, Meaghan L.; Jimenez-Zepeda, Victor H.; Mikhael, Joseph R.; Fonseca, Rafael; Stewart, A. Keith

    2014-01-01

    Background More than 400 preclinical studies report ≥ 1 compound as cytotoxic to multiple myeloma (MM) cells; however, few of these agents became relevant in the clinic. Thus, the utility of such assays in predicting future clinical value is debatable. Patients and Methods We examined the application of early-phase trial experiences to predict future clinical adoption. We identified 129 drugs explored as single agents in 228 trials involving 7421 patients between 1961 and 2013. Results All drugs in common use in MM (melphalan, dexamethasone, prednisone, cyclophosphamide, bendamustine, thalidomide, lenalidomide, pomalidomide, bortezomib, carfilzomib, and doxorubicin) demonstrated a best reported response rate of ≥ 22%. Older agents, including teniposide, fotemustine, paclitaxel, and interferon, also appear active by this criterion; however, if mean response rates from all reported trials for an agent are considered, then only drugs with a mean response rate of 15% partial response are in clinical use. Conclusion Our analysis suggests that thresholds of 20% for best or 15% for mean response are highly predictive of future clinical success. Below these thresholds, no drug has yet reached regulatory approval or widespread use in the clinic. Thus, this benchmark provides 1 element of the framework for guiding choice of drugs for late-stage clinical testing. PMID:24565465

  19. Behaviorally active green leaf volatiles for monitoring the leaf beetle, Diorhabda elongata, a biocontrol agent of saltcedar, Tamarix spp.

    PubMed

    Cossé, Allard A; Bartelt, Robert J; Zilkowski, Bruce W; Bean, Daniel W; Andress, Earl R

    2006-12-01

    Biological activity and chemistry of host plant volatiles were investigated for Diorhabda elongata, Brullé (Coleoptera: Chrysomelidae), a biological control agent for the invasive tree, saltcedar (Tamarix spp., Tamaricaceae). Gas chromatographic-electroantennographic detection (GC-EAD) analysis of volatiles collected from adult D. elongata feeding on saltcedar foliage or from saltcedar foliage alone showed 15 antennally active compounds. These compounds were more abundant in collections from beetle-infested foliage. Antennally active compounds were identified by GC-mass spectrometry (MS) and confirmed with authentic standards. The emissions of the most abundant GC-EAD-active compounds, green leaf volatiles (GLV), were quantitated by GC-MS. A blend of four GLV compounds, mimicking the natural blend ratio, was highly attractive to male and female D. elongata in the field, and a combination of GLV and male-produced aggregation pheromone attracted significantly greater numbers of D. elongata than did either bait alone. A preliminary experiment with a blend of seven additional GC-EAD-active saltcedar volatiles did not show any behavioral activity. The combination of the pheromone and the green leaf odor blend could be a useful attractant in detecting the presence of the biocontrol agent, D. elongata, in stands of saltcedar newly colonized by the beetle.

  20. Detrimental effects of chemotherapeutics and other drugs on the endothelium: A call for endothelial toxicity profiling.

    PubMed

    Wojcik, Tomasz; Szczesny, Ewa; Chlopicki, Stefan

    2015-08-01

    The vascular endothelium is a real "maestro of circulation", and endothelial dysfunction leads to atherothrombosis, its cardiovascular complications, as well as to many other diseases. It is surprising that quite a large number of drugs seem to hamper the vasoprotective mechanisms of the endothelium, possibly promoting the development of cardiovascular diseases in patients initially treated for non-cardiological conditions. Toxicity profiling (including cardiac and liver toxicity assessment) is a routine procedure performed during pre-clinical drug development. Unfortunately, endothelium-dependent side effects are not taken into account in standard toxicity profiling protocols, as the "endothelial safety" of drugs is not required in order to enter the clinical phase of drug development. Presumably, this might be one of the reasons why several efficient therapeutics, including rofecoxib (COX-2 inhibitor), torcetrapib (CETP-inhibitor), and bardoxolone (Nrf2 activator), have unexpectedly displayed clinically significant cardiovascular hazard, resulting in their withdrawal from the market or alarming comments, respectively. In this review, we will briefly characterize the endothelial activity profiles of chemotherapeutics, antidepressants and antipsychotics-all drugs prescribed for severe, life-threatening and/or life-long diseases-and will show that at least some of them may display clinically relevant detrimental effects on endothelial function.

  1. Development of a theoretical model describing sonoporation activity of cells exposed to ultrasound in the presence of contrast agents

    PubMed Central

    Forbes, Monica M.; O’Brien, William D.

    2012-01-01

    Sonoporation uses ultrasound, with the aid of ultrasound contrast agents (UCAs), to enhance cell permeabilization, thereby allowing delivery of therapeutic compounds noninvasively into specific target cells. The objective of this study was to determine if a computational model describing shear stress on a cell membrane due to microstreaming would successfully reflect sonoporation activity with respect to the peak rarefactional pressure. The theoretical models were compared to the sonoporation results from Chinese hamster ovary cells using Definity® at 0.9, 3.15, and 5.6 MHz and were found to accurately describe the maximum sonoporation activity, the pressure where a decrease in sonoporation activity occurs, and relative differences between maximum activity and the activity after that decrease. Therefore, the model supports the experimental findings that shear stress on cell membranes secondary to oscillating UCAs results in sonoporation. PMID:22501051

  2. Preparation of active antibacterial LDPE surface through multistep physicochemical approach: I. Allylamine grafting, attachment of antibacterial agent and antibacterial activity assessment.

    PubMed

    Bílek, František; Křížová, Táňa; Lehocký, Marián

    2011-11-01

    Low-density polyethylene (LDPE) samples were treated in air plasma discharge, coated by polyallyamine brush thought copolymeric grafting surface-from reaction and deposited four common antibacterial agents (benzalkonium chloride, bronopol, chlorhexidine and triclosan) to gain material with active antibacterial properties. Surface characteristics were evaluated by static contact angle measurement with surface energy evaluation ATR-FTIR, X-ray Photoelectron Spectroscopy (XPS) and SEM analysis. Inhibition zone on agar was used as in vitro test of antibacterial properties on two representative gram positive Staphylococcus aureus (S. aureus) and gram negative Escherichia coli (E. coli) strains. It was confirmed, that after grafting of polyallyamine, more antibacterial agent is immobilized on the surface. The highest increase of antibacterial activity was observed by the sample containing triclosan. Samples covered by bronopol did not show significant antibacterial activity.

  3. Silencing Livin induces apoptotic and autophagic cell death, increasing chemotherapeutic sensitivity to cisplatin of renal carcinoma cells.

    PubMed

    Wang, Zhiyang; Liu, Shuai; Ding, Kejia; Ding, Sentai; Li, Chensheng; Lu, Jiaju; Gao, Dexuan; Zhang, Tong; Bi, Dongbin

    2016-11-01

    Renal cell carcinoma (RCC) accounts for 3 % of all adult malignancies and is the most lethal urological cancer. Livin is a member of the inhibitor of apoptosis protein (IAP) family, which is associated with tumor resistance to radiotherapy and chemotherapy. Clinical data also showed that patients with high tumor grades and stages have higher expression levels of Livin in RCC cells. Autophagy is a survival mechanism activated in response to nutrient deprivation. A possible role of Livin in the autophagy of RCC cells has not been investigated; therefore, this pioneer study was carried out. Livin was silenced in RCC cells (slow virus infection [SVI]-shLivin cells) by lentiviral transfection. Then, mRNA and protein expression levels in the transfected cells were assessed by quantitative fluorescence PCR and Western blotting, respectively. In addition, acridine orange staining and electron microscopy were used to assess autophagy in SVI-shLivin cells. The cisplatin IC50 values for RCC cells were measured by the CCK8 assay. Potent antitumor activities were observed in xenograft mouse models generated with Livin-silenced RCC cells in terms of delayed tumor onset and suppressed tumor growth. These results suggested that Livin silencing could increase the chemotherapeutic sensitivity of RCC cells to cisplatin and induce autophagic cell death. A possible mechanism of Bcl-2 and Akt pathway involvement was discussed specifically in this study. Overall, Livin silencing induces apoptotic and autophagic cell death and increases chemotherapeutic sensitivity of RCC cells to cisplatin.

  4. Enhanced delivery of the RAPTA-C macromolecular chemotherapeutic by conjugation to degradable polymeric micelles.

    PubMed

    Blunden, Bianca M; Lu, Hongxu; Stenzel, Martina H

    2013-12-09

    Macromolecular ruthenium complexes are a promising avenue to better and more selective chemotherapeutics. We have previously shown that RAPTA-C [RuCl2(p-cymene)(PTA)], with the water-soluble 1,3,5-phosphaadamantane (PTA) ligand, could be attached to a polymer moiety via nucleophilic substitution of an available iodide with an amide in the PTA ligand. To increase the cell uptake of this macromolecule, we designed an amphiphilic block copolymer capable of self-assembling into polymeric micelles. The block copolymer was prepared by ring-opening polymerization of d,l-lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) using a RAFT agent with an additional hydroxyl functionality, followed by the RAFT copolymerization of 2-hydroxyethyl acrylate (HEA) and 2-chloroethyl methacrylate (CEMA). The Finkelstein reaction and reaction with PTA led to polymers that can readily react with the dimer of RuCl2(p-cymene) to create a macromolecular RAPTA-C drug. RAPTA-C conjugation, micellization, and subsequent cytotoxicity and cell uptake of these polymeric moieties was tested on ovarian cancer A2780, A2780cis, and Ovcar-3 cell lines. Confocal microscopy images confirmed cell uptake of the micelles into the lysosome of the cells, indicative of an endocytic pathway. On average, a 10-fold increase in toxicity was found for the macromolecular drugs when compared to the RAPTA-C molecule. Furthermore, the cell uptake of ruthenium was analyzed and a significant increase was found for the micelles compared to RAPTA-C. Notably, micelles prepared from the polymer containing fewer HEA units had the highest cytotoxicity, the best cell uptake of ruthenium and were highly effective in suppressing the colony-forming ability of cells.

  5. Predictive imaging of chemotherapeutic response in a transgenic mouse model of pancreatic cancer

    PubMed Central

    Wang, Ping; Yoo, Byunghee; Sherman, Sarah; Mukherjee, Pinku; Ross, Alana; Pantazopoulos, Pamela; Petkova, Victoria; Farrar, Christian; Medarova, Zdravka; Moore, Anna

    2016-01-01

    The underglycosylated mucin 1 tumor antigen (uMUC1) is a biomarker that forecasts the progression of adenocarcinomas. In this study, we evaluated the utility of a dual-modality molecular imaging approach based on targeting uMUC1 for monitoring chemotherapeutic response in a transgenic murine model of pancreatic cancer (KCM triple transgenic mice). An uMUC1-specific contrast agent (MN-EPPT) was synthesized for use with magnetic resonance imaging (MRI) and fluorescence optical imaging. It consisted of dextran-coated iron oxide nanoparticles conjugated to the near infrared fluorescent dye Cy5.5 and to a uMUC1-specific peptide (EPPT). KCM triple transgenic mice were given gemcitabine as chemotherapy while control animals received saline injections following the same schedule. Changes in uMUC1 levels following chemotherapy were monitored using T2-weighted MRI and optical imaging before and 24 hr after injection of the MN-EPPT. uMUC1 expression in tumors from both groups was evaluated by histology and qRT-PCR. We observed that the average delta-T2 in the gemcitabine-treated group was significantly reduced compared to the control group indicating lower accumulation of MN-EPPT, and correspondingly, a lower level of uMUC1 expression. In vivo optical imaging confirmed the MRI findings. Fluorescence microscopy of pancreatic tumor sections showed a lower level of uMUC1 expression in the gemcitabine-treated group compared to the control, which was confirmed by qRT-PCR. Our data proved that changes in uMUC1 expression after gemcitabine chemotherapy could be evaluated using MN-EPPT-enhanced in vivo MR and optical imaging. These results suggest that the uMUC1-targeted imaging approach could provide a useful tool for the predictive assessment of therapeutic response. PMID:26996122

  6. Activity of an alkaline 'cleaner' in the inactivation of the scrapie agent.

    PubMed

    Baier, M; Schwarz, A; Mielke, M

    2004-05-01

    The capacity of a routinely available alkaline cleaner for medical devices to inactivate the causative agent of a transmissible spongiform encephalopathy (TSE) was tested. The co-incubation of brain homogenates, prepared from terminally ill scrapie-infected hamsters, with the cleaner led to the denaturation of misfolded protein as the proteinase K-resistant prion protein was no longer detectable after such treatment. In addition, intra-cerebral inoculation of hamsters with the alkaline cleaner-treated and subsequently neutralized samples reduced the level of infectivity of the material below the limit of detection. This report shows the possibility that a routinely available alkaline cleaner could reduce the infectivity of TSE agents and so minimize the risk of iatrogenic transmission of TSEs by asymptomatic carriers. This study is intended to encourage further investigations in this field.

  7. Comparison of the in vitro activities of newer triazoles and established antifungal agents against Trichophyton rubrum.

    PubMed

    Deng, Shuwen; Zhang, Chao; Seyedmousavi, Seyedmojtaba; Zhu, Shuang; Tan, Xin; Wen, Yiyang; Huang, Xin; Lei, Wenzhi; Zhou, Zhaojing; Fang, Wenjie; Shen, Shuaishuai; Deng, Danqi; Pan, Weihua; Liao, Wanqing

    2015-07-01

    One hundred eleven clinical Trichophyton rubrum isolates were tested against 7 antifungal agents. The geometric mean MICs of all isolates were, in increasing order: terbinafine, 0.03 mg/liter; voriconazole, 0.05 mg/liter; posaconazole, 0.11 mg/liter; isavuconazole, 0.13 mg/liter; itraconazole, 0.26 mg/liter; griseofulvin, 1.65 mg/liter; and fluconazole, 2.12 mg/liter.

  8. VP-16 and alkylating agents activate a common metabolic pathway for suppression of DNA replication

    SciTech Connect

    Das, S.K.; Berger, N.A.

    1986-05-01

    The cytotoxic effects of etoposide (VP-16) are mediated by topoisomerase II production of protein crosslinked DNA strand breaks. Previous studies have shown that alkylating agent induced DNA damage results in expansion of dTTP pools and reduction of dCTP pools and DNA replication. Studies were conducted with V79 cells to determine whether the metabolic consequences of VP-16 treatment were similar to those induced by alkylating agents. Treatment with 0.5..mu..M VP-16 prolonged the doubling time of V79 cells from 12 to 18 hrs and caused cell volume to increase from 1.1 to 1.6 x 10/sup -12/l. 2mM caffeine completely blocked the volume increase and substantially prevented the prolongation of doubling time. 5..mu..M VP-16 reduced the rate of (/sup 3/H)TdR incorporation by 70%, whereas in the presence of 2mM caffeine, VP-16 caused only a 10% decrease in the rate of (/sup 3/H)TdR incorporation. 4 hr treatment with 5.0..mu..M VP-16 increased dTTP levels from 65 +/- 10 pmol/10/sup 6/ cells to 80 +/- 13 pmol/10/sup 6/ cells and caused dCTP level to decline from 113 +/- 23 pmol/10/sup 6/ cells to 92 +/- 17 pmol/10/sup 6/ cells. These results indicate that the metabolic consequences of VP-16 treatment are similar to alkylating agent treatment and that an increase in dTTP pools with a subsequent effect on ribonucleotide reductase may be a final common pathway by which many cytotoxic agents suppress DNA synthesis.

  9. Activity of Topical Antimicrobial Agents Against Multidrug-Resistant Bacteria Recovered from Burn Patients

    DTIC Science & Technology

    2010-01-01

    both the prophylaxis and treatment of burn wound infections [18]. Agents such as silver sulfadiazine , silver nitrate, mupirocin, honey, mafenide...include emerging resistance of staphylococci to mupirocin and of Pseudomonas aeruginosa to silver sulfadiazine (Table 1) [9,18–21]. Prior studies...administered routinely peri-operatively and various topical antimicrobials are used to include silver sulfadiazine , mafe- nide acetate, silver nitrate

  10. In vitro evaluation of the antibacterial activity of Arctium lappa as a phytotherapeutic agent used in intracanal dressings.

    PubMed

    Gentil, Marcelo; Pereira, Juliana Vianna; Sousa, Yara T Corrêa Silva; Pietro, Rosimeire; Neto, Manoel D Sousa; Vansan, Luiz Pascoal; de Castro França, Suzelei

    2006-03-01

    The discovery of natural biocomponents from plants with antibacterial activity on endodontic microbiota may lead to new therapies. This study evaluated the antibacterial activity of a phytotherapeutic agent prepared from an ethyl acetate fraction (AcOEt) extracted from Arctium lappa. This agent was compared with calcium hydroxide as an intracanal dressing. Twenty-seven maxillary canines were instrumented, sterilized and inoculated with a mixed bacterial suspension of Pseudomonas aeruginosa, Escherichia coli, Lactobacillus acidophilus, Streptococcus mutans and Candida albicans. The teeth were divided into three groups and their canals filled with: group 1, calcium hydroxide and propylene glycol; group 2, a paste containing AcOEt fraction of A. lappa and propylene glycol; group 3, propylene glycol (control). At 7, 14 and 30 days, three teeth from each group were opened and a paper point was placed in the root canal for 5 min. The paper points were transferred to Petri dishes with Brain Heart Infusion (BHI). The bacterial growth was classified. Mild bacterial growth was found in group 1 at all time intervals; in group 2 there was severe growth at 7 days, but no growth at 14 and 30 days. The phytotherapeutic agent extracted from an AcOEt fraction of A. lappa inhibited the growth of all the microorganisms in this study.

  11. RGTA OTR4120, a heparan sulfate mimetic, is a possible long-term active agent to heal burned skin.

    PubMed

    Garcia-Filipe, S; Barbier-Chassefiere, V; Alexakis, C; Huet, E; Ledoux, D; Kerros, M E; Petit, E; Barritault, D; Caruelle, J P; Kern, P

    2007-01-01

    Burn-related skin fibrosis leads to loss of tissue function and hypertrophic scar formation with damaging consequences for the patient. There is therefore a great need for an efficient agent to treat burned skin. We report that ReGeneraTing Agent (RGTA) reduces burn-induced skin alteration. The tissue-regenerating effect of RGTA OTR4120 was evaluated after 1-6 days and after 10 months in a rat skin burn model. This effect was also examined in vitro using fibroblasts isolated from control and 6-day-old burned skins. We measured production of dermal collagen I, III, and V and activities of metalloproteinases 2 and 9 (MMP-2 and MMP-9). Ratio of collagen III over collagen I production increased 6 days after the burn, because of a decrease in collagen I production. After 10 months, ratio of collagen III over collagen I in burn sites was still increased compared with control skin, because of an increase in collagen III production. Both abnormalities were corrected by OTR4120. OTR4120 increased pro- and active MMP-2 and MMP-9, compared with healthy and burned controls and therefore accelerated remodeling. Similar data were obtained with cultured fibroblasts from healthy and burned skins. OTR4120 enhanced healing in short- and long-term after burns, reducing the formation of fibrotic tissue, and then represents a potential agent to improve burned skin healing.

  12. Cardiotoxicity of Molecularly Targeted Agents

    PubMed Central

    Hedhli, Nadia; Russell, Kerry S

    2011-01-01

    Cardiac toxicity of molecularly targeted cancer agents is increasingly recognized as a significant side effect of chemotherapy. These new potent therapies may not only affect the survival of cancer cells, but have the potential to adversely impact normal cardiac and vascular function. Unraveling the mechanisms by which these therapies affect the heart and vasculature is crucial for improving drug design and finding alternative therapies to protect patients predisposed to cardiovascular disease. In this review, we summarize the classification and side effects of currently approved molecularly targeted chemotherapeutics. PMID:22758623

  13. Enhanced Stability of Blood Matrices Using a Dried Sample Spot Assay to Measure Human Butyrylcholinesterase Activity and Nerve Agent Adducts

    PubMed Central

    Perez, Jonas W.; Pantazides, Brooke G.; Watson, Caroline M.; Thomas, Jerry D.; Blake, Thomas A.; Johnson, Rudolph C.

    2015-01-01

    Dried matrix spots are safer to handle and easier to store than wet blood products, but factors such as intra-spot variability and unknown sample volumes have limited their appeal as a sampling format for quantitative analyses. In this work, we introduce a dried spot activity assay for quantifying butyrylcholinesterase (BChE) specific activity which is BChE activity normalized to the total protein content in a sample spot. The method was demonstrated with blood, serum, and plasma spotted on specimen collection devices (cards) which were extracted to measure total protein and BChE activity using a modified Ellman assay. Activity recovered from dried spots was ∼80% of the initial spotted activity for blood and >90% for plasma and serum. Measuring total protein in the sample and calculating specific activity substantially improved quantification and reduced intra-spot variability. Analyte stability of nerve agent adducts was also evaluated, and the results obtained via BChE-specific activity measurements were confirmed by quantification of BChE adducts using a previously established LC-MS/MS method. The spotted samples were up to 10-times more resistant to degradation compared to unspotted control samples when measuring BChE inhibition by the nerve agents sarin and VX. Using this method, both BChE activity and adducts can be accurately measured from a dried sample spot. This use of a dried sample spot with normalization to total protein is robust, demonstrates decreased intra-spot variability without the need to control for initial sample volume, and enhances analyte stability. PMID:25955132

  14. A highly fluorescent AIE-active theranostic agent with anti-tumor activity to specific cancer cells

    NASA Astrophysics Data System (ADS)

    Zhao, Yueyue; Kwok, Ryan T. K.; Lam, Jacky W. Y.; Tang, Ben Zhong

    2016-06-01

    A tetraphenylethene derivative with a structure resembling Tamoxifen is designed and synthesized as a theranostic agent for cell imaging and anti-breast cancer therapy. Its high brightness, excellent photostability and long-term cell tracing properties enable elucidation of its working mechanism and hence provide new insights into drug development.A tetraphenylethene derivative with a structure resembling Tamoxifen is designed and synthesized as a theranostic agent for cell imaging and anti-breast cancer therapy. Its high brightness, excellent photostability and long-term cell tracing properties enable elucidation of its working mechanism and hence provide new insights into drug development. Electronic supplementary information (ESI) available: Detailed synthesis and characterization of TPE-OH and TPE-TMX PL spectra of TPE-TMX fluorescent photographs of TPE-TMX taken under UV irradiation; various concentrations of TPE-TMX with different incubation times. See DOI: 10.1039/c5nr08782a

  15. Semisynthesis and quantitative structure-activity relationship (QSAR) study of some cholesterol-based hydrazone derivatives as insecticidal agents.

    PubMed

    Yang, Chun; Shao, Yonghua; Zhi, Xiaoyan; Huan, Qu; Yu, Xiang; Yao, Xiaojun; Xu, Hui

    2013-09-01

    In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, four series of novel cholesterol-based hydrazone derivatives were synthesized, and their insecticidal activity was tested against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1mg/mL. All the derivatives showed the better insecticidal activity than their precursor cholesterol. Quantitative structure-activity relationship (QSAR) model demonstrated that six descriptors such as RDF085v, Mor06u, Mor11u, Dv, HATS0v and H-046, are likely to influence the insecticidal activity of these compounds. Among them, two important ones are the Mor06u and RDF085v.

  16. An overview of structure-activity relationship studies of curcumin analogs as antioxidant and anti-inflammatory agents.

    PubMed

    Arshad, Laiba; Haque, Md Areeful; Abbas Bukhari, Syed Nasir; Jantan, Ibrahim

    2017-04-10

    Curcumin, extracted mainly from Curcuma longa rhizomes, has been reported to possess potent anti-inflammatory and anti-oxidant activities. Although safe at higher doses and exhibiting multiple biological activities, curcumin still has the problem of poor bioavailability which has been an attractive area of research over the last few years. A number of efforts have been made by modifying structural features of curcumin. This review highlights the structurally modified and more stable newly synthesized curcumin analogs that have been screened against antioxidant and anti-inflammatory activities. Also the structure-activity relationship to gain insight into future guidelines for scheming new compounds has been discussed, and further these analogs being more stable may serve as promising agents for use in different pathological conditions.

  17. Targeting neddylation induces DNA damage and checkpoint activation and sensitizes chronic lymphocytic leukemia B cells to alkylating agents.

    PubMed

    Paiva, C; Godbersen, J C; Berger, A; Brown, J R; Danilov, A V

    2015-07-09

    Microenvironment-mediated upregulation of the B-cell receptor (BCR) and nuclear factor-κB (NF-κB) signaling in CLL cells resident in the lymph node and bone marrow promotes apoptosis evasion and clonal expansion. We recently reported that MLN4924 (pevonedistat), an investigational agent that inhibits the NEDD8-activating enzyme (NAE), abrogates stromal-mediated NF-κB pathway activity and CLL cell survival. However, the NAE pathway also assists degradation of multiple other substrates. MLN4924 has been shown to induce DNA damage and cell cycle arrest, but the importance of this mechanism in primary neoplastic B cells has not been studied. Here we mimicked the lymph node microenvironment using CD40 ligand (CD40L)-expressing stroma and interleukin-21 (IL-21) to find that inducing proliferation of the primary CLL cells conferred enhanced sensitivity to NAE inhibition. Treatment of the CD40-stimulated CLL cells with MLN4924 resulted in deregulation of Cdt1, a DNA replication licensing factor, and cell cycle inhibitors p21 and p27. This led to DNA damage, checkpoint activation and G2 arrest. Alkylating agents bendamustine and chlorambucil enhanced MLN4924-mediated DNA damage and apoptosis. These events were more prominent in cells stimulated with IL-21 compared with CD40L alone, indicating that, following NAE inhibition, the culture conditions were able to direct CLL cell fate from an NF-κB inhibition to a Cdt1 induction program. Our data provide insight into the biological consequences of targeting NAE in CLL and serves as further rationale for studying the clinical activity of MLN4924 in CLL, particularly in combination with alkylating agents.

  18. BO-1055, a novel DNA cross-linking agent with remarkable low myelotoxicity shows potent activity in sarcoma models

    PubMed Central

    Ambati, Srikanth R.; Shieh, Jae-Hung; Pera, Benet; Lopes, Eloisi Caldas; Chaudhry, Anisha; Wong, Elissa W.P.; Saxena, Ashish; Su, Tsann-Long; Moore, Malcolm A.S.

    2016-01-01

    DNA damaging agents cause rapid shrinkage of tumors and form the basis of chemotherapy for sarcomas despite significant toxicities. Drugs having superior efficacy and wider therapeutic windows are needed to improve patient outcomes. We used cell proliferation and apoptosis assays in sarcoma cell lines and benign cells; γ-H2AX expression, comet assay, immunoblot analyses and drug combination studies in vitro and in patient derived xenograft (PDX) models. BO-1055 caused apoptosis and cell death in a concentration and time dependent manner in sarcoma cell lines. BO-1055 had potent activity (submicromolar IC50) against Ewing sarcoma and rhabdomyosarcoma, intermediate activity in DSRCT (IC50 = 2-3μM) and very weak activity in osteosarcoma (IC50 >10μM) cell lines. BO-1055 exhibited a wide therapeutic window compared to other DNA damaging drugs. BO-1055 induced more DNA double strand breaks and γH2AX expression in cancer cells compared to benign cells. BO-1055 showed inhibition of tumor growth in A673 xenografts and caused tumor regression in cyclophosphamide resistant patient-derived Ewing sarcoma xenografts and A204 xenografts. Combination of BO-1055 and irinotecan demonstrated synergism in Ewing sarcoma PDX models. Potent activity on sarcoma cells and its relative lack of toxicity presents a strong rationale for further development of BO-1055 as a therapeutic agent. PMID:27248664