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Sample records for alkylating chemotherapeutic agents

  1. Chemotherapeutic attack of hypoxic tumor cells by the bioreductive alkylating agent mitomycin C.

    PubMed

    Keyes, S R; Heimbrook, D C; Fracasso, P M; Rockwell, S; Sligar, S G; Sartorelli, A C

    1985-01-01

    Since the cure of solid tumors is limited by the presence of cells with low oxygen contents, we have approached the development of treatment regimens and of new drugs for these tumors by investigating agents which are preferentially bioactivated under hypoxia. Major emphasis has been directed at studying the mode of action of the mitomycin antibiotics, as bioreductive alkylating agents. Using primarily the EMT6 mouse mammary carcinoma as a solid tumor model, we have found that mitomycin C and porfiromycin are preferentially toxic to cells with low oxygen contents. The mitomycin analog BMY-25282 is more toxic to hypoxic cells than are mitomycin C and porfiromycin; however, unlike these antibiotics, BMY-25282 is preferentially toxic to well-oxygenated cells. With these three mitomycins, we have observed a correlation between cytotoxicity to hypoxic cells, the rate of generation of reactive products, and the redox potentials of the drugs. Investigations of the enzymes in EMT6 cells that could possibly activate mitomycin C have revealed that cytochrome P-450 and xanthine oxidase are not present in measurable quantities and therefore are not responsible for activation of mitomycin C. Activities representative of NADPH-cytochrome c reductase and DT-diaphorase are present in these neoplastic cells. Comparison of these enzymatic activities in EMT6, CHO, and V79 cells with the rate of generation of reactive products under hypoxia shows a direct correlation between these two parameters, but there is no quantitative correlation between these two parameters and the amount of cytotoxicity. Use of purified NADPH-cytochrome c reductase and inhibitors of this enzyme demonstrated that NADPH-cytochrome c reductase can activate mitomycin C, but that it is probably not the only enzyme participating in this bioactivation in EMT6 cells. The DT-diaphorase inhibitor dicoumarol was employed to show that this enzyme is not involved in the activation of mitomycin C to a cytotoxic agent

  2. [Extravasation of chemotherapeutic agents: prevention and therapy].

    PubMed

    Jordan, K; Grothe, W; Schmoll, H-J

    2005-01-01

    Based on the potential to cause local tissue injury drugs are classified as vesicant, irritant and non-irritant. The frequency of extravasation is considered to be between 0.6 % and 6 %. More frequently an inflammatory reaction is caused by thrombophlebitis or a local hypersensitivity reaction following chemotherapy administration rather than by an extravasation. A number of factors are known to increase the risk of extravasation. By the consideration of these risk factors preventive guidelines for the safe administration of chemotherapeutic agents have been published. Central venous devices significantly reduce the risk of extravasation. To date there are no generally approved treatment guidelines for the management of extravasations. Treatment is mostly empirical. Nevertheless some general measures are to be recommended: Firstly, aspiration of the extravasated fluids should be attempted. Furthermore local supportive care such as intermittent topical warming or cooling is at least palliative and to a certain degree reduces the extent of the injury. Beside these non pharmacological therapies the beneficial effects of Dimethylsulfoxid (DMSO) -- or Hyaluronidase-administration dependent on the type of paravasation have been proven. The use of sodium bicarbonate, sodium thiosulfate or corticosteroids is no longer recommended. In the case of extravasation rapid and correct management is crucial for the benefit of any treatment. Therefore, written guidelines for both the handling of cytotoxic agents and also the management of an extravasation should be present in all Departments where cytotoxic agents are administered. In addition to these guidelines an extravasation kit including all necessary materials and drugs to treat extravasations should be available. PMID:15619172

  3. Accidental overdose of multiple chemotherapeutic agents.

    PubMed

    Kim, I S; Gratwohl, A; Stebler, C; Hausmann, M; Tichelli, A; Stern, A; Speck, B

    1989-07-01

    A 35-year-old man with refractory low grade diffuse centroblastic centrocytic non-Hodgkin's lymphoma was treated accidentally with an overdose of multiple chemotherapeutic agents. He was given adriamycin 50 mg/m2 and cyclophosphamide 350 mg/m2 for 6 days followed by 4 days of vincristine 1 mg/m2 and bleomycin 10 mg/m2. He was transferred when he developed pancytopenia, fever, severe mucositis, ileus and peripheral neuropathy. He was treated with broad spectrum antibiotics, red cell and single donor platelet transfusions and strict parenteral nutrition. In addition, he was given a continuous infusion of 400 micrograms daily human recombinant granulocyte macrophage-colony stimulating factor (rh GM-CSF) for 17 days. Intractable severe bleeding from his oral mucositis necessitated treatment with a continuous infusion of 8-ornithine-vasopressin for 8 days. He recovered and could be discharged home after 36 days of hospitalization with normal blood counts and without severe sequelae. PMID:2486848

  4. Accidental Overdose of Multiple Chemotherapeutic Agents

    PubMed Central

    Kim, In Soon; Gratwohl, A.; Stebler, C.; Hausmann, M.; Tichelli, A.; Stern, A.; Speck, B.

    1989-01-01

    A 35-year-old man with refractory low grade diffuse centroblastic centrocytic non-Hodgkin’s lymphoma was treated accidentally with an overdose of multiple chemotherapeutic agents. He was given adriamycin 50 mg/m2 and cyclophosphamide 350 mg/m2 for 6 days followed by 4 days of vincristine 1 mg/m2 and bleomycin 10 mg/m2. He was transferred when he developed pancytopenia, fever, severe mucositis, ileus and peripheral neuropathy. He was treated with broad spectrum antibiotics, red cell and single donor platelet transfusions and strict parenteral nutrition. In addition, he was given a continuous infusion of 400 ug daily human recombinant granulocyte macrophage-colony stimulating factor (rh GM-CSF) for 17 days. Intractable severe bleeding from his oral mucositis necessitated treatment with a continuous infusion of 8-ornithine-vasopressin for 8 days. He recovered and could be discharged home after 36 days of hospitalization with normal blood counts and without severe sequelae. PMID:2486848

  5. Chemotherapy-induced pulmonary hypertension: role of alkylating agents.

    PubMed

    Ranchoux, Benoît; Günther, Sven; Quarck, Rozenn; Chaumais, Marie-Camille; Dorfmüller, Peter; Antigny, Fabrice; Dumas, Sébastien J; Raymond, Nicolas; Lau, Edmund; Savale, Laurent; Jaïs, Xavier; Sitbon, Olivier; Simonneau, Gérald; Stenmark, Kurt; Cohen-Kaminsky, Sylvia; Humbert, Marc; Montani, David; Perros, Frédéric

    2015-02-01

    Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents. PMID:25497573

  6. Stabilized dialkyl aluminum complexes as alkylating agents

    SciTech Connect

    Blum, J.; Baidossi, W.; Rosenfeld, A.

    1995-12-31

    Although trialkylaluminum derivatives are widely used as Ziegler-Natta polymerization co-catalysts, their application as routine alkylating agents is limited owing to their pyrophoric nature. The authors have now found that substitution of one of the alkyl moieties by a chelating group reduces the sensitivity of the organoaluminum compounds to air, and enables one to utilize them under normal laboratory conditions.

  7. Resveratrol enhances the sensitivity of cholangiocarcinoma to chemotherapeutic agents

    PubMed Central

    Frampton, Gabriel; Lazcano, Eric; Li, Huang; Mohamad, Akimuddin; DeMorrow, Sharon

    2010-01-01

    Cholangiocarcinomas are devastating cancers that are resistant to chemotherapies. Resveratrol, a food-derived polyphenol with antitumorigenic properties can regulate the expression of Cytochrome p450 1b1 (Cyp1b1), which may confer chemoresistance in various cancers. Our aims were to assess the effects of resveratrol on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents and demonstrate an association between Cyp1b1 expression and chemosensitivity. Cholangiocarcinoma cell lines were treated with resveratrol prior to the addition of 5-fluorouracil (5-FU), gemcitabine or mitomycin C. Cell proliferation and apoptosis were assessed by MTS assays and Annexin staining. Resveratrol effects on cholangiocarcinoma tumor sensitivity to 5-FU was assessed in an in vivo xenograft model using Mz-ChA-1 cells. Following resveratrol treatment, Cyp1b1 expression was assessed by real time PCR and immunoblotting. Stable transfected cell lines with Cyp1b1 expression knocked down (Mz-Cyp1b1) were used to assess sensitivity to chemotherapeutic agents by MTS assays and Annexin staining and in a xenograft model using Mz-ChA-1 and Mz-Cyp1b1 cells, respectively. For each chemotherapeutic agent, co-treatment with resveratrol in vitro decreased cell proliferation and increased apoptosis to a greater extent than with the chemotherapeutic agent alone. In vivo, 5-FU+resveratrol decreased tumor size and increased TUNEL staining to a greater extent than 5-FU alone. In parallel, resveratrol decreased Cyp1b1 expression in Mz-ChA-1 cells and in cholangiocarcinoma tumors. Mz-Cyp1b1 cells were more sensitive to chemotherapeutic agents in vitro than mock-transfected cells, and Mz-Cyp1b1-induced tumors were more susceptible to 5-FU treatment. We suggest that resveratrol treatment may be a useful adjunct therapy to improve chemosensitivity in cholangiocarcinoma. PMID:20458282

  8. Recent approaches for reducing hemolytic activity of chemotherapeutic agents.

    PubMed

    Jeswani, Gunjan; Alexander, Amit; Saraf, Shailendra; Saraf, Swarnlata; Qureshi, Azra; Ajazuddin

    2015-08-10

    Drug induced hemolysis is a frequent complication associated with chemotherapy. It results from interaction of drug with erythrocyte membrane and leads to cell lysis. In recent past, various approaches were made to reduce drug-induced hemolysis, which includes drug polymer conjugation, drug delivery via colloidal carriers and hydrogels, co-administration of botanical agents and modification in molecular chemistry of drug molecules. The basic concept behind these strategies is to protect the red blood cells from membrane damaging effects of drugs. There are several examples of drug polymer conjugate that either are approved by Food and Drug Administration or are under clinical trial for delivering drugs with reduced toxicities. Likewise, colloidal carriers are also used successfully nowadays for the delivery of various chemotherapeutic agents like gemcitabine and amphotericin B with remarkable decrease in their hemolytic activity. Similarly, co-administration of botanical agents with drugs works as secondary system proving protection and strength to erythrocyte membranes. In addition to the above statement, interaction hindrance between RBC and drug molecule by molecular modification plays an important role in reducing hemolysis. This review predominantly describes the above recent approaches explored to achieve the reduced hemolytic activity of drugs especially chemotherapeutic agents. PMID:26047758

  9. MICs and MBCs of chemotherapeutic agents against Renibacterium salmoninarum.

    PubMed Central

    Bandín, I; Santos, Y; Toranzo, A E; Barja, J L

    1991-01-01

    The efficacies of 21 chemotherapeutic agents for controlling bacterial kidney disease were evaluated. The bactericidal and/or bacteriostatic effects of these drugs were tested against 11 Renibacterium salmoninarum strains with different origins. The most effective compounds displaying both bacteriostatic and bactericidal activity for all the isolates were tetracycline and erythromycin, with MICs ranging from less than 0.62 to 10.95 micrograms/ml for tetracycline and from less than 0.62 to 5.47 micrograms/ml for erythromycin. Whereas tetracycline showed identical MICs and MBCs, erythromycin showed bactericidal effects at concentrations of 5.47 to 21.87 micrograms/ml. Similarly, cefazolin and tiamulin proved to be very effective bactericidal compounds against the majority of R. salmoninarum isolates, with MBCs for 90% of the strains tested of 21.87 and 10.95 micrograms/ml, respectively. Neither nitrofuranes, quinolones, nor sulfonamides showed inhibitory effects on the growth of the strains. PMID:1854157

  10. MICs and MBCs of chemotherapeutic agents against Renibacterium salmoninarum.

    PubMed

    Bandín, I; Santos, Y; Toranzo, A E; Barja, J L

    1991-05-01

    The efficacies of 21 chemotherapeutic agents for controlling bacterial kidney disease were evaluated. The bactericidal and/or bacteriostatic effects of these drugs were tested against 11 Renibacterium salmoninarum strains with different origins. The most effective compounds displaying both bacteriostatic and bactericidal activity for all the isolates were tetracycline and erythromycin, with MICs ranging from less than 0.62 to 10.95 micrograms/ml for tetracycline and from less than 0.62 to 5.47 micrograms/ml for erythromycin. Whereas tetracycline showed identical MICs and MBCs, erythromycin showed bactericidal effects at concentrations of 5.47 to 21.87 micrograms/ml. Similarly, cefazolin and tiamulin proved to be very effective bactericidal compounds against the majority of R. salmoninarum isolates, with MBCs for 90% of the strains tested of 21.87 and 10.95 micrograms/ml, respectively. Neither nitrofuranes, quinolones, nor sulfonamides showed inhibitory effects on the growth of the strains. PMID:1854157

  11. Clinical applications of quinone-containing alkylating agents.

    PubMed

    Begleiter, A

    2000-11-01

    Quinone-containing alkylating agents are a class of chemical agents that have received considerable interest as anticancer drugs. These agents contain a quinone moiety that can be reduced and an alkylating group that can form covalent bonds with a variety of cellular components. The oxidation state of the quinone element can modulate the activity of the alkylating element, and reduction of the quinone is required for activation of the alkylating activity of many of these agents. The quinone element may also contribute to the cytotoxic activity of quinone-containing alkylating agents through the formation of reactive oxygen species during redox cycling. The natural product, mitomycin C, has been the most widely used quinone-containing alkylating agent in the clinic, but other quinone-containing alkylating agents like porfiromycin, diaziquone, carbazilquinone, triaziquone and EO9 have also been used in the clinic for the treatment of cancer. In addition, many other quinone-containing alkylating agents have been tested in preclinical studies and the development of new agents is being actively pursued. This chapter describes the current and past clinical uses of these agents in the treatment of cancer and discusses new agents that are currently in clinical trials. PMID:11056078

  12. [Chemotherapeutic effectiveness of a new derivative of 5-alkyl-3N-furanones in experimental staphylococcal infection].

    PubMed

    Tomnikov, A Iu; Shub, G M

    1990-02-01

    High chemotherapeutic efficacy of the compound 1929, a new derivative of 5-alkyl-3H-furanones was shown in albino mice with experimental staphylococcal infection caused by intraperitoneal administration to the animals. The efficacy was found to be higher than that of furagin used for comparison. The average therapeutic dose (AD50) of the compound for intraperitoneal administration amounted to 40 mg/kg while the average lethal dose (LD50) was 3000 mg/kg. PMID:2337370

  13. Detection of Alkylating Agents using Electrical and Mechanical Means

    NASA Astrophysics Data System (ADS)

    Gerchikov, Yulia; Borzin, Elena; Gannot, Yair; Shemesh, Ariel; Meltzman, Shai; Hertzog-Ronen, Carmit; Tal, Shay; Stolyarova, Sara; Nemirovsky, Yael; Tessler, Nir; Eichen, Yoav

    2011-08-01

    Alkylating agents are reactive molecules having at least one polar bond between a carbon atom and a good leaving group. These often simple molecules are frequently used in organic synthesis, as sterilizing agents in agriculture and even as anticancer agents in medicine. Unfortunately, for over a century, some of the highly reactive alkylating agents are also being used as blister chemical warfare agents. Being relatively simple to make, the risk is that these will be applied by terrorists as poor people warfare agents. The detection and identification of such alkylating agents is not a simple task because of their high reactivity and simple structure of the reactive site. Here we report on new approaches to the detection and identification of such alkylating agents using electrical (organic field effect transistors) and mechanical (microcantilevers) means.

  14. Base-Modified Nucleosides as Chemotherapeutic Agents: Past and Future.

    PubMed

    Burke, Matthew P; Borland, Kayla M; Litosh, Vladislav A

    2016-01-01

    Nucleoside and nucleobase antimetabolites have substantially impacted treatment of cancer and infections. Their close resemblance to natural analogs gives them the power to interfere with a variety of intracellular targets, which on one hand gives them high potency, but on the other hand incurs severe side effects, especially of the chemotherapeutics used against malignancies. Therefore, the development of novel nucleoside analogs with widened therapeutic windows represents an attractive target to synthetic organic and medicinal chemists. This review discusses the current antimetabolite drugs: 5- fluorouracil, 6-mercaptopurine, 6-thioguanine, Cladribine, Vidaza, Decitabine, Emtricitabine, Abacavir, Sorivudine, Clofarabine, Fludarabine, and Nelarabine; gives insight into the nucleoside drug candidates that are being developed; and outlines the approaches to nucleobase modifications that may help discover novel bioactive nucleoside analogs with the mechanism of action focused on termination of DNA synthesis, which is expected to diminish the off-target toxicity in non-proliferating human cells. PMID:26369814

  15. Alcohols as alkylating agents in heteroarene C–H functionalization

    PubMed Central

    Jin, Jian; MacMillan, David W. C.

    2015-01-01

    Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage1. One of the core principles that underlies DNA biosynthesis is the radical-mediated elimnation of H2O to deoxygenate ribonucleotides, an example of ‘spin-center shift’ (SCS)2, during which an alcohol C–O bond is cleaved, resulting in a carbon-centered radical intermediate. While SCS is a well-understood biochemical process, it is underutilized by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylations using alcohols as radical precursors. Considering traditional radical-based alkylation methods require the use of stoichiometric oxidants, elevated temperatures, or peroxides3–7, the development of a mild protocol using simple and abundant alkylating agents would have significant utility in the synthesis of diversely functionalized pharmacophores. In this manuscript, we describe the successful execution of this idea via the development of a dual catalytic alkylation of heteroarenes using alcohols as mild alkylating reagents. This method represents the first broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer (HAT) catalysis. The utility of this multi-catalytic protocol has been demonstrated through the late-stage functionalization of the medicinal agents, fasudil and milrinone. PMID:26308895

  16. Alcohols as alkylating agents in heteroarene C-H functionalization

    NASA Astrophysics Data System (ADS)

    Jin, Jian; MacMillan, David W. C.

    2015-09-01

    Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage. One of the core principles underlying DNA biosynthesis is the radical-mediated elimination of H2O to deoxygenate ribonucleotides, an example of `spin-centre shift', during which an alcohol C-O bond is cleaved, resulting in a carbon-centred radical intermediate. Although spin-centre shift is a well-understood biochemical process, it is underused by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors. Because conventional radical-based alkylation methods require the use of stoichiometric oxidants, increased temperatures or peroxides, a mild protocol using simple and abundant alkylating agents would have considerable use in the synthesis of diversely functionalized pharmacophores. Here we describe the development of a dual catalytic alkylation of heteroarenes, using alcohols as mild alkylating reagents. This method represents the first, to our knowledge, broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer catalysis. The value of this multi-catalytic protocol has been demonstrated through the late-stage functionalization of the medicinal agents, fasudil and milrinone.

  17. Alcohols as alkylating agents in heteroarene C-H functionalization.

    PubMed

    Jin, Jian; MacMillan, David W C

    2015-09-01

    Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage. One of the core principles underlying DNA biosynthesis is the radical-mediated elimination of H2O to deoxygenate ribonucleotides, an example of 'spin-centre shift', during which an alcohol C-O bond is cleaved, resulting in a carbon-centred radical intermediate. Although spin-centre shift is a well-understood biochemical process, it is underused by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors. Because conventional radical-based alkylation methods require the use of stoichiometric oxidants, increased temperatures or peroxides, a mild protocol using simple and abundant alkylating agents would have considerable use in the synthesis of diversely functionalized pharmacophores. Here we describe the development of a dual catalytic alkylation of heteroarenes, using alcohols as mild alkylating reagents. This method represents the first, to our knowledge, broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer catalysis. The value of this multi-catalytic protocol has been demonstrated through the late-stage functionalization of the medicinal agents, fasudil and milrinone. PMID:26308895

  18. The effect of alkylating agents on model supported metal clusters

    SciTech Connect

    Erdem-Senatalar, A.; Blackmond, D.G.; Wender, I. . Dept. of Chemical and Petroleum Engineering); Oukaci, R. )

    1988-01-01

    Interactions between model supported metal clusters and alkylating agents were studied in an effort to understand a novel chemical trapping technique developed for identifying species adsorbed on catalyst surfaces. It was found that these interactions are more complex than had previously been suggested. Studies were completed using deuterium-labeled dimethyl sulfate (DMS), (CH{sub 3}){sub 2}SO{sub 4}, as a trapping agent to interact with the supported metal cluster ethylidyne tricobalt enneacarbonyl. Results showed that oxygenated products formed during the trapping reaction contained {minus}OCD{sub 3} groups from the DMS, indicating that the interaction was not a simple alkylation. 18 refs., 1 fig., 3 tabs.

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

    PubMed

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

    2015-05-01

    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

  20. 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

  1. Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents.

    PubMed

    Wang, Wenge; Gallant, Jean-Nicolas; Katz, Sharyn I; Dolloff, Nathan G; Smith, Charles D; Abdulghani, Junaid; Allen, Joshua E; Dicker, David T; Hong, Bo; Navaraj, Arunasalam; El-Deiry, Wafik S

    2011-08-01

    Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that quinacrine stabilizes p53 and induces p53-dependent and independent cell death. Treatment by quinacrine alone at concentrations of 10-20 mM for 1-2 d cannot kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. However, quinacrine renders these cells sensitive to treatment by TRAIL. Co-treatment of these cells with quinacrine and TRAIL induces overwhelming cell death within 3-4 h. Levels of DR5, a pro-apoptotic death receptor of TRAIL, are increased upon treatment with quinacrine, while levels of Mcl-1, an anti-apoptotic member of the Bcl-2 family, are decreased. While the synergistic effect of quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by quinacrine and TRAIL. The mechanism by which quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapies, and the potential for clinical application currently are being further explored. Lastly, quinacrine synergizes with chemotherapeutics, such as adriamycin, 5-FU, etoposide, CPT11, sorafenib, and gemcitabine, in killing hepatocellular carcinoma cells in vitro and the drug enhances the activity of sorafenib to delay tumor growth in vivo. PMID:21725212

  2. Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium

    SciTech Connect

    Konno, T. )

    1990-11-01

    Arterially administered Lipiodol Ultrafluid contrast medium selectively remained in various malignant solid tumors because of the difference in time required for the removal of Lipiodol contrast medium from normal capillaries and tumor neovasculature. Although blood flow was maintained in the tumor, even immediately after injection Lipiodol contrast medium remained in the neovasculature of the tumor. To target anti-cancer agents to tumors by using Lipiodol contrast medium as a carrier, the characteristics of the agents were examined. Anti-cancer agents had to be soluble in Lipiodol, be stable in it, and separate gradually from it so that the anti-cancer agents would selectively remain in the tumor. These conditions were found to be necessary on the basis of the measurement of radioactivity in VX2 tumors implanted in the liver of 16 rabbits that received arterial injections of 14C-labeled doxorubicin. Antitumor activities and side effects of arterial injections of two types of anti-cancer agents were compared in 76 rabbits with VX2 tumors. Oily anti-cancer agents that had characteristics essential for targeting were compared with simple mixtures of anti-cancer agents with Lipiodol contrast medium that did not have these essential characteristics. Groups of rabbits that received oily anti-cancer agents responded significantly better than groups that received simple mixtures, and side effects were observed more frequently in the groups that received the simple mixtures. These results suggest that targeting of the anti-cancer agent to the tumor is important for treatment of solid malignant tumors.

  3. Synthesis and Performance of a Biomimetic Indicator for Alkylating Agents.

    PubMed

    Provencher, Philip A; Love, Jennifer A

    2015-10-01

    4-(4-Nitrobenzyl)pyridine (NBP) is a colorimetric indicator compound for many types of carcinogenic alkylating agents. Because of the similar reactivity of NBP and guanine in DNA, NBP serves as a DNA model. NBP assays are used in the toxicological screening of pharmaceutical compounds, detection of chemical warfare agents, environmental hygiene technology, preliminary toxicology tests, mutagenicity of medicinal compounds, and other chemical analyses. Nevertheless, the use of NBP as a DNA model suffers from the compound's low water solubility, its lack of reactive oxygen sites, and dissimilar steric encumbrance compared to DNA. We report herein the design and synthesis of NBP derivatives that address some of these issues. These derivatives have been tested in solution and found to be superior in the colorimetric assay of the alkylating anticancer drug cyclophosphamide. The derivatives have also been integrated into a polymeric silica material which changes color upon the exposure to dangerous alkylating agents, such as iodomethane vapor, without the need for an exogenous base. This material modernizes the NBP assay from a time-consuming laboratory analysis to a real-time solid state sensor, which requires neither solvent nor additional reagents and can detect both gas- and solution-phase alkylating agents. PMID:26393809

  4. Structure-activity studies on organoselenium alkylating agents.

    PubMed

    Kang, S I; Spears, C P

    1990-01-01

    A variety of organoselenium alkylating agents were synthesized, using 2-hydroxyethyl and 3-hydroxypropyl selenocyanate intermediates, and studied to determine their chemical reactivities with 4-(4-nitrobenzyl)pyridine (NBP) and cytotoxicities against CCRF-CEM, L1210/0, and L1210/L-PAM cells. The comparison between the 2-chloroethyl sulfides and selenides 1-4 revealed the markedly enhanced nucleophilicity of selenium (Se) over sulfur (S) by two or more orders of magnitude. This finding indicates that a major consideration in the design of antitumor alkylating organoselenides is the reactivity of selenium. A Taft plot of the experimental first-order rate constant, knbp, and sigma* in a series of 2-chloroethylseleno compounds gave a slope of -1.73 (rho*), with the exception of 2-chloroethyl 2-nitrophenyl selenide (10). The anomalous behavior of 10 is explained in terms of the ortho-nitro stabilization effect directly interacting with the selenium atom of ethyleneselenonium ion to form a 5-membered cyclic intermediate. In the same series, a 5000-fold difference in alkylating reactivity offered only a sixfold variation in cytotoxicity against CCRF-CEM cells. Increasing the alkylating chain length from ethlene to propylene units markedly reduced alkylating reactivities. In the CH3Se(CH2)n Cl series, 16 (n = 3) was 1.5 X 10(5) times slower than 2 (n = 2) in NBP alkylation, revealing that 3-chloro-n-propyl selenides are not chemically reactive enough to be biological alkylating agents despite the presence of the highly nucleophilic selenium atom. Replacement of chloride with mesylate in 3-substituted propyl selenides, such as 17 and 20, restored desirable reactivities and cytotoxicities. PMID:2313578

  5. Leukemia after therapy with alkylating agents for childhood cancer

    SciTech Connect

    Tucker, M.A.; Meadows, A.T.; Boice, J.D. Jr.; Stovall, M.; Oberlin, O.; Stone, B.J.; Birch, J.; Voute, P.A.; Hoover, R.N.; Fraumeni, J.F. Jr.

    1987-03-01

    The risk of leukemia was evaluated in 9,170 2-or-more-year survivors of childhood cancer in the 13 institutions of the Late Effects Study Group. Secondary leukemia occurred in 22 nonreferred individuals compared to 1.52 expected, based on general population rates (relative risk (RR) = 14; 95% confidence interval (CI), 9-22). The influence of therapy for the first cancer on subsequent leukemia risk was determined by a case-control study conducted on 25 cases and 90 matched controls. Treatment with alkylating agents was associated with a significantly elevated risk of leukemia (RR = 4.8; 95% CI, 1.2-18.9). A strong dose-response relationship was also observed between leukemia risk and total dose of alkylating agents, estimated by an alkylator score. The RR of leukemia reached 23 in the highest dose category. Radiation therapy, however, did not increase risk. Although doxorubicin was also identified as a possible risk factor, the excess risk of leukemia following treatment for childhood cancer appears almost entirely due to alkylating agents.

  6. Antibody against granulin-epithelin precursor sensitizes hepatocellular carcinoma to chemotherapeutic agents.

    PubMed

    Wong, Nicholas C L; Cheung, Phyllis F Y; Yip, Chi Wai; Chan, Kui Fat; Ng, Irene Oi-Lin; Fan, Sheung Tat; Cheung, Siu Tim

    2014-12-01

    Granulin-epithelin precursor (GEP) overexpression has been shown in many cancers with functional role on growth, and recently on regulating chemoresistance and cancer stem cell (CSC) properties. Here, we investigate the combined effect of GEP antibody and chemotherapeutic agent. Combination therapy was compared with monotherapy using hepatocellular carcinoma (HCC) cells in vitro and orthotopic liver tumor models in vivo. CD133 and related hepatic CSC marker expressions were investigated by flow cytometry. Antiproliferative and apoptotic effects and signaling mechanisms were examined by immunohistochemistry, flow cytometry, and Western blot analysis. Secretory GEP levels in the serum and culture supernatant samples were measured by ELISA. We demonstrated that HCC cells that survived under chemotherapeutic agents showed upregulation of hepatic CSC markers CD133/GEP/ABCB5, and enhanced colony and spheroid formation abilities. Importantly, GEP antibody sensitized HCC cells to the apoptosis induced by chemotherapy for both HCC cell lines and the chemoresistant subpopulations, and counteracted the chemotherapy-induced GEP/ABCB5 expressions and Akt/Bcl-2 signaling. In human HCC orthotopic xenograft models, GEP antibody treatment alone was consistently capable of inhibiting the tumor growth. Notably, combination of GEP antibody with high dose of cisplatin resulted in the eradication of all established intrahepatic tumor in three weeks. This preclinical study demonstrated that GEP antibody sensitized HCC cells to apoptosis induced by chemotherapeutic agents. Combination treatment with GEP antibody and chemotherapeutic agent has the potential to be an effective therapeutic regimen for GEP-expressing cancers. PMID:25253787

  7. Anti-invasive activities of experimental chemotherapeutic agents.

    PubMed

    Mareel, M M; De Mets, M

    1989-01-01

    We have discussed a number of agents that affect invasion and we have grouped them according to their most probable targets. This strategy is based on the following hypothesis. Invasion is the result of cellular responses to extracellular signals. Candidate signals are components of the extracellular matrix, which are rendered inactive by the flavonoid (+)-catechin (see Section III). Signals are recognized by receptors on the plasma membrane, possibly glycoproteins, that may lose their recognition function through alteration of the oligosaccharide side chains by inhibitors of protein glycosylation (see Section IV) and possibly also by alkyllysophospholipids (see Section V). Synthetic oligopeptides reflecting sequences from cell-binding domains of extracellular matrix molecules are also effective tools for blocking specific receptors (see Section VI). GTP-binding proteins (G proteins) act as signal transducers and can be inactivated by pertussis toxin (see Section VII). An intriguing aspect of both alkyllysophospholipids and pertussis toxin is that they can either inhibit the invasion of constitutively invasive cells or induce invasion of constitutively noninvasive cells. Without doubt, cellular responses implicated in invasion are many-fold. Discussed here are cell motility and directional migration with inhibition through dipyridamole and its analogs and through microtubule inhibitors, respectively (see Section VIII). Alternative hypotheses and alternative strategies for the dissection of the invasion process do exist, and alternative cellular and molecular mechanisms of action may explain the anti-invasive activity of the agents discussed earlier. The latter are mentioned in each section. It is the authors' opinion that the possibilities for exploiting the battery of anti-invasive agents have by no means been exhausted. Introducing researchers to experiments that may lead to an understanding of the mechanisms of invasion and metastasis and to new rationales for

  8. Mechanisms of Cardiotoxicity of Cancer Chemotherapeutic Agents: Cardiomyopathy and Beyond.

    PubMed

    Moudgil, Rohit; Yeh, Edward T H

    2016-07-01

    Tremendous strides have been made in the treatment of various oncological diseases such that patients are surviving longer and are having better quality of life. However, the success has been tainted by the iatrogenic cardiac toxicities. This is especially concerning in the younger population who are facing cardiac disease such as heart failure in their 30s and 40s as the consequence of the anthracycline's side effects (used for childhood leukemia and lymphoma). This resulted in the awareness of cardiotoxic effects of anticancer drugs and emergence of a new discipline: oncocardiology. Since then, numerous anticancer drugs have been correlated to cardiomyopathy. Additionally, other cardiovascular effects have been identified, which includes but is not limited to myocardial infarction, thrombosis, hypertension, arrhythmias, and pulmonary hypertension. In this review we examine some of the anticancer agents that mitigate cardiotoxicity and present current knowledge of molecular mechanism(s). The aim of the review is to ignite awareness of emerging cardiotoxic effects as new generations of anticancer agents are being tested in clinical trials and introduced as part of the therapeutic armamentarium to our oncological patients. PMID:27117975

  9. [Chalcones and their heterocyclic analogs as potential antifungal chemotherapeutic agents].

    PubMed

    Opletalová, V; Sedivý, D

    1999-11-01

    Chalcones and their heterocyclic analogues show various biological effects, e.g. anti-inflammatory, antitumour, antibacterial, antituberculous, antiviral, antiprotozoal, gastroprotective, and others. The present review discusses in greater detail the fungistatic and fungicide properties of these compounds and presents also their chemical structures. The mechanism of antifungal effects of chalcones and their analogues has not been investigated in greater detail. Due to the presence of a reactive ketovinyl moiety in the molecule the compounds of this type are able to react with the thiol groups of enzymes. It cannot be excluded that chalcones interfere with the normal function of the membranes of fungi and moulds. Further investigation of chemical, physical, and biological properties of chalcones and their analogues could lead to the elucidation of the mechanism of their action and finding of effective fungicidal and fungistatic agents in this group of organic substances. PMID:10748740

  10. Plant-Derived Urease Inhibitors as Alternative Chemotherapeutic Agents.

    PubMed

    Hassan, Sherif T S; Žemlička, Milan

    2016-07-01

    Inhibition of the metalloenzyme urease has important pharmacologic applications in the field of antiulcer and antigastric cancer agents. Urease is involved in many serious infections caused by Helicobacter pylori in the gastric tract as well as by Proteus and related species in the urinary tract. Although numerous studies have described several novel urease inhibitors (UIs) used for the treatment of gastric and urinary infections, all these compounds have exhibited severe side effects, toxicity, and instability. Therefore, to overcome such problems, it is necessary to search for new sources of UIs, such as natural products, that provide reduced side effects, low toxicity, greater stability, and bioavailability. As limited studies have been conducted on plant-derived UIs, this paper aims to highlight and summarize the most promising compounds isolated and identified from plants, such as terpenoids, phenolic compounds, alkaloids, and other substances with inhibitory activities against plant and bacterial ureases; these are in vitro and in vivo studies with an emphasis on structure-activity relationship studies and types of inhibition that show high and promising levels of anti-urease activity. This will aid medicinal chemists in the design and synthesis of novel and pharmacologically potent UIs useful for the development of antiulcer drugs. PMID:27244041

  11. Novel mechanisms of action of classical chemotherapeutic agents on sphingolipid pathways.

    PubMed

    Hajj, Carla; Becker-Flegler, Katrin Anne; Haimovitz-Friedman, Adriana

    2015-06-01

    The prevailing mechanisms of action of traditional chemotherapeutic agents have been challenged by sphingolipid cancer research. Many studies have shown that ceramide generation in response to cytotoxic agents is central to tumor cell death. Ceramide can be generated either via hydrolysis of cell-membrane sphingomyelin by sphingomyelinases, hydrolysis of cerebrosides, or via de novo synthesis by ceramide synthases. Ceramide can act as a second messenger for apoptosis, senescence or autophagy. Inherent or acquired alterations in the sphingolipid pathway can account for resistance to the classic chemotherapeutic agents. In particular, it has been shown that activation of the acid ceramidase can lead to the formation of sphingosine 1-phosphate, which then antagonizes ceramide signaling by initiating a pro-survival signaling pathway. Furthermore, ceramide glycosylation catalyzed by glucosylceramide synthase converts ceramide to glucosylceramide, thus eliminating ceramide and consequently protecting cancer cells from apoptosis. In this review, we describe the effects of some of the most commonly used chemotherapeutic agents on ceramide generation, with a particular emphasis on strategies used to enhance the efficacy of these agents. PMID:25719313

  12. Proteomic analysis of mismatch repair-mediated alkylating agent-induced DNA damage response

    PubMed Central

    2013-01-01

    Background Mediating DNA damage-induced apoptosis is an important genome-maintenance function of the mismatch repair (MMR) system. Defects in MMR not only cause carcinogenesis, but also render cancer cells highly resistant to chemotherapeutics, including alkylating agents. To understand the mechanisms of MMR-mediated apoptosis and MMR-deficiency-caused drug resistance, we analyze a model alkylating agent (N-methyl-N’-nitro-N-nitrosoguanidine, MNNG)-induced changes in protein phosphorylation and abundance in two cell lines, the MMR-proficient TK6 and its derivative MMR-deficient MT1. Results Under an experimental condition that MNNG-induced apoptosis was only observed in MutSα-proficient (TK6), but not in MutSα-deficient (MT1) cells, quantitative analysis of the proteomic data revealed differential expression and phosphorylation of numerous individual proteins and clusters of protein kinase substrates, as well differential activation of response pathways/networks in MNNG-treated TK6 and MT1 cells. Many alterations in TK6 cells are in favor of turning on the apoptotic machinery, while many of those in MT1 cells are to promote cell proliferation and anti-apoptosis. Conclusions Our work provides novel molecular insights into the mechanism of MMR-mediated DNA damage-induced apoptosis. PMID:24330662

  13. 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. PMID:2189947

  14. [Clinical pharmacology of anticancer agents. (Part 1) Introduction, alkylating agents and platinum compounds].

    PubMed

    Fujita, H

    1991-11-01

    Pharmacokinetic concepts as to absorption, distribution, metabolism and excretion of anticancer agents, and how drugs reach to the site of action were reviewed. Then, roles of the liver and kidney to the excretion and metabolism, intracellular pharmacokinetics, and relationships between drug response and cell proliferation kinetics or cell cycle phase were explained. Drug development, mode of action and pharmacokinetics of alkylating agents and platinum compounds were reviewed. This includes: alkylating agents: nitrogen mustard, phenylalanine mustard, estracyte, cyclophosphamide, carboquone, busulfan, nitrosourea, etc., and platinum compounds: cisplatin, carboplatin, 254-S, DWA-2114 R, NK-121. PMID:1952967

  15. Oncolytic reovirus synergizes with chemotherapeutic agents to promote cell death in canine mammary gland tumor.

    PubMed

    Igase, Masaya; Hwang, Chung Chew; Kambayashi, Satoshi; Kubo, Masato; Coffey, Matt; Miyama, Takako Shimokawa; Baba, Kenji; Okuda, Masaru; Noguchi, Shunsuke; Mizuno, Takuya

    2016-01-01

    The oncolytic effects of reovirus in various cancers have been proven in many clinical trials in human medicine. Oncolytic virotherapy using reovirus for canine cancers is being developed in our laboratory. The objective of this study was to examine the synergistic anti-cancer effects of a combination of reovirus and low doses of various chemotherapeutic agents on mammary gland tumors (MGTs) in dogs. The first part of this study demonstrated the efficacy of reovirus in canine MGTs in vitro and in vivo. Reovirus alone exerted significant cell death by means of caspase-dependent apoptosis in canine MGT cell lines. A single injection of reovirus impeded growth of canine MGT tumors in xenografted mice, but was insufficient to induce complete tumor regression. The second part of this study highlighted the anti-tumor effects of reovirus in combination with low doses of paclitaxel, carboplatin, gemcitabine, or toceranib. Enhanced synergistic activity was observed in the MGT cell line treated concomitantly with reovirus and in all the chemotherapeutic agents except toceranib. In addition, combining reovirus with paclitaxel or gemcitabine at half dosage of half maximal inhibitory concentration (IC50) enhanced cytotoxicity by activating caspase 3. Our data suggest that the combination of reovirus and low dose chemotherapeutic agents provides an attractive option in canine cancer therapy. PMID:26733729

  16. Safe Handling of Oral Chemotherapeutic Agents in Clinical Practice: Recommendations From an International Pharmacy Panel

    PubMed Central

    Goodin, Susan; Griffith, Niesha; Chen, Beth; Chuk, Karen; Daouphars, Mikael; Doreau, Christian; Patel, Rinku A.; Schwartz, Rowena; Tamés, Maria José; Terkola, Robert; Vadnais, Barbara; Wright, Debbie; Meier, Klaus

    2011-01-01

    Although there has been a significant increase in the availability and use of oral chemotherapeutic agents, the guidelines around their safe handling are still evolving. Although oral chemotherapy is associated with ease of administration, it has the same exposure risks to health care practitioners, patients, and their caregivers as intravenous formulations, and because it is administered in the home, to the families of patients. However, the general misconception appears to be that exposure risk is low and therefore oral chemotherapeutic agents present little risk and are safer to handle. In a series of three roundtable meetings, a team of international pharmacists from North America and Europe reviewed existing guidelines and identified gaps in recommendations that we believe are important for safe handling. The present article is a compilation of these gaps, especially applicable to manufacturers and distributors, storage and handling, and patient education regarding safe handling. These recommendations, on the basis of our experience and of best practices, provide an international perspective and can be adapted by institutions and practices for development of standardized procedures specific to their needs for the safe handling of oral chemotherapeutic agents. PMID:21532802

  17. 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. PMID:26421434

  18. Decreased stability of DNA in cells treated with alkylating agents

    SciTech Connect

    Frankfurt, O.S. )

    1990-12-01

    A modified highly sensitive procedure for the evaluation of DNA damage in individual cells treated with alkylating agents is reported. The new methodology is based on the amplification of single-strandedness in alkylated DNA by heating in the presence of Mg{sup 2+}. Human ovarian carcinoma cells A2780 were treated with nitrogen mustard (HN2), fixed in methanol, and stained with monoclonal antibody (MOAB) F7-26 generated against HN2-treated DNA. Binding of MOAB was measured by flow cytometry with indirect immunofluorescence. Intensive binding of MOAB to control and drug-treated cells was observed after heating in Tris buffer supplemented with MgCl{sub 2}. Thus, the presence of phosphates and MgCl{sub 2} during heating was necessary for the detection of HN2-induced changes in DNA stability. Fluorescence of HN2-treated cells decreased to background levels after treatment with single-strand-specific S{sub 1} nuclease. MOAB F7-26 interacted with single-stranded regions in DNA and did not bind to dsDNA or other cellular antigens. It is suggested that alkylation of guanines decreased the stability of the DNA molecule and increased the access of MOAB F7-26 to deoxycytidines on the opposite DNA strand.

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

    PubMed Central

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

    2015-01-01

    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. PMID:26564951

  20. Tunable release of chemotherapeutic and vascular disrupting agents from injectable fiber fragments potentiates combination chemotherapy.

    PubMed

    Luo, Xiaoming; Xu, Guisen; Wei, Jiaojun; Chen, Maohua; Zhang, Hong; Li, Xiaohong

    2016-06-15

    Cancer progression and metastasis relies much on vasculature networks in tumor microenvironment, and the combination treatment with chemotherapeutic drugs and vascular disrupting agents represents apparent clinical benefits. In the current study, fiber fragments with loadings of hydroxycamptothecin (HCPT) or combretastatin A-4 (CA4) were proposed for tumor inhibition and blood vessel disruption after local administration in tumors. To address challenges in balancing the disruption of tumor vessels and intratumoral uptake of chemotherapeutic agents, this study is focus on release tuning of HCPT and CA4 from the fiber fragment mixtures. Hydroxypropyl-β-cyclodextrin (HPCD) was blended at ratios from 0 to 10% into CA4-loaded fiber fragments (Fc) to modulate CA4 release durations from 0.5 to 24days, and HCPT-loaded fiber fragments (Fh) indicated a sustained release for over 35days. In vitro cytotoxicity tests indicated a sequential inhibition on the endothelial and tumor cell growth, and the growth inhibition of tumor cells was more significant after treatment with mixtures of Fh and Fc containing 2% HPCD (Fc2) than that of other mixtures. In an orthotopic breast tumor model, compared with those of free CA4, or Fc with a fast or slow release of CA4, Fh/Fc mixtures with CA4 release durations from 2 to 12days indicated a lower tumor growth rate, a prolonged animal survival, a lower vessel density in tumors, and a less significant tumor metastasis. In addition, the tumor cell proliferation rate, hypoxia-inducible factor-1α expression within tumors, and the number of surface metastatic nodules in lungs were significantly lower after treatment with Fh/Fc2 mixtures with a CA4 release duration of 5days than those of other mixtures. It demonstrates the advantages of fiber fragment mixtures in independently modulating the release of multiple drugs and the essential role of release tuning of chemotherapeutic drugs and vascular disrupting agents in improving the therapeutic

  1. Differential in vitro effects of chemotherapeutic agents on primary cultures of human ovarian carcinoma.

    PubMed

    Kornblith, P; Ochs, R L; Wells, A; Gabrin, M J; Piwowar, J; Chattopadhyay, A; George, L D; Burholt, D

    2004-01-01

    The treatment of ovarian cancer principally relies on the use of platinum and taxane chemotherapeutic agents. Short-term clinical results have been encouraging, but long-term responses remain limited. In this report, an in vitro assay system that utilizes cells grown from human tumor explants has been used to quantitatively evaluate responses to relevant concentrations of alternative chemotherapeutic agents. The results suggest that there are significant differences in the responses of explant-derived cultured cells to the different agents tested. In an evaluation of 276 primary ovarian cancer specimens, five nonstandard drugs were tested in 51 cases. Of these 51 cases, cyclophosphamide had the highest rate of response at 67%, followed by doxorubicin at 61%, gemcitabine at 49%, etoposide at 48%, and topotecan at 14%. Venn diagrams, representing the in vitro responses to the platins and taxanes, as well as the responses to the nonstandard drugs, illustrate that there clearly are distinct differences among patients in a given population. These data underscore the potential importance of evaluating each patient's response to a number of different drugs to optimize the therapeutic decision-making process. PMID:15304154

  2. In vitro three dimensional culture of hepatocellular carcinoma to measure prognosis and responsiveness to chemotherapeutic agents

    PubMed Central

    Costello, Penny; McDonald, Warren; Howlett, Christopher; Donnelly, Marisa; McAlister, Vivian C.

    2016-01-01

    Background Understanding the prognosis of hepatocellular carcinoma (HCC) informs plans for care. Tumor morphology and molecular markers have been correlated with outcomes. Three-dimensional tissue culture (3DTC) allows for direct in vitro measurement of a tumor’s ability to grow and metastasize. The impact of chemotherapeutic agents, alone or in combinations, may also be measured. Methods All patients with a presumed diagnosis of HCC were eligible for this study including those undergoing resection, chemoembolization and transplantation. Concomitant diseases and outcomes were recorded. One mm3 HCC specimens were grown in multiwell plates containing gel media, without and with chemotherapeutic agents. Results Tumors were sampled from 17 patients. Only 13 had HCC, all of whom had liver transplantation. Of the confirmed HCC patients, 6 (46%) are alive and disease free 82 months following transplantation, 1 (7%) is alive with recurrence of disease and 6 (46%) died, with a mean survival of 12 months post liver transplant. Ten of thirteen 3DTC samples grew, having an average migration distance of 108.3µm in the first 24 hours. Two of three patients who had prior chemoembolization had successful 3DTC. Migration distances (µm) were 188.8±104.3, 104.5±111.7 and 39.6±32.4 for tumors categorized as high, intermediate and low grade, respectively. Tumor migration was inhibited by irinotecan, paclitaxel and docetaxel (−68%±7%, −61%±19% and −60%±21%, respectively) whereas the effect was variable with 5 fluorouracil (5FU) and doxorubicin (−12%±51% and 9%±76%, respectively). Conclusions It is feasible to grow tissue from HCC in 3DTC to study the tumor’s capacity to grow and migrate and its responsiveness to commonly used chemotherapeutic protocols. PMID:27275461

  3. 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. PMID:27308510

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

    PubMed Central

    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. PMID:27308510

  5. Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents.

    PubMed

    Cragg, Gordon M; Pezzuto, John M

    2016-01-01

    Throughout history, natural products have played a dominant role in the treatment of human ailments. For example, the legendary discovery of penicillin transformed global existence. Presently, natural products comprise a large portion of current-day pharmaceutical agents, most notably in the area of cancer therapy. Examples include Taxol, vinblastine, and camptothecin. These structurally unique agents function by novel mechanisms of action; isolation from natural sources is the only plausible method that could have led to their discovery. In addition to terrestrial plants as sources for starting materials, the marine environment (e.g., ecteinascidin 743, halichondrin B, and dolastatins), microbes (e.g., bleomycin, doxorubicin, and staurosporin), and slime molds (e.g., epothilone B) have yielded remarkable cancer chemotherapeutic agents. Irrespective of these advances, cancer remains a leading cause of death worldwide. Undoubtedly, the prevention of human cancer is highly preferable to treatment. Cancer chemoprevention, the use of vaccines or pharmaceutical agents to inhibit, retard, or reverse the process of carcinogenesis, is another important approach for easing this formidable public health burden. Similar to cancer chemotherapeutic agents, natural products play an important role in this field. There are many examples, including dietary phytochemicals such as sulforaphane and phenethyl isothiocyanate (cruciferous vegetables) and resveratrol (grapes and grape products). Overall, natural product research is a powerful approach for discovering biologically active compounds with unique structures and mechanisms of action. Given the unfathomable diversity of nature, it is reasonable to suggest that chemical leads can be generated that are capable of interacting with most or possibly all therapeutic targets. PMID:26679767

  6. Lapatinib promotes the incidence of hepatotoxicity by increasing chemotherapeutic agent accumulation in hepatocytes

    PubMed Central

    Wang, Fang; Zhao, HongYun; Wu, XingPing; Huang, ZhenCong; Chen, ZheSheng; To, Kenneth; Fu, LiWu

    2015-01-01

    Lapatinib has been used in combination with capecitabine or paclitaxel to treat patients with progressive HER2-overexpressing metastatic breast cancer (MBC). Unfortunately, an increased incidence of hepatotoxicity had been reported in the combinational therapy. The aim of this study was to investigate the potential mechanisms of this combinational therapy. We found that the patients receiving lapatinib and paclitaxel treatment showed a higher incidence of hepatobiliary system disorders than those receiving paclitaxel alone. Lapatinib was shown to increase the accumulation of doxorubicin in ABCB1-overexpressing hepatocellular cancer cells and normal liver tissues without altering the protein level of ABCB1. Pharmacokinetic studies revealed that lapatinib could increase the systematic exposure of paclitaxel and doxorubicin. Moreover, the in vivo experiments showed that the levels of alanine aminotransferase and serious hepatocyte injury in the group of lapatinib plus chemotherapeutic agent were significantly higher than those in the group of single chemotherapeutic agent such as paclitaxel or doxorubicin. Our study thus revealed for the first time that the higher incidence of hepatotoxicity during this combinational treatment was due to the increased drug accumulation in hepatocytes mediated by the inhibition of ABCB1 by lapatinib. Appropriate dose adjustment may be needed to optimize the combination therapy. PMID:26036634

  7. Lapatinib promotes the incidence of hepatotoxicity by increasing chemotherapeutic agent accumulation in hepatocytes.

    PubMed

    Dai, ChunLing; Ma, ShaoLin; Wang, Fang; Zhao, HongYun; Wu, XingPing; Huang, ZhenCong; Chen, ZheSheng; To, Kenneth; Fu, LiWu

    2015-07-10

    Lapatinib has been used in combination with capecitabine or paclitaxel to treat patients with progressive HER2-overexpressing metastatic breast cancer (MBC). Unfortunately, an increased incidence of hepatotoxicity had been reported in the combinational therapy. The aim of this study was to investigate the potential mechanisms of this combinational therapy. We found that the patients receiving lapatinib and paclitaxel treatment showed a higher incidence of hepatobiliary system disorders than those receiving paclitaxel alone. Lapatinib was shown to increase the accumulation of doxorubicin in ABCB1-overexpressing hepatocellular cancer cells and normal liver tissues without altering the protein level of ABCB1. Pharmacokinetic studies revealed that lapatinib could increase the systematic exposure of paclitaxel and doxorubicin. Moreover, the in vivo experiments showed that the levels of alanine aminotransferase and serious hepatocyte injury in the group of lapatinib plus chemotherapeutic agent were significantly higher than those in the group of single chemotherapeutic agent such as paclitaxel or doxorubicin. Our study thus revealed for the first time that the higher incidence of hepatotoxicity during this combinational treatment was due to the increased drug accumulation in hepatocytes mediated by the inhibition of ABCB1 by lapatinib. Appropriate dose adjustment may be needed to optimize the combination therapy. PMID:26036634

  8. Escherichia coli gene that controls sensitivity to alkylating agents.

    PubMed Central

    Yamamoto, Y; Katsuki, M; Sekiguchi, M; Otsuji, N

    1978-01-01

    A new type of Escherichia coli mutant which shows increased sensitivity to methyl methane sulfonate but not to UV light or to gamma rays was isolated after mutagenesis with N-methyl-N'-nitro-N-nitrosoguanidine. The mutant is unable to reactivate phage lambdavir or double-stranded phiX174 DNA (replicative form) that had been treated with methyl methane sulfonate. The mutant is sensitive to other alkylating agents, such as ethyl methane sulfonate, mitomycin C, and N-methyl-N'-nitro-N-nitrosoguanidine, as well. It grows normally and exhibits almost normal recombination proficiency. The mutant possesses normal levels of DNA polymerase I, exonuclease I, exonuclease V, endonuclease specific for methyl methane sulfonate-treated DNA, and 3-methyladenine-DNA glycosidase activities. The genetic locus responsible has been named alk and is located near his on the chromosome. PMID:353028

  9. ADVANCED MOLECULAR DESIGN OF BIOPOLYMERS FOR TRANSMUCOSAL AND INTRACELLULAR DELIVERY OF CHEMOTHERAPEUTIC AGENTS AND BIOLOGICAL THERAPEUTICS

    PubMed Central

    Liechty, William B.; Caldorera-Moore, Mary; Phillips, Margaret A.; Schoener, Cody; Peppas, Nicholas A.

    2011-01-01

    Hydrogels have been instrumental in the development of polymeric systems for controlled release of therapeutic agents. These materials are attractive for transmucosal and intracellular drug delivery because of their facile synthesis, inherent biocompatibility, tunable physicochemical properties, and capacity to respond to various physiological stimuli. In this contribution, we outline a multifaceted hydrogel-based approach for expanding the range of therapeutics in oral formulations from classical small-molecule drugs to include proteins, chemotherapeutics, and nucleic acids. Through judicious materials selection and careful design of copolymer composition and molecular architecture, we can engineer systems capable of responding to distinct physiological cues, with tunable physicochemical properties that are optimized to load, protect, and deliver valuable macromolecular payloads to their intended site of action. These hydrogel carriers, including complexation hydrogels, tethered hydrogels, interpenetrating networks, nanoscale hydrogels, and hydrogels with decorated structures are investigated for their ability respond to changes in pH, to load and release insulin and fluorescein, and remain non-toxic to Caco-2 cells. Our results suggest these novel hydrogel networks have great potential for controlled delivery of proteins, chemotherapeutics, and nucleic acids. PMID:21699934

  10. 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

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

    PubMed

    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

  12. Advanced molecular design of biopolymers for transmucosal and intracellular delivery of chemotherapeutic agents and biological therapeutics.

    PubMed

    Liechty, William B; Caldorera-Moore, Mary; Phillips, Margaret A; Schoener, Cody; Peppas, Nicholas A

    2011-10-30

    Hydrogels have been instrumental in the development of polymeric systems for controlled release of therapeutic agents. These materials are attractive for transmucosal and intracellular drug delivery because of their facile synthesis, inherent biocompatibility, tunable physicochemical properties, and capacity to respond to various physiological stimuli. In this contribution, we outline a multifaceted hydrogel-based approach for expanding the range of therapeutics in oral formulations from classical small-molecule drugs to include proteins, chemotherapeutics, and nucleic acids. Through judicious material selection and careful design of copolymer composition and molecular architecture, we can engineer systems capable of responding to distinct physiological cues, with tunable physicochemical properties that are optimized to load, protect, and deliver valuable macromolecular payloads to their intended site of action. These hydrogel carriers, including complexation hydrogels, tethered hydrogels, interpenetrating networks, nanoscale hydrogels, and hydrogels with decorated structures are investigated for their ability to respond to changes in pH, to load and release insulin and fluorescein, and remain non-toxic to Caco-2 cells. Our results suggest these novel hydrogel networks have great potential for controlled delivery of proteins, chemotherapeutics, and nucleic acids. PMID:21699934

  13. 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. PMID:27014922

  14. Bioactivity of some chemotherapeutic agents in selected polyethylene glycol ointment bases.

    PubMed

    Farouk, A; Béla, S; Géza, R; Mohamed, S; Abdei Hadi, I

    1989-03-01

    Six different chemotherapeutic agents were individually incorporated in each of fourteen selected polyethylene glycol ointment bases, and their bioactivities were assessed using different diffusion techniques. The prepared medicated ointments were evaluated for drug release using the standard microbiological agar cup diffusion, the long period method and the short period method, as well as dialysis through artificial kidney membrane. On the basis of consistency, stability and diffusion results, formulation 11 was the most suitable base for ampicillin, formulation 14 for oxytetracycline HCl, formulation 10 and 9 for neomycin sulphate, and preparation 10 for chloramphenicol. On the basis of the results of drug release, it was evident that formulation 3 was the best for ampicillin and chloramphenicol, formulation 2 for erythromycin, formulation 4 for neomycin sulphate, formulation 12 for sulphadimidine, and formulation 14 for oxytetracycline HCl. PMID:2735193

  15. COX-2 inhibitors block chemotherapeutic agent-induced apoptosis prior to commitment in hematopoietic cancer cells.

    PubMed

    Cerella, Claudia; Sobolewski, Cyril; Chateauvieux, Sébastien; Henry, Estelle; Schnekenburger, Michael; Ghelfi, Jenny; Dicato, Mario; Diederich, Marc

    2011-11-15

    Enzymatic inhibitors of pro-inflammatory cyclooxygenase-2 (COX-2) possess multiple anti-cancer effects, including chemosensitization. These effects are not always linked to the inhibition of the COX-2 enzyme. Here we analyze the effects of three COX-2 enzyme inhibitors (nimesulide, NS-398 and celecoxib) on apoptosis in different hematopoietic cancer models. Surprisingly, COX-2 inhibitors strongly prevent apoptosis induced by a panel of chemotherapeutic agents. We selected U937 cells as a model of sensitive cells for further studies. Here, we provide evidence that the protective effect is COX-independent. No suppression of the low basal prostaglandin (PG)E(2) production may be observed upon treatment by COX-2 inhibitors. Besides, the non-active celecoxib analog 2,5-dimethyl-celecoxib is able to protect from apoptosis as well. We demonstrate early prevention of the stress-induced apoptotic signaling, prior to Bax/Bak activation. This preventive effect fits with an impairment of the ability of chemotherapeutic agents to trigger apoptogenic stress. Accordingly, etoposide-induced DNA damage is strongly attenuated in the presence of COX-2 inhibitors. In contrast, COX-2 inhibitors do not exert any anti-apoptotic activity when cells are challenged with physiological stimuli (anti-Fas, TNFα or Trail) or with hydrogen peroxide, which do not require internalization and/or are not targeted by chemoresistance proteins. Altogether, our findings show a differential off-target anti-apoptotic effect of COX-2 inhibitors on intrinsic vs. extrinsic apoptosis at the very early steps of intracellular signaling, prior to commitment. The results imply that an exacerbation of the chemoresistance phenomena may be implicated. PMID:21745461

  16. Safe Handling of Chemotherapeutic Agents in the Treatment of Nonmalignant Diseases.

    PubMed

    Menonna-Quinn, Denise

    2015-01-01

    Chemotherapy administration was once limited to inpatient oncology units. Over time, outpatient facilities, physicians' private offices, and patients' homes have become popular areas to administer chemotherapeutic agents. Chemotherapy has been successful in treating malignancies and recently has been proved to be effective in nononcology patients as well. The expanded use of these agents has created the need to amplify safe handling practices among health care providers. Evidence indicates that there is a heightened awareness of safe handling practices and the increased availability of the necessary tools. However, health care professionals resist protecting themselves. To avoid the potential risks associated with working with these agents, it is imperative to appreciate the dangers of these hazardous medications, to adhere to the safety mechanisms, and to use the available safety resources on a daily basis. Continuous education of health care providers is fundamental to ensuring safety and positive outcomes. Safe handling procedures can be implemented by adhering to the current standards and integrating them into policies and procedure manuals at practicing institutions. PMID:26536405

  17. Safe handling of chemotherapeutic agents in the treatment of nonmalignant diseases.

    PubMed

    Menonna-Quinn, Denise

    2013-01-01

    Chemotherapy administration was once limited to inpatient oncology units. Over time, outpatient facilities, physicians' private offices, and patients' homes have become popular areas to administer chemotherapeutic agents. Chemotherapy has been successful in treating malignancies and recently has been proved to be effective in nononcology patients as well. The expanded use of these agents has created the need to amplify safe handling practices among health care providers. Evidence indicates that there is a heightened awareness of safe handling practices and the increased availability of the necessary tools. However, health care professionals resist protecting themselves. To avoid the potential risks associated with working with these agents, it is imperative to appreciate the dangers of these hazardous medications, to adhere to the safety mechanisms, and to use the available safety resources on a daily basis. Continuous education of health care providers is fundamental to ensuring safety and positive outcomes. Safe handling procedures can be implemented by adhering to the current standards and integrating them into policies and procedure manuals at practicing institutions. PMID:23558919

  18. Suppression of STN1 enhances the cytotoxicity of chemotherapeutic agents in cancer cells by elevating DNA damage

    PubMed Central

    Zhou, Qing; Chai, Weihang

    2016-01-01

    DNA damage-inducing agents are among the most effective treatment regimens in clinical chemotherapy. However, drug resistance and severe side effects caused by these agents greatly limit their efficacy. Sensitizing malignant cells to chemotherapeutic agents has long been a goal of chemotherapy. In the present study, suppression of STN1, a gene important for safeguarding genome stability, potentiated the anticancer effect of chemotherapeutic agents in tumor cells. Using multiple cancer cells from a variety of origins, it was observed that downregulation of STN1 resulted in a significant decrease in the half maximal inhibitory concentration values of several conventional anticancer agents. When cells are treated with anticancer agents, STN1 suppression leads to a decline in colony formation and diminished anchorage-independent growth. Furthermore, it was additionally observed that STN1 knockdown augmented the levels of DNA damage caused by damage-inducing agents. The present study concluded that suppression of STN1 enhances the cytotoxicity of damage-inducing chemotherapeutic agents by increasing DNA damage in cancer cells. PMID:27446354

  19. 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. PMID:9234068

  20. New synthetic aliphatic sulfonamido-quaternary ammonium salts as anticancer chemotherapeutic agents.

    PubMed

    Song, Doona; Yang, Jee Sun; Oh, Changmok; Cui, Shuolin; Kim, Bo-Kyung; Won, Misun; Lee, Jang-ik; Kim, Hwan Mook; Han, Gyoonhee

    2013-11-01

    RhoB is expressed during tumor cell proliferation, survival, invasion, and metastasis. In malignant progression, the expression levels of RhoB are commonly attenuated. RhoB is known to be linked to the regulation of the PI3K/Akt survival pathways. Based on aliphatic amido-quaternary ammonium salts that induce apoptosis via up-regulation of RhoB, we synthesized novel aliphatic sulfonamido-quaternary ammonium salts. These new synthetic compounds were evaluated for their biological activities using an in vitro RhoB promoter assay in HeLa cells, and in a growth inhibition assay using human cancer cell lines including PC-3, NUGC-3, MDA-MB-231, ACHN, HCT-15, and NCI-H23. Compound 5b (ethyl-dimethyl-{3-[methyl-(tetradecane-1-sulfonyl)-amino]-propyl}-ammonium; iodide) was the most promising anticancer agent in the series, based upon the potency of growth inhibition and RhoB promotion. These new aliphatic sulfonamido-quaternary ammonium salts could be a valuable series for development of new anticancer chemotherapeutic agents. PMID:24095759

  1. Cetuximab enhanced the efficacy of chemotherapeutic agent in ABCB1/P-glycoprotein-overexpressing cancer cells

    PubMed Central

    Liu, Tao; Huang, Yue; Zhao, Jianming; Wang, Xiaokun; Yang, Ke; Ma, Shaolin; Huang, Liyan; Wah To, Kenneth Kin; Gu, Yong; Fu, Liwu

    2015-01-01

    The overexpression of ATP-binding cassette (ABC) transporters is closely associated with the development of multidrug resistance (MDR) in certain types of cancer, which represents a formidable obstacle to the successful cancer chemotherapy. Here, we investigated that cetuximab, an EGFR monoclonal antibody, reversed the chemoresistance mediated by ABCB1, ABCG2 or ABCC1. Our results showed that cetuximab significantly enhanced the cytotoxicity of ABCB1 substrate agent in ABCB1-overexpressing MDR cells but had no effect in their parental drug sensitive cells and ABCC1, ABCG2 overexpressing cells. Furthermore, cetuximab markedly increased intracellular accumulation of doxorubicin (DOX) and rhodamine 123 (Rho 123) in ABCB1-overexpressing MDR cancer cells in a concentration-dependent manner. Cetuximab stimulated the ATPase activity but did not alter the expression level of ABCB1 or block phosphorylation of AKT and ERK. Interestingly, cetuximab decreased the cell membrane fluidity which was known to decrease the function of ABCB1. Our findings advocate further clinical investigation of combination chemotherapy of cetuximab and conventional chemotherapeutic drugs in ABCB1 overexpressing cancer patients. PMID:26506420

  2. 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

  3. Focal therapy of neuroblastoma using silk films to deliver kinase and chemotherapeutic agents in vivo.

    PubMed

    Seib, F Philipp; Coburn, Jeannine; Konrad, Ilona; Klebanov, Nikolai; Jones, Gregory T; Blackwood, Brian; Charest, Alain; Kaplan, David L; Chiu, Bill

    2015-07-01

    Current methods for treatment of high-risk neuroblastoma patients include surgical intervention, in addition to systemic chemotherapy. However, only limited therapeutic tools are available to pediatric surgeons involved in neuroblastoma care, so the development of intraoperative treatment modalities is highly desirable. This study presents a silk film library generated for focal therapy of neuroblastoma; these films were loaded with either the chemotherapeutic agent doxorubicin or the targeted drug crizotinib. Drug release kinetics from the silk films were fine-tuned by changing the amount and physical crosslinking of silk; doxorubicin loaded films were further refined by applying a gold nanocoating. Doxorubicin-loaded, physically crosslinked silk films showed the best in vitro activity and superior in vivo activity in orthotopic neuroblastoma studies when compared to the doxorubicin-equivalent dose administered intravenously. Silk films were also suitable for delivery of the targeted drug crizotinib, as crizotinib-loaded silk films showed an extended release profile and an improved response both in vitro and in vivo when compared to freely diffusible crizotinib. These findings, when combined with prior in vivo data on silk, support a viable future for silk-based anticancer drug delivery systems. PMID:25861948

  4. Increased γ-H2AX and Rad51 DNA Repair Biomarker Expression in Human Cell Lines Resistant to the Chemotherapeutic Agents Nitrogen Mustard and Cisplatin.

    PubMed

    Adam-Zahir, Sheba; Plowman, Piers N; Bourton, Emma C; Sharif, Fariha; Parris, Christopher N

    2014-01-01

    Chemotherapeutic anticancer drugs mediate cytotoxicity by a number of mechanisms. However, alkylating agents which induce DNA interstrand crosslinks (ICL) are amongst the most effective anticancer agents and often form the mainstay of many anticancer therapies. The effectiveness of these drugs can be limited by the development of drug resistance in cancer cells and many studies have demonstrated that alterations in DNA repair kinetics are responsible for drug resistance. In this study we developed two cell lines resistant to the alkylating agents nitrogen mustard (HN2) and cisplatin (Pt). To determine if drug resistance was associated with enhanced ICL DNA repair we used immunocytochemistry and imaging flow cytometry to quantitate the number of γ-H2AX and Rad51 foci in the nuclei of cells after drug exposure. γ-H2AX was used to evaluate DNA strand breaks caused by repair incision nucleases and Rad51 was used to measure the activity of homologous recombination in the repair of ICL. In the drug-resistant derivative cell lines there was overall a significant increase in the number and persistence of both γ-H2AX and Rad51 foci in the nuclei of cells over a 72-hour period, when compared to the non-resistant parental cell lines (ANOVA p < 0.0001). In a Pt-resistant ovarian cancer cell line (A2780cis(R)) a similar enhancement of DNA repair was observed when compared to the non-drug-resistant wild-type ovarian cancer cells (A2780) following exposure to HN2. Our data suggest that using DNA repair biomarkers to evaluate mechanisms of resistance in cancer cell lines and human tumours may be of experimental and clinical benefit. We concede, however, that examination of a larger population of cell lines and tumours is required to fully evaluate the validity of this approach. PMID:26138778

  5. Alkyl phospholipid antihypertensive agents in method of lowering blood pressure

    DOEpatents

    Snyder, Fred L.; Blank, Merle L.; Muirhead, Ernest E.; Leach, deceased, Byron E.; Byers, Lawrence W.

    1988-01-01

    The composition of this invention is 1-O-alkyl-2-acetoyl-sn-glycero-3-phosphocholine, having the ionic structural formula; ##STR1## wherein R is saturated alkyl having 9-21 carbon atoms, or salts or hydrates of the composition. Preferably R has 13-19 carbon atoms and most preferably R has 15 carbon atoms. The composition of this invention is useful for reducing hypertension in warm-blooded animals, including humans, when administered either orally or by injection or innoculation, e.g., intravenous injection. The composition can be prepared from naturally occurring lipids or synthetically from commercially available material.

  6. Use of a human endometrial carcinoma cell line (RL-95) for in vitro testing of chemotherapeutic agents

    SciTech Connect

    Christensen, C.; Deppe, G.; Saunders, D.; Malviya, V.

    1987-09-01

    RL-95, a moderately well-differentiated adenosquamous endometrial carcinoma cell line, can be used as a model for testing chemotherapeutic agents in vitro. Cells are grown in T-75 flasks, transferred to scintillation vials, and grown for 24 hr. Following this, medium is removed and new medium containing Adriamycin (Adr) and cis-platinum (CP) is added. Effects of the two drugs are measured by cell counts and DNA synthesis. To measure DNA synthesis, cells are incubated with (/sup 3/H)thymidine (/sup 3/H-THY) for up to 24 hr. Decreased DNA synthesis is reflected in decreased /sup 3/H-THY uptake. Cell kill is obtained with levels of drugs that are clinically achievable. Evidence is presented for increased cytotoxicity with concomitant, rather than sequential, chemotherapy. Results are also confirmed by testing the agent on MCF-7, a well-known breast cancer cell line. The results indicate that (1) endometrial carcinoma responds to Adriamycin and cis-platinum chemotherapeutic agents in vitro, and (2) RL-95 can be used as a model for testing varying concentrations, time of exposure, and combinations of chemotherapeutic agents.

  7. Preferential effects of the chemotherapeutic DNA crosslinking agent mitomycin C on inducible gene expression in vivo.

    PubMed

    Caron, R M; Hamilton, J W

    1995-01-01

    The immediate effects of a single dose of the chemotherapeutic DNA crosslinking agent, mitomycin C (MMC), on the expression of several constitutive and drug-inducible genes were examined in a simple in vivo system, the 14 day chick embryo. We observed no effect of MMC on the steady-state mRNA expression of the constitutively expressed beta-actin, transferrin, or albumin genes. In contrast, MMC treatment significantly altered both the basal and drug-inducible mRNA expression of two glutethimide-inducible genes, 5-aminolevulinic acid (ALA) synthase and cytochrome P450 CYP2H1. The basal expression of these genes was transiently but significantly increased over a 24 hr period following a single dose of MMC. Conversely, MMC significantly suppressed the glutethimide-inducible expression of these genes when administered 1 to 24 hr prior to the inducing drug. The effects of MMC on both basal and drug-inducible ALA synthase and CYP2H1 mRNA expression were principally a result of changes in the transcription rates of these genes. In contrast, MMC treatment had little or no effect on glutethimide-induced expression of ALA synthase or CYP2H1 when administered 1 hr after the inducing drug, suggesting that a very early event in the induction process represents the target for these MMC effects. Covalent binding studies demonstrated that the effects of MMC on gene expression were closely correlated temporally with formation of [3H]-porfiromycin-DNA adducts. These results support the hypothesis that genotoxic chemicals specifically target their effects to inducible genes in vivo. PMID:7875125

  8. Suppression of alkylating agent induced cell transformation and gastric ulceration by low-dose alkylating agent pretreatment

    SciTech Connect

    Onodera, Akira; Kawai, Yuichi; Kashimura, Asako; Ogita, Fumiya; Tsutsumi, Yasuo; Itoh, Norio

    2013-06-14

    Highlights: •Low-dose MNNG pretreatment suppresses high-dose MNNG induced in vitro transformation. •Gastric ulcers induced by high-dose MNNG decreased after low-dose MNNG pretreatment. •Efficacy of low-dose MNNG related to resistance of mutation and oxidative stress. -- Abstract: Exposure to mild stress by chemicals and radiation causes DNA damage and leads to acquired stress resistance. Although the linear no-threshold (LNT) model of safety assessment assumes risk from any dose, evidence from radiological research demonstrates a conflicting hormetic phenomenon known as the hormesis effect. However, the mechanisms underlying radiation hormesis have not yet been clarified, and little is known about the effects of low doses of chemical carcinogens. We analyzed the efficacy of pretreatment with low doses of the alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) on the subsequent induction of cell transformation and gastric ulceration by high-dose MNNG. We used an in vitro Balb/3T3 A31-1-1 cell transformation test and monitored the formation of gastric ulcers in 5-week-old male ICR mice that were administered MNNG in drinking water. The treatment concentrations of MNNG were determined by the cell survival rate and past reports. For low-dose in vitro and in vivo experiments, MNNG was used at 0.028 μM, and 2.8 μg/mL, respectively. The frequency of cell transformation induced by 10 μm MNNG was decreased by low-dose MNNG pretreatment to levels similar to that of spontaneous transformation. In addition, reactive oxygen species (ROS) and mutation frequencies induced by 10 μm MNNG were decreased by low-dose MNNG pretreatment. Importantly, low-dose MNNG pretreatment had no effect on cell proliferation. In vivo studies showed that the number of gastric ulcers induced by 1 mg/mL MNNG decreased after low-dose MNNG pretreatment. These data indicate that low-dose pretreatment with carcinogens may play a beneficial role in the prevention of chemical toxicity

  9. Anti-cancer effects of newly developed chemotherapeutic agent, glycoconjugated palladium (II) complex, against cisplatin-resistant gastric cancer cells

    PubMed Central

    2013-01-01

    Background Cisplatin (CDDP) is the most frequently used chemotherapeutic agent for various types of advanced cancer, including gastric cancer. However, almost all cancer cells acquire resistance against CDDP, and this phenomenon adversely affects prognosis. Thus, new chemotherapeutic agents that can overcome the CDDP-resistant cancer cells will improve the survival of advanced cancer patients. Methods We synthesized new glycoconjugated platinum (II) and palladium (II) complexes, [PtCl2 (L)] and [PdCl2 (L)]. CDDP-resistant gastric cancer cell lines were established by continuous exposure to CDDP, and gene expression in the CDDP-resistant gastric cancer cells was analyzed. The cytotoxicity and apoptosis induced by [PtCl2 (L)] and [PdCl2 (L)] in CDDP-sensitive and CDDP-resistant gastric cancer cells were evaluated. DNA double-strand breaks by drugs were assessed by evaluating phosphorylated histone H2AX. Xenograft tumor mouse models were established and antitumor effects were also examined in vivo. Results CDDP-resistant gastric cancer cells exhibit ABCB1 and CDKN2A gene up-regulation, as compared with CDDP-sensitive gastric cancer cells. In the analyses of CDDP-resistant gastric cancer cells, [PdCl2 (L)] overcame cross-resistance to CDDP in vitro and in vivo. [PdCl2 (L)] induced DNA double-strand breaks. Conclusion These results indicate that [PdCl2 (L)] is a potent chemotherapeutic agent for CDDP-resistant gastric cancer and may have clinical applications. PMID:23672493

  10. ATM regulates 3-Methylpurine-DNA glycosylase and promotes therapeutic resistance to alkylating agents

    PubMed Central

    Agnihotri, Sameer; Burrell, Kelly; Buczkowicz, Pawel; Remke, Marc; Golbourn, Brian; Chornenkyy, Yevgen; Gajadhar, Aaron; Fernandez, Nestor A.; Clarke, Ian D.; Barszczyk, Mark S.; Pajovic, Sanja; Ternamian, Christian; Head, Renee; Sabha, Nesrin; Sobol, Robert W.; Taylor, Michael D; Rutka, James T.; Jones, Chris; Dirks, Peter B.; Zadeh, Gelareh; Hawkins, Cynthia

    2014-01-01

    Alkylating agents are a frontline therapy for the treatment of several aggressive cancers including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed; increasing therapeutic response while minimizing toxicity. Using a siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM) were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent-induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM-MPG axis will lead to improved treatment of alkylating agent-resistant tumors. PMID:25100205

  11. Mutagenesis by Cytostatic Alkylating Agents in Yeast Strains of Differing Repair Capacities

    PubMed Central

    Ruhland, Axel; Brendel, Martin

    1979-01-01

    Reversion of two nuclear ochre nonsense alleles and cell inactivation induced by mono-, bi-, and tri-functional alkylating agents and by UV has been investigated in stationary-phase haploid cells of yeast strains with differing capacities for DNA repair. The ability to survive alkylation damage is correlated with UV repair capacity, a UV-resistant and UV-mutable strain (RAD REV) being least and a UV-sensitive and UV-nonmutable strain (rad1 rev3) most sensitive. Mutagenicity of alkylating agents is highest in the former and is abolished in the latter strain. Deficiency in excision repair (rad1 rad2) or in the RAD18 function does not lead to enhanced mutability. Mutagenesis by the various agents is characterized by a common pattern of induction of locus-specific revertants and suppressor mutants. Induction kinetics are mostly linear, but UV-induced reversion in the RAD REV strain follows higher-than-linear (probably "quadratic") kinetics. The alkylating agent cyclophosphamide, usually considered inactive without metabolic conversion, reduces colony-forming ability and induces revertants in a manner similar but not identical to the other chemicals tested. These findings are taken to support the concept of mutagenesis by misrepair after alkylation, which albeit sharing common features with the mechanism of UV-induced reversion, can be distinguished therefrom. PMID:387518

  12. Profilin potentiates chemotherapeutic agents mediated cell death via suppression of NF-κB and upregulation of p53.

    PubMed

    Zaidi, Adeel H; Raviprakash, Nune; Mokhamatam, Raveendra B; Gupta, Pankaj; Manna, Sunil K

    2016-04-01

    The molecular mechanism by which Profilin acts as a tumor suppressor is still unclear. Several chemotherapeutic agents, used till date either have unfavorable side effects or acquired resistance in tumor cells. Our findings show that Profilin enhances cell death mediated by several chemotherapeutic-agents. The activation of NF-κB and its dependent genes, mediated by paclitaxel and vinblastine, was completely inhibited in Profilin overexpressing cells. This inhibition was due to the Profilin mediated attenuation of IκBα degradation, thereby preventing p65 nuclear translocation and low NF-κB DNA binding activity.Moreover, Profilin increases level of p53 in the presence of known inducers, such as doxorubicin, vinblastine, and benzofuran. This increased p53 level leads to enhanced cell death as indicated by activation of caspases 3, 8, 9, which results in cleavage of PARP.Furthermore, knocking down of p53 in Profilin overexpressing cells leads to decreased cell death. Ectopic expression of Profilin in HCT116 p53 knock out cells showed lesser cell death as compared to the HCT116 p53 wild type cells. For the first time, we provide evidences, which suggest that Profilin synergizes with chemotherapeutic drugs to induce tumor cell death by regulating NF-κB and p53. Thus, modulation of Profilin may be a useful strategy for effective combination therapy. PMID:26842845

  13. Chemotherapeutic Agents for the Treatment of Hepatocellular Carcinoma: Efficacy and Mode of Action

    PubMed Central

    Shaaban, Saad; Negm, Amr; Ibrahim, Elsayed E.; Elrazak, Ahmed A.

    2014-01-01

    Hepatocellular carcinoma (HCC) is a dreaded malignancy that every year causes half a million deaths worldwide. Being an aggressive cancer, its incidence exceeds 700,000 new cases per year worldwide with a median survival of 6-8 months. Despite advances in prognosis and early detection, effective HCC chemoprevention or treatment strategies are still lacking, therefore its dismal survival rate remains largely unchanged. This review will characterize currently available chemotherapeutic drugs used in the treatment of HCC. The respective mode(s) of action, side effects and recommendations will be also described for each drug. PMID:25992234

  14. Optimal Classes of Chemotherapeutic Agents Sensitized by Specific Small-Molecule Inhibitors of Akt In Vitro and In Vivo

    PubMed Central

    Shi, Yan; Liu, Xuesong; Han, Edward K.; Guan, Ran; Shoemaker, Alexander R.; Oleksijew, Anatol; Woods, Keith W.; Fisher, John P.; Klinghofer, Vered; Lasko, Loren; McGonigal, Thomas; Li, Qun; Rosenberg, Saul H.; Giranda, Vincent L.; Luo, Yan

    2005-01-01

    Abstract Akt is a serine/threonine kinase that transduces survival signals from survival/growth factors. Deregulation and signal imbalance in cancer cells make them prone to apoptosis. Upregulation or activation of Akt to aid the survival of cancer cells is a common theme in human malignancies. We have developed small-molecule Akt inhibitors that are potent and specific. These Akt inhibitors can inhibit Akt activity and block phosphorylation by Akt on multiple downstream targets in cells. Synergy in apoptosis induction was observed when Akt inhibitors were combined with doxorubicin or camptothecin. Akt inhibitor–induced enhancement of topoisomerase inhibitor cytotoxicity was also evident in long-term cell survival assay. Synergy with paclitaxel in apoptosis induction was evident in cells pretreated with paclitaxel, and enhancement of tumor delay by paclitaxel was demonstrated through cotreatment with Akt inhibitor Compound A (A-443654). Combination with other classes of chemotherapeutic agents did not yield any enhancement of cytotoxicity. These findings provide important guidance in selecting appropriate classes of chemotherapeutic agents for combination with Akt inhibitors in cancer treatment. PMID:16331885

  15. Antimetastasis and antitumor efficacy promoted by sequential release of vascular disrupting and chemotherapeutic agents from electrospun fibers.

    PubMed

    Luo, Xiaoming; Zhang, Hong; Chen, Maohua; Wei, Jiaojun; Zhang, Yun; Li, Xiaohong

    2014-11-20

    The vasculature in tumor microenvironment plays important roles in the tumor growth and metastasis, and the combination of vascular disrupting agents with chemotherapeutic drugs should be effective in inhibiting tumor progression. But the dosing schedules are essential to achieve a balance between vascular collapse and intratumoral uptake of chemotherapeutic agents. In the current study, emulsion and blend electrospinning were used to create compartmental fibers accommodating both combretastatin A-4 (CA4) and hydroxycamptothecin (HCPT). The release durations of CA4 and HCPT were modulated through the structure of fibers for dual drug loadings and the inoculation of 2-hydroxypropyl-β-cyclodextrin in fiber matrices. Under a noncontact cell coculture in Transwell, the sequential release of CA4 and HCPT indicated a sequential killing of endothelial and tumor cells. In an orthotopic breast tumor model, all the CA4/HCPT-loaded fibers showed superior antitumor efficacy and higher survival rate than fibers with loaded individual drug. Compared with fibrous mats with infiltrated free CA4 and fibers with extended release of CA4 for over 30 days, fibers with sustained release of CA4 for 3-7 days from CA4/HCPT-loaded fibers resulted in the most significant antitumor efficacy, tumor vasculature destruction, and the least tumor metastasis to lungs. A judicious selection of CA4 release durations in the combination therapy should be essential to enhance the tumor suppression efficacy and antimetastasis activity. PMID:25218185

  16. Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor.

    PubMed

    Sahu, Ravi P; Ocana, Jesus A; Harrison, Kathleen A; Ferracini, Matheus; Touloukian, Christopher E; Al-Hassani, Mohammed; Sun, Louis; Loesch, Mathew; Murphy, Robert C; Althouse, Sandra K; Perkins, Susan M; Speicher, Paul J; Tyler, Douglas S; Konger, Raymond L; Travers, Jeffrey B

    2014-12-01

    Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation. PMID:25304264

  17. Synthesis and Biological Evaluation of Novel N-phenyl-5-carboxamidyl Isoxazoles as Potential Chemotherapeutic Agents for Colon Cancer.

    PubMed

    Shaw, Jiajiu; Chen, Ben; Bourgault, Jean P; Jiang, Hao; Kumar, Narendra; Mishra, Jayshree; Valeriote, Frederick A; Media, Joe; Bobbitt, Kevin; Pietraszkiewicz, Halina; Edelstein, Matthew; Andreana, Peter R

    2012-01-01

    A new series of isoxazole derivatives, N-phenyl-5-carboxamidyl isoxazoles, was investigated for their anticancer activity with solid tumor selectivity. Six N-phenyl-5-carboxamidylisoxazoles were chemically synthesized and evaluated by the in vitro disk-diffusion assay and IC50 cytotoxicity determination. The results showed that one of the derivatives, compound 3, N-(4-chlorophenyl)-5-carboxamidyl isoxazole, was the most active against colon 38 and CT-26 mouse colon tumor cells with an IC50 of 2.5 μg/mL for both cell lines. Western blot analysis showed that compound 3 significantly down-regulated the expression of phosphorylated STAT3 in both human and mouse colon cancer cells indicating that the mechanism of action for compound 3 may involve the inhibition of JAK3/STAT3 signaling pathways. Flow cytometric analysis with Annexin V staining showed that the death induced by compound 3 is mediated through cell necrosis and not apoptotic pathway. In summary, our results show that compound 3 is a new N-phenyl-5-carboxamidyl isoxazole with potential anticancer activity. Compound 3 inhibits the phosphorylation of STAT3, a novel target for chemotherapeutic drugs, and is worthy of further investigation as a potential chemotherapeutic agent for treating colon cancer. PMID:25285182

  18. Synthesis and Characterization of DNA Minor Groove Binding Alkylating Agents

    PubMed Central

    Iyer, Prema; Srinivasan, Ajay; Singh, Sreelekha K.; Mascara, Gerard P.; Zayitova, Sevara; Sidone, Brian; Fouquerel, Elise; Svilar, David; Sobol, Robert W.; Bobola, Michael S.; Silber, John R.; Gold, Barry

    2012-01-01

    Derivatives of methyl 3-(1-methyl-5-(1-methyl-5-(propylcarbamoyl)-1H-pyrrol-3-ylcarbamoyl)-1H-pyrrol-3-ylamino)-3-oxopropane-1-sulfonate (1), a peptide-based DNA minor groove binding methylating agent, were synthesized and characterized. In all cases the N-terminus was appended with a O-methyl sulfonate ester while the C-terminus group was varied with non-polar and polar sidechains. In addition, the number of pyrrole rings was varied from 2 (dipeptide) to 3 (tripeptide). The ability of the different analogues to efficiently generate N3-methyladenine was demonstrated as was their selectivity for minor groove (N3-methyladenine) vs. major groove (N7-methylguanine) methylation. Induced circular dichroism studies were used to measure the DNA equilibrium binding properties of the stable sulfone analogues; the tripeptide binds with affinity that is > 10-fold higher than the dipeptide. The toxicities of the compounds were evaluated in alkA/tag glycosylase mutant E. coli and in human WT glioma cells and in cells over-expressing and under-expressing N-methylpurine-DNA glycosylase, which excises N3-methyladenine from DNA. The results show that equilibrium binding correlates with the levels of N3-methyladenine produced and cellular toxicity. The toxicity of 1 was inversely related to expression of MPG in both the bacterial and mammalian cell lines. The enhanced toxicity parallels the reduced activation of PARP and diminished rate of formation of aldehyde reactive sites observed in the MPG knockdown cells. It is proposed that unrepaired N3-methyladenine is toxic due to its ability to directly block DNA polymerization. PMID:23234400

  19. Synthesis and characterization of DNA minor groove binding alkylating agents.

    PubMed

    Iyer, Prema; Srinivasan, Ajay; Singh, Sreelekha K; Mascara, Gerard P; Zayitova, Sevara; Sidone, Brian; Fouquerel, Elise; Svilar, David; Sobol, Robert W; Bobola, Michael S; Silber, John R; Gold, Barry

    2013-01-18

    Derivatives of methyl 3-(1-methyl-5-(1-methyl-5-(propylcarbamoyl)-1H-pyrrol-3-ylcarbamoyl)-1H-pyrrol-3-ylamino)-3-oxopropane-1-sulfonate (1), a peptide-based DNA minor groove binding methylating agent, were synthesized and characterized. In all cases, the N-terminus was appended with an O-methyl sulfonate ester, while the C-terminus group was varied with nonpolar and polar side chains. In addition, the number of pyrrole rings was varied from 2 (dipeptide) to 3 (tripeptide). The ability of the different analogues to efficiently generate N3-methyladenine was demonstrated as was their selectivity for minor groove (N3-methyladenine) versus major groove (N7-methylguanine) methylation. Induced circular dichroism studies were used to measure the DNA equilibrium binding properties of the stable sulfone analogues; the tripeptide binds with affinity that is >10-fold higher than that of the dipeptide. The toxicities of the compounds were evaluated in alkA/tag glycosylase mutant E. coli and in human WT glioma cells and in cells overexpressing and under-expressing N-methylpurine-DNA glycosylase, which excises N3-methyladenine from DNA. The results show that equilibrium binding correlates with the levels of N3-methyladenine produced and cellular toxicity. The toxicity of 1 was inversely related to the expression of MPG in both the bacterial and mammalian cell lines. The enhanced toxicity parallels the reduced activation of PARP and the diminished rate of formation of aldehyde reactive sites observed in the MPG knockdown cells. It is proposed that unrepaired N3-methyladenine is toxic due to its ability to directly block DNA polymerization. PMID:23234400

  20. 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.

  1. NOTCH1 inhibition enhances the efficacy of conventional chemotherapeutic agents by targeting head neck cancer stem cell

    PubMed Central

    Zhao, Zhi-Li; Zhang, Lu; Huang, Cong-Fa; Ma, Si-Rui; Bu, Lin-Lin; Liu, Jian-Feng; Yu, Guang-Tao; Liu, Bing; Gutkind, J. Silvio; Kulkarni, Ashok B.; Zhang, Wen-Feng; Sun, Zhi-Jun

    2016-01-01

    Cancer stem cells (CSCs) are considered responsible for tumor initiation and chemoresistance. This study was aimed to investigate the possibility of targeting head neck squamous cell carcinoma (HNSCC) by NOTCH1 pathway inhibition and explore the synergistic effect of combining NOTCH inhibition with conventional chemotherapy. NOTCH1/HES1 elevation was found in human HNSCC, especially in tissue post chemotherapy and lymph node metastasis, which is correlated with CSCs markers. NOTCH1 inhibitor DAPT (GSI-IX) significantly reduces CSCs population and tumor self-renewal ability in vitro and in vivo. Flow cytometry analysis showed that NOTCH1 inhibition reduces CSCs frequency either alone or in combination with chemotherapeutic agents, namely, cisplatin, docetaxel, and 5-fluorouracil. The combined strategy of NOTCH1 blockade and chemotherapy synergistically attenuated chemotherapy-enriched CSC population, promising a potential therapeutic exploitation in future clinical trial. PMID:27108536

  2. 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.

  3. Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells

    PubMed Central

    Lu, Xiaoyun; Ding, Zhi-Chun; Cao, Yang; Liu, Chufeng; Habtetsion, Tsadik; Yu, Miao; Lemos, Henrique; Salman, Huda; Xu, Hongyan; Mellor, Andrew L.; Zhou, Gang

    2014-01-01

    In recent years the immune-potentiating effects of some widely used chemotherapeutic agents have been increasingly appreciated. This provides a rationale for combining conventional chemotherapy with immunotherapy strategies to achieve durable therapeutic benefits. Previous studies have implicated the immunomodulatory effects of melphalan, an alkylating agent commonly used to treat multiple myeloma, but the underlying mechanisms remain obscure. In the current study, we investigated the impact of melphalan on endogenous immune cells as well as adoptively transferred tumor-specific CD4+ T cells in tumor-bearing mice. We showed that melphalan treatment resulted in a rapid burst of inflammatory cytokines and chemokines during the cellular recovery phase after melphalan-induced myelo-leukodepletion. After melphalan treatment, tumor cells exhibited characteristics of immunogenic cell death, including membrane translocation of the endoplasmic reticulum resident calreticulin (CRT), and extracellular release of high-mobility group box 1 (HMGB1). In addition, there was enhanced tumor antigen uptake by dendritic cells in the tumor-draining lymph node. Consistent with these immunomodulatory effects, melphalan treatment of tumor-bearing mice led to the activation of the endogenous CD8+ T cells, and more importantly, effectively drove the clonal expansion and effector differentiation of adoptively transferred tumor-specific CD4+ T cells. Notably, the combination of melphalan and CD4+ T-cell adoptive cell therapy (ACT) was more efficacious than either treatment alone in prolonging the survival of mice with advanced B-cell lymphomas or colorectal tumors. These findings provide mechanistic insights into melphalan’s immunostimulatory effects, and demonstrate the therapeutic potential of combining melphalan with adoptive cell therapy utilizing antitumor CD4+ T cells. PMID:25560408

  4. 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

  5. The DNA damage/repair cascade in glioblastoma cell lines after chemotherapeutic agent treatment.

    PubMed

    Annovazzi, Laura; Caldera, Valentina; Mellai, Marta; Riganti, Chiara; Battaglia, Luigi; Chirio, Daniela; Melcarne, Antonio; Schiffer, Davide

    2015-01-01

    Therapeutic resistance in glioblastoma multiforme (GBM) has been linked to a subpopulation of cells with stem cell-like properties, the glioma stem cells (GSCs), responsible for cancer progression and recurrence. This study investigated the in vitro cytotoxicity of three chemotherapeutics, temozolomide (TMZ), doxorubicin (Dox) and paclitaxel (PTX) on glioma cell lines, by analyzing the molecular mechanisms leading to DNA repair and cell resistance, or to cell death. The drugs were tested on 16 GBM cell lines, grown as neurospheres (NS) or adherent cells (AC), by studying DNA damage occurrence by Comet assay, the expression by immunofluorescence and western blotting of checkpoint/repair molecules and apoptosis. The three drugs were able to provoke a genotoxic injury and to inhibit dose- and time-dependently cell proliferation, more evidently in AC than in NS. The first cell response to DNA damage was the activation of the damage sensors (p-ATM, p-53BP1, γ-H2AX), followed by repair effectors; the expression of checkpoint/repair molecules appeared higher in NS than in AC. The non-homologous repair pathway (NHEJ) seemed more involved than the homologous one (HR). Apoptosis occurred after long treatment times, but only a small percentage of cells in NS underwent death, even at high drug concentration, whereas most cells survived in a quiescent state and resumed proliferation after drug removal. In tumor specimens, checkpoint/repair proteins were constitutively expressed in GBMs, but not in low-grade gliomas. PMID:25892134

  6. 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

  7. Nearest neighbor affects G:C to A:T transitions induced by alkylating agents.

    PubMed Central

    Glickman, B W; Horsfall, M J; Gordon, A J; Burns, P A

    1987-01-01

    The influence of local DNA sequence on the distribution of G:C to A:T transitions induced in the lacI gene of E. coli by a series of alkylating agents has been analyzed. In the case of nitrosoguanidine, two nitrosoureas and a nitrosamine, a strong preference for mutation at sites proceeded 5' by a purine base was noted. This preference was observed with both methyl and ethyl donors where the predicted common ultimate alkylating species is the alkyl diazonium ion. In contrast, this preference was not seen following treatment with ethylmethanesulfonate. The observed preference for 5'PuG-3' site over 5'-PyG-3' sites corresponds well with alterations observed in the Ha-ras oncogene recovered after treatment with NMU. This indicates that the mutations recovered in the oncogenes are likely the direct consequence of the alkylation treatment and that the local sequence effects seen in E. coli also appear to occur in mammalian cells. PMID:3329097

  8. Cytotoxicity of alkylating agents towards sensitive and resistant strains of Escherichia coli in relation to extent and mode of alkylation of cellular macromolecules and repair of alkylation lesions in deoxyribonucleic acids

    PubMed Central

    Lawley, P. D.; Brookes, P.

    1968-01-01

    1. A quantitative study was made of the relationship between survival of colony-forming ability in Escherichia coli strains B/r and Bs–1 and the extents of alkylation of cellular DNA, RNA and protein after treatment with mono- or di-functional sulphur mustards, methyl methanesulphonate or iodoacetamide. 2. The mustards and methyl methanesulphonate react with nucleic acids in the cells, in the same way as found previously from chemical studies in vitro, and with proteins. Iodoacetamide reacts only with protein, principally with the thiol groups of cysteine residues. 3. The extents of alkylation of cellular constituents required to prevent cell division vary widely according to the strain of bacteria and the nature of the alkylating agent. 4. The extents of alkylation of the sensitive and resistant strains at a given dose of alkylating agent do not differ significantly. 5. Removal of alkyl groups from DNA of cells of the resistant strains B/r and 15T− after alkylation with difunctional sulphur mustard was demonstrated; the product di(guanin-7-ylethyl) sulphide, characteristic of di- as opposed to mono-functional alkylation, was selectively removed; the time-scale of this effect suggests an enzymic rather than a chemical mechanism. 6. The sensitive strain Bs–1 removed alkyl groups from DNA in this way only at very low extents of alkylation. When sensitized to mustard action by treatment with iodoacetamide, acriflavine or caffeine, the extent of alkylation of cellular DNA corresponding to a mean lethal dose was decreased to approximately 3 molecules of di(guanin-7-ylethyl) sulphide in the genome of this strain. 7. Relatively large numbers of monofunctional alkylations per genome can be withstood by this sensitive strain. Iodoacetamide had the weakest cytotoxic action of the agents investigated; methyl methanesulphonate was significantly weaker in effect than the monofunctional sulphur mustard, which was in turn weaker than the difunctional sulphur mustard. 8

  9. Sites of Alkylation of Human Keap1 by Natural Chemoprevention Agents

    PubMed Central

    Luo, Yan; Eggler, Aimee L.; Liu, Dongting; Liu, Guowen; Mesecar, Andrew D.; van Breemen, Richard B.

    2007-01-01

    Under basal conditions, the interaction of the cytosolic protein Keap1 with the transcription factor Nrf2 results in a low level of expression of cytoprotective genes whose promoter region contains the antioxidant response element (ARE). Alkylation of one or more of the 27 cysteine sulfhydryl groups of human Keap1 is proposed to lead to Nrf2 nuclear accumulation, to upregulation of cytoprotective gene expression via the ARE, and to prevention of degenerative diseases, such as cancer. Therefore, identification of the most reactive of these cysteine residues towards specific electrophiles should help clarify this mechanism of cancer prevention, also known as chemoprevention. To address this issue, preliminary analyses of tryptic digests of Keap1 alkylated by the model electrophile 1-biotinamido-4-(4′-[maleimidoethyl-cyclohexane]-carboxamido) butane were carried out using LC-MS/MS with a cylindrical ion trap mass spectrometer and also using LC-MS/MS with a hybrid linear ion trap FT ICR mass spectrometer. Since the FT ICR instrument provided more complete peptide sequencing coverage and enabled the identification of more alkylated cysteine residues, only this instrument was used in subsequent studies of Keap1 alkylation by three electrophilic natural products that can up-regulate the ARE, xanthohumol, isoliquiritigenin and 10-shogaol. Among the various cysteine residues of Keap1, C151 was most reactive towards these three electrophiles. These in vitro results agree with evidence from in vivo experiments, and indicate that C151 is the most important site of alkylation on Keap1 by chemoprevention agents that function by activating the ARE through Nrf2. PMID:17980616

  10. Examination of the activities of 43 chemotherapeutic agents against Neospora caninum tachyzoites in cultured cells.

    PubMed

    Lindsay, D S; Rippey, N S; Cole, R A; Parsons, L C; Dubey, J P; Tidwell, R R; Blagburn, B L

    1994-07-01

    Neospora caninum causes serious disease in dogs, and it, or a similar parasite, is a major cause of abortion in cattle. Little is known about the susceptibility of this protozoan to antimicrobial agents. We studied several antimicrobial agents to determine which classes might have activity against this parasite. We also determined whether activity of such agents was coccidiocidal or coccidiostatic. A 2-day of treatment, monoclonal antibody-based enzyme immunoassay and a 5-day of treatment, cell culture flask (CCF), lesion-based assay were developed to examine the ability of test agents to inhibit tachyzoite multiplication. Seven sulfonamides were examined, with the following activities observed: sulfathiazole > or = sulfamethoxazole > sulfadiazine > sulfaquinoxaline > or = sulfamethazine > sulfadimethoxine > sulfamerazine. Dapsone, a sulfone, had little activity. Six dihydrofolate reductase/thymidylate synthase inhibitors were examined, with the following activities observed: piritrexim > pyrimethamine > ormetoprim > trimethoprim = diaveridine > methotrexate. Six ionophorous antibiotics were examined; lasalocid, maduramicin, monensin, narasin, and salinomycin had equivalent activities, but alborixin was toxic for host cells at the lowest concentration examined. Three macrolide antibiotics--azithromycin, clarithromycin, and erythromycin--were examined and had equivalent activities. Two tetracycline antibiotics, doxycycline and minocycline, were examined and had equivalent activities. Three lincosamide antibiotics were examined, with the following activities observed: clindamycin hydrochloride > clindamycin phosphate > lincomycin hydrochloride. Pentamidine and 6 of its analogs were examined, and only hexamidine and 1,4-Di[4-(2-imidazolinyl)-2-methoxy-phenoxy]butane had activity. Eight miscellaneous antiprotozoal agents were examined for activity. Amprolium, metronidazole, paromomycin, and roxarsone had little activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7978638

  11. Covalent binding to glutathione of the DNA-alkylating antitumor agent, S23906-1.

    PubMed

    David-Cordonnier, Marie-Hélène; Laine, William; Joubert, Alexandra; Tardy, Christelle; Goossens, Jean-François; Kouach, Mostafa; Briand, Gilbert; Thi Mai, Huong Doan; Michel, Sylvie; Tillequin, Francois; Koch, Michel; Leonce, Stéphane; Pierre, Alain; Bailly, Christian

    2003-07-01

    The benzoacronycine derivative, S23906-1, was characterized recently as a novel potent antitumor agent through alkylation of the N2 position of guanines in DNA. We show here that its reactivity towards DNA can be modulated by glutathione (GSH). The formation of covalent adducts between GSH and S23906-1 was evidenced by EI-MS, and the use of different GSH derivatives, amino acids and dipeptides revealed that the cysteine thiol group is absolutely required for complex formation because glutathione disulfide (GSSG) and other S-blocked derivatives failed to react covalently with S23906-1. Gel shift assays and fluorescence measurements indicated that the binding of S23906-1 to DNA and to GSH are mutually exclusive. Binding of S23906-1 to an excess of GSH prevents DNA alkylation. Additional EI-MS measurements performed with the mixed diester, S28053-1, showed that the acetate leaving group at the C1 position is the main reactive site in the drug: a reaction scheme common to GSH and guanines is presented. At the cellular level, the presence of GSH slightly reduces the cytotoxic potential of S23906-1 towards KB-3-1 epidermoid carcinoma cells. The GSH-induced threefold reduction of the cytotoxicity of S23906-1 is attributed to the reduced formation of lethal drug-DNA covalent complexes in cells. Treatment of the cells with buthionine sulfoximine, an inhibitor of GSH biosynthesis, facilitates the formation of drug-DNA adducts and promotes the cytotoxic activity. This study identifies GSH as a reactant for the antitumor drug, S23906-1, and illustrates a pathway by which GSH may modulate the cellular sensitivity to this DNA alkylating agent. The results presented here, using GSH as a biological nucleophile, fully support our initial hypothesis that DNA alkylation is the major mechanism of action of the promising anticancer drug S23906-1. PMID:12823555

  12. 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.

  13. 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. PMID:25395009

  14. 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. PMID:25233072

  15. 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

  16. 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.

  17. Small interfering RNAs targeting cyclin D1 and cyclin D2 enhance the cytotoxicity of chemotherapeutic agents in mantle cell lymphoma cell lines.

    PubMed

    Tiemann, Katrin; Alluin, Jessica V; Honegger, Anja; Chomchan, Pritsana; Gaur, Shikha; Yun, Yen; Forman, Stephen J; Rossi, John J; Chen, Robert W

    2011-11-01

    Cyclin D1 (CCND1) is a known cell cycle regulator whose overexpression is a hallmark of mantle cell lymphoma (MCL). Although molecular techniques have unified the diagnostic approach to MCL, no therapeutic advances have been made to target this particular pathway. The significance of CCND1 in the pathogenesis and treatment of MCL has yet to be defined. We have taken advantage of RNA interference (RNAi) to down-regulate CCND1 expression in two MCL cell lines (Granta-519 and Jeko-1) to investigate the cytotoxic effect of combining RNAi with conventional chemotherapeutic agents. We designed four small interfering RNAs (siRNAs) specific to CCND1, one specific to CCND2, and one dual-targeting siRNA that simultaneously down-regulates CCND1 and CCND2. Etoposide and doxorubicin were used as chemotherapeutics in combination with the siRNAs. The transfected siRNAs in MCL cell lines triggered 40-60% reduction in target mRNA and protein levels. Importantly, the siRNA-mediated reduction in cyclins resulted in decreased IC(50) (50% inhibitory concentration) values for both doxorubicin and etoposide. The combination of siRNA-mediated inhibition of the cyclins along with chemotherapeutic agents could potentially be used to lower the effective doses of the chemotherapeutic agents and reduce drug-related toxicities. PMID:21745168

  18. [Ebola hemorrhagic fever: Properties of the pathogen and development of vaccines and chemotherapeutic agents].

    PubMed

    Kiselev, O I; Vasin, A V; Shevyryova, M P; Deeva, E G; Sivak, K V; Egorov, V V; Tsvetkov, V B; Egorov, A Yu; Romanovskaya-Romanko, E A; Stepanova, L A; Komissarov, A B; Tsybalova, L M; Ignatjev, G M

    2015-01-01

    Ebola hemorrhagic fever (EHF) epidemic currently ongoing in West Africa is not the first among numerous epidemics in the continent. Yet it seems to be the worst EHF epidemic outbreak caused by Ebola virus Zaire since 1976 as regards its extremely large scale and rapid spread in the population. Experiments to study the agent have continued for more than 20 years. The EHF virus has a relatively simple genome with seven genes and additional reading frame resulting from RNA editing. While being of a relatively low genetic capacity, the virus can be ranked as a standard for pathogenicity with the ability to evade the host immune response in uttermost perfection. The EHF virus has similarities with retroviruses, but belongs to (-)RNA viruses of a nonretroviral origin. Genetic elements of the virus, NIRV, were detected in animal and human genomes. EHF virus glycoprotein (GP) is a class I fusion protein and shows more similarities than distinctions in tertiary structure with SIV and HIV gp41 proteins and even influenza virus hemagglutinin. EHF is an unusual infectious disease, and studying the molecular basis of its pathogenesis may contribute to new findings in therapy of severe conditions leading to a fatal outcome. PMID:26299853

  19. 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.

  20. Molecular characterization of an adaptive response to alkylating agents in the opportunistic pathogen Aspergillus fumigatus

    PubMed Central

    O’Hanlon, Karen A.; Margison, Geoffrey P.; Hatch, Amy; Fitzpatrick, David A.; Owens, Rebecca A.; Doyle, Sean; Jones, Gary W.

    2012-01-01

    An adaptive response to alkylating agents based upon the conformational change of a methylphosphotriester (MPT) DNA repair protein to a transcriptional activator has been demonstrated in a number of bacterial species, but this mechanism appears largely absent from eukaryotes. Here, we demonstrate that the human pathogen Aspergillus fumigatus elicits an adaptive response to sub-lethal doses of the mono-functional alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). We have identified genes that encode MPT and O6-alkylguanine DNA alkyltransferase (AGT) DNA repair proteins; deletions of either of these genes abolish the adaptive response and sensitize the organism to MNNG. In vitro DNA repair assays confirm the ability of MPT and AGT to repair methylphosphotriester and O6-methylguanine lesions respectively. In eukaryotes, the MPT protein is confined to a select group of fungal species, some of which are major mammalian and plant pathogens. The evolutionary origin of the adaptive response is bacterial and rooted within the Firmicutes phylum. Inter-kingdom horizontal gene transfer between Firmicutes and Ascomycete ancestors introduced the adaptive response into the Fungal kingdom. Our data constitute the first detailed characterization of the molecular mechanism of the adaptive response in a lower eukaryote and has applications for development of novel fungal therapeutics targeting this DNA repair system. PMID:22669901

  1. 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.

  2. 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.

  3. Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer.

    PubMed

    Ma, Liang; Sato, Fuminori; Sato, Ryuta; Matsubara, Takanori; Hirai, Kenichi; Yamasaki, Mutsushi; Shin, Toshitaka; Shimada, Tatsuo; Nomura, Takeo; Mori, Kenichi; Sumino, Yasuhiro; Mimata, Hiromitsu

    2014-06-01

    Heat shock proteins (HSPs), which are molecular chaperones that stabilize numerous vital proteins, may be attractive targets for cancer therapy. The aim of the present study was to investigate the possible anticancer effect of single or dual targeting of HSP90 and HSP70 and the combination treatment with HSP inhibitors and chemotherapeutic agents in bladder cancer cells. The expression of HSP90 and the anticancer effect of the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) coupled with cisplatin, docetaxel, or gemcitabine were examined using immunohistochemistry, quantitative real-time PCR, cell growth, flow cytometry, immunoblots and caspase-3/7 assays. The expression of HSP70 under HSP90 inhibition and the additive effect of HSP70 inhibitor pifithrin-μ (PFT-μ) were examined by the same assays and transmission electron microscopy. HSP90 was highly expressed in bladder cancer tissues and cell lines. 17-AAG enhanced the antiproliferative and apoptotic effects of each chemotherapeutic agent. 17-AAG also suppressed Akt activity but induced the upregulation of HSP70. PFT-μ enhanced the effect of 17-AAG or chemotherapeutic agents; the triple combination of 17-AAG, PFT-μ and a chemotherapeutic agent showed the most significant anticancer effect on the T24 cell line. The combination of 17-AAG and PFT-μ markedly suppressed Akt and Bad activities. With HSP90 suppression, HSP70 overexpression possibly contributes to the avoidance of cell death and HSP70 may be a key molecule for overcoming resistance to the HSP90 inhibitor. The dual targeting of these two chaperones and the combination with conventional anticancer drugs could be a promising therapeutic option for patients with advanced bladder cancer. PMID:24718854

  4. Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer

    PubMed Central

    MA, LIANG; SATO, FUMINORI; SATO, RYUTA; MATSUBARA, TAKANORI; HIRAI, KENICHI; YAMASAKI, MUTSUSHI; SHIN, TOSHITAKA; SHIMADA, TATSUO; NOMURA, TAKEO; MORI, KENICHI; SUMINO, YASUHIRO; MIMATA, HIROMITSU

    2014-01-01

    Heat shock proteins (HSPs), which are molecular chaperones that stabilize numerous vital proteins, may be attractive targets for cancer therapy. The aim of the present study was to investigate the possible anticancer effect of single or dual targeting of HSP90 and HSP70 and the combination treatment with HSP inhibitors and chemotherapeutic agents in bladder cancer cells. The expression of HSP90 and the anticancer effect of the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) coupled with cisplatin, docetaxel, or gemcitabine were examined using immunohistochemistry, quantitative real-time PCR, cell growth, flow cytometry, immunoblots and caspase-3/7 assays. The expression of HSP70 under HSP90 inhibition and the additive effect of HSP70 inhibitor pifithrin-μ (PFT-μ) were examined by the same assays and transmission electron microscopy. HSP90 was highly expressed in bladder cancer tissues and cell lines. 17-AAG enhanced the antiproliferative and apoptotic effects of each chemotherapeutic agent. 17-AAG also suppressed Akt activity but induced the upregulation of HSP70. PFT-μ enhanced the effect of 17-AAG or chemotherapeutic agents; the triple combination of 17-AAG, PFT-μ and a chemotherapeutic agent showed the most significant anticancer effect on the T24 cell line. The combination of 17-AAG and PFT-μ markedly suppressed Akt and Bad activities. With HSP90 suppression, HSP70 overexpression possibly contributes to the avoidance of cell death and HSP70 may be a key molecule for overcoming resistance to the HSP90 inhibitor. The dual targeting of these two chaperones and the combination with conventional anticancer drugs could be a promising therapeutic option for patients with advanced bladder cancer. PMID:24718854

  5. 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells.

    PubMed

    Bauer, Matthias R; Joerger, Andreas C; Fersht, Alan R

    2016-09-01

    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-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. PMID:27551077

  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. PMID:27357488

  7. 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

  8. A comparison of the antifertility effects of alkylating agents and vinca alkaloids in male rats.

    PubMed Central

    Cooke, R A; Nikles, A; Roeser, H P

    1978-01-01

    1 The anti-fertility effects of cyclophosphamide, nitrogen mustard, vincristine and vinblastine were studied and compared in male rats. 2 The effects of the drugs on body weight and haematological values were used to monitor the pharmacological actions of the drugs. 3 All four drugs impaired fertility, the severity of the impairment depending on dose and duration of treatment. 4 Testicular size and histological appearances remained mostly normal, even in infertile animals, but seminiferous tubules were fewer in number and maturation arrest at the spermatid level was evident in some sections. 5 Recovery of drug-induced infertility occurred in 64% of treated animals, 9 to 40 weeks after cessation of treatment. 6 Morbidity and mortality were much higher with alkylating agents than with vinca alkaloids for approximately similar degrees of impairment in fertility. PMID:687878

  9. Effect of the antitumoral alkylating agent 3-bromopyruvate on mitochondrial respiration: role of mitochondrially bound hexokinase.

    PubMed

    Rodrigues-Ferreira, Clara; da Silva, Ana Paula Pereira; Galina, Antonio

    2012-02-01

    The alkylating agent 3-Bromopyruvate (3-BrPA) has been used as an anti-tumoral drug due to its anti-proliferative property in hepatomas cells. This propriety is believed to disturb glycolysis and respiration, which leads to a decreased rate of ATP synthesis. In this study, we evaluated the effects of the alkylating agent 3-BrPA on the respiratory states and the metabolic steps of the mitochondria of mice liver, brain and in human hepatocarcinoma cell line HepG2. The mitochondrial membrane potential (ΔΨ(m)), O(2) consumption and dehydrogenase activities were rapidly dissipated/or inhibited by 3-BrPA in respiration medium containing ADP and succinate as respiratory substrate. 3-BrPA inhibition was reverted by reduced glutathione (GSH). Respiration induced by yeast soluble hexokinase (HK) was rapidly inhibited by 3-BrPA. Similar results were observed using mice brain mitochondria that present HK naturally bound to the outer mitochondrial membrane. When the adenine nucleotide transporter (ANT) was blocked by the carboxyatractiloside, the 3-BrPA effect was significantly delayed. In permeabilized human hepatoma HepG2 cells that present HK type II bound to mitochondria (mt-HK II), the inhibiting effect occurred faster when the endogenous HK activity was activated by 2-deoxyglucose (2-DOG). Inhibition of mt-HK II by glucose-6-phosphate retards the mitochondria to react with 3-BrPA. The HK activities recovered in HepG2 cells treated or not with 3-BrPA were practically the same. These results suggest that mitochondrially bound HK supporting the ADP/ATP exchange activity levels facilitates the 3-BrPA inhibition reaction in tumors mitochondria by a proton motive force-dependent dynamic equilibrium between sensitive and less sensitive SDH in the electron transport system. PMID:22322891

  10. Epipodophyllotoxins, alkylating agents, and radiation and risk of secondary leukaemia after childhood cancer.

    PubMed Central

    Hawkins, M. M.; Wilson, L. M.; Stovall, M. A.; Marsden, H. B.; Potok, M. H.; Kingston, J. E.; Chessells, J. M.

    1992-01-01

    OBJECTIVE--To investigate the incidence and aetiology of secondary leukaemia after childhood cancer in Britain. DESIGN--Cohort study and a case-control study. SETTING--Britain and population based National Register of Childhood Tumours. SUBJECTS--Cohort of 16,422 one year survivors of childhood cancer diagnosed in Britain between 1962 and 1983, among whom 22 secondary leukaemias were observed. A case-control study of 26 secondary leukaemias observed among survivors of childhood cancer diagnosed in Britain between 1940 and 1983; 96 controls were selected matched for sex, type of first cancer, age at first cancer, and interval to diagnosis of secondary leukaemia. MAIN OUTCOME MEASURES--Dose of radiation averaged over patients' active bone marrow and total accumulated dose of epipodophyllotoxins, alkylating agents, vinca alkaloids, antimetabolites, and antibiotics (mg/m2) given for the original cancer. RESULTS--Cumulative risk of secondary leukaemia within the cohort did not exceed 0.5% over the initial five years beyond one year survival, except that after non-Hodgkin's lymphomas 1.4% of patients developed secondary leukaemia. Corresponding figure for patients treated for non-Hodgkin's lymphomas in the early 1980s was 4%. The relative risk of secondary leukaemia increased significantly with exposure to epipodophyllotoxins and dose of radiation averaged over patients' active bone marrow. Ten patients developed leukaemia after having an epipodophyllotoxin-teniposide in nine cases, etoposide in one. Chromosomal translocations involving 11q23 were observed relating to two secondary leukaemias from a total of six for which there were successful cytogenetic studies after administration of an epipodophyllotoxin. CONCLUSIONS--Epipodophyllotoxins acting alone or together with alkylating agents or radiation seem to be involved in secondary leukaemia after childhood cancer. PMID:1581717

  11. Correlation between HER-2/neu(erbB-2) expression level and therapeutic effect of combination treatment with HERCEPTIN and chemotherapeutic agents in gastric cancer cell lines

    PubMed Central

    2014-01-01

    Introduction Although advanced gastric cancer has many limitations and response rate is marginal in chemotherapy. Overexpression of human epidermal growth factor receptor 2(HER-2/neu) gene and its protein are associated with increased cell division and a high rate of tumor growth and have been reported in several malignancies. Especially, approximately 30% of breast cancer patients have overexpression of HER-2/neu protein and the overexpression metastasize faster, induces resistance of the chemotherapy and down-regulate function of estrogen receptor. Recombinant humanized anti-HER2 antibody (Herceptin) inhibits proliferation of HER-2/neu overexpressing tumor cells and the use of that in combination in metastatic breast cancer have increased cytotoxicity of chemotherapeutic agents. Methods We evaluated the expression of HER-2/neu protein in gastric cell lines by FACS and then comparing the cytotoxicity in chemotherapeutics (doxorubicin, cisplatin, paclitaxel, 5-FU) alone and in combination with Herceptin according to the expression of HER-2/neu protein by MTT assay. Results 1. NCI-N87 (88%) gastric cancer cell line and SK-BR-3 (89%) breast cancer cell line with strong positivity of HER-2/neu expression. YBC-2 (55%) and YBC-3 (48%) gastric cancer cell line with intermediated, weak positivity respectively. Negative control U-87 MG (6%) brain cancer cell line were showed low expression of HER-2/neu. 2. Cell growth was dose-dependently inhibited in HER-2/neu positive, control cell line SK-BR-3 by Herceptin treatment but not observed in HER-2/neu negative control cell line U-87 MG. Effective growth inhibition was not observed in gastric cancer cell lines with single treatment of Herceptin, all cell lines observed the dose-dependent growth inhibition to chemotherapeutic agents (doxorubicin, cisplatin, paclitaxel and 5-FU). 3. Combination of Herceptin with doxorubicin observed synergistic effects in all cancer cell lines except YBC-3, combination of Herceptin with

  12. Kinetics of micronucleus induction and cytotoxicity caused by distinct antineoplastics and alkylating agents in vivo.

    PubMed

    Morales-Ramírez, Pedro; Vallarino-Kelly, Teresita; Cruz-Vallejo, Virginia

    2014-01-30

    This mini-review aims to compare the differences in the kinetics of the induction of micronucleated polychromatic erythrocytes (MN-PCE) and cytotoxicity by distinct antineoplastic and genotoxic agents in murine peripheral blood in vivo and to correlate these kinetics with the underlying processes. Comparisons were carried out using our previously obtained data with nominal doses causing similar levels of cytotoxicity, as measured in terms reduction of PCE. The aneuploidogens caused the most rapid induction of MN-PCEs and had the highest rates of cytotoxicity and genotoxicity. The promutagens cyclophosphamide and dimethylnitrosamine showed the most delayed responses and had the lowest genotoxic and cytotoxic efficiencies. DNA crosslinking agents had a similar delay of 4-5 h, greater than those of aneuploidogens, but differed in their cytotoxic and genotoxic efficiencies. Methylnitrosourea and 5-aza-cytidine caused greater delays than crosslinking agents. These delays can be due to the methylnitrosourea-mediated induction of formation of mono alkyl adducts which are interpreted as mismatches during DNA duplication, whereas 5-aza-cytidine requires incorporation into the DNA to induce breakage. This review allows us to conclude that the requirement for metabolic activation and the mechanisms of DNA breakage and of micronucleus induction are the main factors that affect the time of maximal MN-PCE induction. PMID:24269717

  13. Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents.

    PubMed

    Wang, Pu; Wu, Jing; Ma, Shenghong; Zhang, Lei; Yao, Jun; Hoadley, Katherine A; Wilkerson, Matthew D; Perou, Charles M; Guan, Kun-Liang; Ye, Dan; Xiong, Yue

    2015-12-22

    Chemotherapy of a combination of DNA alkylating agents, procarbazine and lomustine (CCNU), and a microtubule poison, vincristine, offers a significant benefit to a subset of glioma patients. The benefit of this regimen, known as PCV, was recently linked to IDH mutation that occurs frequently in glioma and produces D-2-hydroxyglutarate (D-2-HG), a competitive inhibitor of α-ketoglutarate (α-KG). We report here that D-2-HG inhibits the α-KG-dependent alkB homolog (ALKBH) DNA repair enzymes. Cells expressing mutant IDH display reduced repair kinetics, accumulate more DNA damages, and are sensitized to alkylating agents. The observed sensitization to alkylating agents requires the catalytic activity of mutant IDH to produce D-2-HG and can be reversed by the deletion of mutant IDH allele or overexpression of ALKBH2 or AKLBH3. Our results suggest that impairment of DNA repair may contribute to tumorigenesis driven by IDH mutations and that alkylating agents may merit exploration for treating IDH-mutated cancer patients. PMID:26686626

  14. 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.

  15. Sensitivity of Human Intrahepatic Cholangiocarcinoma Subtypes to Chemotherapeutics and Molecular Targeted Agents: A Study on Primary Cell Cultures

    PubMed Central

    Fraveto, Alice; Cardinale, Vincenzo; Bragazzi, Maria Consiglia; Giuliante, Felice; De Rose, Agostino Maria; Grazi, Gian Luca; Napoletano, Chiara; Semeraro, Rossella; Lustri, Anna Maria; Costantini, Daniele; Nevi, Lorenzo; Di Matteo, Sabina; Renzi, Anastasia; Carpino, Guido; Gaudio, Eugenio; Alvaro, Domenico

    2015-01-01

    We investigated the sensitivity of intrahepatic cholangiocarcinoma (IHCCA) subtypes to chemotherapeutics and molecular targeted agents. Primary cultures of mucin- and mixed-IHCCA were prepared from surgical specimens (N. 18 IHCCA patients) and evaluated for cell proliferation (MTS assay) and apoptosis (Caspase 3) after incubation (72 hours) with increasing concentrations of different drugs. In vivo, subcutaneous human tumor xenografts were evaluated. Primary cultures of mucin- and mixed-IHCCA were characterized by a different pattern of expression of cancer stem cell markers, and by a different drug sensitivity. Gemcitabine and the Gemcitabine-Cisplatin combination were more active in inhibiting cell proliferation in mixed-IHCCA while Cisplatin or Abraxane were more effective against mucin-IHCCA, where Abraxane also enhances apoptosis. 5-Fluoracil showed a slight inhibitory effect on cell proliferation that was more significant in mixed- than mucin-IHCCA primary cultures and, induced apoptosis only in mucin-IHCCA. Among Hg inhibitors, LY2940680 and Vismodegib showed slight effects on proliferation of both IHCCA subtypes. The tyrosine kinase inhibitors, Imatinib Mesylate and Sorafenib showed significant inhibitory effects on proliferation of both mucin- and mixed-IHCCA. The MEK 1/2 inhibitor, Selumetinib, inhibited proliferation of only mucin-IHCCA while the aminopeptidase-N inhibitor, Bestatin was more active against mixed-IHCCA. The c-erbB2 blocking antibody was more active against mixed-IHCCA while, the Wnt inhibitor, LGK974, similarly inhibited proliferation of mucin- and mixed-IHCCA. Either mucin- or mixed-IHCCA showed high sensitivity to nanomolar concentrations of the dual PI3-kinase/mTOR inhibitor, NVP-BEZ235. In vivo, in subcutaneous xenografts, either NVP-BEZ235 or Abraxane, blocked tumor growth. In conclusion, mucin- and mixed-IHCCA are characterized by a different drug sensitivity. Cisplatin, Abraxane and the MEK 1/2 inhibitor, Selumetinib were more

  16. A Phase I Study of DMS612, a Novel Bi-functional Alkylating Agent

    PubMed Central

    Appleman, Leonard J.; Balasubramaniam, Sanjeeve; Parise, Robert A; Bryla, Christine; Redon, Christophe E.; Nakamura, Asako J.; Bonner, William M.; Wright, John J; Piekarz, Richard; Kohler, David R; Jiang, Yixing; Belani, Chandra P.; Eiseman, Julie; Chu, Edward; Beumer, Jan H.; Bates, Susan E.

    2016-01-01

    Purpose DMS612 is a dimethane sulfonate analog with bifunctional alkylating activity and preferential cytotoxicity to human renal cell carcinoma (RCC) in the NCI-60 cell panel. This first-in-human phase I study aimed to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of DMS612 administered by 10-min intravenous infusion on days 1, 8, and 15 of an every 28-day schedule. Experimental Design Patients with advanced solid malignancies were eligible. Enrollment followed a 3+3 design. Pharmacokinetics of DMS612 and metabolites were assessed by mass spectroscopy and pharmacodynamics by γ-H2AX immunofluorescence. Results A total of 31 patients with colorectal (11), RCC (4), cervical (2), and urothelial (1) cancers were enrolled. Six dose levels were studied, from 1.5 mg/m2 to 12 mg/m2. DLTs of grade 4 neutropenia and prolonged grade 3 thrombocytopenia were observed at 12 mg/m2. The MTD was determined to be 9 mg/m2 with a single DLT of grade 4 thrombocytopenia in 1 of 12 patients. Two patients had a confirmed partial response at the 9 mg/m2 dose level, in renal (1) and cervical (1) cancer. DMS612 was rapidly converted into active metabolites. γ-H2AX immunofluorescence revealed dose-dependent DNA damage in both peripheral blood lymphocytes and scalp hairs. Conclusions The MTD of DMS12 on days 1, 8, and 15 every 28 days was 9 mg/m2. DMS612 appears to be an alkylating agent with unique tissue specificities. Dose-dependent pharmacodynamic signals and 2 partial responses at the MTD support further evaluation of DMS612 in phase II trials. PMID:25467180

  17. Preferential kill of hypoxic EMT6 mammary tumor cells by the bioreductive alkylating agent porfiromycin.

    PubMed

    Sartorelli, A C; Belcourt, M F; Hodnick, W F; Keyes, S R; Pritsos, C A; Rockwell, S

    1995-01-01

    Hypoxic cells in solid tumors represent a therapeutically resistant population that limits the curability of many solid tumors by irradiation and by most chemotherapeutic agents. The oxygen deficit, however, creates an environment conducive to reductive processes; this results in a major exploitable difference between normal and neoplastic tissues. The mitomycin antibiotics can be reductively activated by a number of oxidoreductases, in a process required for the production of their therapeutic effects. Preferential activation of these drugs under hypoxia and greater toxicity to oxygen-deficient cells than to their oxygenated counterparts are obtained in most instances. The demonstration that mitomycin C and porfiromycin, used to kill the hypoxic fraction, in combination with irradiation, to eradicate the oxygenated portion of the tumor, produced enhanced cytodestructive effects on solid tumors in animals has led to the clinical evaluation of the mitomycins in combination with radiation therapy in patients with head and neck cancer. The findings from these clinical trials have demonstrated the value of directing a concerted therapeutic attack on the hypoxic fraction of solid tumors as an approach toward enhancing the curability of localized neoplasms by irradiation. PMID:7572339

  18. Effect of ceritinib (LDK378) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo

    PubMed Central

    Hu, Jing; Zhang, Xu; Wang, Fang; Wang, Xiaokun; Yang, Ke; Xu, Meng; To, Kenneth K.W.

    2015-01-01

    Multidrug resistance (MDR) is the leading cause of treatment failure in cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2, play a key role in mediating MDR by pumping anticancer drugs out from cancer cells. Ceritinib (LDK378) is a second-generation tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) currently in phase III clinical trial for the treatment of non-small cell lung cancer. Here, we found that ceritinib remarkably enhanced the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 over-expressing cancer cells in vitro and in vivo. Ceritinib significantly increased the intracellular accumulation of chemotherapeutic agents such as doxorubicin (DOX) by inhibiting ABCB1 or ABCG2-mediated drug efflux in the transporters-overexpressing cells. Mechanistically, ceritinib is likely a competitive inhibitor of ABCB1 and ABCG2 because it competed with [125I]-iodoarylazidoprazosin for photo affinity labeling of the transporters. On the other hand, at the transporters-inhibiting concentrations, ceritinib did not alter the expression level of ABCB1 and ABCG2, and phosphorylation status of AKT and ERK1/2. Thus the findings advocate further clinical investigation of combination chemotherapy of ceritinib and other conventional chemotherapeutic drugs in chemo-refractory cancer patients. PMID:26556876

  19. 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

  20. 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

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

    PubMed

    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

  2. Re-Directing an Alkylating Agent to Mitochondria Alters Drug Target and Cell Death Mechanism

    PubMed Central

    Wisnovsky, Simon P.; Pereira, Mark P.; Wang, Xiaoming; Hurren, Rose; Parfitt, Jeremy; Larsen, Lesley; Smith, Robin A. J.; Murphy, Michael P.; Schimmer, Aaron D.; Kelley, Shana O.

    2013-01-01

    We have successfully delivered a reactive alkylating agent, chlorambucil (Cbl), to the mitochondria of mammalian cells. Here, we characterize the mechanism of cell death for mitochondria-targeted chlorambucil (mt-Cbl) in vitro and assess its efficacy in a xenograft mouse model of leukemia. Using a ρ° cell model, we show that mt-Cbl toxicity is not dependent on mitochondrial DNA damage. We also illustrate that re-targeting Cbl to mitochondria results in a shift in the cell death mechanism from apoptosis to necrosis, and that this behavior is a general feature of mitochondria-targeted Cbl. Despite the change in cell death mechanisms, we show that mt-Cbl is still effective in vivo and has an improved pharmacokinetic profile compared to the parent drug. These findings illustrate that mitochondrial rerouting changes the site of action of Cbl and also alters the cell death mechanism drastically without compromising in vivo efficacy. Thus, mitochondrial delivery allows the exploitation of Cbl as a promiscuous mitochondrial protein inhibitor with promising therapeutic potential. PMID:23585833

  3. Influence of Mikania laevigata Extract over the Genotoxicity Induced by Alkylating Agents

    PubMed Central

    Nicolau, Vanessa; de Aguiar Amaral, Patrícia; de Andrade, Vanessa Moraes

    2013-01-01

    Medicinal plants are still widely used worldwide; yet for some species, little or no information is available concerning their biological activity, specially their genotoxic and antimutagenic potential. Mikania laevigata (Asteraceae) is a native plant from South America, and its extracts are largely used to treat respiratory complaints. The aim of the present work was then to evaluate, in vivo, the potential biological activity of M. laevigata on the genotoxicity induced by methyl methanesulfonate (MMS) and cyclophosphamide (CP), using the comet assay. Male CF1 mice were divided into groups of 5-6 animals, received by gavage 0.1 mL/10 g body wt of water, Mikania laevigata extract (MLE), MMS, and CP. Results showed that treatment with 200 mg/kg of the MLE previously to MMS and CP administration, respectively, reduced the damage index (DI) in 52% and 60%, when compared to DI at 24 h. Pretreatment also reduced the damage frequency (DF) in 56% (MMS) and 58% (CP), compared to DF at 24 h. MLE administration has been shown to protect mouse DNA from damage induced by alkylating agents; this corroborates to the biological activities of M. laevigata and points towards the need of plant compounds isolation to proceed with further studies. PMID:23724299

  4. 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

  5. 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

  6. Non-alkaloids extract from Stemona sessilifolia enhances the activity of chemotherapeutic agents through P-glycoprotein-mediated multidrug-resistant cancer cells.

    PubMed

    Han, Lu; Ma, Yang-Mei; An, Li; Zhang, Qiao; Wang, Chang-Li; Zhao, Qing-Chun

    2016-01-01

    One of the major impediments to the successful treatment of cancer is the development of resistant cancer cells, which could cause multidrug resistance (MDR), and overexpression of ABCB1/P-glycoprotein (P-gp) is one of the most common causes of MDR in cancer cells. Recently, natural products or plant-derived chemicals have been investigated more and more widely as potential multidrug-resistant (MDR) reversing agents. The current study demonstrated for the first time that non-alkaloids extract from Stemona sessilifolia significantly reversed the resistance of chemotherapeutic agents, adriamycin, paclitaxel and vincristine to MCF-7/ADR cells compared with MCF-7/S cells in a dose-dependent manner. The results obtained from these studies indicated that the non-alkaloids extract from S. sessilifolia plays an important role in reversing MDR of cancer as a P-gp modulator in vitro and may be effective in the treatment of multidrug-resistant cancers. PMID:26190165

  7. The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models.

    PubMed

    Foster, Paul; Yamaguchi, Kyoko; Hsu, Pin P; Qian, Fawn; Du, Xiangnan; Wu, Jianming; Won, Kwang-Ai; Yu, Peiwen; Jaeger, Christopher T; Zhang, Wentao; Marlowe, Charles K; Keast, Paul; Abulafia, Wendy; Chen, Jason; Young, Jenny; Plonowski, Artur; Yakes, F Michael; Chu, Felix; Engell, Kelly; Bentzien, Frauke; Lam, Sanh T; Dale, Stephanie; Yturralde, Olivia; Matthews, David J; Lamb, Peter; Laird, A Douglas

    2015-04-01

    Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents. PMID:25637314

  8. Cyclooxygenase inhibitors - invitro and invivo effects on antitumor alkylating-agents in the emt-6 murine mammary-carcinoma.

    PubMed

    Teicher, B; Holden, S; Ara, G; Liu, J; Robinson, M; Flodgren, P; Dupuis, N; Northey, D

    1993-02-01

    The nonsteroidal antiinflammatory drugs that inhibit cyclooxygenase block the formation of prostanoids in vivo. These agents may be useful as modulators of cytotoxic anticancer therapies. EMT-6 mouse mammary carcinoma cells growing in culture were exposed for 1 h or 24 h to eleven different nonsteroidal antiinflammatory agents or acetaminophen. None of these drugs was very cytotoxic. A concentration of 50muM of the nonsteroidal antiinflammatory drugs or acetaminophen was chosen for modulator combination studies with the antitumor alkylating agents CDDP, L-PAM, BCNU and 4-HC in cell culture. Several of the modulators protected the EMT-6 cells from the cytotoxicity of the antitumor alkylating agents; however, diflunisal, sulindac, indomethacin, acetaminophen and in some cases ibuprofen and tolmetin were positive modulators of the antitumor alkylating agents under the cell culture conditions tested. EMT-6 tumor cell survival studies and bone marrow CFU-GM survival studies were carried out with seven of the modulators and various doses of cyclophosphamide. Tolmetin, ibuprofen, sulindac, piroxicam and diflunisal in combination with cyclophosphamide produced increased tumor cell killing compared with cyclophosphamide alone without marked changes in toxicity to the bone marrow derived CFU-GM. In EMT-6 tumor growth delay experiments, none of the six modulators tested affected the growth of the tumors; however, tolmetin, ibuprofen, diflunisal and sulindac increased the tumor growth delay obtained with standard dose-schedules of cyclophosphamide or CDDP. When minocycline, a collagenase inhibitor, was added to treatment regimens including diflunisal or sulindac and either cyclophosphamide, CDDP or L-PAM further increases in tumor growth delay were obtained especially when L-PAM was the cytotoxic therapeutic agent. The number of lung metastases and the percentage lung metastases with diameters >3 mm were reduced by treatment with the modulator combinations alone and further

  9. A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells.

    PubMed

    Ray, Arghya; Ravillah, Durgadevi; Das, Deepika S; Song, Yan; Nordström, Eva; Gullbo, Joachim; Richardson, Paul G; Chauhan, Dharminder; Anderson, Kenneth C

    2016-08-01

    Our prior study utilized both in vitro and in vivo multiple myeloma (MM) xenograft models to show that a novel alkylator melphalan-flufenamide (Melflufen) is a more potent anti-MM agent than melphalan and overcomes conventional drug resistance. Here we examined whether this potent anti-MM activity of melflufen versus melphalan is due to their differential effect on DNA damage and repair signalling pathways via γ-H2AX/ATR/CHK1/Ku80. Melflufen-induced apoptosis was associated with dose- and time-dependent rapid phosphorylation of γ-H2AX. Melflufen induces γ-H2AX, ATR, and CHK1 as early as after 2 h exposure in both melphalan-sensitive and -resistant cells. However, melphalan induces γ-H2AX in melphalan-sensitive cells at 6 h and 24 h; no γ-H2AX induction was observed in melphalan-resistant cells even after 24 h exposure. Similar kinetics was observed for ATR and CHK1 in meflufen- versus melphalan-treated cells. DNA repair is linked to melphalan-resistance; and importantly, we found that melphalan, but not melflufen, upregulates Ku80 that repairs DNA double-strand breaks. Washout experiments showed that a brief (2 h) exposure of MM cells to melflufen is sufficient to initiate an irreversible DNA damage and cytotoxicity. Our data therefore suggest that melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in MM cells. PMID:27098276

  10. Evidence for abasic site sugar phosphate-mediated cytotoxicity in alkylating agent treated Saccharomyces cerevisiae.

    PubMed

    Heacock, Michelle; Poltoratsky, Vladimir; Prasad, Rajendra; Wilson, Samuel H

    2012-01-01

    To better understand alkylating agent-induced cytotoxicity and the base lesion DNA repair process in Saccharomyces cerevisiae, we replaced the RAD27(FEN1) open reading frame (ORF) with the ORF of the bifunctional human repair enzyme DNA polymerase (Pol) β. The aim was to probe the effect of removal of the incised abasic site 5'-sugar phosphate group (i.e., 5'-deoxyribose phosphate or 5'-dRP) in protection against methyl methanesulfonate (MMS)-induced cytotoxicity. In S. cerevisiae, Rad27(Fen1) was suggested to protect against MMS-induced cytotoxicity by excising multinucleotide flaps generated during repair. However, we proposed that the repair intermediate with a blocked 5'-end, i.e., 5'-dRP group, is the actual cytotoxic lesion. In providing a 5'-dRP group removal function mediated by dRP lyase activity of Pol β, the effects of the 5'-dRP group were separated from those of the multinucleotide flap itself. Human Pol β was expressed in S. cerevisiae, and this partially rescued the MMS hypersensitivity observed with rad27(fen1)-null cells. To explore this rescue effect, altered forms of Pol β with site-directed eliminations of either the 5'-dRP lyase or polymerase activity were expressed in rad27(fen1)-null cells. The 5'-dRP lyase, but not the polymerase activity, conferred the resistance to MMS. These results suggest that after MMS exposure, the 5'-dRP group in the repair intermediate is cytotoxic and that Rad27(Fen1) protection against MMS in wild-type cells is due to elimination of the 5'-dRP group. PMID:23144716

  11. Molecular docking of chemotherapeutic agents to CYP3A4 in non-small cell lung cancer.

    PubMed

    Subhani, Syed; Jamil, Kaiser

    2015-07-01

    CYP3A4, a "heme" containing isoform, abundantly found in the liver, gastro-intestinal tract, lungs and renal cells, also known as drug metabolising enzyme (DME) may be responsible for the disease progression in cancers such as lung cancer. Hence, we have targeted this protein for improving drug selection and in preventing adverse reactions. The aim of this study was to examine chemotherapeutic drug binding to CYP3A4 and the interactions therein. We have used Schrödinger suite 2014, to perform molecular docking of human CYP3A4, by Induced Fit Docking using gemcitabine, cisplatin, carboplatin, docetaxel and paclitaxel drugs. We evaluated drug-binding affinities using Prime/MMGBSA and using these scores we compared the affinities of combination therapies against CYP3A4. Analysis of the docking results showed gemcitabine>carboplatin>cisplatin as the order of binding affinities, with gemcitabine having the best docking score. Interestingly, docetaxel and paclitaxel did not bind to CYP3A4*1B. The combination drug-binding affinity analysis showed gemcitabine+carboplatin to have the best docking score and hence, efficacy. Our investigation has identified the residue Arg 105 to be more frequently involved in drug binding to CYP3A4. Our results suggest that gemcitabine or combination of gemcitabine+carboplatin could serve as an excellent therapy against CYP3A4 in NSCLC patients. Thus, our study depicts binding of chemotherapeutic drugs to CYP3A4 and has identified the residues that may be targeted for therapy in NSCLC patients. PMID:26211584

  12. Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents.

    PubMed

    Klapacz, Joanna; Pottenger, Lynn H; Engelward, Bevin P; Heinen, Christopher D; Johnson, George E; Clewell, Rebecca A; Carmichael, Paul L; Adeleye, Yeyejide; Andersen, Melvin E

    2016-01-01

    From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance of a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations. PMID:27036068

  13. 5-(1-Substituted) alkyl pyrimidine nucleosides as antiviral (herpes) agents.

    PubMed

    Kumar, Rakesh

    2004-10-01

    -substituent of pyrimidine nucleosides have been well established for anti-herpes activity. However, there is little qualitative or mechanistic knowledge of the derivatives with substitution at the C-1 carbon of the 5-substituent of pyrimidine nucleosides. During the last few years of our research, we have investigated a variety of C-1 functionalized substituents at the 5-position of the pyrimidine nucleosides to determine their usefulness as antiviral (herpes) agents. In the 5-(1-substituted) group of pyrimidine nucleosides, we demonstrated that novel substituents present at the C-1 carbon of the 5-side chain of the pyrimidine nucleosides are important determinants of potent and broad spectrum antiviral (herpes) activity including EBV and HCMV. In this article the work on design, synthesis and structure activity relationships of several 5-[(1-substituted) alkyl (or vinyl)] pyrimidine nucleoside derivatives as potential inhibitors of herpes viruses is reviewed. PMID:15544474

  14. STAT3 blockade enhances the efficacy of conventional chemotherapeutic agents by eradicating head neck stemloid cancer cell

    PubMed Central

    Bu, Lin-Lin; Zhao, Zhi-Li; Liu, Jian-Feng; Ma, Si-Rui; Huang, Cong-Fa; Liu, Bing; Zhang, Wen-Feng; Sun, Zhi-Jun

    2015-01-01

    Signaling transducer and activator 3 (STAT3) and cancer stem cells (CSCs) have garnered huge attention as a therapeutic focus, based on evidence that they may represent an etiologic root of tumor initiation and radio-chemoresistance. Here, we investigated the high phosphorylation status of STAT3 (p-STAT3) and its correlation with self-renewal markers in head neck squamous cell carcinoma (HNSCC). Over-expression of p-STAT3 was found to have increased in post chemotherapy HNSCC tissue. We showed that blockade of p-STAT3 eliminated both bulk tumor and side population (SP) cells with characteristics of CSCs in vitro. Inhibition of p-STAT3 using small molecule S3I-201 significantly delayed tumorigenesis of spontaneous HNSCC in mice. Combining blockade of p-STAT3 with cytotoxic drugs cisplatin, docetaxel, 5-fluorouracil (TPF) enhanced the antitumor effect in vitro and in vivo with decreased tumor sphere formation and SP cells. Taken together, our results advocate blockade of p-STAT3 in combination with conventional chemotherapeutic drugs enhance efficacy by improving CSCs eradication in HNSCC. PMID:26556875

  15. STAT3 blockade enhances the efficacy of conventional chemotherapeutic agents by eradicating head neck stemloid cancer cell.

    PubMed

    Bu, Lin-Lin; Zhao, Zhi-Li; Liu, Jian-Feng; Ma, Si-Rui; Huang, Cong-Fa; Liu, Bing; Zhang, Wen-Feng; Sun, Zhi-Jun

    2015-12-01

    Signaling transducer and activator 3 (STAT3) and cancer stem cells (CSCs) have garnered huge attention as a therapeutic focus, based on evidence that they may represent an etiologic root of tumor initiation and radio-chemoresistance. Here, we investigated the high phosphorylation status of STAT3 (p-STAT3) and its correlation with self-renewal markers in head neck squamous cell carcinoma (HNSCC). Over-expression of p-STAT3 was found to have increased in post chemotherapy HNSCC tissue. We showed that blockade of p-STAT3 eliminated both bulk tumor and side population (SP) cells with characteristics of CSCs in vitro. Inhibition of p-STAT3 using small molecule S3I-201 significantly delayed tumorigenesis of spontaneous HNSCC in mice. Combining blockade of p-STAT3 with cytotoxic drugs cisplatin, docetaxel, 5-fluorouracil (TPF) enhanced the antitumor effect in vitro and in vivo with decreased tumor sphere formation and SP cells. Taken together, our results advocate blockade of p-STAT3 in combination with conventional chemotherapeutic drugs enhance efficacy by improving CSCs eradication in HNSCC. PMID:26556875

  16. Quantum molecular modeling of the interaction between guanine and alkylating agents--1--sulfur mustard.

    PubMed

    Broch, H; Hamza, A; Vasilescu, D

    1996-06-01

    Interaction between Guanine and the episulfonium form of Sulfur mustard (HD) was studied using the ab initio LCAO-MO method at the HF/6-31G level. The alkylation mechanism on guanine-N7 was analyzed by using a supermolecular modeling. Our stereostructural results associated with the molecular electrostatic potentials and HOMO-LUMO properties, show that in vacuum the alkylation of the N7 of guanine by HD in the aggressive episulfonium form is a direct process without transition state and of which the pathway is determined. PMID:8832373

  17. 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. PMID:27196753

  18. The Cyclophosphamide Equivalent Dose as an Approach for Quantifying Alkylating Agent Exposure. A Report from the Childhood Cancer Survivor Study

    PubMed Central

    Green, Daniel M.; Nolan, Vikki G.; Goodman, Pamela J.; Whitton, John A.; Srivastava, DeoKumar; Leisenring, Wendy M.; Neglia, Joseph P.; Sklar, Charles A.; Kaste, Sue C.; Hudson, Melissa M.; Diller, Lisa R.; Stovall, Marilyn; Donaldson, Sarah S.; Robison, Leslie L.

    2014-01-01

    BACKGROUND Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses. METHODS We compared the performance of the Cyclophosphamide Equivalent Dose (CED), a unit for quantifying alkylating agent exposure independent of study population, to the AAD. Comparisons included associations from three Childhood Cancer Survivor Study (CCSS)outcome analyses, receiver operator characteristic (ROC) curves and goodness of fit based on the Akaike’s Information Criterion (AIC). RESULTS The CED and AAD performed essentially identically in analyses of risk for pregnancy among the partners of male CCSS participants, risk for adverse dental outcomes among all CCSS participants and risk for premature menopause among female CCSS participants, based on similar associations, lack of statistically significant differences between the areas under the ROC curves and similar model fit values for the AIC between models including the two measures of exposure. CONCLUSION The CED is easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. We recommend the use of the CED in future research assessing cumulative alkylating agent exposure. PMID:23940101

  19. Introduction of Peripheral Carboxylates to Decrease the Charge on Tm(3+) DOTAM-Alkyl Complexes: Implications for Detection Sensitivity and in Vivo Toxicity of PARACEST MRI Contrast Agents.

    PubMed

    Suchý, Mojmír; Milne, Mark; Elmehriki, Adam A H; McVicar, Nevin; Li, Alex X; Bartha, Robert; Hudson, Robert H E

    2015-08-27

    A series of structurally modified Tm(3+) DOTAM-alkyl complexes as potential PARACEST MRI contrast agents has been synthesized with the aim to decrease the overall positive charge associated with these molecules and increase their biocompatibility. Two types of structural modification have been performed, an introduction of terminal carboxylate arms to the alkyl side chains and a conjugation of one of the alkyl side chains with aspartic acid. Detailed evaluation of the magnetic resonance imaging chemical exchange contrast associated with the structurally modified contrast agents has been performed. In contrast to the acutely toxic Tm(3+) DOTAM-alkyl complexes, the structurally modified compounds were found to be tolerated well during in vivo MRI studies in mice; however, only the aspartic acid modified chelates produced an amide proton-based PARACEST signal. PMID:26214576

  20. 3-methyladenine-DNA-glycosylase and O6-alkyl guanine-DNA-alkyltransferase activities and sensitivity to alkylating agents in human cancer cell lines.

    PubMed Central

    Damia, G.; Imperatori, L.; Citti, L.; Mariani, L.; D'Incalci, M.

    1996-01-01

    The activities and the expression of 3-methyladenine glycosylase (3-meAde gly) and O6-alkylguanine-DNA-alkyltransferase (O6 ATase) were investigated in ten human cancer cell lines. Both 3-meAde gly and O6 ATase activities were variable among different cell lines. mRNA levels of the O6 ATase gene, appeared to be related to the content of O6 ATase in different cell lines, whereas no apparent correlation was found between mRNA of 3-meAde gly and the enzyme activity. No correlation was found between the activity of the two enzymes and the sensitivity to alkylating agents of different structures such as CC-1065, tallimustine, dimethylsulphate (DMSO), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), cis-diamminedichloroplatinum (cDDP) and melphalan (L-PAM). The most striking finding of this study is that a correlation exists between the activity of O6 ATase and 3-meAde gly in the various cell lines investigated (P<0.01), suggesting a common mechanism of regulation of two DNA repair enzymes. Images Figure 2 PMID:8611396

  1. Stability of solutions of antineoplastic agents during preparation and storage for in vitro assays. General considerations, the nitrosoureas and alkylating agents.

    PubMed

    Bosanquet, A G

    1985-01-01

    In vitro drug sensitivity of tumour biopsies is currently being determined using a variety of methods. For these chemosensitivity assays many drugs are required at short notice, and this in turn means that the drugs must generally be stored in solution. There are, however, a number of potential problems associated with dissolving and storing drugs for in vitro use, which include (a) drug adsorption; (b) effects of freezing; (c) drug stability under the normal conditions of dilution and setting up of an in vitro assay; and (d) insolubility of drugs in normal saline (NS) or phosphate-buffered saline (PBS). These problems are considered in general, and some recommendations for use of solutions of drugs in in vitro assays are suggested. The nitrosoureas and alkylating agents are also investigated in greater detail in this respect. The nitrosoureas are found to be very labile in PBS at pH 7, with 5% degradation (t0.95) occurring in 10-50 min at room temperature. These values are increased about 10-fold on refrigeration and about 5- to 10-fold on reduction of the pH of the medium to pH 4-5. At pH 7 and room temperature, t0.95 is observed in under 1 h with the alkylating agents nitrogen mustard, chlorambucil, melphalan, 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ), dibromodulcitol, dibromomannitol, treosulphan, and procarbazine. Of the other alkylating agents, 4-hydroperoxycylophosphamide (sometimes used in vitro in place of cyclophosphamide), busulphan, dianhydrogalactitol, aziridinylbenzoquinone (AZQ), and dacarbazine have a t0.95 of between 2 and 24 h, while ifosfamide and pentamethylmelamine are both stable in aqueous solution for greater than 7 days. About half the drugs studied in detail have been stored frozen in solution for in vitro use, although very little is known about their stability under these conditions. PMID:3882257

  2. Influence of promoter/enhancer region haplotypes on MGMT transcriptional regulation: a potential biomarker for human sensitivity to alkylating agents

    PubMed Central

    Abdel-Rahman, Sherif Z.

    2014-01-01

    The O 6-methylguanine-DNA methyltransferase gene (MGMT) encodes the direct reversal DNA repair protein that removes alkyl adducts from the O 6 position of guanine. Several single-nucleotide polymorphisms (SNPs) exist in the MGMT promoter/enhancer (P/E) region. However, the haplotype structure encompassing these SNPs and their functional/biological significance are currently unknown. We hypothesized that MGMT P/E haplotypes, rather than individual SNPs, alter MGMT transcription and can thus alter human sensitivity to alkylating agents. To identify the haplotype structure encompassing the MGMT P/E region SNPs, we sequenced 104 DNA samples from healthy individuals and inferred the haplotypes using the data generated. We identified eight SNPs in this region, namely T7C (rs180989103), T135G (rs1711646), G290A (rs61859810), C485A (rs1625649), C575A (rs113813075), G666A (rs34180180), C777A (rs34138162) and C1099T (rs16906252). Phylogenetics and Sequence Evolution analysis predicted 21 potential haplotypes that encompass these SNPs ranging in frequencies from 0.000048 to 0.39. Of these, 10 were identified in our study population as 20 paired haplotype combinations. To determine the functional significance of these haplotypes, luciferase reporter constructs representing these haplotypes were transfected into glioblastoma cells and their effect on MGMT promoter activity was determined. Compared with the most common (reference) haplotype 1, seven haplotypes significantly upregulated MGMT promoter activity (18–119% increase; P < 0.05), six significantly downregulated MGMT promoter activity (29–97% decrease; P < 0.05) and one haplotype had no effect. Mechanistic studies conducted support the conclusion that MGMT P/E haplotypes, rather than individual SNPs, differentially regulate MGMT transcription and could thus play a significant role in human sensitivity to environmental and therapeutic alkylating agents. PMID:24163400

  3. The influence of oxazaphosphorines alkylating agents on autonomic nervous system activity in rat experimental cystitis model.

    PubMed

    Dobrek, Łukasz; Baranowska, Agnieszka; Thor, Piotr J

    2013-01-01

    The oxazaphosphorines alkylating agents (cyclophosphamide; CP and ifosfamide; IF) are often used in common clinical practice. However, treatment with CP/IF is burdened with the risk of many adverse drug reactions, especially including hemorrhagic cystitis (HC) that is associated with bladder overactivity symptoms (OAB). The HC pathophysiology is still not fully displayed; it seems that autonomic nervous system (ANS) functional abnormalities play important role in this disturbance. The aim of our study was to reveal the potential ANS differences in rat experimental HC model, evoked by CP and IF by an indirect ANS assessment--heart rate variability (HRV) study. We carried out our experimental research in three essential groups: control group (group 1), cyclophosphamide-induced HC (CP-HC; group 2) one and ifosfamide-induced HC (IF-HC; group 3) one. CP was i.p. administrated four times in dose of 75 mg/kg body weight while IF-treated rats received i.p. five drug doses; 50 mg/kg body weight. Control rats were administrated i.p. vehicle in appropriate volumes as CP/IF treated animals. HRV studies were performed the next day after the last oxazaphosphorines dose. Standard time- and spectral (frequency) domain parameters were estimated. We confirmed the HC development after both CP/IF in macroscopic assessment and bladder wet weight measurement; however, it was more aggravated in CP-HC group. Moreover, we demonstrated HRV disturbances, suggesting ANS impairment after both studied oxazaphosphorines, however, consistent with the findings mentioned above, the autonomic dysfunction was more emphasized after CP. CP treatment was also associated with changes of non-normalized HRV spectral components percentage distribution--a marked very low frequency--VLF [%] increase together with low frequency--LF [%] and high frequency--HF [%] decrease were observed. Taking into consideration the next findings, demonstrating the lack of both normalized power spectral components (nLF and n

  4. Integrin Targeted Delivery of Chemotherapeutics

    PubMed Central

    Chen, Kai; Chen, Xiaoyuan

    2011-01-01

    Targeted delivery of chemotherapeutics is defined in the sense, that is, to maximize the therapeutic index of a chemotherapeutic agent by strictly localizing its pharmacological activity to the site or tissue of action. Integrins are a family of heterodimeric transmembrane glycoproteins involved in a wide range of cell-to-extracellular matrix (ECM) and cell-to-cell interactions. As cell surface receptors, integrins readily interact with extracellular ligands and play a vital role in angiogenesis, leukocytes function and tumor development, which sets up integrins as an excellent target for chemotherapy treatment. The peptide ligands containing the arginine-glycine-aspartic acid (RGD), which displays a strong binding affinity and selectivity to integrins, particularly to integrin αvβ3, have been developed to conjugate with various conventional chemotherapeutic agents, such as small molecules, peptides and proteins, and nanoparticle-carried drugs for integtrin targeted therapeutic studies. This review highlights the recent advances in integrin targeted delivery of chemotherapeutic agents with emphasis on target of integrin αvβ3, and describes the considerations for the design of the diverse RGD peptide-chemotherapeutics conjugates and their major applications. PMID:21547159

  5. Influence of anoxia and respiratory deficiency on the genotoxicity of some direct-acting alkylating agents in yeast.

    PubMed

    Deorukhakar, V V; Murthy, M S

    1991-01-01

    We have studied the influence of anoxia and respiratory deficiency (RD) in yeast on the cytotoxic and recombinogenic effects of 5 direct-acting alkylating agents, namely N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), methylnitrosourea (MNU), ethylnitrosourea (ENU), methyl methanesulphonate (MMS) and ethyl methanesulphonate (EMS). We found that the effects of both conditions parallel each other for MMS, MNNG, MNU and ENU. Both anoxia and RD did not modify the effects of MMS to any significant extent. On the other hand, anoxic and respiratory-deficient cells were found to be more resistant than euoxic and respiratory-proficient cells respectively for MNNG, MNU and ENU. In the case of EMS, which is similar to MMS in its chemical reaction with DNA, the respiratory-deficient cells were found to be more sensitive than the respiratory-proficient ones. These studies indicate that the response of anoxic and respiratory-deficient cells cannot be predicted solely on the basis of the chemical reactivity pattern of the alkylating agents. The physiological state which exists under these conditions may exert considerable influence on the cellular response. PMID:1846028

  6. 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. PMID:24388503

  7. Long-term genetic and reproductive effects of ionizing radiation and chemotherapeutic agents on cancer patients and their offspring.

    PubMed

    Byrne, J

    1999-04-01

    The continuing search for a cure for cancer has lead to more aggressive therapies as new agents are developed with largely unknown late complications. Standard therapy for the majority of cancers today, following surgery, often consists of combinations of high doses of radiation and multi-drug therapy. Compared with exposures experienced by atomic bomb survivors, cancer survivors have been exposed to higher doses of partial body irradiation and combination chemotherapy over longer periods. Thus, cancer survivors provide a model system with which to evaluate the long-term effects on the human organism of high doses of agents known to damage DNA. Five-year survival after cancer diagnosis is now greater than 56%; more than 5 million Americans are considered cured of cancer. However, the late complications of cancer in long-term survivors has been poorly evaluated, especially in adults, and little is known of the most troubling possibility, that is, that the effects of cancer treatments could be passed on to the next generation. What little we know comes from studies of at most 5,000 survivors of childhood cancer, treated decades ago. So far, results are reassuring that with the means now available, we cannot detect clinical evidence of heritable damage. However, reproductive effects, including infertility, are common consequences of cancer therapy and may represent germ cell damage. We are just in the infancy of studies of germ cell mutagenesis in cancer survivors. The relatively small numbers of survivors, and the few types of exposures studied so far, provide only limited grounds for reassurance. More comprehensive, properly designed, studies of modern new agents are urgently need. PMID:10331521

  8. The possibility of simvastatin as a chemotherapeutic agent for all-trans retinoic acid-resistant promyelocytic leukemia.

    PubMed

    Tomiyama, Naoki; Matzno, Sumio; Kitada, Chihiro; Nishiguchi, Eri; Okamura, Noboru; Matsuyama, Kenji

    2008-03-01

    In this study, the authors evaluated the possible use of 3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in anti-leukemic chemotherapy. Cytotoxic potency against HL-60 was as follows; simvastatin (SV)>atorvastatin>cerivastatin>fluvastatin. Interestingly, HL-60-R2, an all-trans retinoic acid (ATRA)-resistant HL-60 variant, was twice as sensitive to SV than HL-60. Further studies revealed the particular mechanism of action of SV-induced apoptosis in leukemia. SV directly and rapidly disordered mitochondria with a loss of its membrane potential, reactive oxygen species (ROS) generation and subsequent irreversible damage with cytochrome c leakage and, finally, SV induced apoptosis through caspase-9 activation, whereas several studies have shown that other statins induced apoptosis to leukemia by the depletion of isoprenoids used for the prenylation of small GTPases, which are essential for cellular signal transduction. Our findings suggest that the mitochondrial pathway plays an important role in the higher potency of SV as a new class of agents for anti-leukemic therapy alone and/or in combination with agents. PMID:18310894

  9. A robust and rapid xenograft model to assess efficacy of chemotherapeutic agents for human acute myeloid leukemia

    PubMed Central

    Saland, E; Boutzen, H; Castellano, R; Pouyet, L; Griessinger, E; Larrue, C; de Toni, F; Scotland, S; David, M; Danet-Desnoyers, G; Vergez, F; Barreira, Y; Collette, Y; Récher, C; Sarry, J-E

    2015-01-01

    Relevant preclinical mouse models are crucial to screen new therapeutic agents for acute myeloid leukemia (AML). Current in vivo models based on the use of patient samples are not easy to establish and manipulate in the laboratory. Our objective was to develop robust xenograft models of human AML using well-characterized cell lines as a more accessible and faster alternative to those incorporating the use of patient-derived AML cells. Five widely used AML cell lines representing various AML subtypes were transplanted and expanded into highly immunodeficient non-obese diabetic/LtSz-severe combined immunodeficiency IL2Rγcnull mice (for example, cell line-derived xenografts). We show here that bone marrow sublethal conditioning with busulfan or irradiation has equal efficiency for the xenotransplantation of AML cell lines. Although higher number of injected AML cells did not change tumor engraftment in bone marrow and spleen, it significantly reduced the overall survival in mice for all tested AML cell lines. On the basis of AML cell characteristics, these models also exhibited a broad range of overall mouse survival, engraftment, tissue infiltration and aggressiveness. Thus, we have established a robust, rapid and straightforward in vivo model based on engraftment behavior of AML cell lines, all vital prerequisites for testing new therapeutic agents in preclinical studies. PMID:25794133

  10. Synthesis and characterization of a new retinoic acid ECPIRM as potential chemotherapeutic agent for human cutaneous squamous carcinoma.

    PubMed

    Zhang, Mengli; Tao, Yue; Ma, Pengcheng; Wang, Dechuan; He, Chundi; Cao, Yuping; Wei, Jun; Li, Lingjun; Tao, Lei

    2015-01-01

    Cutaneous squamous cell carcinoma (CSCC) is one of the most common cancers worldwide, requiring effective therapeutic interventions. Retinoids are important chemopreventive and therapeutic agents for a variety of human cancers including CSCC. In this study we synthesized a novel retinoic derivative N-(4-ethoxycarbonylphenyl) isoretinamide (ECPIRM) and evaluated its biological activities and possible mechanisms in human cutaneous squamous cell lines. ECPIRM had better inhibitory effect on the proliferation of squamous carcinoma cells SCL-1 and colo-16, compared with All-trans retinoic acid and 13-cis retinoic acid. ECPIRM had less toxicity to normal keratinocyte cell line HaCaT. Mechanistically, ECPIRM induced G1 cell cycle arrest in SCL-1 cells, via the downregulation of CDK2, CDK4, cycling D1 and cyclin E expression and upregulation of p21. In addition, these effects were at least partially due to the inhibition of JNK/ ERK-AP-1 signaling pathway by ECPIRM. Importantly, these effects of ECPIRM are independent of the classical retinoid receptor pathway, suggesting that the novel compound will have less side-effects in chemotherapy. These findings demonstrate that ECPIRM is a potential inhibitor of MPAK-AP-1 pathway, and is a potential therapeutic agent against CSCC. PMID:25991427

  11. Bifunctional alkylating agent-mediated MGMT-DNA cross-linking and its proteolytic cleavage in 16HBE cells.

    PubMed

    Cheng, Jin; Ye, Feng; Dan, Guorong; Zhao, Yuanpeng; Wang, Bin; Zhao, Jiqing; Sai, Yan; Zou, Zhongmin

    2016-08-15

    Nitrogen mustard (NM), a bifunctional alkylating agent (BAA), contains two alkyl arms and can act as a cross-linking bridge between DNA and protein to form a DNA-protein cross-link (DPC). O(6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme for alkyl adducts removal, is found to enhance cell sensitivity to BAAs and to promote damage, possibly due to its stable covalent cross-linking with DNA mediated by BAAs. To investigate MGMT-DNA cross-link (mDPC) formation and its possible dual roles in NM exposure, human bronchial epithelial cell line 16HBE was subjected to different concentrations of HN2, a kind of NM, and we found mDPC was induced by HN2 in a concentration-dependent manner, but the mRNA and total protein of MGMT were suppressed. As early as 1h after HN2 treatment, high mDPC was achieved and the level maintained for up to 24h. Quick total DPC (tDPC) and γ-H2AX accumulation were observed. To evaluate the effect of newly predicted protease DVC1 on DPC cleavage, we applied siRNA of MGMT and DVC1, MG132 (proteasome inhibitor), and NMS-873 (p97 inhibitor) and found that proteolysis plays a role. DVC1 was proven to be more important in the cleavage of mDPC than tDPC in a p97-dependent manner. HN2 exposure induced DVC1 upregulation, which was at least partially contributed to MGMT cleavage by proteolysis because HN2-induced mDPC level and DNA damage was closely related with DVC1 expression. Homologous recombination (HR) was also activated. Our findings demonstrated that MGMT might turn into a DNA damage promoter by forming DPC when exposed to HN2. Proteolysis, especially DVC1, plays a crucial role in mDPC repair. PMID:27342729

  12. 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

  13. 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. PMID:25279177

  14. Porfiromycin as a bioreductive alkylating agent with selective toxicity to hypoxic EMT6 tumor cells in vivo and in vitro.

    PubMed

    Keyes, S R; Rockwell, S; Sartorelli, A C

    1985-08-01

    Hypoxic cells may limit the curability of solid tumors by conventional chemotherapeutic agents and radiotherapy. Agents which are preferentially toxic to cells with low oxygen contents could therefore be useful as adjuncts to the regimens now used to treat these cancers. To date, the best agent of this type that we have tested is porfiromycin. Porfiromycin is similar to mitomycin C in its toxicity to hypoxic EMT6 cells in vitro but has much less toxicity than mitomycin C to well-oxygenated EMT6 cells. EMT6 cell sonicates reduce mitomycin C and porfiromycin to reactive electrophiles at similar rates under hypoxic conditions, a finding that correlates with cytotoxicity, whereas the rate of production of reactive species from both drugs is very slow under aerobic conditions. We also show that porfiromycin is capable of killing hypoxic radiation-resistant cells in solid EMT6 tumors. Appropriate regimens combining porfiromycin (which preferentially kills hypoxic cells) and radiation (which preferentially kills aerated cells) may therefore be especially efficacious for the treatment of solid tumors. PMID:3926306

  15. UMMS-4 enhanced sensitivity of chemotherapeutic agents to ABCB1-overexpressing cells via inhibiting function of ABCB1 transporter.

    PubMed

    Qiao, Dongjuan; Tang, Shangjun; Aslam, Sana; Ahmad, Matloob; To, Kenneth Kin Wah; Wang, Fang; Huang, Zhencong; Cai, Jiye; Fu, Liwu

    2014-01-01

    Multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters through efflux of antineoplastic agents from cancer cells is a major obstacle to successful cancer chemotherapy. The inhibition of these ABC transporters is thus a logical approach to circumvent MDR. There has been intensive research effort to design and develop novel inhibitors for the ABC transporters to achieve this goal. In the present study, we evaluated the ability of UMMS-4 to modulate P-glycoprotein (P-gp/ABCB1)-, breast cancer resistance protein (BCRP/ABCG2)- and multidrug resistance protein (MRP1/ABCC1)-mediated MDR in cancer cells. Our findings showed that UMMS-4, at non-cytotoxic concentrations, apparently circumvents resistance to ABCB1 substrate anticancer drugs in ABCB1-overexpressing cells. When used at a concentration of 20 μmol/L, UMMS-4 produced a 17.53-fold reversal of MDR, but showed no effect on the sensitivity of drug-sensitive parental cells. UMMS-4, however, did not significantly alter the sensitivity of non-ABCB1 substrates in all cells and was unable to reverse ABCG2- and ABCC1-mediated MDR. Additionally, UMMS-4 profoundly inhibited the transport of rhodamine 123 (Rho 123) and doxorubicin (Dox) by the ABCB1 transporter. Furthermore, UMMS-4 did not alter the expression of ABCB1 at the mRNA and protein levels. In addition, the results of ATPase assays showed that UMMS-4 stimulated the ATPase activity of ABCB1. Taken together, we conclude that UMMS-4 antagonizes ABCB1-mediated MDR in cancer cells through direct inhibition of the drug efflux function of ABCB1. These findings may be useful for the development of safer and more effective MDR modulator. PMID:24660104

  16. Low-density lipoprotein as a potential vehicle for chemotherapeutic agents and radionucleotides in the management of gynecologic neoplasms

    SciTech Connect

    Gal, D.; Ohashi, M.; MacDonald, P.C.; Buchsbaum, H.J.; Simpson, E.R.

    1981-04-15

    Cholesterol metabolism was studied in cells from two established gynecologic cancer cell lines which were maintained in monolayer cultures. The cell lines were derived and established from poorly differentiated epidermoid cervical carcinoma and endometrial adenocarcinoma. The specific activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of cholesterol de novo synthesis, in AC-258 cells was three times higher than that found in EC-50 cells. However, epidermoid cervical cancer cells metabolized low-density lipoprotein, the major transport vehicle for cholesterol in plasma, at a very high rate. This rate is fifteen times greater than the rate observed in fetal adrenal tissue and fifty times greater than the rate observed in nonneoplastic gynecologic tissue, each in organ culture. Both cancer cells in monolayer culture were shown to have specific receptors for LDL. These cancer cells demonstrate no defect in LDL metabolism, and lysosomal degradation of LDL was blocked by chloroquine. From the results of studies of specific binding of LDL in tissues obtained from nude mice it was demonstrated that membrane fractions prepared from EC-50 cells, after propagation in the mice, contained fifteen to thirty times more specific binding capacity for (125I)iodo-LDL than vital organs of the mouse, such as the liver, heart, lung, kidney, or brain. The results of these studies are suggestive that certain tumor cells might have a higher affinity for LDL than normal tissues and cytotoxic drugs or radionucleotides ligated to the LDL macromolecule may be utilized for the specific delivery of these agents.

  17. Low-density lipoprotein as a potential vehicle for chemotherapeutic agents and radionucleotides in the management of gynecologic neoplasms

    SciTech Connect

    Gal, D.; Ohashi, M.; MacDonald, P.C.; Buchsbaum, H.J.; Simpson, E.R.

    1981-04-15

    Cholesterol metabolism was studied in cells from two established gynecologic cancer cell lines which were maintained in monolayer cultures. The cell lines were derived and established from poorly differentiated epidermoid cervical carcinoma (EC-50) and endometrial adenocarcinoma (AC-258). The specific activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme of cholesterol de novo synthesis, in AC-258 cells (1700 pmoles x mg-1 microsomal protein x min-1) was three times higher than that found in EC-50 cells (550 pmoles x mg-1 microsomal protein x min-1). However, epidermoid cervical cancer cells (EC-50) metabolized low-density lipoprotein (LDL), the major transport vehicle for cholesterol in plasma, at a very high rate (14,000 ng x mg-1 cell protein x 6 hours). This rate is fifteen times greater than the rate observed in fetal adrenal tissue and fifty times greater than the rate observed in nonneoplastic gynecologic tissue, each in organ culture. Both cancer cells (EC-50 and AC-258) in monolayer culture were shown to have specific receptors for LDL. These cancer cells demonstrate no defect in LDL metabolism, and lysosomal degradation of LDL was blocked by chloroquine. From the results of studies of specific binding of LDL in tissues obtained from nude mice it was demonstrated that membrane fractions prepared from EC-50 cells, after propagation in the mice, contained fifteen to thirty times more specific binding capacity for (125I)iodo-LDL than vital organs of the mouse, such as the liver, heart, lung, kidney, or brain. The results of these studies are suggestive that certain tumor cells might have a higher affinity for LDL than normal tissues and cytotoxic drugs or radionucleotides ligated to the LDL macromolecule may be utilized for the specific delivery of these agents.

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

    PubMed Central

    McEwan, Gregor F.; Groner, Maya L.; Fast, Mark D.; 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. PMID:26485023

  19. The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents

    PubMed Central

    Dos Santos, Cedric; McDonald, Tinisha; Ho, Yin Wei; Liu, Hongjun; Lin, Allen; Forman, Stephen J.; Kuo, Ya-Huei

    2013-01-01

    The SRC family kinases (SFKs) and the receptor tyrosine kinase c-Kit are activated in human acute myeloid leukemia (AML) cells. We show here that the SFKs LYN, HCK, or FGR are overexpressed and activated in AML progenitor cells. Treatment with the SFK and c-KIT inhibitor dasatinib selectively inhibits human AML stem/progenitor cell growth in vitro. Importantly, dasatinib markedly increases the elimination of AML stem cells capable of engrafting immunodeficient mice by chemotherapeutic agents. In vivo dasatinib treatment enhances chemotherapy-induced targeting of primary murine AML stem cells capable of regenerating leukemia in secondary recipients. Our studies suggest that enhanced targeting of AML cells by the combination of dasatinib with daunorubicin may be related to inhibition of AKT-mediated human mouse double minute 2 homolog phosphorylation, resulting in enhanced p53 activity in AML cells. Combined treatment using dasatinib and chemotherapy provides a novel approach to increasing p53 activity and enhancing targeting of AML stem cells. PMID:23896410

  20. A novel copper(I) complex induces ER-stress-mediated apoptosis and sensitizes B-acute lymphoblastic leukemia cells to chemotherapeutic agents

    PubMed Central

    Porcù, Elena; Consolaro, Francesca; Marzano, Cristina; Pellei, Maura; Gandin, Valentina; Basso, Giuseppe

    2014-01-01

    A phosphine copper(I) complex [Cu(thp)4][PF6] (CP) was recently identified as an efficient in vitro antitumor agent. In this study, we evaluated the antiproliferative activity of CP in leukemia cell lines finding a significant efficacy, especially against SEM and RS4;11 cells. Immunoblot analysis showed the activation of caspase-12 and caspase-9 and of the two effector caspase-3 and -7, suggesting that cell death occurred in a caspase-dependent manner. Interestingly we did not observe mitochondrial involvement in the process of cell death. Measures on semipurified proteasome from RS4;11 and SEM cell extracts demonstrated that chymotrypsin-, trypsin- and caspase-like activity decreased in the presence of CP. Moreover, we found an accumulation of ubiquitinated proteins and a remarkable increase of ER stress markers: GRP78, CHOP, and the spliced form of XBP1. Accordingly, the protein synthesis inhibitor cycloheximide significantly protected cancer cells from CP-induced cell death, suggesting that protein synthesis machinery was involved. In well agreement with results obtained on stabilized cell lines, CP induced ER-stress and apoptosis also in primary cells from B-acute lymphoblastic leukemia patients. Importantly, we showed that the combination of CP with some chemotherapeutic drugs displayed a good synergy that strongly affected the survival of both RS4;11 and SEM cells. PMID:24980813

  1. 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. PMID:25634447

  2. 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. PMID:26485023

  3. 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.

  4. Alkylating agent methyl methanesulfonate (MMS) induces a wave of global protein hyperacetylation: Implications in cancer cell death

    SciTech Connect

    Lee, Min-Young; Kim, Myoung-Ae; Kim, Hyun-Ju; Bae, Yoe-Sik; Park, Joo-In; Kwak, Jong-Young; Chung, Jay H.; Yun, Jeanho . E-mail: yunj@dau.ac.kr

    2007-08-24

    Protein acetylation modification has been implicated in many cellular processes but the direct evidence for the involvement of protein acetylation in signal transduction is very limited. In the present study, we found that an alkylating agent methyl methanesulfonate (MMS) induces a robust and reversible hyperacetylation of both cytoplasmic and nuclear proteins during the early phase of the cellular response to MMS. Notably, the acetylation level upon MMS treatment was strongly correlated with the susceptibility of cancer cells, and the enhancement of MMS-induced acetylation by histone deacetylase (HDAC) inhibitors was shown to increase the cellular susceptibility. These results suggest protein acetylation is important for the cell death signal transduction pathway and indicate that the use of HDAC inhibitors for the treatment of cancer is relevant.

  5. Alkyl and aryl sulfonyl p-pyridine ethanone oximes are efficient DNA photo-cleavage agents.

    PubMed

    Andreou, Nicolaos-Panagiotis; Dafnopoulos, Konstantinos; Tortopidis, Christos; Koumbis, Alexandros E; Koffa, Maria; Psomas, George; Fylaktakidou, Konstantina C

    2016-05-01

    Sulfonyloxyl radicals, readily generated upon UV irradiation of p-pyridine sulfonyl ethanone oxime derivatives, effectively cleave DNA, in a pH independent manner, and under either aerobic or anaerobic conditions. p-Pyridine sulfonyl ethanone oxime derivatives were synthesized from the reaction of p-pyridine ethanone oxime with the corresponding sulfonyl chlorides in good to excellent yields. All compounds, at a concentration of 100μM, were irradiated at 312nm for 15min, after incubation with supercoiled circular pBluescript KS II DNA and resulted in extended single- and double- strand cleavages. The cleavage ability was found to be concentration dependent, with some derivatives exhibiting activity even at nanomolar levels. Besides that, p-pyridine sulfonyl ethanone oxime derivatives showed good affinity to DNA, as it was observed with UV interaction and viscosity experiments with CT DNA and competitive studies with ethidium bromide. The compounds interact to CT DNA probably by non-classical intercalation (i.e. groove-binding) and at a second step they may intercalate within the DNA base pairs. The fluorescence emission spectra of pre-treated EB-DNA exhibited a significant or moderate quenching. Comparing with the known aryl carbonyloxyl radicals the sulfonyloxyl ones are more powerful, with both aryl and alkyl sulfonyl substituted derivatives to exhibit DNA photo-cleaving ability, in significantly lower concentrations. These properties may serve in the discovery of new leads for "on demand" biotechnological and medical applications. PMID:26945644

  6. Synergistic activities of a silver(I) glutamic acid complex and reactive oxygen species (ROS): a novel antimicrobial and chemotherapeutic agent.

    PubMed

    Batarseh, K I; Smith, M A

    2012-01-01

    The antimicrobial and chemotherapeutic activities of a silver(I) glutamic acid complex with the synergistic concomitant generation of reactive oxygen species (ROS) were investigated here. The ROS generation system employed was via Fenton chemistry. The antimicrobial and chemotherapeutic activities were investigated on Staphylococcus aureus ATCC 43300 and Escherichia coli bacteria, and Vero and MCF-7 tumor cell lines, respectively. Antimicrobial activities were conducted by determining minimum inhibitory concentration (MIC), while chemotherapeutic efficacies were done by serial dilution using standard techniques to determine the half maximal inhibitory concentration (IC50). The antimicrobial and chemotherapeutic results obtained were compared with positive control drugs gentamicin, oxacillin, penicillin, streptomycin and cisplatin, a ubiquitously used platinum-based antitumor drug, and with the silver(I) glutamic acid complex and hydrogen peroxide separately. Based on MIC and IC50 values, it was determined that this synergistic approach was very effective at extremely low concentrations, especially when compared with the other drugs evaluated here. This finding might be of great significance regarding metronomic dosing when this synergistic approach is clinically implemented. Since silver at low concentrations exhibits no toxic, mutagenic and carcinogenic activities, this might offer an alternative approach for the development of safer silver-based antimicrobial and chemotherapeutic drugs, thereby reducing or even eliminating the toxicity associated with current drugs. Accordingly, the present approach might be integrated into the systemic clinical treatment of infectious diseases and cancer. PMID:22680634

  7. 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

  8. 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.

  9. In vitro and In vivo Antitumor Activity of a Novel Alkylating Agent Melphalan-flufenamide Against Multiple Myeloma Cells

    PubMed Central

    Chauhan, Dharminder; Ray, Arghya; Viktorsson, Kristina; Spira, Jack; Paba-Prada, Claudia; Munshi, Nikhil; Richardson, Paul; Lewensohn, Rolf; Anderson, Kenneth C.

    2014-01-01

    Purpose The alkylating agent melphalan prolongs survival in multiple myeloma (MM) patients; however, it is associated with toxicities and development of drug-resistance. Here, we evaluated the efficacy of melphalan-flufenamide (Mel-flufen), a novel dipeptide prodrug of melphalan in MM. Experimental Design MM cell lines, primary patient cells, and the human MM xenograft animal model were utilized to study the antitumor activity of mel-flufen. Results Low doses of mel-flufen triggers a more rapid and higher intracellular concentrations of melphalan in MM cells than is achievable by free melphalan. Cytotoxicity analysis showed significantly lower IC50 of mel-flufen than melphalan in MM cells. Importantly, mel-flufen induces apoptosis even in melphalan-, and bortezomib-resistant MM cells. Mechanistic studies show that siRNA knockdown of aminopeptidase N, a key enzyme mediating intracellular conversion of mel-flufen to melphalan, attenuates anti-MM activity of mel-flufen. Furthermore, mel-flufen-induced apoptosis was associated with: 1) activation of caspases and PARP cleavage; 2) ROS generation; 3) mitochondrial dysfunction and release of cytochrome-c; and 4) induction of DNA damage. Moreover, mel-flufen inhibits MM cell migration and tumor-associated angiogenesis. Human MM xenograft studies showed a more potent inhibition of tumor growth in mice treated with mel-flufen than mice receiving equimolar doses of melphalan. Finally, combining mel-flufen with lenalidomide, bortezomib, or dexamethasone triggers synergistic anti-MM activity. Conclusion Our preclinical study supports clinical evaluation of mel-flufen to enhance therapeutic potential of melphalan, overcome drug-resistance, and improve MM patient outcome. PMID:23584492

  10. N-methylpurine DNA glycosylase overexpression increases alkylation sensitivity by rapidly removing non-toxic 7-methylguanine adducts

    PubMed Central

    Rinne, M. L.; He, Y.; Pachkowski, B. F.; Nakamura, J.; Kelley, M. R.

    2005-01-01

    Previous studies indicate that overexpression of N-methylpurine DNA glycosylase (MPG) dramatically sensitizes cells to alkylating agent-induced cytotoxicity. We recently demonstrated that this sensitivity is preceded by an increased production of AP sites and strand breaks, confirming that overexpression of MPG disrupts normal base excision repair and causes cell death through overproduction of toxic repair intermediates. Here we establish through site-directed mutagenesis that MPG-induced sensitivity to alkylation is dependent on enzyme glycosylase activity. However, in contrast to the sensitivity seen to heterogeneous alkylating agents, MPG overexpression generates no cellular sensitivity to MeOSO2(CH2)2-lexitropsin, an alkylator which exclusively induces 3-meA lesions. Indeed, MPG overexpression has been shown to increase the toxicity of alkylating agents that produce 7-meG adducts, and here we demonstrate that MPG-overexpressing cells have dramatically increased removal of 7-meG from their DNA. These data suggest that the mechanism of MPG-induced cytotoxicity involves the conversion of non-toxic 7-meG lesions into highly toxic repair intermediates. This study establishes a mechanism by which a benign DNA modification can be made toxic through the overexpression of an otherwise well-tolerated gene product, and the application of this principle could lead to improved chemotherapeutic strategies that reduce the peripheral toxicity of alkylating agents. PMID:15905475

  11. O6-methylguanine-DNA methyltransferase activity is associated with response to alkylating agent therapy and with MGMT promoter methylation in glioblastoma and anaplastic glioma

    PubMed Central

    Bobola, Michael S.; Alnoor, Mohammad; Chen, John Y.-S.; Kolstoe, Douglas D.; Silbergeld, Daniel L.; Rostomily, Robert C.; Blank, A.; Chamberlain, Marc C.; Silber, John R.

    2014-01-01

    Background CpG methylation in the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with better outcome following alkylating agent chemotherapy in glioblastoma (GBM) and anaplastic glioma (AG). To what extent improved response reflects low or absent MGMT activity in glioma tissue has not been unequivocally assessed. This information is central to developing anti-resistance therapies. Methods We examined the relationship of MGMT activity in 91 GBMs and 84 AGs with progression-free survival (PFS) following alkylator therapy and with promoter methylation status determined by methylation-specific PCR (MSP). Results Cox regression analysis revealed that GBMs with high activity had a significantly greater risk for progression in dichotomous (P ≤ 0.001) and continuous (P ≤ 0.003) models, an association observed for different alkylator regimens, including concurrent chemo-radiation with temozolomide. Analysis of MGMT promoter methylation status in 47 of the GBMs revealed that methylated tumors had significantly lower activity (P ≤ 0.005) and longer PFS (P ≤ 0.036) compared to unmethylated tumors, despite overlapping activities. PFS was also significantly greater in methylated vs. unmethylated GBMs with comparable activity (P ≤ 0.005), and among unmethylated tumors with less than median activity (P ≤ 0.026), suggesting that mechanisms in addition to MGMT promote alkylator resistance. Similar associations of MGMT activity with PFS and promoter methylation status were observed for AGs. Conclusions Our results provide strong support for the hypotheses that MGMT activity promotes alkylator resistance and reflects promoter methylation status in malignant gliomas. General significance MGMT activity is an attractive target for anti-resistance therapy regardless of methylation status. PMID:25558448

  12. Alterations in Bacillus subtilis transforming DNA induced by beta-propiolactone and 1,3-propane sultone, two mutagenic and carcinogenic alkylating agents.

    PubMed Central

    Kubinski, Z O; Kubinski, H

    1978-01-01

    than did some of the apparently smaller molecules which sedimented more slowly through the gradient. An increase in cotransformation of distant markers was evident in DNA molecules after a short exposure to an alkylating agent, but cotransformation of such markers was absent in DNA treated for longer periods. The observed changes in the transforming and cotransforming activities of the alkylated DNA can be explained by what is known about the physicochemistry of such DNA and in particular about the propensity of the alkylated and broken molecules to form complexes with themselves and with other macromolecules. PMID:102637

  13. Reactions of 4-nitro-1,2,3-triazole with alkylating agents and compounds with activated multiple bonds

    SciTech Connect

    Vereshchagin, L.I.; Kuznetsova, N.I.; Kirillova, L.P.; Shcherbakov, V.V.; Sukhanov, G.T.; Gareev, G.A.

    1987-01-01

    When 4-nitro-1,2,3-triazole is alkylated, a mixture of N1- and N2-isomers is formed, with the latter usually predominating. The same behavior is also observed in addition reactions of 4-nitrotriazole to activated multiple bonds.

  14. Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study

    PubMed Central

    Green, Daniel M; Liu, Wei; Kutteh, William H; Ke, Raymond W; Shelton, Kyla C; Sklar, Charles A; Chemaitilly, Wassim; Pui, Ching-Hon; Klosky, James L; Spunt, Sheri L; Metzger, Monika L; Srivastava, DeoKumar; Ness, Kirsten K; Robison, Leslie L; Hudson, Melissa M

    2014-01-01

    Summary Background Few data define the dose-specific relation between alkylating agent exposure and semen variables in adult survivors of childhood cancer. We undertook this study to test the hypothesis that increased exposure to alkylating agents would be associated with decreased sperm concentration in a cohort of adult male survivors of childhood cancer who were not exposed to radiation therapy for their childhood cancer. Methods We did semen analysis on 214 adult male survivors of childhood cancer (median age 7·7 years [range 0·01–20·3] at diagnosis, 29·0 years [18·4–56·1] at assessment, and a median of 21·0 years [10·5–41·6] since diagnosis) who had received alkylating agent chemotherapy but no radiation therapy. Alkylating agent exposure was estimated using the cyclophosphamide equivalent dose (CED). Odds ratios (ORs) and 95% CIs for oligospermia (sperm concentration >0 and <15 million per mL) and azoospermia were calculated with logistic regression modelling. Findings Azoospermia was noted in 53 (25%) of 214 participants, oligospermia in 59 (28%), and normospermia (sperm concentration ≥15 million per mL) in 102 (48%) participants. 31 (89%) of 35 participants who received CED less than 4000 mg/m2 were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=–0·37, p<0·0001). Mean CED was 10 830 mg/m2 (SD 7274) in patients with azoospermia, 8480 mg/m2 (4264) in patients with oligospermia, and 6626 mg/m2 (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m2 CED for azoospermia (OR 1·22, 95% CI 1·11–1·34), and for oligospermia (1·14, 1·04–1·25), but age at diagnosis and age at assessment were not. Interpretation Impaired spermatogenesis was unlikely when the CED was less than 4000 mg/m2. Although sperm concentration decreases with increasing CED, there was substantial overlap of CED associated with normospermia

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

    PubMed

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

    2016-05-01

    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

  16. (Radiopharmaceutical and chemotherapeutic drug technology)

    SciTech Connect

    Srivastava, P.C.

    1988-01-14

    The purpose was to undertake a TOKTEN Distinguished Scientist Award assignment sponsored by the United Nations Development Programme (UNDP) in cooperation with the Council of Scientific and Industrial Research (CSIR) of India to conduct research in the areas of nucleosides and protein labeling agents at the Central Drug Research Institute (CDRI), Lucknow, and to help research scientists develop chemotherapeutic drugs in India. His work at CDRI consisted of syntheses of imidazole nucleosides, iodination reactions of nucleosides, synthesis of a bifunctional bismaleimide protein labeling agent, coordination of protein labeling studies with the Membrane Biology Group of CDRI, and initiation of several new collaborative research projects at CDRI. In addition, as a part of the CSIR-UNDP, the traveler visited several academic and industrial research institutions in India, delivered five seminars describing various aspects of radiopharmaceutical development at ORNL, and interacted extensively with scientists in India on current drug and radiopharmaceutical develop technologies in India and abroad.

  17. Genomic Phenotyping by Barcode Sequencing Broadly Distinguishes between Alkylating Agents, Oxidizing Agents, and Non-Genotoxic Agents, and Reveals a Role for Aromatic Amino Acids in Cellular Recovery after Quinone Exposure

    PubMed Central

    Svensson, J. Peter; Quirós Pesudo, Laia; McRee, Siobhan K.; Adeleye, Yeyejide; Carmichael, Paul; Samson, Leona D.

    2013-01-01

    Toxicity screening of compounds provides a means to identify compounds harmful for human health and the environment. Here, we further develop the technique of genomic phenotyping to improve throughput while maintaining specificity. We exposed cells to eight different compounds that rely on different modes of action: four genotoxic alkylating (methyl methanesulfonate (MMS), N-Methyl-N-nitrosourea (MNU), N,N′-bis(2-chloroethyl)-N-nitroso-urea (BCNU), N-ethylnitrosourea (ENU)), two oxidizing (2-methylnaphthalene-1,4-dione (menadione, MEN), benzene-1,4-diol (hydroquinone, HYQ)), and two non-genotoxic (methyl carbamate (MC) and dimethyl sulfoxide (DMSO)) compounds. A library of S. cerevisiae 4,852 deletion strains, each identifiable by a unique genetic ‘barcode’, were grown in competition; at different time points the ratio between the strains was assessed by quantitative high throughput ‘barcode’ sequencing. The method was validated by comparison to previous genomic phenotyping studies and 90% of the strains identified as MMS-sensitive here were also identified as MMS-sensitive in a much lower throughput solid agar screen. The data provide profiles of proteins and pathways needed for recovery after both genotoxic and non-genotoxic compounds. In addition, a novel role for aromatic amino acids in the recovery after treatment with oxidizing agents was suggested. The role of aromatic acids was further validated; the quinone subgroup of oxidizing agents were extremely toxic in cells where tryptophan biosynthesis was compromised. PMID:24040048

  18. A dual-responsive superparamagnetic Fe 3O 4/Silica/PAH/PSS material used for controlled release of chemotherapeutic agent, keggin polyoxotungstate, PM-19

    NASA Astrophysics Data System (ADS)

    Xu, Rui; Sun, Guoying; Li, Qiuyu; Wang, Enbo; Gu, Jianmin

    2010-10-01

    A bicontrollable drug release system was developed by layer-by-layer assembly of poly(allylamine hydrochloride) (PAH)/sodium poly(styrene sulfonate) (PSS) multilayers onto a Fe 3O 4/SiO 2 composite core. The saturated magnetization of this system reaches up to 38.6 emu/g at RT, making targeting easily controlled by an external magnetic field. Meanwhile, the packing of the polyelectrolyte multilayers is sensitive to pH values, generating a pH-switch on-off mode for the release of loaded drugs. In this specific case, the release of a chemotherapeutic polyoxometalate K 7Ti 2W 10PO 40·6H 2O (PM-19) was tested. Transmission electron microscopy (TEM) was used to examine the nanostructure of the composite drug release system. UV-vis absorption was used to monitor the drug release. Fourier transform infrared (FTIR), Powder X-ray diffraction, and Elemental analyses were used to study the composition of tested systems. The structure and composition of the composite system was also studied using magnetism measurement and nitrogen adsorption-desorption.

  19. Alkylating potential of oxetanes.

    PubMed

    Gómez-Bombarelli, Rafael; Palma, Bernardo Brito; Martins, Célia; Kranendonk, Michel; Rodrigues, Antonio S; Calle, Emilio; Rueff, José; Casado, Julio

    2010-07-19

    Small, highly strained heterocycles are archetypical alkylating agents (oxiranes, beta-lactones, aziridinium, and thiirinium ions). Oxetanes, which are tetragonal ethers, are higher homologues of oxiranes and reduced counterparts of beta-lactones, and would therefore be expected to be active alkylating agents. Oxetanes are widely used in the manufacture of polymers, especially in organic light-emitting diodes (OLEDs), and are present, as a substructure, in compounds such as the widely used antimitotic taxol. Whereas the results of animal tests suggest that trimethylene oxide (TMO), the parent compound, and beta,beta-dimethyloxetane (DMOX) are active carcinogens at the site of injection, no studies have explored the alkylating ability and genotoxicity of oxetanes. This work addresses the issue using a mixed methodology: a kinetic study of the alkylation reaction of 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilicity similar to that of DNA bases, by three oxetanes (TMO, DMOX, and methyloxetanemethanol), and a mutagenicity, genotoxicity, and cell viability study (Salmonella microsome test, BTC E. coli test, alkaline comet assay, and MTT assay). The results suggest either that oxetanes lack genotoxic capacity or that their mode of action is very different from that of epoxides and beta-lactones. PMID:20550097

  20. Vibrational spectroscopic and molecular docking study of 2-Benzylsulfanyl-4-[(4-methylphenyl)-sulfanyl]-6-pentylpyrimidine-5-carbonitrile, a potential chemotherapeutic agent

    NASA Astrophysics Data System (ADS)

    Haress, Nadia G.; El-Emam, Ali A.; Al-Deeb, Omar A.; Panicker, C. Yohannan; Al-Saadi, Abdulaziz A.; Van Alsenoy, Christian; War, Javeed Ahmad; Srivastava, S. K.

    2015-02-01

    FT-IR and FT-Raman spectra of 2-Benzylsulfanyl-4-[(4-methylphenyl)-sulfanyl]-6-pentylpyrimidine-5-carbonitrile were recorded and analyzed. The structure of the molecule has been optimized and the structural characteristics have been determined by density functional theory. The geometrical parameters (DFT) are in agreement with the XRD results. HOMO and LUMO and other chemical properties are reported. Nonlinear optical properties are reported. A detailed molecular picture of the title compound and its interactions were obtained from NBO analysis. The negative (red and yellow) regions of the MEP are related to electrophilic reactivity and the positive (blue) regions to nucleophilic reactivity, as shown in the MEP plot and the title compound has several possible sites, Ctbnd N, N atom of pyrimidine ring and sulfur atoms for electrophilic attack. From the molecular docking studies it is clear that the title compound binds at the catalytic site of the substrate by weak non-covalent interactions most prominent of which are H-bonding, π-π, alkyl-π, and amide-π interactions.

  1. Quantitative comparison of carcinogenicity, mutagenicity and electrophilicity of 10 direct-acting alkylating agents and of the initial O6:7-alkylguanine ratio in DNA with carcinogenic potency in rodents.

    PubMed

    Bartsch, H; Terracini, B; Malaveille, C; Tomatis, L; Wahrendorf, J; Brun, G; Dodet, B

    1983-08-01

    The quantitative relationship between carcinogenicity in rodents and mutagenicity in Salmonella typhimurium was examined, by using 10 monofunctional alkylating agents, including N-nitrosamides, alkyl methanesulfonates, epoxides, beta-propiolactone and 1,3-propane sultone. The compounds were assayed for mutagenicity in two S. typhimurium strains (TA1535 and TA100) and in plate and liquid assays. The mutagenic activity of the agents was compared with their alkylating activity towards 4-(4'-nitrobenzyl)pyridine and with their half-lives (solvolysis constants) in an aqueous medium. No correlations between these variables were found, nor was mutagenic activity correlated with estimates of carcinogenicity in rodents. There was a positive relationship between carcinogenicity and the initial ratios of 7-:O6-alkylguanine formed or expected after their reaction with double-stranded DNA in vitro. The results suggest that alkylation of guanine at position O6 (or at other O atoms of DNA bases) may be a critical DNA-base modification that determines the overall carcinogenicity of these alkylating agents in rodents. PMID:6348521

  2. Aryl-Alkyl-Lysines: Agents That Kill Planktonic Cells, Persister Cells, Biofilms of MRSA and Protect Mice from Skin-Infection

    PubMed Central

    Ghosh, Chandradhish; Manjunath, Goutham B.; Konai, Mohini M.; Uppu, Divakara S. S. M.; Hoque, Jiaul; Paramanandham, Krishnamoorthy; Shome, Bibek R.; Haldar, Jayanta

    2015-01-01

    Development of synthetic strategies to combat Staphylococcal infections, especially those caused by methicillin resistant Staphyloccus aureus (MRSA), needs immediate attention. In this manuscript we report the ability of aryl-alkyl-lysines, simple membrane active small molecules, to treat infections caused by planktonic cells, persister cells and biofilms of MRSA. A representative compound, NCK-10, did not induce development of resistance in planktonic cells in multiple passages and retained activity in varying environments of pH and salinity. At low concentrations the compound was able to depolarize and permeabilize the membranes of S. aureus persister cells rapidly. Treatment with the compound not only eradicated pre-formed MRSA biofilms, but also brought down viable counts in bacterial biofilms. In a murine model of MRSA skin infection, the compound was more effective than fusidic acid in bringing down the bacterial burden. Overall, this class of molecules bears potential as antibacterial agents against skin-infections. PMID:26669634

  3. In vitro study of cytotoxicity by U. V. radiation and differential sensitivity in combination with alkylating agents on established cell systems

    SciTech Connect

    Ramudu, K. )

    1991-01-01

    The effect of U.V. radiation or alkylating agents, such as actinomycin-D, cycloheximide and mitomycin-C (MMC), was studied on CHO, BHK and HeLa cells. U.V. radiation caused DNA ssb and dsb and were prevented by cycloheximide and actinomycin-D. MMC is known to be cytotoxic in CHO/BHK cells by forming free radical generation. MMC in combination with U.V. radiation enhanced DNA ssb dsb in these cell types. However, HeLa cells were insensitive to U.V. radiation. This insensitivity to U.V. radiation could be ascribed to the presence of glutathione transferase which is absent in CHO/BHK cell line.

  4. In vitro synergistic anticancer activity of the combination of T-type calcium channel blocker and chemotherapeutic agent in A549 cells.

    PubMed

    Byun, Joon Seok; Sohn, Joo Mi; Leem, Dong Gyu; Park, Byeongyeon; Nam, Ji Hye; Shin, Dong Hyun; Shin, Ji Sun; Kim, Hyoung Ja; Lee, Kyung-Tae; Lee, Jae Yeol

    2016-02-01

    As a result of our continuous research, new 3,4-dihydroquinazoline derivative containing ureido group, KCP10043F was synthesized and evaluated for T-type Ca(2+) channel (Cav3.1) blockade, cytotoxicity, and cell cycle arrest against human non-small cell lung (A549) cells. KCP10043F showed both weaker T-type Ca(2+) channel blocking activity and less cytotoxicity against A549 cells than parent compound KYS05090S [4-(benzylcarbamoylmethyl)-3-(4-biphenylyl)-2-(N,N',N'-trimethyl-1,5-pentanediamino)-3,4-dihydroquinazoline 2 hydrochloride], but it exhibited more potent G1-phase arrest than KYS05090S in A549 cells. This was found to be accompanied by the downregulations of cyclin-dependent kinase (CDK) 2, CDK4, CDK6, cyclin D2, cyclin D3, and cyclin E at the protein levels. However, p27(KIP1) as a CDK inhibitor was gradually upregulated at the protein levels and increased recruitment to CDK2, CDK4 and CDK6 after KCP10043F treatment. Based on the strong G1-phase cell cycle arrest of KCP10043F in A549 cells, the combination of KCP10043F with etoposide (or cisplatin) resulted in a synergistic cell death (combination index=0.2-0.8) via the induction of apoptosis compared with either agent alone. Taken together with these overall results and the favorable in vitro ADME (absorption, distribution, metabolism, and excretion) profiles of KCP10043F, therefore, it could be used as a potential agent for the combination therapy on human lung cancer. PMID:26739776

  5. Spiro-fused carbohydrate oxazoline ligands: Synthesis and application as enantio-discrimination agents in asymmetric allylic alkylation.

    PubMed

    Kraft, Jochen; Golkowski, Martin; Ziegler, Thomas

    2016-01-01

    In the present work, we describe a convenient synthesis of spiro-fused D-fructo- and D-psico-configurated oxazoline ligands and their application in asymmetric catalysis. The ligands were synthesized from readily available 3,4,5-tri-O-benzyl-1,2-O-isopropylidene-β-D-fructopyranose and 3,4,5-tri-O-benzyl-1,2-O-isopropylidene-β-D-psicopyranose, respectively. The latter compounds were partially deprotected under acidic conditions followed by condensation with thiocyanic acid to give an anomeric mixture of the corresponding 1,3-oxazolidine-2-thiones. The anomeric 1,3-oxazolidine-2-thiones were separated after successive benzylation, fully characterized and subjected to palladium catalyzed Suzuki-Miyaura coupling with 2-pyridineboronic acid N-phenyldiethanolamine ester to give the corresponding 2-pyridyl spiro-oxazoline (PyOx) ligands. The spiro-oxazoline ligands showed high asymmetric induction (up to 93% ee) when applied as chiral ligands in palladium-catalyzed allylic alkylation of 1,3-diphenylallyl acetate with dimethyl malonate. The D-fructo-PyOx ligand provided mainly the (R)-enantiomer while the D-psico-configurated ligand gave the (S)-enantiomer with a lower enantiomeric excess. PMID:26877819

  6. Spiro-fused carbohydrate oxazoline ligands: Synthesis and application as enantio-discrimination agents in asymmetric allylic alkylation

    PubMed Central

    Kraft, Jochen; Golkowski, Martin

    2016-01-01

    Summary In the present work, we describe a convenient synthesis of spiro-fused D-fructo- and D-psico-configurated oxazoline ligands and their application in asymmetric catalysis. The ligands were synthesized from readily available 3,4,5-tri-O-benzyl-1,2-O-isopropylidene-β-D-fructopyranose and 3,4,5-tri-O-benzyl-1,2-O-isopropylidene-β-D-psicopyranose, respectively. The latter compounds were partially deprotected under acidic conditions followed by condensation with thiocyanic acid to give an anomeric mixture of the corresponding 1,3-oxazolidine-2-thiones. The anomeric 1,3-oxazolidine-2-thiones were separated after successive benzylation, fully characterized and subjected to palladium catalyzed Suzuki–Miyaura coupling with 2-pyridineboronic acid N-phenyldiethanolamine ester to give the corresponding 2-pyridyl spiro-oxazoline (PyOx) ligands. The spiro-oxazoline ligands showed high asymmetric induction (up to 93% ee) when applied as chiral ligands in palladium-catalyzed allylic alkylation of 1,3-diphenylallyl acetate with dimethyl malonate. The D-fructo-PyOx ligand provided mainly the (R)-enantiomer while the D-psico-configurated ligand gave the (S)-enantiomer with a lower enantiomeric excess. PMID:26877819

  7. Hot foam for weed control-Do alkyl polyglucoside surfactants used as foaming agents affect the mobility of organic contaminants in soil?

    PubMed

    Cederlund, H; Börjesson, E

    2016-08-15

    Use of alkyl polyglucosides (APGs) as a foaming agent during hot water weed control may influence the environmental fate of organic contaminants in soil. We studied the effects of the APG-based foaming agent NCC Spuma (C8-C10) on leaching of diuron, glyphosate, and polycyclic aromatic hydrocarbons (PAHs) in sand columns. We also examined how APG concentration affected the apparent water solubility and adsorption of the herbicides and of the PAHs acenaphthene, acenaphthylene and fluorene. Application of APGs at the recommended concentration of 0.3% did not significantly affect leaching of any of the compounds studied. However, at a concentration of 1.5%, leaching of both diuron and glyphosate was significantly increased. The increased leaching corresponded to an increase in apparent water solubility of diuron and a decrease in glyphosate adsorption to the sand. However, APG addition did not significantly affect the mobility of PAHs even though their apparent water solubility was increased. These results suggest that application of APG-based foam during hot water weed control does not significantly affect the mobility of organic contaminants in soil if used according to recommendations. Moreover, they suggest that APGs could be useful for soil bioremediation purposes if higher concentrations are used. PMID:27149400

  8. 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

    2016-09-01

    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. PMID:27530316

  9. Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, TAS-102, with Oxaliplatin on Human Colorectal and Gastric Cancer Xenografts.

    PubMed

    Nukatsuka, Mamoru; Nakagawa, Fumio; Takechi, Teiji

    2015-09-01

    TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluridine (FTD) and the thymidine phosphorylase inhibitor tipiracil hydrochloride (at a molar ratio of 1:0.5) that was approved in Japan in 2014 for the treatment of unresectable advanced or recurrent colorectal cancer. In the present study, the enhancement of therapeutic efficacy using a combination of TAS-102 and oxaliplatin was evaluated in a xenograft-bearing nude mouse model of colorectal and gastric cancer. TAS-102 was orally administered twice-a-day from day 1 to 14, and oxaliplatin was administered intravenously on days 1 and 8. The in vivo growth-inhibitory activity was evaluated based on the tumor volume and the growth-delay period, was estimated based on the period required to reach a tumor volume five-times greater than the initial volume (RTV5). The tumor growth-inhibitory activity and RTV5 in mice administered TAS-102 with oxaliplatin were significantly superior to those associated with either monotherapy in mice with colorectal (HCT 116, SW-48; p<0.001) and gastric cancer (SC-2, MKN74; p<0.001). MKN74/5FU, a 5-fluorouracil-resistant MKN74 sub-line, was sensitive to both FTD and oxaliplatin in vitro. In vivo, TAS-102 alone was effective in MKN74/5FU, and its anti-tumor activity was significantly enhanced in combination with oxaliplatin (p<0.001). No significant decrease in body weight or toxicity was observed compared to either monotherapy. The present pre-clinical findings indicate that combination of TAS-102 and oxaliplatin is a promising treatment option for colorectal or gastric cancer, and can be utilized in both chemo-naïve tumors and recurrent tumors after 5-fluorouracil treatment. PMID:26254349

  10. Spectroscopic and electronic structure calculation of a potential chemotherapeutic agent 5-propyl-6-(p-tolylsulfanyl)pyrimidine-2,4(1H,3H)-dione using first principles

    NASA Astrophysics Data System (ADS)

    Al-Alshaikh, Monirah A.; Al-Deeb, Omar A.; Alzoman, Nourah Z.; El-Emam, Ali A.; Srivastava, Ruchi; Sachan, Alok K.; Prasad, Onkar; Sinha, Leena

    2015-11-01

    Quantum chemical calculations of energy, geometrical structure and vibrational wavenumbers of a potential chemotherapeutic agent namely, 5-propyl-6-(p-tolylsulfanyl)pyrimidine-2,4(1H,3H)-dione were carried out, using DFT method. Comprehensive interpretation of the experimental FT-IR and FT-Raman spectra of the compound under study is based on potential energy distribution. The difference between the observed and scaled wavenumbers of most of the normal modes is very small with B3LYP/6-311 + +G(d,p) method. The UV-Vis spectrum of the compound was recorded and the electronic properties, such as frontier orbitals and band gap energies were calculated by the TD-DFT approach. The values of the electric dipole moment, polarizability and first static hyperpolarizability of the title compound have also been investigated. NBO analysis has been performed to explain the charge transfer within the molecule along with the calculation of different thermo-dynamical properties.

  11. Prevalence and safety of off-label use of chemotherapeutic agents in older breast cancer patients: estimates from SEER-Medicare data

    PubMed Central

    Eaton, Anne A.; Sima, Camelia S.; Panageas, Katherine S.

    2016-01-01

    Background The practice of prescribing oncology drugs outside of the label indication is legal and may reflect standard practice. However, some off-label use is against practice guidelines and may be inappropriate. We aimed to measure the prevalence and safety of off-label use in accordance with NCCN guidelines and off-label use inconsistent with guidelines in older breast cancer patients. Patients and Methods The SEER-Medicare dataset was used to identify women diagnosed with a first primary breast cancer between 2000-2007. Intravenous chemotherapy agents were identified using Medicare claims and classified as on-label, off-label/NCCN supported or off-label/unsupported using contemporary FDA approvals and NCCN guidelines. Off-label/unsupported regimens were matched to off-label/supported and on-label regimens using 1:1:1 matching on patient factors, and hospitalization/ER admission rates were compared across indication categories using conditional logistic regression. Results 13,347 women were treated with 16,127 regimens (12% of women switched to a new regimen during followup). Sixty-four percent (10,391) of regimens were off-label/supported, 25% (3,987) were on-label and 11% (1,749) were off-label/unsupported. Drugs never supported for breast cancer accounted for 19% of off-label/unsupported use and 1% of total use. Hospitalization/ER admission occurred in 32% of off-label/unsupported regimens, compared to 27% of off-label/supported and 25% of on-label regimens (p<.0001). Conclusions Off-label use of chemotherapy without scientific support was not common in this cohort. Off-label/supported use accounted for 64% of use, reflecting the fact that widely-accepted indications are often not tested in registration trials. Off-label/supported use will likely increase as more drugs are expected to have activity across cancer sites, and understanding the safety implications of such use is critical. PMID:26733555

  12. Toward Hypoxia-Selective DNA-Alkylating Agents Built by Grafting Nitrogen Mustards onto the Bioreductively Activated, Hypoxia-Selective DNA-Oxidizing Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine)

    PubMed Central

    2015-01-01

    Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a heterocyclic di-N-oxide that undergoes enzymatic deoxygenation selectively in the oxygen-poor (hypoxic) cells found in solid tumors to generate a mono-N-oxide metabolite. This work explored the idea that the electronic changes resulting from the metabolic deoxygenation of tirapazamine analogues might be exploited to activate a DNA-alkylating species selectively in hypoxic tissue. Toward this end, tirapazamine analogues bearing nitrogen mustard units were prepared. In the case of the tirapazamine analogue 18a bearing a nitrogen mustard unit at the 6-position, it was found that removal of the 4-oxide from the parent di-N-oxide to generate the mono-N-oxide analogue 17a did indeed cause a substantial increase in reactivity of the mustard unit, as measured by hydrolysis rates and DNA-alkylation yields. Hammett sigma values were measured to quantitatively assess the magnitude of the electronic changes induced by metabolic deoxygenation of the 3-amino-1,2,4-benzotriazine 1,4-dioxide heterocycle. The results provide evidence that the 1,2,4-benzotiazine 1,4-dioxide unit can serve as an oxygen-sensing prodrug platform for the selective unmasking of bioactive agents in hypoxic cells. PMID:25029663

  13. A Novel Pentamethoxyflavone Down-Regulates Tumor Cell Survival and Proliferative and Angiogenic Gene Products through Inhibition of IκB Kinase Activation and Sensitizes Tumor Cells to Apoptosis by Cytokines and Chemotherapeutic Agents

    PubMed Central

    Phromnoi, Kanokkarn; Reuter, Simone; Sung, Bokyung; Prasad, Sahdeo; Kannappan, Ramaswamy; Yadav, Vivek R.; Chanmahasathien, Wisinee; Limtrakul, Pornngarm

    2011-01-01

    Most anticancer drugs have their origin in traditional medicinal plants. We describe here a flavone, 5,3′-dihydroxy-3,6,7,8,4′-pentamethoxyflavone (PMF), from the leaves of the Thai plant Gardenia obtusifolia, that has anti-inflammatory and anticancer potential. Because the nuclear factor-κB (NF-κB) pathway is linked to inflammation and tumorigenesis, we investigated the effect of PMF on this pathway. We found that PMF suppressed NF-κB activation induced by inflammatory agents, tumor promoters, and carcinogens. This suppression was not specific to the cell type. Although PMF did not directly modify the ability of NF-κB proteins to bind to DNA, it inhibited IκBα (inhibitory subunit of NF-κB) kinase, leading to suppression of phosphorylation and degradation of IκBα, and suppressed consequent p65 nuclear translocation, thus abrogating NF-κB-dependent reporter gene expression. Suppression of the NF-κB cell signaling pathway by the flavone led to the inhibition of expression of NF-κB-regulated gene products that mediate inflammation (cyclooxygenase-2), survival (XIAP, survivin, Bcl-xL, and cFLIP), proliferation (cyclin D1), invasion (matrix metalloproteinase-9), and angiogenesis (vascular endothelial growth factor). Suppression of antiapoptotic gene products by PMF correlated with the enhancement of apoptosis induced by tumor necrosis factor-α and the chemotherapeutic agents cisplatin, paclitaxel, and 5-flurouracil. Overall, our results indicate that PMF suppresses the activation of NF-κB and NF-κB-regulated gene expression, leading to the enhancement of apoptosis. This is the first report to demonstrate that this novel flavone has anti-inflammatory and anticancer effects by targeting the IKK complex. PMID:20930110

  14. Gadolinium(III) Complexes with N-Alkyl-N-methylglucamine Surfactants Incorporated into Liposomes as Potential MRI Contrast Agents

    PubMed Central

    Silva, Simone Rodrigues; Duarte, Érica Correia; Ramos, Guilherme Santos; Kock, Flávio Vinícius Crizóstomo; Andrade, Fabiana Diuk; Frézard, Frédéric; Colnago, Luiz Alberto; Demicheli, Cynthia

    2015-01-01

    Complexes of gadolinium(III) with N-octanoyl-N-methylglucamine (L8) and N-decanoyl-N-methylglucamine (L10) with 1 : 2 stoichiometry were synthesized and characterized by elemental analysis, electrospray ionization-tandem mass spectrometry (ESI-MS), infrared (IR) spectroscopy, and molar conductivity measurements. The transverse (r2) and longitudinal (r1) relaxivity protons were measured at 20 MHz and compared with those of the commercial contrasts. These complexes were incorporated in liposomes, resulting in the increase of the vesicle zeta potential. Both the free and liposome-incorporated gadolinium complexes showed high relaxation effectiveness, compared to commercial contrast agent gadopentetate dimeglumine (Magnevist). The high relaxivity of these complexes was attributed to the molecular rotation that occurs more slowly, because of the elevated molecular weight and incorporation in liposomes. The results establish that these paramagnetic complexes are highly potent contrast agents, making them excellent candidates for various applications in molecular MR imaging. PMID:26347596

  15. Design, synthesis and pharmacological evaluation of N-[4-(4-(alkyl/aryl/heteroaryl)-piperazin-1-yl)-phenyl]-carbamic acid ethyl ester derivatives as novel anticonvulsant agents.

    PubMed

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

    2015-03-01

    A series of alkyl/aryl/heteroaryl piperazine derivatives (37-54) were designed and synthesized as potential anticonvulsant agents. The target compounds are endowed with satisfactory physicochemical as well as pharmacokinetic properties. The synthesized compounds were screened for their in vivo anticonvulsant activity in maximal electroshock (MES) and subcutaneous pentylenetetrazole (sc-PTZ) seizure tests. Further, neurotoxicity evaluation was carried out using rotarod method. Structure activity relationship studies showed that compounds possessing aromatic group at the piperazine ring displayed potent anticonvulsant activity. Majority of the compounds showed anti-MES activity whereas compounds 39, 41, 42, 43, 44, 50, 52, and 53 exhibited anticonvulsant activity in both seizure tests. All the compounds except 42, 46, 47, and 50 did not show neurotoxicity. The most active derivative, 45 demonstrated potent anticonvulsant activity in MES test at the dose of 30mg/kg (0.5h) and 100mg/kg (4h) and also delivered excellent protection in sc-PTZ test (100mg/kg) at both time intervals. Therefore, compound 45 was further assessed in PTZ-kindling model of epilepsy which is widely used model for studying epileptogenesis. This compound was effective in delaying onset of PTZ-evoked seizures at the dose of 5mg/kg in kindled animals and significantly reduced oxidative stress better than standard drug phenobarbital (PB). In result, compound 45 emerged as a most potent and safer anticonvulsant lead molecule. PMID:25619635

  16. (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.

  17. Somatic reversion of some copia-like induced mutations, at the white locus of Drosophila melanogaster, after treatment with alkylating agents.

    PubMed

    Soriano, S; Creus, A; Marcos, R; Xamena, N

    1995-01-01

    It has been suggested that transposable elements can be associated with different types of genotoxic effects. For this reason it seems appropriate to outline suitable systems to detect changes in the phenotypic expression of the loci containing transposable elements, as well as those agents that induce such changes. The sex-linked white locus offers a suitable experimental system for studying such events because most of the spontaneous mutations at the white locus are the result of insertions of repeated mobile sequences, and it is easy to follow mutational changes of the locus due to the possibility of detecting even slight changes in eye color. Here we report the results obtained in different strains of Drosophila melanogaster with copia-like induced mutations at the white locus, after treatment with three alkylating agents: ethyl methanesulfonate (EMS), methyl methanesulfonate (MMS), and N-nitroso-N-ethylurea (ENU). The three insertional white mutants used in this work were wa4, wbf, and wsp55, with the wa2 mutation used as control because its mutant phenotype is the result of a point mutation instead of the insertion of a DNA fragment. Our data constitute evidence that EMS, MMS, and ENU induce a clear increase in the frequencies of somatic-revertant sectors in the three strains carrying a white allele with an inserted copia-like element. For the wa2 strain, whose mutant phenotype is the result of a point mutation, only ENU at the highest concentration tested is able to induce a significant increase in the somatic reversion frequency. In addition, our results indicate that the use of D. melanogaster strains with transposable elements in the white locus is suitable for detecting genotoxic damage induced by chemicals. PMID:7698106

  18. Dose-Response for Multiple Biomarkers of Exposure and Genotoxic Effect Following Repeated Treatment of Rats with the Alkylating Agents, MMS and MNU.

    PubMed

    Ji, Zhiying; LeBaron, Matthew J; Schisler, Melissa R; Zhang, Fagen; Bartels, Michael J; Gollapudi, B Bhaskar; Pottenger, Lynn H

    2016-05-01

    The nature of the dose-response relationship for various in vivo endpoints of exposure and effect were investigated using the alkylating agents, methyl methanesulfonate (MMS) and methylnitrosourea (MNU). Six male F344 rats/group were dosed orally with 0, 0.5, 1, 5, 25 or 50mg/kg bw/day (mkd) of MMS, or 0, 0.01, 0.1, 1, 5, 10, 25 or 50 mkd of MNU, for 4 consecutive days and sacrificed 24h after the last dose. The dose-responses for multiple biomarkers of exposure and genotoxic effect were investigated. In MMS-treated rats, the hemoglobin adduct level, a systemic exposure biomarker, increased linearly with dose (r (2) = 0.9990, P < 0.05), indicating the systemic availability of MMS; however, the N7MeG DNA adduct, a target exposure biomarker, exhibited a non-linear dose-response in blood and liver tissues. Blood reticulocyte micronuclei (MN), a genotoxic effect biomarker, exhibited a clear no-observed-genotoxic-effect-level (NOGEL) of 5 mkd as a point of departure (PoD) for MMS. Two separate dose-response models, the Lutz and Lutz model and the stepwise approach using PROC REG both supported a bilinear/threshold dose-response for MN induction. Liver gene expression, a mechanistic endpoint, also exhibited a bilinear dose-response. Similarly, in MNU-treated rats, hepatic DNA adducts, gene expression changes and MN all exhibited clear PoDs, with a NOGEL of 1 mkd for MN induction, although dose-response modeling of the MNU-induced MN data showed a better statistical fit for a linear dose-response. In summary, these results provide in vivo data that support the existence of clear non-linear dose-responses for a number of biologically significant events along the pathway for genotoxicity induced by DNA-reactive agents. PMID:26040483

  19. Modification of the metabolism and cytotoxicity of bioreductive alkylating agents by dicoumarol in aerobic and hypoxic murine tumor cells.

    PubMed

    Keyes, S R; Rockwell, S; Sartorelli, A C

    1989-06-15

    We have demonstrated previously that dicoumarol (DIC) increased the generation of reactive metabolites from mitomycin C (MC) in EMT6 cells under hypoxic conditions in vitro. This increased reaction rate was associated with an increased toxicity of MC to hypoxic EMT6 cells. In contrast, aerobic cells treated with DIC in vitro were protected from MC toxicity. We now demonstrate that DIC sensitizes EMT6 cells to two MC analogues, porfiromycin (POR) and the 7-N-dimethylaminomethylene analogue of mitomycin C (BMY-25282), in hypoxia and protects cells from these agents in air, despite the fact that POR is preferentially toxic to hypoxic cells and BMY-25282 is preferentially toxic to aerobic cells. In contrast, DIC increases menadione cytotoxicity in both air and hypoxia and has no effect on the cytotoxicity of Adriamycin. We have also shown previously that the preferential toxicity of POR to hypoxic cells is associated with an increased rate of drug uptake. In the present study, DIC had no measurable effect on the uptake of [3H]POR but increased the extent of efflux of this agent. MC-induced DNA cross-links, which have been proposed as the lesions responsible for the lethality of MC, are decreased by DIC in air and increased by DIC in hypoxia, in concert with the observed modifications of MC cytotoxicity by DIC. However, in aerobic cells treated with DIC and MC, the decrease in DNA interstrand cross-links is not directly associated with a decrease in cytotoxicity. L1210 cells, which have no measurable quinone reductase activity, demonstrate increased toxicity when treated with DIC and MC in hypoxia, as observed with EMT6 cells. Unlike EMT6 cells, however, L1210 cells are not protected by DIC from MC toxicity in air. Taken together, these findings suggest that DIC is altering the intracellular metabolism of MC and that quinone reductase or another, unidentified, enzyme sensitive to DIC may be involved in activating MC to a toxic product in aerobic EMT6 cells. PMID:2470504

  20. Repair-deficient 3-methyladenine DNA glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation-induced chromosome damage and cell killing.

    PubMed Central

    Engelward, B P; Dreslin, A; Christensen, J; Huszar, D; Kurahara, C; Samson, L

    1996-01-01

    In Escherichia coli, the repair of 3-methyladenine (3MeA) DNA lesions prevents alkylation-induced cell death because unrepaired 3MeA blocks DNA replication. Whether this lesion is cytotoxic to mammalian cells has been difficult to establish in the absence of 3MeA repair-deficient cell lines. We previously isolated and characterized a mouse 3MeA DNA glycosylase cDNA (Aag) that provides resistance to killing by alkylating agents in E. coli. To determine the in vivo role of Aag, we cloned a large fragment of the Aag gene and used it to create Aag-deficient mouse cells by targeted homologous recombination. Aag null cells have no detectable Aag transcripts or 3MeA DNA glycosylase activity. The loss of Aag renders cells significantly more sensitive to methyl methanesulfonate-induced chromosome damage, and to cell killing induced by two methylating agents, one of which produces almost exclusively 3MeAs. Aag null embryonic stem cells become sensitive to two cancer chemotherapeutic alkylating agents, namely 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C, indicating that Aag status is an important determinant of cellular resistance to these agents. We conclude that this mammalian 3MeA DNA glycosylase plays a pivotal role in preventing alkylation-induced chromosome damage and cytotoxicity. Images PMID:8631315

  1. Motor fuel alkylation process utilizing low acid

    SciTech Connect

    Kocal, J.A.; Imai, T.

    1987-01-06

    A process is described for the alkylation of an isoparaffin with an olefin acting agent comprising contacting the isoparaffin with the olefin acting agent at alkylation conditions in the presence of a catalyst. The catalyst consists essentially of an anhydrous, nonalcoholic mixture of from about 5 to 15 wt. % methyl tert-butyl ether and from 85 to 95 wt. % hydrofluoric acid. The volumetric ratio of hydrofluoric acid to isoparaffin and olefin acting agent is less than 0.75.

  2. Bioreductive alkylating agent porfiromycin in combination with radiation therapy for the management of squamous cell carcinoma of the head and neck.

    PubMed

    Haffty, B G; Son, Y H; Wilson, L D; Papac, R; Fischer, D; Rockwell, S; Sartorelli, A C; Ross, D; Sasaki, C T; Fischer, J J

    1997-01-01

    statistically significant differences between the two arms with respect to white blood cell count (WBC), platelet, or hemoglobin nadirs. Acute nonhematological toxicities including mucositis, epidermitis, odynophagia, and nausea have also been comparable. Two patients in this current randomized trial died during treatment, apparently of nondrug-related causes. We conclude that the bioreductive alkylating agent porfiromycin has demonstrated an acceptable toxicity profile to date. Final analysis of the phase I trial, which revealed a 5-year no evidence of disease survival rate of 32% in patients with locally advanced disease and a low probability of cure, appears encouraging. We anticipate completion of the current ongoing trial comparing mitomycin C to porfiromycin in the next 2 years. Further investigations, including large-scale multiinstitutional trials employing bioreductive alkylating agents or other hypoxic cell cytotoxins as adjuncts to RT, are warranted. PMID:9372546

  3. Enhancement of radiosensitivity in human glioblastoma cells by the DNA N-mustard alkylating agent BO-1051 through augmented and sustained DNA damage response

    PubMed Central

    2011-01-01

    Background 1-{4-[Bis(2-chloroethyl)amino]phenyl}-3-[2-methyl-5-(4-methylacridin-9-ylamino)phenyl]urea (BO-1051) is an N-mustard DNA alkylating agent reported to exhibit antitumor activity. Here we further investigate the effects of this compound on radiation responses of human gliomas, which are notorious for the high resistance to radiotherapy. Methods The clonogenic assay was used to determine the IC50 and radiosensitivity of human glioma cell lines (U87MG, U251MG and GBM-3) following BO-1051. DNA histogram and propidium iodide-Annexin V staining were used to determine the cell cycle distribution and the apoptosis, respectively. DNA damage and repair state were determined by γ-H2AX foci, and mitotic catastrophe was measure using nuclear fragmentation. Xenograft tumors were measured with a caliper, and the survival rate was determined using Kaplan-Meier method. Results BO-1051 inhibited growth of human gliomas in a dose- and time-dependent manner. Using the dosage at IC50, BO-1051 significantly enhanced radiosensitivity to different extents [The sensitizer enhancement ratio was between 1.24 and 1.50 at 10% of survival fraction]. The radiosensitive G2/M population was raised by BO-1051, whereas apoptosis and mitotic catastrophe were not affected. γ-H2AX foci was greatly increased and sustained by combined BO-1051 and γ-rays, suggested that DNA damage or repair capacity was impaired during treatment. In vivo studies further demonstrated that BO-1051 enhanced the radiotherapeutic effects on GBM-3-beared xenograft tumors, by which the sensitizer enhancement ratio was 1.97. The survival rate of treated mice was also increased accordingly. Conclusions These results indicate that BO-1051 can effectively enhance glioma cell radiosensitivity in vitro and in vivo. It suggests that BO-1051 is a potent radiosensitizer for treating human glioma cells. PMID:21244709

  4. Induction of resistance to alkylating agents in E. coli: the ada+ gene product serves both as a regulatory protein and as an enzyme for repair of mutagenic damage.

    PubMed Central

    Teo, I; Sedgwick, B; Demple, B; Li, B; Lindahl, T

    1984-01-01

    The expression of several inducible enzymes for repair of alkylated DNA in Escherichia coli is controlled by the ada+ gene. This regulatory gene has been cloned into a multicopy plasmid and shown to code for a 37-kd protein. Antibodies raised against homogeneous O6-methylguanine-DNA methyltransferase (the main repair activity for mutagenic damage in alkylated DNA) were found to cross-react with this 37-kd protein. Cell extracts from several independently derived ada mutants contain variable amounts of an altered 37-kd protein after an inducing alkylation treatment. In addition, an 18-kd protein identical with the previously isolated O6-methyl-guanine-DNA methyltransferase has been identified as a product of the ada+ gene. The smaller polypeptide is derived from the 37-kd protein by proteolytic processing. Images Fig. 1. Fig. 2. Fig. 4. Fig. 5. Fig. 6. Fig. 7. Fig. 8. PMID:6092060

  5. Combined Gene Expression and RNAi Screening to Identify Alkylation Damage Survival Pathways from Fly to Human

    PubMed Central

    Zanotto-Filho, Alfeu; Dashnamoorthy, Ravi; Loranc, Eva; de Souza, Luis H. T.; Moreira, José C. F.; Suresh, Uthra; Chen, Yidong

    2016-01-01

    Alkylating agents are a key component of cancer chemotherapy. Several cellular mechanisms are known to be important for its survival, particularly DNA repair and xenobiotic detoxification, yet genomic screens indicate that additional cellular components may be involved. Elucidating these components has value in either identifying key processes that can be modulated to improve chemotherapeutic efficacy or may be altered in some cancers to confer chemoresistance. We therefore set out to reevaluate our prior Drosophila RNAi screening data by comparison to gene expression arrays in order to determine if we could identify any novel processes in alkylation damage survival. We noted a consistent conservation of alkylation survival pathways across platforms and species when the analysis was conducted on a pathway/process level rather than at an individual gene level. Better results were obtained when combining gene lists from two datasets (RNAi screen plus microarray) prior to analysis. In addition to previously identified DNA damage responses (p53 signaling and Nucleotide Excision Repair), DNA-mRNA-protein metabolism (transcription/translation) and proteasome machinery, we also noted a highly conserved cross-species requirement for NRF2, glutathione (GSH)-mediated drug detoxification and Endoplasmic Reticulum stress (ER stress)/Unfolded Protein Responses (UPR) in cells exposed to alkylation. The requirement for GSH, NRF2 and UPR in alkylation survival was validated by metabolomics, protein studies and functional cell assays. From this we conclude that RNAi/gene expression fusion is a valid strategy to rapidly identify key processes that may be extendable to other contexts beyond damage survival. PMID:27100653

  6. The level of intracellular glutathione is a key regulator for the induction of stress-activated signal transduction pathways including Jun N-terminal protein kinases and p38 kinase by alkylating agents.

    PubMed Central

    Wilhelm, D; Bender, K; Knebel, A; Angel, P

    1997-01-01

    Monofunctional alkylating agents like methyl methanesulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are potent inducers of cellular stress leading to chromosomal aberrations, point mutations, and cell killing. We show that these agents induce a specific cellular stress response program which includes the activation of Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPKs), p38 mitogen-activated protein kinase, and the upstream kinase SEK1/MKK4 and which depends on the reaction mechanism of the alkylating agent in question. Similar to another inducer of cellular stress, UV irradiation, damage of nuclear DNA by alkylation is not involved in the MMS-induced response. However, in contrast to UV and other inducers of the JNK/SAPKs and p38 pathways, activation of growth factor and G-protein-coupled receptors does not play a role in the MMS response. We identified the intracellular glutathione (GSH) level as critical for JNK/SAPK activation by MMS: enhancing the GSH level by pretreatment of the cells with GSH or N-acetylcysteine inhibits, whereas depletion of the cellular GSH pool causes hyperinduction of JNK/SAPK activity by MMS. In light of the JNK/SAPK-dependent induction of c-jun and c-fos transcription, and the Jun/Fos-induced transcription of xenobiotic-metabolizing enzymes, these data provide a potential critical role of JNK/SAPK and p38 in the induction of a cellular defense program against cytotoxic xenobiotics such as MMS. PMID:9234735

  7. Using Cytochalasins to Improve Current Chemotherapeutic Approaches

    PubMed Central

    Trendowski, Matthew

    2015-01-01

    Although the amount of progress cancer therapy has made in recent years is commendable, considerable limitations still remain. Most agents preferentially target rapidly proliferating cells, thereby destroying tumorigenic growths. Unfortunately, there are many labile cells in the patient that are also rapidly dividing, ultimately perpetuating significant side effects, including immunosuppression. Cytochalasins are microfilament-directed agents most commonly known for their use in basic research to understand cytoskeletal mechanisms. However, such agents also exhibit profound anticancer activity, as indicated by numerous in vitro and in vivo studies. Cytochalasins appear to preferentially damage malignant cells, as shown by their minimal effects on normal epithelial and immune cells. Further, cytochalasins influence the end stages of mitosis, suggesting that such agents could be combined with microtubule-directed agents to elicit a profound synergistic effect on malignant cells. Therefore, it is likely that cytochalasins could be used to supplement current chemotherapeutic measures to improve efficacy rates, as well as decrease the prevalence of drug resistance in the clinical setting. PMID:25322987

  8. Dietary chalcones with chemopreventive and chemotherapeutic potential.

    PubMed

    Orlikova, Barbora; Tasdemir, Deniz; Golais, Frantisek; Dicato, Mario; Diederich, Marc

    2011-05-01

    Chalcones are absorbed in the daily diet and appear to be promising cancer chemopreventive agents. Chalcones represent an important group of the polyphenolic family, which includes a large number of naturally occurring molecules. This family possesses an interesting spectrum of biological activities, including antioxidative, antibacterial, anti-inflammatory, anticancer, cytotoxic, and immunosuppressive potential. Compounds of this family have been shown to interfere with each step of carcinogenesis, including initiation, promotion and progression. Moreover, numerous compounds from the family of dietary chalcones appear to show activity against cancer cells, suggesting that these molecules or their derivatives may be considered as potential anticancer drugs. This review will focus primarily on prominent members of the chalcone family with an 1,3-diphenyl-2-propenon core structure. Specifically, the inhibitory effects of these compounds on the different steps of carcinogenesis that reveal interesting chemopreventive and chemotherapeutic potential will be discussed. PMID:21484163

  9. Alkylating reactivity and herbicidal activity of chloroacetamides.

    PubMed

    Jablonkai, Istvan

    2003-04-01

    The relationship between S- and N-alkylating reactivity and herbicidal activity within a series of chloroacetamides, including several commercial herbicides and newly synthesised analogues was studied. The S-alkylating reactivity of selected chloroacetamides, as well as those of atrazine and chlorfenprop-methyl, was determined by in vitro GSH conjugation at a ratio of GSH to alkylating agent of 25:1. A spectrophotometric reaction using 4-(4-nitrobenzyl)pyridine was used to characterise the N-alkylating reactivity of the chemicals. Our results indicate that a reduced level of N-alkylating reactivity correlates with an improved herbicidal efficacy at a practical rate. However, the phytoxicity of the molecules is not simply dependent on chemical reactivities, but strictly related to the molecular structure, indicating that lipophilicity, uptake, mobility and induction of detoxifying enzymes may also be decisive factors in the mode of action. PMID:12701706

  10. Catalytic alkylation apparatus

    SciTech Connect

    Hann, P.D.; VanPool, J.

    1989-09-05

    This patent describes an apparatus. It comprises alkylation reactor means for producing alkylate product; acid catalyst settler means having an upper portion, an intermediate portion and a lower portion; means for withdrawing alkylate product from the alkylation reactor means and for providing alkylate product from the alkylation reactor means to a point of introduction in the intermediate portion of the acid catalyst settler means; and means for establishing a temperature gradient in the upper the gas lines to the detector so that a flow rate of a sample gas passing through the detector is constant.

  11. Pretreatment drugs against organophosphorus agents based on azabicyclic n-alkyl oximino o-carbamates. Annual report, 24 September 1991-23 September 1992

    SciTech Connect

    Moriarty, R.M.

    1992-11-11

    During the past year, 27 compounds of azabicyclic and carbocyclic oximino carbamate structural types have been prepared and submitted for biological testing as pretreatment agents against organophosphorus nerve agent poisoning. Biological data has been tabulated and has shown that the carbocyclic norbornanone derived oximino carbamates offer potential as pretreatment agents.

  12. Silencing of PKCη induces cycle arrest of EBV(+) B lymphoma cells by upregulating expression of p38-MAPK/TAp73/GADD45α and increases susceptibility to chemotherapeutic agents.

    PubMed

    Park, Ga Bin; Choi, Yunock; Kim, Yeong-Seok; Lee, Hyun-Kyung; Kim, Daejin; Hur, Dae Young

    2014-08-01

    PKCη is involved in proliferation, differentiation, and drug resistance. However, PKCη function in EBV(+) B lymphoma remains poorly understood. Gene silencing of PKCη through siRNA knockdown inhibited cellular proliferation, induced cell cycle arrest in G0/G1 and G2/M phases, and sensitized cells to chemotherapeutic drugs. Upon PKCη knockdown, expression levels of p21, GADD45α, and TAp73 were all increased, whereas expression levels of CDK2, CDK4, CDK6, cyclin E, cyclin B1, and cdc2 were all downregulated. PKCη silencing also activated p38-MAPK, which in turn contributed to the expression of cell cycle arrest-related molecules. These results suggest that siRNA-mediated silencing of PKCη can be a potent tool to complement existing chemotherapy regimens for treating EBV(+) B lymphoma. PMID:24784886

  13. When alcohol is the answer: Trapping, identifying and quantifying simple alkylating species in aqueous environments.

    PubMed

    Penketh, Philip G; Shyam, Krishnamurthy; Baumann, Raymond P; Zhu, Rui; Ishiguro, Kimiko; Sartorelli, Alan C; Ratner, Elena S

    2016-09-01

    Alkylating agents are a significant class of environmental carcinogens as well as commonly used anticancer therapeutics. Traditional alkylating activity assays have utilized the colorimetric reagent 4-(4-nitrobenzyl)pyridine (4NBP). However, 4NBP based assays have a relatively low sensitivity towards harder, more oxophilic alkylating species and are not well suited for the identification of the trapped alkyl moiety due to adduct instability. Herein we describe a method using water as the trapping agent which permits the trapping of simple alkylating electrophiles with a comparatively wide range of softness/hardness and permits the identification of donated simple alkyl moieties. PMID:27188264

  14. Pretreatment drugs against organophosphorus agents based on azabicyclic n-alkyl oximino o-carbamates. Annual report, 24 September 1990-23 September 1991

    SciTech Connect

    Moriarty, R.M.

    1991-11-12

    During the past year, a number of purely carbocyclic norbonanone derived oximino carbamates and their methiodide salts have been synthesized and submitted for biological evaluation as pretreatment agents against organophosphorus agents. Additionally, a synthetic route has been devised and employed for the preparation of 2-tropinone, a key precursor for the synthesis of structurally important oximino carbamate derivatives.

  15. 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

  16. Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent

    PubMed Central

    Williams, Declan; Resetca, Diana; Wilson, Derek J.; Gunning, Patrick T.

    2016-01-01

    The Signal Transducer and Activator of Transcription 3 (STAT3) oncogene is a master regulator of many human cancers, and a well-recognized target for therapeutic intervention. A well known STAT3 inhibitor, S3I-201 (NSC 74859), is hypothesized to block STAT3 function in cancer cells by binding the STAT3 SH2 domain and disrupt STAT3 protein complexation events. In this study, liquid chromatography tandem mass spectrometry analysis revealed that STAT3, in the presence of S3I-201, showed a minimum of five specific sites of modification, cysteine's 108, 259, 367, 542, and 687. Moreover, a prepared fluorescently labeled chemical probe of S3I-201 (DB-6-055) revealed that S3I-201 non-specifically and globally alkylated intracellular proteins at concentrations consistent with S3I-201's reported IC50. These data are consistent with the hypothesis that S3I-201 is a sub-optimal probe for interrogating STAT3-related cell biology. PMID:26942696

  17. Labelling of living mammalian spermatozoa with the fluorescent thiol alkylating agent, monobromobimane (MB): immobilization upon exposure to ultraviolet light and analysis of acrosomal status

    SciTech Connect

    Cummins, J.M.; Fleming, A.D.; Crozet, N.; Kuehl, T.J.; Kosower, N.S.; Yanagimachi, R.

    1986-03-01

    Living spermatozoa of seven mammalian species were treated with the thiol-alkylating fluorescent labelling compound, monobromobimane (MBBR). MB-labelling alone had no effect on sperm motility, nor on the time course or ability of golden hamster spermatozoa to undergo the acrosome reaction when capacitated in vitro. Exposure of MB-labelled spermatozoa to ultraviolet (UV) light and excitation of the MB fluorochrome resulted in virtually immediate immobilization of the spermatozoa without affecting acrosomal status. UV exposure of unlabelled spermatozoa for up to 30 sec had no effect upon motility. Immobilization of MB-labelled spermatozoa depended on the midpiece being irradiated, as irradiation of the head alone, or of the more distal parts of the principal piece, had little or no effect upon motility. Labelling with MB followed by immobilization of individually selected spermatozoa was most useful for detailing the course and site of occurrence of the acrosome reaction during penetration of the cumulus oophorus by golden hamster spermatozoa in vitro. In these often hyperactivated spermatozoa, precise determination of the acrosomal status could not often otherwise be made due to the difficulty in visualizing the acrosomal region of a vigorously thrashing, hyperactivated spermatozoon. This technique should prove valuable in a variety of studies on sperm motility, capacitation and fertilization, and could also be extended to other cell systems.

  18. Design and synthesis of some new 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-ureas as potent anticonvulsant and antidepressant agents.

    PubMed

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

    2016-05-01

    A series of 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-urea derivatives (29-42) were designed, synthesized and evaluated for their anticonvulsant activity by using maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurotoxicity was checked by rotarod assay. Most of the test compounds were found effective in both seizure tests. Compound 30 (1-{4-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3-phenyl-urea) exhibited marked anticonvulsant activity in MES as well as scPTZ tests. The phase II anticonvulsant quantification study of compound 30 indicates the ED50 value of 28.5 mg/kg against MES induced seizures. In addition, this compound also showed considerable protection against pilocarpine induced status epilepticus in rats. Seizures induced by 3-mercaptopropionic acid model and thiosemicarbazide were significantly attenuated by compound 30, which suggested its broad spectrum of anticonvulsant activity. Interestingly, compound 30 displayed better antidepressant activity than standard drug fluoxetine. Moreover, compound 30 appeared as a non-toxic chemical entity in sub-acute toxicity studies. PMID:26891908

  19. 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.

  20. 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. PMID:27470411

  1. 1-vinyl-4-alkyl-1,2,4-triazolium salts

    SciTech Connect

    Ermakova, T.G.; Chipanina, N.N.; Gritza, A.I.; Kuznetsova, N.P.; Lopyrev, V.A.; Tatarova, L.A.

    1985-04-01

    Quaternary salts based on 1-vinyl-1,2,4-triazole have been synthesized. Alkyl iodides and bromides and dimethyl sulfate served as the quaternizing agent. Polymeric quaternary salts of 1-vinyl-1,2,4-triazole have been obtained by alkylation of its polymer.

  2. 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

  3. Lapatinib as a chemotherapeutic drug.

    PubMed

    Obajimi, Oluwakemi

    2009-11-01

    Human epidermal growth factor receptor (HER) signaling is frequently associated with the development and progression of several types of cancers. Both the MAPK and the PI3K/Akt pathways have been implicated as effectors of HER signaling by promoting anti-apoptotic and pro-proliferative effects in cancer cells. As a result, many anti-HER drugs have been developed and patented for use in cancer therapy. One such drug that was recently approved for clinical trials is lapatinib (Tykerb, GW572016). Lapatinib is a small molecule inhibitor that is active at the ATP binding site of the tyrosine kinase involved in HER signaling. Importantly, this drug has dual specificity acting at the ATP binding sites of both HER-2 and HER-1 (EGFR). This review therefore summarizes the current knowledge based on pre-clinical and clinical evidence of the therapeutic effects of lapatinib against cancer and the promising strategy of combination therapy with the possibility of circumventing the problems of drug resistance commonly faced by chemotherapeutic drugs. PMID:19522695

  4. Immunochemical analysis of poly(ADP-ribosyl)ation in HaCaT keratinocytes induced by the mono-alkylating agent 2-chloroethyl ethyl sulfide (CEES): Impact of experimental conditions.

    PubMed

    Debiak, Malgorzata; Lex, Kirsten; Ponath, Viviane; Burckhardt-Boer, Waltraud; Thiermann, Horst; Steinritz, Dirk; Schmidt, Annette; Mangerich, Aswin; Bürkle, Alexander

    2016-02-26

    Sulfur mustard (SM) is a bifunctional alkylating agent with a long history of use as a chemical weapon. Although its last military use is dated for the eighties of the last century, a potential use in terroristic attacks against civilians remains a significant threat. Thus, improving medical therapy of mustard exposed individuals is still of particular interest. PARP inhibitors were recently brought into the focus as a potential countermeasure for mustard-induced pathologies, supported by the availability of efficient compounds successfully tested in cancer therapy. PARP activation after SM treatment was reported in several cell types and tissues under various conditions; however, a detailed characterization of this phenomenon is still missing. This study provides the basis for such studies by developing and optimizing experimental conditions to investigate poly(ADP-ribosyl)ation (PARylation) in HaCaT keratinocytes upon treatment with the monofunctional alkylating agent 2-chloroethyl ethyl sulfide ("half mustard", CEES). By using an immunofluorescence-based approach, we show that optimization of experimental conditions with regards to the type of solvent, dilution factors and treatment procedure is essential to obtain a homogenous PAR staining in HaCaT cell cultures. Furthermore, we demonstrate that different CEES treatment protocols significantly influence the cytotoxicity profiles of treated cells. Using an optimized treatment protocol, our data reveals that CEES induces a dose- and time-dependent dynamic PARylation response in HaCaT cells that could be completely blocked by treating cells with the clinically relevant pharmacological PARP inhibitor ABT888 (also known as veliparib). Finally, siRNA experiments show that CEES-induced PAR formation is predominantly due to the activation of PARP1. In conclusion, this study provides a detailed analysis of the CEES-induced PARylation response in HaCaT keratinocytes, which forms an experimental basis to study the

  5. Comparison of the Lonidamine Potentiated Effect of Nitrogen Mustard Alkylating Agents on the Systemic Treatment of DB-1 Human Melanoma Xenografts in Mice

    PubMed Central

    Nath, Kavindra; Nelson, David S.; Putt, Mary E.; Leeper, Dennis B.; Garman, Bradley; Nathanson, Katherine L.; Glickson, Jerry D.

    2016-01-01

    Previous NMR studies demonstrated that lonidamine (LND) selectively diminishes the intracellular pH (pHi) of DB-1 melanoma and mouse xenografts of a variety of other prevalent human cancers while decreasing their bioenergetic status (tumor βNTP/Pi ratio) and enhancing the activities of melphalan and doxorubicin in these cancer models. Since melphalan and doxorubicin are highly toxic agents, we have examined three other nitrogen (N)-mustards, chlorambucil, cyclophosphamide and bendamustine, to determine if they exhibit similar potentiation by LND. As single agents LND, melphalan and these N-mustards exhibited the following activities in DB-1 melanoma xenografts; LND: 100% tumor surviving fraction (SF); chlorambucil: 100% SF; cyclophosphamide: 100% SF; bendamustine: 79% SF; melphalan: 41% SF. When combined with LND administered 40 min prior to administration of the N-mustard (to maximize intracellular acidification) the following responses were obtained; chlorambucil: 62% SF; cyclophosphamide: 42% SF; bendamustine: 36% SF; melphalan: 10% SF. The effect of LND on the activities of these N-mustards is generally attributed to acid stabilization of the aziridinium active intermediate, acid inhibition of glutathione-S-transferase, which acts as a scavenger of aziridinium, and acid inhibition of DNA repair by O6-alkyltransferase. Depletion of ATP by LND may also decrease multidrug resistance and increase tumor response. At similar maximum tolerated doses, our data indicate that melphalan is the most effective N-mustard in combination with LND when treating DB-1 melanoma in mice, but the choice of N-mustard for coadministration with LND will also depend on the relative toxicities of these agents, and remains to be determined. PMID:27285585

  6. Tumour suppressor genes in chemotherapeutic drug response

    PubMed Central

    Lai, Dulcie; Visser-Grieve, Stacy; Yang, Xiaolong

    2012-01-01

    Since cancer is one of the leading causes of death worldwide, there is an urgent need to find better treatments. Currently, the use of chemotherapeutics remains the predominant option for cancer therapy. However, one of the major obstacles for successful cancer therapy using these chemotherapeutics is that patients often do not respond or eventually develop resistance after initial treatment. Therefore identification of genes involved in chemotherapeutic response is critical for predicting tumour response and treating drug-resistant cancer patients. A group of genes commonly lost or inactivated are tumour suppressor genes, which can promote the initiation and progression of cancer through regulation of various biological processes such as cell proliferation, cell death and cell migration/invasion. Recently, mounting evidence suggests that these tumour suppressor genes also play a very important role in the response of cancers to a variety of chemotherapeutic drugs. In the present review, we will provide a comprehensive overview on how major tumour suppressor genes [Rb (retinoblastoma), p53 family, cyclin-dependent kinase inhibitors, BRCA1 (breast-cancer susceptibility gene 1), PTEN (phosphatase and tensin homologue deleted on chromosome 10), Hippo pathway, etc.] are involved in chemotherapeutic drug response and discuss their applications in predicting the clinical outcome of chemotherapy for cancer patients. We also propose that tumour suppressor genes are critical chemotherapeutic targets for the successful treatment of drug-resistant cancer patients in future applications. PMID:22762204

  7. A sensitive gas chromatographic-tandem mass spectrometric method for detection of alkylating agents in water: application to acrylamide in drinking water, coffee and snuff.

    PubMed

    Pérez, Hermes Licea; Osterman-Golkar, Siv

    2003-08-01

    A sensitive analytical method for the analysis of acrylamide and other electrophilic agents in water has been developed. The amino acid L-valine served as a nucleophilic trapping agent. The method was applied to the analysis of acrylamide in 0.2-1 mL samples of drinking water or Millipore-filtered water, brewed coffee, or water extracts of snuff. The reaction product, N-(2-carbamoylethyl)valine, was incubated with pentafluorophenyl isothiocyanate to give a pentafluorophenylthiohydantoin (PFPTH) derivative. This derivative was extracted with diethyl ether, separated from excess reagent and impurities by a simple extraction procedure, and analyzed by gas chromatography-tandem mass spectrometry. (2H3)Acrylamide, added before the reaction with L-valine, was used as internal standard. Acrylamide and the related compound, N-methylolacrylamide, gave the same PFPTH derivative. The concentrations of acrylamides were < or = 0.4 nmol L(-1) (< or = 0.03 microg acrylamide L(-1)) in water, 200 to 350 nmol L(-1) in brewed coffee, and 10 to 34 nmol g(-1) snuff in portion bags, respectively. The precision (the coefficient of variation was 5%) and accuracy of the method were good. The detection limit was considerably lower than that of previously published methods for the analysis of acrylamide. PMID:12964603

  8. Orthomolecular oncology: a mechanistic view of intravenous ascorbate's chemotherapeutic activity.

    PubMed

    González, Michael J; Miranda-Massari, Jorge R; Mora, Edna M; Jiménez, Ivonne Z; Matos, María Isabel; Riordan, Hugh D; Casciari, Joseph J; Riordan, Neil H; Rodríguez, Marielys; Guzmán, Angelik

    2002-03-01

    The effect of vitamin C in cancer has been a subject of great controversy; mainly because of the inconsistent results obtained by oral intakes of ascorbate when used as an anticancer agent. We believe the intravenous application of ascorbate will provide more consistent results in cancer patients since Vitamin C blood levels attained are substantially higher in a range proven cytotoxic to malignant cells. In this article we will present and discuss our proposed mechanism on the chemotherapeutic activity exhibited by ascorbate. PMID:12013679

  9. Molecular biology basis for the response of poly(ADP-rib) polymerase and NAD metabolism to dna damage caused by mustard alkylating agents. Final report, 30 April 1990-30 July 1994

    SciTech Connect

    Smulson, M.E.

    1994-08-30

    During the course of this contract, we have performed a variety of experiments whose intent has been to provide a strategy to modulate the nuclear enzyme poly(ADP-ribose) polymerase (PADPRP) in cultured keratinocytes. During this study, human keratinocyte lines were stably transfected with the cDNA for human PADPRP in the antisense orientation under an inducible promoter. Induction of this antisense RNA by dexamethasone in cultured cells selectively lowered levels of PADPRP in RNA, protein, and enzyme activity. Induction of antisense RNA led to a reduction in the levels of PADPRP in individual cell nuclei, as well as the loss of the ability of cells to synthesize and modify proteins by poly(ADP-ribose) polymer in response to an alkylating agent. When keratinocyte clones containing the antisense construct or empty vector alone were grafted onto nude mice they formed histologically normal human skin. The PADPRP antisense construct was also inducible in vivo by the topical application of dexamethasone to the reconstituted epidermis. In addition, poly(ADP-ribose) polymer could be induced and detected in vivo following the topical application of a sulfur mustard to the grafted transfected skin layers. Accordingly, a model system has been developed in which the levels of PADPRP can be selectively manipulated in human keratinocytes in cell culture, and potentially in reconstituted epidermis as well.

  10. MGMT Promoter Methylation Correlates with an Overall Survival Benefit in Chinese High-Grade Glioblastoma Patients Treated with Radiotherapy and Alkylating Agent-Based Chemotherapy: A Single-Institution Study

    PubMed Central

    Shen, Dong; Liu, Tao; Lin, Qingfen; Lu, Xiangdong; Wang, Qiong; Lin, Feng; Mao, Weidong

    2014-01-01

    Promoter methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has been considered a prognostic marker and has become more important in the treatment of glioblastoma. However, reports on the correlation between MGMT and clinical outcomes in Chinese glioblastoma patients are very scarce. In this study, quantitative methylation data were obtained by the pyrosequencing of tumor tissues from 128 GBM patients. The median overall survival (OS) was 13.1 months, with a 1-year survival of 45.3%. The pyrosequencing data were reproducible based on archived samples yielding data for all glioblastomas. MGMT promoter methylation was detected in 75/128 cases (58.6%), whereas 53/128 (41.4%) cases were unmethylated. Further survival analysis also revealed that methylation was an independent prognostic factor associated with prolonged OS but not with progression-free survival (PFS) (p = 0.029 and p = 0.112, respectively); the hazard radios were 0.63 (95% CI: 0.42–0.96) and 0.72 (95% CI: 0.48–1.09), respectively. These data indicated that MGMT methylation has prognostic significance in patients with newly diagnosed high-grade glioblastoma undergoing alkylating agent-based chemotherapy after surgical resection. PMID:25211033

  11. Method for reactivating solid catalysts used in alkylation reactions

    DOEpatents

    Ginosar, Daniel M.; Thompson, David N.; Coates, Kyle; Zalewski, David J.; Fox, Robert V.

    2003-06-17

    A method for reactivating a solid alkylation catalyst is provided which can be performed within a reactor that contains the alkylation catalyst or outside the reactor. Effective catalyst reactivation is achieved whether the catalyst is completely deactivated or partially deactivated. A fluid reactivating agent is employed to dissolve catalyst fouling agents and also to react with such agents and carry away the reaction products. The deactivated catalyst is contacted with the fluid reactivating agent under pressure and temperature conditions such that the fluid reactivating agent is dense enough to effectively dissolve the fouling agents and any reaction products of the fouling agents and the reactivating agent. Useful pressures and temperatures for reactivation include near-critical, critical, and supercritical pressures and temperatures for the reactivating agent. The fluid reactivating agent can include, for example, a branched paraffin containing at least one tertiary carbon atom, or a compound that can be isomerized to a molecule containing at least one tertiary carbon atom.

  12. The synthesis and biological evaluation of new DNA-directed alkylating agents, phenyl N-mustard-4-anilinoquinoline conjugates containing a urea linker.

    PubMed

    Marvania, Bhavin; Kakadiya, Rajesh; Christian, Wilson; Chen, Tai-Lin; Wu, Ming-Hsi; Suman, Sharda; Tala, Kiran; Lee, Te-Chang; Shah, Anamik; Su, Tsann-Long

    2014-08-18

    We synthesized a series of phenyl N-mustard-4-anilinoquinoline conjugates to study their antitumorigenic effects. These agents were prepared by the condensation of 4-[N,N-bis(2-chloroethyl)amino]phenyl isocyanate with 6-amino-4-methylamino or 4-anilinoquinolines. The structure-activity relationship (SAR) studies revealed that the C2-methylquinoline derivatives (18a-o) were generally more cytotoxic than the C2-phenylquinoline conjugates (23a-d) in inhibiting the cell growth of various human tumor cell lines in vitro. However, the methylamino or aniline substituents at C4 of quinoline did not influence the cytotoxic effects. The title conjugates were capable of inducing DNA cross-linking and promoting cell-cycle arrest at the G2/M phase. This study demonstrates that phenyl N-mustard-4-anilinoquinoline conjugates are generally more potent than phenyl N-mustard-4-anilinoquinazoline conjugates against the cell growth of various tumor cell-lines. PMID:25014640

  13. Low density lipoprotein for delivery of a water-insoluble alkylating agent to malignant cells. In vitro and in vivo studies of a drug-lipoprotein complex.

    PubMed Central

    Vitols, S.; Söderberg-Reid, K.; Masquelier, M.; Sjöström, B.; Peterson, C.

    1990-01-01

    Previous studies have shown that human leukaemic cells and certain tumour tissues have a higher receptor-mediated uptake of low density lipoprotein (LDL) than the corresponding normal cells or tissues. LDL has therefore been proposed as a carrier for anti-cancer agents. In the current study, a water-insoluble mitoclomine derivative (WB 4291) was incorporated into LDL. The WB 4291-LDL complex contained about 1,500 drug molecules per LDL particle and showed receptor-mediated toxicity in vitro as judged from the difference in growth inhibitory effect on normal and mutant (LDL-receptor-negative) cultured Chinese hamster ovary cells. However, cellular drug uptake did not exclusively occur by the receptor pathway since mutant cells were also affected to some extent. The LDL part of the complex had the same plasma clearance and organ distribution as native LDL after i.v. injection in mice and rabbits. Therapeutic effects were observed when Balb-C mice with experimental leukaemia were treated with the complex. After i.p. administration to mice with i.p. leukaemia median survival time was prolonged 2.5-fold and 40% became long time survivors. The effect was weaker (42% increase in life span) after i.v. injections of the complex to mice with i.v. leukaemia. Images Figure 3 PMID:2245164

  14. Synthesis and preclinical evaluation of a new C-6 alkylated pyrimidine derivative as a PET imaging agent for HSV1-tk gene expression

    PubMed Central

    Müller, Ursina; Ross, Tobias L; Ranadheera, Charlene; Slavik, Roger; Müller, Adrienne; Born, Mariana; Trauffer, Evelyn; Sephton, Selena Milicevic; Scapozza, Leonardo; Krämer, Stefanie D; Ametamey, Simon M

    2013-01-01

    [18F]FHOMP (6-((1-[18F]-fluoro-3-hydroxypropan-2-yloxy)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione), a C-6 substituted pyrimidine derivative, has been synthesized and evaluated as a potential PET agent for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression. [18F]FHOMP was prepared by the reaction of the tosylated precursor with tetrabutylammonium [18F]-fluoride followed by acidic cleavage of the protecting groups. In vitro cell accumulation of [18F]FHOMP and [18F]FHBG (reference) was studied with HSV1-tk transfected HEK293 (HEK293TK+) cells. Small animal PET and biodistribution studies were performed with HEK293TK+ xenograft-bearing nude mice. The role of equilibrative nucleoside transporter 1 (ENT1) in the transport and uptake of [18F] FHOMP was also examined in nude mice after treatment with ENT1 inhibitor nitrobenzylmercaptopurine ribonucleoside phosphate (NBMPR-P). [18F]FHOMP was obtained in a radiochemical yield of ~25% (decay corrected) and the radiochemical purity was greater than 95%. The uptake of [18F]FHOMP in HSV1-TK containing HEK293TK+ cells was 52 times (at 30 min) and 244 times (at 180 min) higher than in control HEK293 cells. The uptake ratios between HEK293TK+ and HEK293 control cells for [18F]FHBG were significantly lower i.e. 5 (at 30 min) and 81 (240 min). In vivo, [18F]FHOMP accumulated to a similar extend in HEK293TK+ xenografts as [18F]FHBG but with a higher general background. Blocking of ENT1 reduced [18F]FHOMP uptake into brain from a standardized uptake value (SUV) of 0.10±0.01 to 0.06±0.02, but did not reduce the general background signal in PET. Although [18F]FHOMP does not outperform [18F]FHBG in its in vivo performance, this novel C-6 pyrimidine derivative may be a useful probe for monitoring HSV1-tk gene expression in vivo. PMID:23342302

  15. 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. PMID:25469267

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

    PubMed Central

    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. PMID:25469267

  17. 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

  18. Dissociative electron attachment to the radiosensitizing chemotherapeutic agent hydroxyurea.

    PubMed

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

    2016-06-14

    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 (-). PMID:27306009

  19. 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-.

  20. Role of chemotherapeutic agents in the management of cystic echinococcosis.

    PubMed

    Nazligul, Yasar; Kucukazman, Metin; Akbulut, Sami

    2015-01-01

    Hydatid disease is caused by infection with the metacestode stage of Echinococcus tapeworms of the family Taeniidae. The primary carriers are dogs and wolves, and humans are accidental hosts that do not contribute to the normal life cycle of this organism. The liver is the most commonly involved organ in the body by cystic echinococcosis (CE) secondary to infection with Echinococcus granulosus . Management options for CE should depend on the World Health Organization (WHO) diagnostic classification. Small (<5 cm) WHO stage CE1 and CE3a cysts may be primarily treated with benzimidazoles; the first-choice drug is albendazole. In some situations the combination of albendazole and praziquantel may be preferred. Chemotherapy with a benzimidazole or albendazole plus praziquantel is also used as adjunctive treatment to surgery and percutaneous treatment. Drug treatments have been the indispensable therapeutic modalities for cystic echinococcosis. PMID:25594649

  1. Acetamides: chemotherapeutic agents for inflammation-associated cancers.

    PubMed

    Rani, Priyanka; Pal, Dilipkumar; Hegde, Rahul Rama; Hashim, Syed Riaz

    2016-08-01

    Now clear evidences are available to support the hypothesis that inflammation accelerates the conditions including events and molecules that reach to various types of cancers. Inflammation is a normal response to infection containing the innate and adaptive immune systems. However, when allowed to continue, unresolved, perturbation of cellular microenvironment takes place; therefore, it leads to adaptations in genes that are linked to cancer. In addition, a lot of data are accessible confirming the concept that tumour microenvironment is orchestrated by various inflammatory cells and goes to neoplastic process and finally invasion, migration and metastasis. However, infiltrations of leucocytes lead to angiogenesis, propagation and invasion. An inflammatory microenvironment that perhaps fostering impact of angiogenesis include cytokines, chemokines, enzymes and growth factors that play key role for expansion and invasion of cancer cells. This insight highlights the pathogenesis of inflammation-associated cancers and also touches and fosters the role of acetamides for the treatment and chemoprevention of carcinomas that are allied with inflammation. PMID:26198312

  2. ALKYL PYROPHOSPHATE METAL SOLVENT EXTRACTANTS AND PROCESS

    DOEpatents

    Long, R.L.

    1958-09-30

    A process is presented for the recovery of uranium from aqueous mineral acidic solutions by solvent extraction. The extractant is a synmmetrical dialkyl pyrophosphate in which the alkyl substituents have a chain length of from 4 to 17 carbon atoms. Mentioned as a preferred extractant is dioctyl pyrophosphate. The uranium is precipitated irom the organic extractant phase with an agent such as HF, fluoride salts. alcohol, or ammonia.

  3. Ultrasound-targeted microbubble destruction for chemotherapeutic drug delivery to solid tumors

    PubMed Central

    2013-01-01

    Ultrasound-targeted microbubble destruction (UTMD) is a promising technique for non-invasive, targeted drug delivery, and its applications in chemotherapeutic drug delivery to solid tumors have attracted growing interest. Ultrasound, which has been conventionally used for diagnostic imaging, has evolved as a promising tool for therapeutic applications mainly because of its ability to be focused deep inside the human body, providing a modality for targeted delivery. Although originally being introduced into clinics as ultrasound contrast agents, microbubbles (MBs) have been developed as a diagnostic and therapeutic agent that can both be tracked through non-invasive imaging and deliver therapeutic agents selectively at ultrasound-targeted locations. Whereas free drugs often possess harmful side effects, their encapsulation in MBs and subsequent local release at the targeted tissue by ultrasound triggering may help improve the margin of safety. In the past 10 years, the feasibility and safety of UTMD have been extensively tested using normal animal models. Most recently, a growing number of preclinical studies have been reported on the therapeutic benefits of UTMD in the delivery of chemotherapeutic drugs to various malignant tumors, such as brain, liver, eyelid, pancreas, and breast tumors. Increased drug concentration in tumors and reduced tumor sizes were achieved in those tumors treated with UTMD in combination with chemotherapeutic drugs, when compared to tumors treated with chemotherapy drugs alone. This review presents an overview of current preclinical applications of UTMD in chemotherapeutic drug delivery for the treatment of cancers along with a discussion of its future developments. PMID:25512858

  4. Hydrogen Peroxide Inducible DNA Cross-Linking Agents: Targeted Anticancer Prodrugs

    PubMed Central

    Kuang, Yunyan; Balakrishnan, Kumudha; Gandhi, Varsha; Peng, Xiaohua

    2011-01-01

    The major concern for anticancer chemotherapeutic agents is the host toxicity. The development of anti-cancer prodrugs targeting the unique biochemical alterations in cancer cells is an attractive approach to achieve therapeutic activity and selectivity. We designed and synthesized a new type of nitrogen mustard prodrug that can be activated by high level of reactive oxygen species (ROS) found in cancer cells to release the active chemotherapy agent. The activation mechanism was determined by NMR analysis. The activity and selectivity of these prodrugs towards ROS was determined by measuring DNA interstrand crosslinks and/or DNA alkylations. These compounds showed 60–90% inhibition toward various cancer cells, while normal lymphocytes were not affected. To the best of our knowledge, this is the first example of H2O2-activated anticancer prodrugs. PMID:22035519

  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. 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

  7. Chemotherapy Agents: A Primer for the Interventional Radiologist

    PubMed Central

    Mihlon, Frank; Ray, Charles E.; Messersmith, Wells

    2010-01-01

    In this article, the authors review the basic principles of cancer chemotherapy and provide an overview of each of the general classes of chemotherapeutic agents with a target audience of interventional radiologists in mind. Special attention is paid to agents used in regional chemotherapy as well as agents commonly included in systemic chemotherapeutic regimens for patients who also require regional chemotherapy. PMID:22550380

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

    PubMed

    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. 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

  10. Safety Assessment of Alkyl PEG/PPG Ethers as Used in Cosmetics.

    PubMed

    Fiume, Monice M; Heldreth, Bart; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

    2016-07-01

    The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of 131 alkyl polyethylene glycol (PEG)/polypropylene glycol ethers as used in cosmetics, concluding that these ingredients are safe in the present practices of use and concentration described in this safety assessment when formulated to be nonirritating. Most of the alkyl PEG/PPG ethers included in this review are reported to function in cosmetics as surfactants, skin-conditioning agents, and/or emulsifying agents. The alkyl PEG/PPG ethers share very similar physiochemical properties as the alkyl PEG ethers, which were reviewed previously by the CIR Expert Panel and found safe when formulated to be nonirritating. The alkyl PEG ethers differ by the inclusion of PPG repeat units, which are used to fine-tune the surfactant properties of this group. The Panel relied heavily on data on analogous ingredients, extracted from the alkyl PEG ethers and PPG reports, when making its determination of safety. PMID:27383199

  11. Boron-Catalyzed N-Alkylation of Amines using Carboxylic Acids.

    PubMed

    Fu, Ming-Chen; Shang, Rui; Cheng, Wan-Min; Fu, Yao

    2015-07-27

    A boron-based catalyst was found to catalyze the straightforward alkylation of amines with readily available carboxylic acids in the presence of silane as the reducing agent. Various types of primary and secondary amines can be smoothly alkylated with good selectivity and good functional-group compatibility. This metal-free amine alkylation was successfully applied to the synthesis of three commercial medicinal compounds, Butenafine, Cinacalcet. and Piribedil, in a one-pot manner without using any metal catalysts. PMID:26150397

  12. In vivo kinetics of micronuclei induction by bifunctional alkylating antineoplastics.

    PubMed

    Morales-Ramírez, Pedro; Vallarino-Kelly, Teresita; Cruz-Vallejo, Virginia L; López-Iturbe, Rosario; Alvaro-Delgadillo, Horacio

    2004-05-01

    The aim of the present study was to determine in vivo the kinetics of micronucleated polychromatic erythrocyte (MN-PCE) induction in mice, as an approach for studying the mechanism of micronuclei induction by mitomycin C, cis-diamine dichloroplatinum, busulfan and bis-chloroethylnitrosourea, bifuctional alkylating antineoplastic agents having different patterns of crosslink induction. The kinetics of MN-PCE induction was established by scoring the frequency of MN-PCE in 2000 PCE in peripheral blood, for periods of 8 or 10 h after acute treatment and up to 80 h, with different doses of the agent. The kinetics of MN-PCE induction and particularly the times of maximal induction by different bifunctional alkylating agents were compared with the kinetics previously obtained for ethylnitrosourea, methylnitrosourea and 6-mercaptopurine, agents that cause MN-PCE mainly in the first, second and third divisions after exposure, respectively. The results obtained in the present study allow us to conclude that: (i) bifunctional alkylating agents have very different efficiencies of genotoxic and cytotoxic action; (ii) all assayed bifunctional alkylating agents induced micronuclei during the first cell division, owing to the mistaken repair of primary lesions, e.g. excision; (iii) busulfan and bis-chloroethylnitrosourea showed an additional late mechanism of micronuclei induction, which is expressed at the third division and seems to be related to the mismatch repair process. PMID:15123786

  13. Radical-based alkylation of guanine derivatives in aqueous medium.

    PubMed

    Chatgilialoglu, Chryssostomos; Caminal, Clara; Mulazzani, Quinto G

    2011-05-01

    The radical-based alkylation of 8-bromoguanosine (1a) and 8-bromo-2'-deoxyguanosine (1b) at the C8 position has been investigated in aqueous solutions. Alkyl radicals were generated by scavenging of the primary species of γ-radiolysis by the alcohol substrate. These reactions result in the efficient formation of intermolecular C-C bonds in aqueous media, by using the reactivity of α-hydroxyalkyl radicals derived from alcohols with 1a and 1b. A mechanism for the formation of C8 guanine alkylated adducts has been proposed, based on the quantification of radiation chemical yields for the disappearance of starting material and the formation of all products. Two α-hydroxyalkyl radicals are needed to form an alkylated guanine, the first one adding to C8 followed by ejection of Br(-) with formation of guanyl adduct and the second one acting as reducing agent of the guanyl adduct. PMID:21431230

  14. Method of making alkyl esters

    DOEpatents

    Elliott, Brian

    2010-09-14

    Methods of making alkyl esters are described herein. The methods are capable of using raw, unprocessed, low-cost feedstocks and waste grease. Generally, the method involves converting a glyceride source to a fatty acid composition and esterifying the fatty acid composition to make alkyl esters. In an embodiment, a method of making alkyl esters comprises providing a glyceride source. The method further comprises converting the glyceride source to a fatty acid composition comprising free fatty acids and less than about 1% glyceride by mass. Moreover, the method comprises esterifying the fatty acid composition in the presence of a solid acid catalyst at a temperature ranging firm about 70.degree. C. to about 120.degree. C. to produce alkyl esters, such that at least 85% of the free fatty acids are converted to alkyl esters. The method also incorporates the use of packed bed reactors for glyceride conversion and/or fatty acid esterification to make alkyl esters.

  15. Chemotherapeutic-Induced Apoptosis – A Phenotype for Pharmacogenomics Studies

    PubMed Central

    Wen, Yujia; Gorsic, Lidija K.; Wheeler, Heather E.; Ziliak, Dana M.; Huang, R. Stephanie; Dolan, M. Eileen

    2011-01-01

    Lymphoblastoid cell lines have been used as a model system to identify genetic determinants of chemotherapeutic-induced cytotoxicity, a phenotype thought to represent cellular sensitivity to drug. However, cytotoxicity is a broad measurement encompassing cell cycle inhibition as well as cell death (apoptotic and non-apoptotic). We evaluated caspase 3/7 mediated cellular apoptosis with six chemotherapeutic agents: 5′-deoxy-fluorouridine, pemetrexed, cytarabine, paclitaxel, carboplatin and cisplatin. Using monozygotic twin pair and sibling pair lymphoblastoid cell lines, we identified conditions for measurement of caspase activity. Although treatment with 5′-deoxy-fluorouridine and pemetrexed for up to 24 h did not result in significant apoptosis or inter-individual variation in caspase dependent cell death; paclitaxel, cisplatin, carboplain and cytarabine treatment for 24 h resulted in 9.4, 9.1, 7.0 and 6.0 fold increases in apoptosis relative to control, respectively. There was a weak correlation between caspase activity and cytotoxicity (r2=0.03 to 0.29) demonstrating that cytotoxicity and apoptosis are two distinct phenotypes that may produce independent genetic associations. Estimated heritability (h2) for apoptosis was 0.57 and 0.29 for cytarabine (5 μM and 40 μM respectively), 0.22 for paclitaxel (12.5 nM), and 0.34 for cisplatin (5 μM). The HapMap CEU panel of lymphoblastoid cell lines (n = 77) were evaluated for sensitivity to cisplatin followed by genome wide association studies with over 2 million SNPs at p < 0.001. We identified a significant enrichment of cisplatin-induced apoptosis SNPs within the significant cisplatin induced cytotoxicity SNPs and an enrichment of expression quantitative trait loci. PMID:21642893

  16. N-O Chemistry for Antibiotics: Discovery of N-Alkyl-N-(pyridin-2-yl)hydroxylamine Scaffolds as Selective Antibacterial Agents Using Nitroso Diels-Alder and Ene Chemistry

    PubMed Central

    Wencewicz, Timothy A.; Yang, Baiyuan; Rudloff, James R.; Oliver, Allen G.; Miller, Marvin J.

    2011-01-01

    The discovery, syntheses, and structure-activity relationships (SAR) of a new family of heterocyclic antibacterial compounds based on N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds are described. A structurally diverse library of ~100 heterocyclic molecules generated from Lewis acid-mediated nucleophilic ring opening reactions with nitroso Diels-Alder cycloadducts and nitroso ene reactions with substituted alkenes was evaluated in whole cell antibacterial assays. Compounds containing the N-alkyl-N-(pyridin-2-yl)hydroxylamine structure demonstrated selective and potent antibacterial activity against the Gram-positive bacterium Micrococcus luteus ATCC 10240 (MIC90 = 2.0 μM or 0.41 μg/mL) and moderate activity against other Gram-positive strains including antibiotic resistant strains of Staphylococcus aureus (MRSA) and Enterococcus faecalis (VRE). A new synthetic route to the active core was developed using palladium-catalyzed Buchwald-Hartwig amination reactions of N-alkyl-O-(4-methoxybenzyl)hydroxylamines with 2-halo-pyridines that facilitated SAR studies and revealed the simplest active structural fragment. This work shows the value of using a combination of diversity-oriented synthesis (DOS) and parallel synthesis for identifying new antibacterial scaffolds. PMID:21859126

  17. 40 CFR 721.9595 - Alkyl benzene sulfonic acids and alkyl sulfates, amine salts (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Alkyl benzene sulfonic acids and alkyl... Significant New Uses for Specific Chemical Substances § 721.9595 Alkyl benzene sulfonic acids and alkyl...) The chemical substances identified generically as alkyl benzene sulfonic acids and alkyl...

  18. 40 CFR 721.9595 - Alkyl benzene sulfonic acids and alkyl sulfates, amine salts (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkyl benzene sulfonic acids and alkyl... Significant New Uses for Specific Chemical Substances § 721.9595 Alkyl benzene sulfonic acids and alkyl...) The chemical substances identified generically as alkyl benzene sulfonic acids and alkyl...

  19. 40 CFR 721.9595 - Alkyl benzene sulfonic acids and alkyl sulfates, amine salts (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Alkyl benzene sulfonic acids and alkyl... Significant New Uses for Specific Chemical Substances § 721.9595 Alkyl benzene sulfonic acids and alkyl...) The chemical substances identified generically as alkyl benzene sulfonic acids and alkyl...

  20. 40 CFR 721.9595 - Alkyl benzene sulfonic acids and alkyl sulfates, amine salts (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Alkyl benzene sulfonic acids and alkyl... Significant New Uses for Specific Chemical Substances § 721.9595 Alkyl benzene sulfonic acids and alkyl...) The chemical substances identified generically as alkyl benzene sulfonic acids and alkyl...

  1. 40 CFR 721.9595 - Alkyl benzene sulfonic acids and alkyl sulfates, amine salts (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Alkyl benzene sulfonic acids and alkyl... Significant New Uses for Specific Chemical Substances § 721.9595 Alkyl benzene sulfonic acids and alkyl...) The chemical substances identified generically as alkyl benzene sulfonic acids and alkyl...

  2. BMX Negatively Regulates BAK Function, Thereby Increasing Apoptotic Resistance to Chemotherapeutic Drugs.

    PubMed

    Fox, Joanna L; Storey, Alan

    2015-04-01

    The ability of chemotherapeutic agents to induce apoptosis, predominantly via the mitochondrial (intrinsic) apoptotic pathway, is thought to be a major determinant of the sensitivity of a given cancer to treatment. Intrinsic apoptosis, regulated by the BCL2 family, integrates diverse apoptotic signals to determine cell death commitment and then activates the nodal effector protein BAK to initiate the apoptotic cascade. In this study, we identified the tyrosine kinase BMX as a direct negative regulator of BAK function. BMX associates with BAK in viable cells and is the first kinase to phosphorylate the key tyrosine residue needed to maintain BAK in an inactive conformation. Importantly, elevated BMX expression prevents BAK activation in tumor cells treated with chemotherapeutic agents and is associated with increased resistance to apoptosis and decreased patient survival. Accordingly, BMX expression was elevated in prostate, breast, and colon cancers compared with normal tissue, including in aggressive triple-negative breast cancers where BMX overexpression may be a novel biomarker. Furthermore, BMX silencing potentiated BAK activation, rendering tumor cells hypersensitive to otherwise sublethal doses of clinically relevant chemotherapeutic agents. Our finding that BMX directly inhibits a core component of the intrinsic apoptosis machinery opens opportunities to improve the efficacy of existing chemotherapy by potentiating BAK-driven cell death in cancer cells. PMID:25649765

  3. Chemotherapeutic activities of Carthami Flos and its reversal effect on multidrug resistance in cancer cells.

    PubMed

    Wu, Jimmy Yiu-Cheong; Yu, Zhi-Ling; Fong, Wang-Fun; Shi, Yi-Qian

    2013-01-01

    Multidrug-resistance (MDR) represents a major cause of failure in cancer chemotherapy. The need for a reduction in MDR by natural-product-based drugs of low toxicity led to the current investigation of applying medicinal herbs in future cancer adjuvant therapy. Carthami Flos (CF), the dried flower of safflower (Carthamus tinctorius L.), is one of the most popular traditional Chinese medicinal herbs used to alleviate pain, increase circulation, and reduce blood-stasis syndrome. The drug resistance index of the total extract of CF in MDR KB-V1 cells and its synergistic effects with other chemotherapeutic agents were studied. SRB cell viability assays were used to quantify growth inhibition after exposure to single drug and in combinations with other chemotherapeutic agents using the median effect principle. The combination indexes were then calculated according to the classic isobologram equation. The results revealed that CF showed a drug resistance index of 0.096. In combination with other chemotherapeutic agents, it enhanced their chemo-sensitivities by 2.8 to 4.0 folds and gave a general synergism in cytotoxic effect. These results indicate that CF could be a potential alternative adjuvant antitumour herbal medicine representing a promising approach to the treatment of some malignant and MDR cancers in the future. PMID:24146498

  4. Noncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase

    PubMed Central

    Zhao, Yu; Majid, Mona C; Soll, Jennifer M; Brickner, Joshua R; Dango, Sebastian; Mosammaparast, Nima

    2015-01-01

    Repair of DNA alkylation damage is critical for genomic stability and involves multiple conserved enzymatic pathways. Alkylation damage resistance, which is critical in cancer chemotherapy, depends on the overexpression of alkylation repair proteins. However, the mechanisms responsible for this upregulation are unknown. Here, we show that an OTU domain deubiquitinase, OTUD4, is a positive regulator of ALKBH2 and ALKBH3, two DNA demethylases critical for alkylation repair. Remarkably, we find that OTUD4 catalytic activity is completely dispensable for this function. Rather, OTUD4 is a scaffold for USP7 and USP9X, two deubiquitinases that act directly on the AlkB proteins. Moreover, we show that loss of OTUD4, USP7, or USP9X in tumor cells makes them significantly more sensitive to alkylating agents. Taken together, this work reveals a novel, noncanonical mechanism by which an OTU family deubiquitinase regulates its substrates, and provides multiple new targets for alkylation chemotherapy sensitization of tumors. PMID:25944111

  5. Polyimides with pendant alkyl groups

    NASA Technical Reports Server (NTRS)

    Jensen, B. J.; Young, P. R.

    1982-01-01

    The effect on selected polyimide properties when pendant alkyl groups were attached to the polymer backbone was investigated. A series of polymers were prepared using benzophenone tetracarboxylic acid dianhydride (BTDA) and seven different p-alkyl-m,p'-diaminobenzophenone monomers. The alkyl groups varied in length from C(1) (methyl) to C(9) (nonyl). The polyimide prepared from BTDA and m,p'-diaminobenzophenone was included as a control. All polymers were characterized by various chromatographic, spectroscopic, thermal, and mechanical techniques. Increasing the length of the pendant alkyl group resulted in a systematic decrease in glass transition temperature (Tg) for vacuum cured films. A 70 C decrease in Tg to 193 C was observed for the nonyl polymer compared to the Tg for the control. A corresponding systematic increase in Tg indicative of crosslinking, was observed for air cured films. Thermogravimetric analysis revealed a slight sacrifice in thermal stability with increasing alkyl length. No improvement in film toughness was observed.

  6. A Review of the Role of the Sequence-Dependent Electrostatic Landscape in DNA Alkylation Patterns

    PubMed Central

    Gold, Barry; Marky, Luis M.; Stone, Michael P.; Williams, Loren D.

    2008-01-01

    Alkylating agents, including environmental and endogenous carcinogens, and DNA targeting antineoplastic agents, that adduct DNA via intermediates with significant cationic charge show a sequence selectively in their covalent bonding to nucleobases. The resulting patterns of alkylation eventually contribute to the agent-dependent distributions and types of mutations. The origin of the regioselective modification of DNA by electrophiles has been attributed to steric and/or electronic factors, but attempts to mechanistically model and predict alkylation patterns have had limited success. In this review, we present data consistent with the role of the intrinsic sequence-dependent electrostatic landscape (SDEL) in DNA that modulates the equilibrium binding of cations and the bonding of reactive charged alkylating agents to atoms that line the floor of the major groove of DNA. PMID:17112226

  7. C-Alkylation of Ketones and Related Compounds by Alcohols: Transition-Metal-Catalyzed Dehydrogenation.

    PubMed

    Huang, Fei; Liu, Zhuqing; Yu, Zhengkun

    2016-01-18

    Transition-metal-catalyzed C-alkylation of ketones and secondary alcohols, with alcohols, avoids use of organometallic or environmentally unfriendly alkylating agents by means of borrowing hydrogen (BH) or hydrogen autotransfer (HA) activation of the alcohol substrates. Water is formed as the only by-product, thus making the BH process atom-economical and environmentally benign. Diverse homogeneous and heterogeneous transition-metal catalysts, ketones, and alcohols can be used for this transformation, thus rendering the BH process promising for replacing those procedures that use traditional alkylating agents. This Minireview summarizes the advances during the last five years in transition-metal-catalyzed BH α-alkylation of ketones, and β-alkylation of secondary alcohols with alcohols. A discussion on the application of the BH strategy for C-C bond formation is included. PMID:26639633

  8. The Role of Transporters in the Toxicity of Chemotherapeutic Drugs: Focus on Transporters for Organic Cations.

    PubMed

    Hucke, Anna; Ciarimboli, Giuliano

    2016-07-01

    The introduction of chemotherapy in the treatment of cancer is one of the most important achievements of modern medicine, even allowing the cure of some lethal diseases such as testicular cancer and other malignant neoplasms. The number and type of chemotherapeutic agents available have steadily increased and have developed until the introduction of targeted tumor therapy. It is now evident that transporters play an important role for determining toxicity of chemotherapeutic drugs not only against target but also against nontarget cells. This is of special importance for intracellularly active hydrophilic drugs, which cannot freely penetrate the plasma membrane. Because many important chemotherapeutic agents are substrates of transporters for organic cations, this review discusses the known interaction of these substances with these transporters. A particular focus is given to the role of transporters for organic cations in the development of side effects of chemotherapy with platinum derivatives and in the efficacy of recently developed tyrosine kinase inhibitors to specifically target cancer cells. It is evident that specific inhibition of uptake transporters may be a possible strategy to protect against undesired side effects of platinum derivatives without compromising their antitumor efficacy. These transporters are also important for efficient targeting of tyrosine kinase inhibitors to cancer cells. However, in order to achieve the aims of protecting from undesired toxicities and improving the specificity of uptake by tumor cells, an exact knowledge of transporter expression, function, regulation under normal and pathologic conditions, and of genetically and epigenetically regulation is mandatory. PMID:27385173

  9. Ferulic acid in combination with PARP inhibitor sensitizes breast cancer cells as chemotherapeutic strategy.

    PubMed

    Choi, Young Eun; Park, Eunmi

    2015-03-13

    Homologous-recombination (HR)-dependent repair defective cells are hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Combinations of defective HR pathway and PARP inhibitors have been an effective chemotherapeutic modality. We previously showed that knockdown of the WD40-repeat containing protein, Uaf1, causes an HR repair defect in mouse embryo fibroblast cells and therefore, increases sensitivity to PARP inhibitor, ABT-888. Similarly, here, we show that ferulic acid reduces HR repair, inhibits RAD 51 foci formation, and accumulates γ-H2AX in breast cancer cells. Moreover, ferulic acid, when combined with ABT-888, renders breast cancer cells become hypersensitive to ABT-888. Our study indicates that ferulic acid in combination with ABT-888 treatment may serve as an effective combination chemotherapeutic agent as a natural bioactive compound. PMID:25677620

  10. ESCHERICHIA COLI Gene Induction by Alkylation Treatment

    PubMed Central

    Volkert, Michael R.; Nguyen, Dinh C.; Beard, K. Christopher

    1986-01-01

    Searches for alkylation-inducible (aid) genes of Escherichia coli have been conducted by screening random fusions of the Mu-dl(ApR lac) phage for fusions showing increased β-galactosidase activity after treatment with methylating agents, but not after treatments with UV-irradiation. In this report we describe gene fusions that are specifically induced by alkylation treatments. Nine new mutants are described, and their properties are compared with the five mutants described previously. The total of 14 fusion mutants map at five distinct genetic loci. They can be further subdivided on the basis of their induction by methyl methanesulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). alkA, aidB and aidD are induced by both agents and appear to be regulated by ada. Neither aidC nor aidI is regulated by ada. Moreover, since aidC is induced only by MNNG and aidI is induced only by MMS, these two genes are likely to be individually regulated. Thus, there appear to be at least three different regulatory mechanisms controlling aid genes. PMID:3080354

  11. Synthetic lethal approaches for assessing combinatorial efficacy of chemotherapeutic drugs.

    PubMed

    Jackson, Rebecca A; Chen, Ee Sin

    2016-06-01

    The recent advances in pharmacogenomics have made personalized medicine no longer a pipedream but a precise and powerful way to tailor individualized cancer treatment strategies. Cancer is a devastating disease, and contemporary chemotherapeutic strategies now integrate several agents in the treatment of some types of cancer, with the intent to block more than one target simultaneously. This constitutes the premise of synthetic lethality, an attractive therapeutic strategy already demonstrating clinical success in patients with breast and ovarian cancers. Synthetic lethal combinations offer the potential to also target the hitherto "undruggable" mutations that have challenged the cancer field for decades. However, synthetic lethality in clinical cancer therapy is very much still in its infancy, and selecting the most appropriate combinations-or synthetic lethal pairs-is not always an intuitive process. Here, we review some of the recent progress in identifying synthetic lethal combinations and their potential for therapy and highlight some of the tools through which synthetic lethal pairs are identified. PMID:26803999

  12. Chemotherapeutic potential of quercetin on human bladder cancer cells.

    PubMed

    Oršolić, Nada; Karač, Ivo; Sirovina, Damir; Kukolj, Marina; Kunštić, Martina; Gajski, Goran; Garaj-Vrhovac, Vera; Štajcar, Damir

    2016-07-28

    In an effort to improve local bladder cancer control, we investigated the cytotoxic and genotoxic effects of quercetin on human bladder cancer T24 cells. The cytotoxic effect of quercetin against T24 cells was examined by MTT test, clonogenic assay as well as DNA damaging effect by comet assay. In addition, the cytotoxic effect of quercetin on the primary culture of papillary urothelial carcinoma (PUC), histopathological stage T1 of low- or high-grade tumours, was investigated. Our analysis demonstrated a high correlation between reduced number of colony and cell viability and an increase in DNA damage of T24 cells incubated with quercetin at doses of 1 and 50 µM during short term incubation (2 h). At all exposure times (24, 48 and 72 h), the efficacy of quercetin, administered at a 10× higher dose compared to T24 cells, was statistically significant (P < 0.05) for the primary culture of PUC. In conclusion, our study suggests that quercetin could inhibit cell proliferation and colony formation of human bladder cancer cells by inducing DNA damage and that quercetin may be an effective chemopreventive and chemotherapeutic agent for papillary urothelial bladder cancer after transurethral resection. PMID:27149655

  13. Effects of changes in intracellular iron pool on AlkB-dependent and AlkB-independent mechanisms protecting E.coli cells against mutagenic action of alkylating agent.

    PubMed

    Sikora, Anna; Maciejewska, Agnieszka M; Poznański, Jarosław; Pilżys, Tomasz; Marcinkowski, Michał; Dylewska, Małgorzata; Piwowarski, Jan; Jakubczak, Wioletta; Pawlak, Katarzyna; Grzesiuk, Elżbieta

    2015-08-01

    An Escherichia coli hemH mutant accumulates protoporphyrin IX, causing photosensitivity of cells to visible light. Here, we have shown that intracellular free iron in hemH mutants is double that observed in hemH(+) strain. The aim of this study was to recognize the influence of this increased free iron concentration on AlkB-directed repair of alkylated DNA by analyzing survival and argE3 → Arg(+) reversion induction after λ>320 nm light irradiation and MMS-treatment in E. coli AB1157 hemH and alkB mutants. E.coli AlkB dioxygenase constitutes a direct single-protein repair system using non-hem Fe(II) and cofactors 2-oxoglutarate (2OG) and oxygen (O2) to initiate oxidative dealkylation of DNA/RNA bases. We have established that the frequency of MMS-induced Arg(+) revertants in AB1157 alkB(+)hemH(-)/pMW1 strain was 40 and 26% reduced comparing to the alkB(+)hemH(-) and alkB(+)hemH(+)/pMW1, respectively. It is noteworthy that the effect was observed only when bacteria were irradiated with λ>320 nm light prior MMS-treatment. This finding indicates efficient repair of alkylated DNA in photosensibilized cells in the presence of higher free iron pool and AlkB concentrations. Interestingly, a 31% decrease in the level of Arg(+) reversion was observed in irradiated and MMS-treated hemH(-)alkB(-) cells comparing to the hemH(+)alkB(-) strain. Also, the level of Arg(+) revertants in the irradiated and MMS treated hemH(-) alkB(-) mutant was significantly lower (by 34%) in comparison to the same strain but MMS-treated only. These indicate AlkB-independent repair involving Fe ions and reactive oxygen species. According to our hypothesis it may be caused by non-enzymatic dealkylation of alkylated dNTPs in E. coli cells. In in vitro studies, the absence of AlkB protein in the presence of iron ions allowed etheno(ϵ) dATP and ϵdCTP to spontaneously convert to dAMP and dCMP, respectively. Thus, hemH(-) intra-cellular conditions may favor Fe-dependent dealkylation of modified d

  14. 40 CFR 721.1875 - Boric acid, alkyl and substituted alkyl esters (generic name).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Boric acid, alkyl and substituted... Significant New Uses for Specific Chemical Substances § 721.1875 Boric acid, alkyl and substituted alkyl... chemical substance boric acid, alkyl and substituted alkyl esters (PMN P-86-1252) is subject to...

  15. 40 CFR 721.1875 - Boric acid, alkyl and substituted alkyl esters (generic name).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Boric acid, alkyl and substituted... Significant New Uses for Specific Chemical Substances § 721.1875 Boric acid, alkyl and substituted alkyl... chemical substance boric acid, alkyl and substituted alkyl esters (PMN P-86-1252) is subject to...

  16. 40 CFR 721.1875 - Boric acid, alkyl and substituted alkyl esters (generic name).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Boric acid, alkyl and substituted... Significant New Uses for Specific Chemical Substances § 721.1875 Boric acid, alkyl and substituted alkyl... chemical substance boric acid, alkyl and substituted alkyl esters (PMN P-86-1252) is subject to...

  17. 40 CFR 721.1875 - Boric acid, alkyl and substituted alkyl esters (generic name).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Boric acid, alkyl and substituted... Significant New Uses for Specific Chemical Substances § 721.1875 Boric acid, alkyl and substituted alkyl... chemical substance boric acid, alkyl and substituted alkyl esters (PMN P-86-1252) is subject to...

  18. 40 CFR 721.1875 - Boric acid, alkyl and substituted alkyl esters (generic name).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Boric acid, alkyl and substituted... Significant New Uses for Specific Chemical Substances § 721.1875 Boric acid, alkyl and substituted alkyl... chemical substance boric acid, alkyl and substituted alkyl esters (PMN P-86-1252) is subject to...

  19. Mismatch repair-dependent G2 checkpoint induced by low doses of SN1 type methylating agents requires the ATR kinase.

    PubMed

    Stojic, Lovorka; Mojas, Nina; Cejka, Petr; Di Pietro, Massimiliano; Ferrari, Stefano; Marra, Giancarlo; Jiricny, Josef

    2004-06-01

    S(N)1-type alkylating agents represent an important class of chemotherapeutics, but the molecular mechanisms underlying their cytotoxicity are unknown. Thus, although these substances modify predominantly purine nitrogen atoms, their toxicity appears to result from the processing of O(6)-methylguanine ((6Me)G)-containing mispairs by the mismatch repair (MMR) system, because cells with defective MMR are highly resistant to killing by these agents. In an attempt to understand the role of the MMR system in the molecular transactions underlying the toxicity of alkylating agents, we studied the response of human MMR-proficient and MMR-deficient cells to low concentrations of the prototypic methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). We now show that MNNG treatment induced a cell cycle arrest that was absolutely dependent on functional MMR. Unusually, the cells arrested only in the second G(2) phase after treatment. Downstream targets of both ATM (Ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) kinases were modified, but only the ablation of ATR, or the inhibition of CHK1, attenuated the arrest. The checkpoint activation was accompanied by the formation of nuclear foci containing the signaling and repair proteins ATR, the S(*)/T(*)Q substrate, gamma-H2AX, and replication protein A (RPA). The persistence of these foci implied that they may represent sites of irreparable damage. PMID:15175264

  20. Alkylation and acylation of cyclotriphosphazenes.

    PubMed

    Benson, Mark A; Zacchini, Stefano; Boomishankar, Ramamoorthy; Chan, Yuri; Steiner, Alexander

    2007-08-20

    Phosphazenes (RNH)6P3N3 (R = n-propyl, isobutyl, isopropyl, cyclohexyl, tert-butyl, benzyl) are readily alkylated at ring N sites by alkyl halides forming N-alkyl phosphazenium cations. Alkylation of two ring N sites occurred after prolonged heating in the presence of methyl iodide or immediately at room temperature with methyl triflate yielding N,N'-dimethyl phosphazenium dications. Geminal dichloro derivatives Cl2(RNH)4P3N3 are methylated by methyl iodide at the ring N site adjacent to both P centers carrying four RNH groups. X-ray crystal structures showed that the alkylation of ring N sites leads to substantial elongation of the associated P-N bonds. Both N-alkyl and N,N'-dialkyl phosphazenium salts form complex supramolecular networks in the solid state via NH...X interactions. Systems carrying less-bulky RNH groups show additional NH...N bonds between N-alkyl phosphazenium ions. N-Alkyl phosphazenium halides form complexes with silver ions upon treatment with silver nitrate. Depending on the steric demand of RNH substituents, either one or both of the vacant ring N sites engage in coordination to silver ions. Treatment of (RNH)6P3N3 (R = isopropyl) with acetyl chloride and benzoyl chloride, respectively, yielded N-acyl phosphazenium ions. X-ray crystal structures revealed that elongation of P-N bonds adjacent to the acylated ring N site is more pronounced than it is in the case of N-alkylated species. Salts containing N-alkyl phosphazenium ions are stable toward water and other mild nucleophiles, while N,N'-dialkyl and N-acyl phosphazenium salts are readily hydrolyzed. The reaction of (RNH)6P3N3 with bromoacetic acid led to N-alkylation at one ring N site in addition to formation of an amide via condensation of an adjacent RNH substituent with the carboxylic acid group. The resulting bromide salt contains mono cations of composition (RNH)5P3N3CH2CONR in which a CH2-C(O) unit is embedded between a ring N and an exocyclic N site of the phosphazene. PMID

  1. Safety Assessment of Alkyl PEG Sulfosuccinates as Used in Cosmetics.

    PubMed

    Johnson, Wilbur; Heldreth, Bart; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

    2015-09-01

    The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed the safety of alkyl polyethylene glycol (PEG) sulfosuccinates, which function in cosmetics mostly as surfactants/cleansing agents. Although these ingredients may cause ocular and skin irritation, dermal penetration is unlikely because of the substantial polarity and molecular size of these ingredients. The Panel considered the negative oral carcinogenicity and reproductive and developmental toxicity data on chemically related laureths (PEG lauryl ethers) and negative repeated dose toxicity and skin sensitization data on disodium laureth sulfosuccinate supported the safety of these alkyl PEG sulfosuccinates in cosmetic products, but. The CIR Expert Panel concluded that the alkyl PEG sulfosuccinates are safe in the present practices of use and concentration when formulated to be nonirritating. PMID:26362121

  2. Safety Assessment of Alkyl Ethylhexanoates as Used in Cosmetics.

    PubMed

    Fiume, Monice; Heldreth, Bart; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

    2015-01-01

    The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) assessed the safety of 16 alkyl ethylhexanoates for use in cosmetics, concluding that these ingredients are safe in cosmetic formulations in the present practices of use and concentrations when formulated to be nonirritating. The alkyl ethylhexanoates primarily function as skin-conditioning agents in cosmetics. The highest concentration of use reported for any of the alkyl ethylhexanoates is 77.3% cetyl ethylhexanoate in rinse-off formulations used near the eye, and the highest leave-on use reported is 52% cetyl ethylhexanoate in lipstick formulations. The Panel reviewed available animal and clinical data related to these ingredients, and the similarities in structure, properties, functions, and uses of ingredients from previous CIR assessments on constituent alcohols that allowed for extrapolation of the available toxicological data to assess the safety of the entire group. PMID:26684798

  3. Chemotherapeutic Approaches Against Trypanosoma evansi: Retrospective Analysis, Current Status and Future Outlook.

    PubMed

    Rathore, Nitu S; Manuja, Anju; Manuja, Balvinder Kumar; Choudhary, Shalki

    2016-01-01

    Trypanosoma evansi, the causative agent of surra, is pathogenic to a wide variety of wild and domestic animals, including equines, camels, goats, sheep, cattle, buffaloes, pigs, dogs, tigers, elephants etc. The infection is mainly restricted to animals but ability to infect human beings has also been reported due to the lack of efficient apolipoprotein L 1. The parasite is mechanically transmitted by blood-sucking flies such as Tabanus and Stomoxys species. The disease has a major economic impact in tropical countries. The control of trypanosomosis may be aimed either at the fly or against the parasite. Due to difficulties in large scale fly control, trypanocides have been widely used to control the disease. However, current chemotherapeutic agents are limited in number and usually associated with severe side effects. Moreover, current therapeutic agents are far from ideal. The emergence of drug resistant trypanosomes results in failure of prophylaxis and treatment of the disease. Retrospective and prospective studies on drug and delivery against T. evansi will provide an overview of the chemotherapeutic and prophylactic measures in vogue and suggest future strategies for combating this neglected disease. In this perspective, we have reviewed the currently used drugs available for prophylaxis and therapy, their mechanism of action and associated limitations. The options available for prophylaxis and therapy along with potential new molecules/therapeutic agents and novel approaches for delivery of the drugs to enhance their therapeutic value are presented in this review. PMID:27072712

  4. mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy

    PubMed Central

    Weiler, Markus; Blaes, Jonas; Pusch, Stefan; Sahm, Felix; Czabanka, Marcus; Luger, Sebastian; Bunse, Lukas; Solecki, Gergely; Eichwald, Viktoria; Jugold, Manfred; Hodecker, Sibylle; Osswald, Matthias; Meisner, Christoph; Hielscher, Thomas; Rübmann, Petra; Pfenning, Philipp-Niklas; Ronellenfitsch, Michael; Kempf, Tore; Schnölzer, Martina; Abdollahi, Amir; Lang, Florian; Bendszus, Martin; von Deimling, Andreas; Winkler, Frank; Weller, Michael; Vajkoczy, Peter; Platten, Michael; Wick, Wolfgang

    2014-01-01

    A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O6-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids. PMID:24367102

  5. Based on Nucleotides Analysis of Tumor Cell Lines to Construct and Validate a Prediction Model of Mechanisms of Chemotherapeutics.

    PubMed

    Liu, Cuichai; Wang, Fang; Liu, Xi; Liu, Min; Liu, Zheng; Sun, Lixin

    2016-01-01

    Cancer is one of the diseases that seriously threaten to human life worldwide. Up to now, chemotherapy remains to be a critical means of cancer treatment, thus the development of chemotherapeutical drugs has become a top priority. An ion pair high performance liquid chromatography (ion pair RP-HPLC) was established for analyzing intracellular nucleotides of tumor cell lines. In this article, a partial least-squares discriminant analysis (PLS-DA) prediction model of mechanisms of chemotherapeutics was established based on four types of drugs with different mechanisms, including antimetabolic agents, antineoplastic agents that affect protein synthesis, agents directly acting on DNA, and RNA interference agents. Then four anti-tumor agents commonly used in clinical were used to validate the availability of the prediction model. Three natural compounds, including 16- dehydropregnenolone (16-DHP), apigenin (API) and diosgenin (DIO), were reported to display anti-tumor effect with unclear mechanisms. The three components were applied to this prediction model firstly. In conclusion, the recognition model was proved to be accurate and feasible to some degree and might become a promising auxiliary method in the process of chemotherapeutic drugs development. PMID:26234361

  6. Mild Catalytic methods for Alkyl-Alkyl Bond Formation

    SciTech Connect

    Vicic, David A

    2009-08-10

    Overview of Research Goals and Accomplishments for the Period 07/01/06 – 06/30/07: Our overall research goal is to transform the rapidly emerging synthetic chemistry involving alkyl-alkyl cross-couplings into more of a mechanism-based field so that that new, rationally-designed catalysts can be performed under energy efficient conditions. Our specific objectives for the previous year were 1) to obtain a proper electronic description of an active catalyst for alkyl-alkyl cross-coupling reactions and 2) to determine the effect of ligand structure on the rate, scope, selectivity, and functional group compatibility of C(sp3)-C(sp3) cross-coupling catalysis. We have completed both of these initial objectives and established a firm base for further studies. The specific significant achievements of the current grant period include: 1) we have performed magnetic and computational studies on (terpyridine)NiMe, an active catalyst for alkyl-alkyl cross couplings, and have discovered that the unpaired electron resides heavily on the terpyridine ligand and that the proper electronic description of this nickel complex is a Ni(II)-methyl cation bound to a reduced terpyridine ligand; 2) we have for the first time shown that alkyl halide reduction by terpyridyl nickel catalysts is substantially ligand based; 3) we have shown by isotopic labeling studies that the active catalyst (terpyridine)NiMe is not produced via a mechanism that involves the formation of methyl radicals when (TMEDA)NiMe2 is used as the catalyst precursor; 4) we have performed an extensive ligand survey for the alkyl-alkyl cross-coupling reactions and have found that electronic factors only moderately influence reactivity in the terpyridine-based catalysis and that the most dramatic effects arise from steric and solubility factors; 5) we have found that the use of bis(dialkylphosphino)methanes as ligands for nickel does not produce active catalysts for cross-coupling but rather leads to bridging hydride

  7. Activation of the Nrf2/ARE pathway via S-alkylation of cysteine 151 in the chemopreventive agent-sensor Keap1 protein by falcarindiol, a conjugated diacetylene compound

    SciTech Connect

    Ohnuma, Tomokazu; Nakayama, Shinji; Anan, Eisaburo; Nishiyama, Takahito; Ogura, Kenichiro; Hiratsuka, Akira

    2010-04-01

    Under basal conditions, the interaction of the cytosolic protein Kelch-like ECH-associated protein 1 (Keap1) with the transcription factor nuclear factor-E2-related factor 2 (Nrf2) results in a low level of expression of cytoprotective genes whose promoter region contains the antioxidant response element (ARE). In response to oxidants and electrophiles, Nrf2 is stabilized and accumulates in the nucleus. The mechanism for this effect has been proposed to involve thiol-dependent modulation of Keap1, leading to loss of its ability to negatively regulate Nrf2. We previously reported that falcarindiol (heptadeca-1,9(Z)-diene-4,6-diyne-3,8-diol), which occurs in Apiaceae and the closely related Araliaceae plants, causes nuclear accumulation of Nrf2 and induces ARE-regulated enzymes. Here, we report the mechanism of Nrf2 induction by falcarindiol. NMR analysis revealed that the conjugated diacetylene carbons of falcarindiol acted as electrophilic moieties to form adducts with a cysteine (Cys) thiol. In addition, using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and circular dichroism spectroscopy, it was demonstrated that falcarindiol alkylated Cys residues in Keap1 and altered the Keap1 secondary structure. Transfection studies using the purified Keap1 protein, a luciferase reporter construct, and an Nrf2-expressing plasmid indicated that the intact Keap1 protein suppressed Nrf2-mediated ARE-luciferase activity. On the other hand, the falcarindiol-alkylated Keap1 protein did not suppress such activity. Treatment of HEK293 cells overexpressing Keap1 with falcarindiol generated a high molecular weight (HMW) form of Keap1. Furthermore, the Cys151 residue in Keap1 was found to be uniquely required for not only the formation of HMW Keap1 but also an increase in ARE-luciferase activity by falcarindiol. Our results demonstrate that falcarindiol having conjugated diacetylene carbons covalently modifies the Cys151 residue in Keap1 and that the

  8. 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.

  9. Manganese-Mediated C-H Alkylation of Unbiased Arenes Using Alkylboronic Acids.

    PubMed

    Castro, Susana; Fernández, Juan J; Fañanás, Francisco J; Vicente, Rubén; Rodríguez, Félix

    2016-06-27

    The alkylation of arenes is an essential synthetic step of interest not only from the academic point of view but also in the bulk chemical industry. Despite its limitations, the Friedel-Crafts reaction is still the method of choice for most of the arene alkylation processes. Thus, the development of new strategies to synthesize alkyl arenes is a highly desirable goal, and herein, we present an alternative method to those conventional reactions. Particularly, a simple protocol for the direct C-H alkylation of unbiased arenes with alkylboronic acids in the presence of Mn(OAc)3 ⋅2H2 O is reported. Primary or secondary unactivated alkylboronic acids served as alkylating agents for the direct functionalization of representative polyaromatic hydrocarbons (PAHs) or benzene. The results are consistent with a free-radical mechanism. PMID:27124250

  10. Schistosoma mansoni Sirtuins: Characterization and Potential as Chemotherapeutic Targets

    PubMed Central

    Lancelot, Julien; Caby, Stéphanie; Dubois-Abdesselem, Florence; Vanderstraete, Mathieu; Trolet, Jacques; Oliveira, Guilherme; Bracher, Franz; Jung, Manfred; Pierce, Raymond J.

    2013-01-01

    Background The chemotherapy of schistosomiasis currently depends on the use of a single drug, praziquantel. In order to develop novel chemotherapeutic agents we are investigating enzymes involved in the epigenetic modification of chromatin. Sirtuins are NAD+ dependent lysine deacetylases that are involved in a wide variety of cellular processes including histone deacetylation, and have been demonstrated to be therapeutic targets in various pathologies, including cancer. Methodology, Principal Findings In order to determine whether Schistosoma mansoni sirtuins are potential therapeutic targets we first identified and characterized their protein sequences. Five sirtuins (SmSirt) are encoded in the S. mansoni genome and phylogenetic analysis showed that they are orthologues of mammalian Sirt1, Sirt2, Sirt5, Sirt6 and Sirt7. Both SmSirt1 and SmSirt7 have large insertion in the catalytic domain compared to their mammalian orthologues. SmSirt5 is the only mitochondrial sirtuin encoded in the parasite genome (orthologues of Sirt3 and Sirt4 are absent) and transcripts corresponding to at least five splicing isoforms were identified. All five sirtuins are expressed throughout the parasite life-cycle, but with distinct patterns of expression. Sirtuin inhibitors were used to treat both schistosomula and adult worms maintained in culture. Three inhibitors in particular, Sirtinol, Salermide and MS3 induced apoptosis and death of schistosomula, the separation of adult worm pairs, and a reduction in egg laying. Moreover, Salermide treatment led to a marked disruption of the morphology of ovaries and testes. Transcriptional knockdown of SmSirt1 by RNA interference in adult worms led to morphological changes in the ovaries characterized by a marked increase in mature oocytes, reiterating the effects of sirtuin inhibitors and suggesting that SmSirt1 is their principal target. Conclusion, Significance Our data demonstrate the potential of schistosome sirtuins as therapeutic targets

  11. 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

  12. Alkylation of toluene with ethanol

    SciTech Connect

    Walendziewski, J.; Trawczynski, J.

    1996-10-01

    A series of Y and ZSM-5 zeolite based catalysts was prepared. Zeolites were cation exchanged and formed with 50% of aluminum hydroxide as a binder, and the obtained catalysts were finally thermally treated. Activity tests in alkylation of toluene with ethanol were carried out in the temperature range of 325--400 C, in nitrogen or hydrogen stream, and a pressure up to 3 MPa. The feed consisted of toluene and ethanol mixed in a mole ratio 1/1 or 2/1. The obtained results showed that among the studied catalysts the highest activity in the alkylation reaction was attained by ZSM-5 zeolite based catalyst with a moderate acidity and medium silica to alumina ratio, i.e., {approximately}50. Activity and selectivity of the most active catalyst as well as conversion of the feed components were similar to those reported in other papers. The content of p-ethyltoluene in alkylation products attained ca. 60%.

  13. A biological source of oceanic alkyl nitrates

    NASA Astrophysics Data System (ADS)

    Dahl, E. E.; Lewis, C. B.; Velasco, F. L.; Escobar, C.; Kellogg, D.; Velcamp, M.

    2013-12-01

    Alkyl nitrates are an important component of reactive nitrogen in the troposphere. The oceans are a source of alkyl nitrates to the atmosphere, however the source of alkyl nitrates in the oceans is unknown. It has been demonstrated that the reaction of alkyl peroxy radicals (ROO) with nitric oxide (NO) produces alkyl nitrates in the aqueous phase. We hypothesize that alkyl nitrates may be formed by organisms through the same reaction and therefore biological production could be a source of alkyl nitrates to the troposphere. This work focuses on the production of alkyl nitrates by the diatoms Chaetoceros muelleri and Thalassiosira weisfloggi. Using chemostats, we measure alkyl nitrates formed under nitrate limited conditions. We also use triggers and inhibitors of nitric oxide formation to determine if alkyl nitrate formation is affected by changes in NO production. To date, the rates of production of alkyl nitrates in our cultures, lead us to estimate a production rate on the order of femtomolar/day for C1-C3 alkyl nitrates by diatom species in the equatorial Pacific Ocean. This suggests that diatoms may contribute to the overall ocean source of alkyl nitrates; however, it is possible that other types of phytoplankton, such as cyanobacteria, that are more abundant in the open ocean, may contribute to a greater extent.

  14. Pd and Mo Catalyzed Asymmetric Allylic Alkylation

    PubMed Central

    Trost, Barry M.

    2012-01-01

    The ability to control the alkylation of organic substrates becomes ever more powerful by using metal catalysts. Among the major benefits of metal catalysis is the possibility to perform such processes asymmetrically using only catalytic amounts of the chiral inducing agent which is a ligand to the metal of the catalyst. A unique aspect of asymmetric metal catalyzed processes is the fact that many mechanisms exist for stereoinduction. Furthermore, using the same catalyst system, many types of bonds including but not limited to C-C, C-N, C-O, C-S, C-P, and C-H can be formed asymmetrically. An overview of this process using palladium and molybdenum based metals being developed in my laboratories and how they influence strategy in synthesizing bioactive molecular targets is presented. PMID:22736934

  15. Phosphine-alkene ligand-mediated alkyl-alkyl and alkyl-halide elimination processes from palladium(II).

    PubMed

    Tuxworth, Luke; Baiget, Lise; Phanopoulos, Andreas; Metters, Owen J; Batsanov, Andrei S; Fox, Mark A; Howard, Judith A K; Dyer, Philip W

    2012-10-28

    N-Diphenylphosphino-7-aza-benzobicyclo[2.2.1]hept-2-ene (2) behaves as a chelating phosphine-alkene ligand for Pd(0) and Pd(II), promoting direct alkyl-alkyl and indirect alkyl-halide reductive elimination reactions due to the stabilisation of the resulting bis(phosphine-alkene)Pd(0) complex. PMID:22986447

  16. New potential of the reductive alkylation of amines

    NASA Astrophysics Data System (ADS)

    Gusak, K. N.; Ignatovich, Zh V.; Koroleva, E. V.

    2015-03-01

    Available data on the reductive alkylation of amines with carbonyl compounds — a key method for the preparation of secondary and tertiary amines — are described systematically. The review provides information on the relevant reducing agents and catalysts and on the use of chiral catalysts in stereo- and enantiocontrolled reactions of amine synthesis. The effect of the reactant and catalyst structures on the reaction rates and chemo- and stereo(enantio)selectivity is considered. The bibliography includes 156 references.

  17. 40 CFR 721.9892 - Alkylated urea.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkylated urea. 721.9892 Section 721... Alkylated urea. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as an alkylated urea (PMN P-93-1649) is subject to reporting under...

  18. 40 CFR 721.9892 - Alkylated urea.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Alkylated urea. 721.9892 Section 721... Alkylated urea. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as an alkylated urea (PMN P-93-1649) is subject to reporting under...

  19. 40 CFR 721.9892 - Alkylated urea.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Alkylated urea. 721.9892 Section 721... Alkylated urea. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as an alkylated urea (PMN P-93-1649) is subject to reporting under...

  20. 40 CFR 721.9892 - Alkylated urea.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Alkylated urea. 721.9892 Section 721... Alkylated urea. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as an alkylated urea (PMN P-93-1649) is subject to reporting under...

  1. 40 CFR 721.9892 - Alkylated urea.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Alkylated urea. 721.9892 Section 721... Alkylated urea. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as an alkylated urea (PMN P-93-1649) is subject to reporting under...

  2. Oil compositions containing alkyl amine or alkyl mercaptan derivatives of copolymers of an alpha olefin or an alkyl vinyl ether

    SciTech Connect

    Le, H.T.

    1990-02-13

    This patent describes an oil composition. It comprises a major amount of an oil selected from a crude oil or fuel oil and a minor amount of an alkyl amine or alkyl mercaptan derivative of an alpha olefin or alkyl vinyl ether and an unsaturated alpha, beta-dicarboxylic compound copolymer having pour point depressant ;properties. The copolymer comprising the reaction product of an alpha olefin having from about 2 to about 30 carbon atoms or mixtures of alpha olefins having from about 2 to about 30 carbon atoms or an alkyl vinyl ether or mixture of alkyl vinyl ethers.

  3. PTCH-1 and MDM2 expression in ameloblastoma from a West African sub-population: implication for chemotherapeutics

    PubMed Central

    Udeabor, Samuel Ebele; Adisa, Akinyele Olumuyiwa; Lawal, Ahmed Oluwatoyin; Barbeck, Mike; Booms, Patrick; Sader, Robert Alexander; Ghanaati, Shahram

    2015-01-01

    Introduction Ameloblastoma is a slow growing, painless odontogenic swelling which can attain sizes that result in severe deformities of the craniofacial complex. It is the most commonly encountered odontogenic tumor in Nigeria. Surgical intervention is currently the method of treatment; however identification of altered molecular pathways may inform chemotherapeutic potential. The Protein Patched homolog 1 (PTCH-1) is overexpressed in ameloblastoma. Also, mutation in the MDM2 gene can reduce the tumor suppressor function of p53 and promote ameloblastoma growth. No study however has characterized the molecular profile of African cases of ameloblastoma with a view to developing chemotherapeutic alternatives. The objective was to characterize the PTCH-1 genetic profile of Ameloblastoma in Nigerian patients as a first step in investigating its potential for chemotherapeutic intervention. Methods Twenty-eight FFPE blocks of ameloblastoma cases from Nigerian patients were prepared for antibody processing to PTCH-1 (Polyclonal Anti-PTCH antibody ab39266) and MDM2 (Monoclonal Anti-MDM2 antibody (2A10) ab16895). Cytoplasmic brown staining was considered as positive for PTCH while nuclear staining was positive for MDM2. Results Moderate and strong expressions for PTCH in ameloblast and stellate reticulum were 78.6% and 60.7% respectively. Only 3 (10.7%) cases expressed MDM2. Conclusion The importance of our study is that it supports, in theory, anti-PTCH/SHH chemotherapeutics for Nigerian ameloblastoma cases and also infers the possible additional use of anti-p53 agents. PMID:27386018

  4. 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. PMID:26262951

  5. DNA Binding and Photocleavage Properties, Cellular Uptake and Localization, and in-Vitro Cytotoxicity of Dinuclear Ruthenium(II) Complexes with Varying Lengths in Bridging Alkyl Linkers.

    PubMed

    Liu, Ping; Wu, Bao-Yan; Liu, Jin; Dai, Yong-Cheng; Wang, You-Jun; Wang, Ke-Zhi

    2016-02-15

    Two new dinuclear Ru(II) polypyridyl complexes containing three and ten methylene chains in their bridging linkers are synthesized and characterized. Their calf thymus DNA-binding and plasmid DNA photocleavage behaviors are comparatively studied with a previously reported, six-methylene-containing analog by absorption and luminescence spectroscopy, steady-state emission quenching by [Fe(CN)6](4-), DNA competitive binding with ethidium bromide, DNA viscosity measurements, DNA thermal denaturation, and agarose gel electrophoresis analyses. Theoretical calculations applying the density functional theory (DFT) method for the three complexes are also performed to understand experimentally observed DNA binding properties. The results show that the two complexes partially intercalate between the base pairs of DNA. Cellular uptake and colocalization studies have demonstrated that the complexes could enter HeLa cells efficiently and localize within lysosomes. The in-vitro antitumor activity against HeLa and MCF-7 tumor cells of the complexes are studied by MTT cytotoxic analysis. A new method, high-content analysis (HCA), is also used to assess cytotoxicity, apoptosis and cell cycle arrest of the three complexes. The results show that the lengths of the alkyl linkers could effectively tune their biological properties and that HCA is suitable for rapidly identifying cytotoxicity and can be substituted for MTT assays to evaluate the cell cytotoxicity of chemotherapeutic agents. PMID:26811966

  6. 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

  7. 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

  8. Application of 23Na MRI to Monitor Chemotherapeutic Response in RIF-1 Tumors1

    PubMed Central

    Babsky, Andriy M; Hekmatyar, Shahryar K; Zhang, Hong; Solomon, James L; Bansal, Navin

    2005-01-01

    Abstract Effects of an alkylating anticancer drug, cyclophosphamide (Cp), on 23Na signal intensity (23Na SI) and water apparent diffusion coefficient (ADC) were examined in subcutaneously-implanted radiation-induced fibrosarcoma (RIF-1) tumors by in vivo 23Na and 1H magnetic resonance imaging (MRI). MRI experiments were performed on untreated control (n = 5) and Cp-treated (n = 6) C3H mice, once before Cp injection (300 mg/kg) then daily for 3 days after treatment. Tumor volumes were significantly lower in treated animals 2 and 3 days posttreatment. At the same time points, MRI experiments showed an increase in both 23Na SI and water ADC in treated tumors, whereas control tumors did not show any significant changes. The correlation between 23Na SI and water ADC changes was dramatically increased in the Cp-treated group, suggesting that the observed increases in 23Na SI and water ADC were caused by the same mechanism. Histologic sections showed decreased cell density in the regions of increased 23Na and water ADC SI. Destructive chemical analysis showed that Cp treatment increased the relative extracellular space and tumor [Na+]. We conclude that the changes in water ADC and 23Na SI were largely due to an increase in extracellular space. 23Na MRI and 1H water ADC measurements may provide valuable noninvasive techniques for monitoring chemotherapeutic responses. PMID:16026645

  9. Methods of making alkyl esters

    DOEpatents

    Elliott, Brian

    2010-08-03

    A method comprising contacting an alcohol, a feed comprising one or more glycerides and equal to or greater than 2 wt % of one or more free fatty acids, and a solid acid catalyst, a nanostructured polymer catalyst, or a sulfated zirconia catalyst in one or more reactors, and recovering from the one or more reactors an effluent comprising equal to or greater than about 75 wt % alkyl ester and equal to or less than about 5 wt % glyceride.

  10. PREPARATION OF ALKYL PYROPHOSPHATE EXTRACTANTS

    DOEpatents

    Levine, C.A.; Skiens, W.E.; Moore, G.R.

    1960-08-01

    A process for providing superior solvent extractants for metal recovery processes is given wherein the extractant comprises an alkyl pyrophosphoric acid ester dissolved in an organic solvent diluent. Finely divided solid P/sub 2/O/ sub 5/ is slurried in an organic solvent-diluent selected from organic solvents such as kerosene, benzene, chlorobenzene, toluene, etc. An alcohol selected from the higher alcohols having 4 to 17 carbon atoms. e.g.. hexanol-1. heptanol-3, octanol-1. 2.6-dimethyl-heptanol-4, and decanol-1, is rapidly added to the P/sub 2/O/sub 5/ slurry in the amount of about 2 moles of alcohol to 1 mole of P/sub 2/ O/sub 5/. The temperature is maintained below about 110 deg C during the course of the P/sub 2/O/sub 5/-alcohol reaction. An alkyl pyrophosphate extractant compound is formed as a consequence of the reaction process. The alkyl pyrophosphate solvent-diluent extractant phase is useful in solvent extraction metal recovery processes.

  11. Smac mimetics increase cancer cell response to chemotherapeutics in a TNF-α-dependent manner

    PubMed Central

    Probst, BL; Liu, L; Ramesh, V; Li, L; Sun, H; Minna, JD; Wang, L

    2011-01-01

    Second mitochondria-derived activator of caspase (Smac) is a mitochondrial protein released into the cytosol during apoptosis. Smac mimetics have recently been touted as a novel therapeutic to induce apoptosis in cancer cells. The ability of Smac mimetics to induce apoptosis in vitro has been shown to be dependent upon both XIAP neutralization and cancer cell autocrine tumor necrosis factor-α (TNF-α) production. In this study we provide new evidence for the utility of Smac mimetics in combination with conventional chemotherapy agents to exacerbate caspase activation and induce cancer cell death. Furthermore, we find that the combination effect is because of a multifaceted mechanism involving both inhibition of cell proliferation by the chemotherapy agents and an enhanced autocrine TNF-α feedback loop by the Smac mimetic/chemotherapy agent combination. Surprisingly, although genotoxic agents typically induce apoptosis through the mitochondrial intrinsic pathway, we show that this synergism is mediated through a TNF-α/RIP1-dependent pathway, leading to activation of the extrinsic apoptotic pathway. Finally, we report that autocrine TNF-α contributes to Smac mimetic-induced tumor regression as a single agent or in combination with chemotherapeutics in xenograft mouse models. Collectively, we provide mechanistic and applicable data to support translational studies in the use of a Smac mimetic/chemotherapy antineoplasm modality. PMID:20431601

  12. Safety Assessment of Alkyl Esters as Used in Cosmetics.

    PubMed

    Fiume, Monice M; Heldreth, Bart A; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

    2015-09-01

    The Cosmetic Ingredient Review Expert Panel (Panel) assessed the safety of 237 alkyl esters for use in cosmetics. The alkyl esters included in this assessment have a variety of reported functions in cosmetics, with skin-conditioning agent being the most common function. The Panel reviewed available animal and clinical data in making its determination of safety on these ingredients, and where there were data gaps, similarity in structure, properties, functions, and uses of these ingredients allowed for extrapolation of the available toxicological data to assess the safety of the entire group. The Panel concluded that these ingredients are safe in cosmetic formulations in the present practices of use and concentration when formulated to be nonirritating. PMID:26362120

  13. Structure of a DNA Repair Substrate Containing an Alkyl Interstrand Crosslink at 1.65 Å Resolution†‡

    PubMed Central

    Swenson, Matthew C.; Paranawithana, Shanthi R.; Miller, Paul S.; Kielkopf, Clara L.

    2008-01-01

    Chemotherapeutic alkylating agents, such as bifunctional nitrogen mustards and cisplatins, generate interstrand DNA crosslinks that inhibit cell proliferation by arresting DNA transcription and replication. A synthetic N4C-ethyl-N4C interstrand crosslink between opposing cytidines mimics the DNA damage produced by this class of clinically important compounds, and can be synthesized in large quantities to study the repair, physical properties, and structures of these DNA adducts. The X-ray structure of a DNA duplex d(CCAAC*GTTGG)2 containing a synthetic N4C-ethyl-N4C interstrand crosslink between the cytosines of the central CpG step (*) has been determined at 1.65 Å resolution. This structure reveals that the ethyl crosslink in the CpG major groove does not significantly disrupt the B-form DNA helix. Comparison of the N4C-ethyl-N 4C crosslinked structure with the structure of an uncrosslinked oligonucleotide of the same sequence reveals that the crosslink selectively stabilizes a pre-existing alternative conformation. The conformation preferred by the crosslinked DNA is constrained by the geometry of the ethyl group bridging the cytosine amines. Characteristics of the crosslinked CpG step include subtle differences in the roll of the base pairs, optimized Watson-Crick hydrogen bonds, and loss of a divalent cation binding site. Given that the N4C-ethyl-N4C crosslink stabilizes a pre-existing conformation of the CpG step, this synthetically accessible substrate presents an ideal model system for studying the genomic effects of covalently coupling the DNA strands, independent of gross alterations in DNA structure. PMID:17375936

  14. Capsaicin Enhances the Drug Sensitivity of Cholangiocarcinoma through the Inhibition of Chemotherapeutic-Induced Autophagy

    PubMed Central

    Hong, Zai-Fa; Zhao, Wen-Xiu; Yin, Zhen-Yu; Xie, Cheng-Rong; Xu, Ya-Ping; Chi, Xiao-Qin; Zhang, Sheng; Wang, Xiao-Min

    2015-01-01

    Cholangiocarcinoma (CCA), a devastating cancer with a poor prognosis, is resistant to the currently available chemotherapeutic agents. Capsaicin, the major pungent ingredient found in hot red chili peppers of the genus Capsicum, suppresses the growth of several malignant cell lines. Our aims were to investigate the role and mechanism of capsaicin with respect to the sensitivity of CCA cells to chemotherapeutic agents. The effect of capsaicin on CCA tumor sensitivity to 5-fluorouracil (5-FU) was assessed in vitro in CCA cells and in vivo in a xenograft model. The drug sensitivity of QBC939 to 5-FU was significantly enhanced by capsaicin compared with either agent alone. In addition, the combination of capsaicin with 5-FU was synergistic, with a combination index (CI) < 1, and the combined treatment also suppressed tumor growth in the CCA xenograft to a greater extent than 5-FU alone. Further investigation revealed that the autophagy induced by 5-FU was inhibited by capsaicin. Moreover, the decrease in AKT and S6 phosphorylation induced by 5-FU was effectively reversed by capsaicin, indicating that capsaicin inhibits 5-FU-induced autophagy by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in CCA cells. Taken together, these results demonstrate that capsaicin may be a useful adjunct therapy to improve chemosensitivity in CCA. This effect likely occurs via PI3K/AKT/mTOR pathway activation, suggesting a promising strategy for the development of combination drugs for CCA. PMID:25933112

  15. Capsaicin Enhances the Drug Sensitivity of Cholangiocarcinoma through the Inhibition of Chemotherapeutic-Induced Autophagy.

    PubMed

    Hong, Zai-Fa; Zhao, Wen-Xiu; Yin, Zhen-Yu; Xie, Cheng-Rong; Xu, Ya-Ping; Chi, Xiao-Qin; Zhang, Sheng; Wang, Xiao-Min

    2015-01-01

    Cholangiocarcinoma (CCA), a devastating cancer with a poor prognosis, is resistant to the currently available chemotherapeutic agents. Capsaicin, the major pungent ingredient found in hot red chili peppers of the genus Capsicum, suppresses the growth of several malignant cell lines. Our aims were to investigate the role and mechanism of capsaicin with respect to the sensitivity of CCA cells to chemotherapeutic agents. The effect of capsaicin on CCA tumor sensitivity to 5-fluorouracil (5-FU) was assessed in vitro in CCA cells and in vivo in a xenograft model. The drug sensitivity of QBC939 to 5-FU was significantly enhanced by capsaicin compared with either agent alone. In addition, the combination of capsaicin with 5-FU was synergistic, with a combination index (CI) < 1, and the combined treatment also suppressed tumor growth in the CCA xenograft to a greater extent than 5-FU alone. Further investigation revealed that the autophagy induced by 5-FU was inhibited by capsaicin. Moreover, the decrease in AKT and S6 phosphorylation induced by 5-FU was effectively reversed by capsaicin, indicating that capsaicin inhibits 5-FU-induced autophagy by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in CCA cells. Taken together, these results demonstrate that capsaicin may be a useful adjunct therapy to improve chemosensitivity in CCA. This effect likely occurs via PI3K/AKT/mTOR pathway activation, suggesting a promising strategy for the development of combination drugs for CCA. PMID:25933112

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

    PubMed Central

    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. PMID:25624758

  17. Use of Targeted Liposome-based Chemotherapeutics to Treat Breast Cancer

    PubMed Central

    Khan, David R; Webb, Maggie N; Cadotte, Thomas H; Gavette, Madison N

    2015-01-01

    The use of nanocarriers such as liposomes to deliver anticancer drugs to tumors can significantly enhance the therapeutic index of otherwise unencapsulated cytotoxic agents. This is in part because of the fact that the phospholipid bilayer can protect healthy sensitive tissue from the damaging effects of these types of drugs. Furthermore, the ease with which the phospholipid bilayer surface can be modified to allow for polyethylene glycol incorporation resulting in pegylated liposomes allow for increased circulation times in vivo, and thus an overall increase in the concentration of the drug delivered to the tumor site. This explains the clinical success of the liposomal-based drug Doxil, which has proven to be quite efficacious in the treatment of breast cancer. However, significant challenges remain involving poor drug transfer between the liposome and tumor cells with this type of nontargeted drug delivery system. Thus, future work involves the development of “smart” drugs, or targeted drug delivery intended for improved colocalization between the drug and cancerous cells. While it is not possible to entirely discuss such a rapidly growing field of study involving many different types of chemotherapeutics here, in this review, we discuss some of the recent advancements involving the development of targeted liposome-based chemotherapeutics to treat breast cancer. PMID:26309409

  18. 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. PMID:25624758

  19. Suppression of PRKAR1A expression enhances anti-proliferative and apoptotic effects of protein kinase inhibitors and chemotherapeutic drugs on cholangiocarcinoma cells.

    PubMed

    Loilome, Watcharin; Juntana, Sirinun; Pinitsoontorn, Chadamas; Namwat, Nisana; Tassaneeyakul, Wichittra; Yongvanit, Puangrat

    2012-01-01

    Suppression of protein kinase A regulatory subunit 1 alpha (PRKAR1A) has been proven to inhibit cholangiocarcinoma (CCA) cell growth and enhance apoptosis. In the present study, we aimed to determine synergistic and/or additive effects of chemotherapeutic agents, including protein kinase inhibitors (i.e. sorafenib, sunitinib, gefitinib, Met inhibitor) and conventional chemotherapeutic drugs (i.e. 5-fluorouracil, doxorubicin, paclitaxel, gemcitabine), in PRKARIA knockdown CCA cell lines. The results revealed that PRKAR1A suppressed CCA cell lines demonstrated enhanced sensitivity to some chemotherapeutic drugs when compared to control cells. Moreover, PRKAR1A knockdown in combination with either sorafenib or 5-fluorouracil increased apoptotic effects on CCA cell lines. Therefore, selective inhibition of PRKAR1A appears to enhance the growth inhibitory effects of chemotherapeutic drugs as well as induce apoptotic cell death. Our findings suggest that additional suppression of PRKAR1A expression may increase the efficacy of conventional CCA chemotherapeutic treatment. Clinical studies in CCA patients now need to be conducted. PMID:23480756

  20. 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

  1. 40 CFR 721.8673 - [(Disubstituted phenyl)]azo dihydro hydroxy alkyl oxo alkyl-substituted-pyridines (generic name).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false azo dihydro hydroxy alkyl oxo alkyl... Significant New Uses for Specific Chemical Substances § 721.8673 azo dihydro hydroxy alkyl oxo alkyl...) The chemical substances identified generically as azo dihydro hydroxy alkyl oxo...

  2. 40 CFR 721.8673 - [(Disubstituted phenyl)]azo dihydro hydroxy alkyl oxo alkyl-substituted-pyridines (generic name).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false azo dihydro hydroxy alkyl oxo alkyl... Significant New Uses for Specific Chemical Substances § 721.8673 azo dihydro hydroxy alkyl oxo alkyl...) The chemical substances identified generically as azo dihydro hydroxy alkyl oxo...

  3. 40 CFR 721.8673 - [(Disubstituted phenyl)]azo dihydro hydroxy alkyl oxo alkyl-substituted-pyridines (generic name).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false azo dihydro hydroxy alkyl oxo alkyl... Significant New Uses for Specific Chemical Substances § 721.8673 azo dihydro hydroxy alkyl oxo alkyl...) The chemical substances identified generically as azo dihydro hydroxy alkyl oxo...

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

    PubMed

    Kevin Baird, J

    2012-12-01

    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

  5. Survivin suppressor (YM155) enhances chemotherapeutic efficacy against canine histiocytic sarcoma in murine transplantation models.

    PubMed

    Yamazaki, Hiroki; Takagi, Satoshi; Hosoya, Kenji; Okumura, Masahiro

    2015-04-01

    Histiocytic sarcoma (HS) in dogs exhibits aggressive clinical and biological behavior. Currently, no effective treatments are available for dogs with HS. Survivin, a member of a family of apoptosis protein inhibitors, could serve as a potential therapeutic target in several canine cancers. Sepantronium bromide (YM155) has recently been established as a novel survivin-targeting agent. The aim of this study was to use YM155 as a tool for evaluating survivin-targeted therapies against dogs with HS, and to investigate how YM155 treatment affects antitumor and chemotherapeutic efficacies in murine xenograft models using canine HS cells. The results showed that in HS cells with lomustine (CCNU) resistance, YM155 treatment suppressed both the cell-growth potential and cell resistance to CCNU, which essentially increases the chemotherapy efficacy in the murine models. The evidence presented here supports the favorable preclinical evaluation that survivin-targeted therapies might be effective against HS in dogs. PMID:25744435

  6. Copper complexes of bis(thiosemicarbazones): from chemotherapeutics to diagnostic and therapeutic radiopharmaceuticals.

    PubMed

    Paterson, Brett M; Donnelly, Paul S

    2011-05-01

    The molecules known as bis(thiosemicarbazones) derived from 1,2-diones can act as tetradentate ligands for Cu(II), forming stable, neutral complexes. As a family, these complexes possess fascinating biological activity. This critical review presents an historical perspective of their progression from potential chemotherapeutics through to more recent applications in nuclear medicine. Methods of synthesis are presented followed by studies focusing on their potential application as anti-cancer agents and more recent investigations into their potential as therapeutics for Alzheimer's disease. The Cu(II) complexes are of sufficient stability to be used to coordinate copper radioisotopes for application in diagnostic and therapeutic radiopharmaceuticals. Detailed understanding of the coordination chemistry has allowed careful manipulation of the metal based properties to engineer specific biological activities. Perhaps the most promising complex radiolabelled with copper radioisotopes to date is Cu(II)(atsm), which has progressed to clinical trials in humans (162 references). PMID:21409228

  7. The use of ultrasound to release chemotherapeutic drugs from micelles and liposomes.

    PubMed

    Ahmed, Salma E; Martins, Ana M; Husseini, Ghaleb A

    2015-01-01

    Several drug delivery systems have been investigated to reduce the side effects of chemotherapy by encapsulating the therapeutic agent in a nanosized carrier until it reaches the tumor site. Many of these particles are designed to be responsive to the mechanical and thermal perturbations delivered by ultrasound. Once the nanoparticle reaches the desired location, ultrasound is applied to release the chemotherapy drug only in the vicinity of the targeted (cancer) site, thus avoiding any detrimental interaction with healthy cells in the body. Studies using liposomes and micelles have shown promising results in this area, as these nanoparticles with simple, yet effective structures, showed high efficiency as drug delivery vehicles both in vitro and in vivo. This article reviews the design and application of two novel nanosized chemotherapeutic carriers (i.e. micelles and liposomes) intended to be actuated by ultrasound. PMID:25203857

  8. Occupational asthma due to alkyl cyanoacrylate

    SciTech Connect

    Nakazawa, T. )

    1990-08-01

    A case of bronchial asthma induced by occupational exposure to alkyl cyanoacrylate, an adhesive, occurred in an assembly operation. Provocative exposure testing induced immediate and delayed asthmatic responses. Alkyl cyanoacrylate seemed to act as an allergen or as an irritant, resulting in the development of asthma.

  9. MITOMYCIN C: CHEMICAL AND BIOLOGICAL STUDIES ON ALKYLATION.

    PubMed

    SCHWARTZ, H S; SODERGREN, J E; PHILIPS, F S

    1963-11-29

    The presence of an aziridine ring in mitomycin C suggests that the mechanism of action of the antibiotic is like that of the antitumor alkylating agents. However the compound is unexpectedly stable during aerobic incubation with rat liver homogenates although rapidly metabolized anaerobically. Mitomycin is not reactive with gamma-(4-nitrobenzyl) pyridine and reacts only slowly at acid p(H) with thiosulfate. It is proposed that mitomycin is activated in vivo, possibly by a reduction which "unmasks" the potential activity of the fused aziridine ring. PMID:14069241

  10. Synthesis and cytotoxic activity of some derivatives of alkyl piperidine.

    PubMed

    Jahan, Sarwat; Akhtar, Shamim; Saify, Zafar Saied; Mushtaq, Nousheen; Sial, Ali Akbar; Kamil, Arfa; Arif, Muhammed

    2013-05-01

    Synthesis of novel phenacyl derivatives of alkyl piperidine as cytotoxic agents via simple and single step reaction procedure is going to be reported here. Twelve new compounds were successfully synthesized in moderate yield and in solid form. Their synthesis was confirmed by TLC, melting point, CHN analysis and through different spectral studies such as UV, IR, Mass and proton NMR. The advantages of this synthetic route are simple operation, mild reaction conditions and good yields. These newly synthesized derivatives were extensively explored for their cytotoxicity by brine shrimp lethality assay. PMID:23625425

  11. Reactions in water: alkyl nitrile coupling reactions using Fenton's reagent.

    PubMed

    Keller, Christopher L; Dalessandro, James D; Hotz, Richard P; Pinhas, Allan R

    2008-05-01

    The coupling reaction of water-soluble alkyl nitriles using Fenton's reagent (Fe(II) and H2O2) is described. The best metal for the reaction is iron(II), and the greatest yields are obtained when the concentration of the metal is kept low. Hydrogen-atom abstraction is selective, preferentially producing the radical alpha to the nitrile. In order to increase the production of dinitrile, in situ reduction of iron(III) to iron(II), using a variety of reducing agents, was investigated. PMID:18363368

  12. Relationships between ablation of distinct haematopoietic cell subsets and the development of donor bone marrow engraftment following recipient pretreatment with different alkylating drugs.

    PubMed Central

    Down, J. D.; Boudewijn, A.; Dillingh, J. H.; Fox, B. W.; Ploemacher, R. E.

    1994-01-01

    A number of different alkylating chemotherapeutic agents--busulphan, dimethylbusulphan (DMB), isopropylmethane sulphonate (IMS), melphalan, cyclophosphamide (CY) and bischloroethylnitrosourea (BCNU)--were investigated for their cytotoxic effects on different haemopoietic cell populations in host mice and for their ability to induce short- and long-term engraftment of transplanted bone marrow. At 24 h after drug treatment the femoral content of transient and permanent repopulating stem cell subsets was assessed, respectively, from the frequency of early- (day 5-15) and late- (day 25-35) developing cobblestone area-forming cells (CAFCs), growing in vitro in long-term bone marrow cultures (LTBMCs). At this time a fixed complement of 10(7) congenically marked donor bone marrow cells (B6-Gpi-1a-->B6-Gpi-1b) was infused in the drug-treated mice and erythroid engraftment was followed over 36 weeks. Diverse effects on early- and late-developing CAFC frequencies were found for the different drugs; these were generally related to the pattern of donor bone marrow engraftment in treated recipients. Melphalan was more toxic to early-developing than to late-developing CAFC subsets, and the transplant only offered an early wave of blood chimerism followed by return of host cells. CY and BCNU had minimal to moderate effects on CAFC content and engraftment with no apparent preference for any particular haemopoietic cell subset. IMS also had a relatively low toxic effect on host marrow CAFC frequencies but appeared exceptional in its ability to allow for more donor-type engraftment. The dimethane sulphonate compounds busulphan and DMB were especially potent at depleting late CAFC subsets and ensured high and lasting levels of donor bone marrow engraftment. These studies support the value of CAFC measurements for predicting the fate and growth of transplanted bone marrow cells in recipients pretreated with a variety of cytotoxic agents. PMID:7917905

  13. Distribution coefficients of purine alkaloids in water-ammonium sulfate-alkyl acetate-dialkyl phthalate systems

    NASA Astrophysics Data System (ADS)

    Korenman, Ya. I.; Krivosheeva, O. A.; Mokshina, N. Ya.

    2012-12-01

    The distribution of purine alkaloids (caffeine, theobromine, theophylline) was studied in the systems: alkyl acetates-dialkyl phtalate-salting-out agent (ammonium sulfate). The quantitative characteristics of the extraction-distribution coefficients ( D) and the degree of extraction ( R, %) are calculated. The relationships between the distribution coefficients of alkaloids and the length of the hydrocarbon radical in the molecule of alkyl acetate (dialkyl phtalate) are determined. The possibility of predicting the distribution coefficients is demonstrated.

  14. C-Alkylation by Hydrogen Autotransfer Reactions.

    PubMed

    Obora, Yasushi

    2016-04-01

    The development of practical, efficient, and atom-economical methods for the formation of carbon-carbon bonds remains a topic of considerable interest in current synthetic organic chemistry. In this review, we have summarized selected topics from the recent literature with particular emphasis on C-alkylation processes involving hydrogen transfer using alcohols as alkylation reagents. This review includes selected highlights concerning recent progress towards the modification of catalytic systems for the α-alkylation of ketones, nitriles, and esters. Furthermore, we have devoted a significant portion of this review to the methylation of ketones, alcohols, and indoles using methanol. Lastly, we have also documented recent advances in β-alkylation methods involving the dimerization of alcohols (Guerbet reaction), as well as new developments in C-alkylation methods based on sp (3) C-H activation. PMID:27573136

  15. Theory Of Alkyl Terminated Silicon Quantum Dots

    SciTech Connect

    Reboredo, F; Galli, G

    2004-08-19

    We have carried out a series of ab-initio calculations to investigate changes in the optical properties of Si quantum dots as a function of surface passivation. In particular, we have compared hydrogen passivated dots with those having alkyl groups at the surface. We find that, while on clusters with reconstructed surfaces a complete alkyl passivation is possible, steric repulsion prevents full passivation of Si dots with unreconstructed surfaces. In addition, our calculations show that steric repulsion may have a dominant effect in determining the surface structure, and eventually the stability of alkyl passivated clusters, with results dependent on the length of the carbon chain. Alkyl passivation weakly affects optical gaps of silicon quantum dots, while it substantially decreases ionization potentials and electron affinities and affect their excited state properties. On the basis of our results we propose that alkyl terminated quantum dots may be size selected taking advantage of the change in ionization potential as a function of the cluster size.

  16. Adsorption of alkyl-dimethyl-benzyl-ammonium chloride on differently pretreated nonwoven cotton substrate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The adsorption of alkyl-dimethyl-benzyl-ammonium chloride (ADBAC), a cationic surfactant commonly employed as an antimicrobial agent, on greige, alkaline scoured, and bleached nonwoven cotton fabrics was investigated at varying surfactant concentrations and liquor ratios using UV-vis absorption spec...

  17. 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

    2016-01-01

    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. PMID:27232632

  18. 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

  19. Culture at a Higher Temperature Mildly Inhibits Cancer Cell Growth but Enhances Chemotherapeutic Effects by Inhibiting Cell-Cell Collaboration

    PubMed Central

    Zhu, Shengming; Wang, Jiangang; Xie, Bingkun; Luo, Zhiguo; Lin, Xiukun; Liao, D. Joshua

    2015-01-01

    Acute febrile infections have historically been used to treat cancer. To explore the underlying mechanism, we studied chronic effects of fever on cancer cell growth and chemotherapeutic efficacy in cell culture. We found that culturing cancer cells at 39°C mildly inhibited cell growth by arresting the cells at the G1 phase of the cell cycle. When cells were seeded in culture dishes at a lower density, e.g. about 1000–2000 cells per 35-mm dish, the growth inhibition was much greater, manifested as many fewer cell colonies in the 39°C dishes, compared with the results at a higher density seeding, e.g. 20,000 cells per dish, suggesting that cell-cell collaboration as the Allee effect in cell culture is inhibited at 39°C. Withdrawal of cells from serum enhanced the G1 arrest at 39°C and, for some cell lines such as A549 lung cancer cells, serum replenishment failed to quickly drive the cells from the G1 into the S and G2-M phases. Therapeutic effects of several chemotherapeutic agents, including clove bud extracts, on several cancer cell lines were more potent at 39°C than at 37°C, especially when the cells were seeded at a low density. For some cell lines and some agents, this enhancement is long-lasting, i.e. continuing after the cessation of the treatment. Collectively these results suggest that hyperthermia may inhibit cancer cell growth by G1 arrest and by inhibition of cell-cell collaboration, and may enhance the efficacy of several chemotherapeutic agents, an effect which may persist beyond the termination of chemotherapy. PMID:26495849

  20. Culture at a Higher Temperature Mildly Inhibits Cancer Cell Growth but Enhances Chemotherapeutic Effects by Inhibiting Cell-Cell Collaboration.

    PubMed

    Zhu, Shengming; Wang, Jiangang; Xie, Bingkun; Luo, Zhiguo; Lin, Xiukun; Liao, D Joshua

    2015-01-01

    Acute febrile infections have historically been used to treat cancer. To explore the underlying mechanism, we studied chronic effects of fever on cancer cell growth and chemotherapeutic efficacy in cell culture. We found that culturing cancer cells at 39°C mildly inhibited cell growth by arresting the cells at the G1 phase of the cell cycle. When cells were seeded in culture dishes at a lower density, e.g. about 1000-2000 cells per 35-mm dish, the growth inhibition was much greater, manifested as many fewer cell colonies in the 39°C dishes, compared with the results at a higher density seeding, e.g. 20,000 cells per dish, suggesting that cell-cell collaboration as the Allee effect in cell culture is inhibited at 39°C. Withdrawal of cells from serum enhanced the G1 arrest at 39°C and, for some cell lines such as A549 lung cancer cells, serum replenishment failed to quickly drive the cells from the G1 into the S and G2-M phases. Therapeutic effects of several chemotherapeutic agents, including clove bud extracts, on several cancer cell lines were more potent at 39°C than at 37°C, especially when the cells were seeded at a low density. For some cell lines and some agents, this enhancement is long-lasting, i.e. continuing after the cessation of the treatment. Collectively these results suggest that hyperthermia may inhibit cancer cell growth by G1 arrest and by inhibition of cell-cell collaboration, and may enhance the efficacy of several chemotherapeutic agents, an effect which may persist beyond the termination of chemotherapy. PMID:26495849

  1. Genome-Wide Local Ancestry Approach Identifies Genes and Variants Associated with Chemotherapeutic Susceptibility in African Americans

    PubMed Central

    Wheeler, Heather E.; Gorsic, Lidija K.; Welsh, Marleen; Stark, Amy L.; Gamazon, Eric R.; Cox, Nancy J.; Dolan, M. Eileen

    2011-01-01

    Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5′-deoxyfluorouridine (5′-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−4). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5′-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−3). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information. PMID:21755009

  2. 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

  3. Alkylation of organic aromatic compounds

    DOEpatents

    Smith, L.A. Jr.; Arganbright, R.P.; Hearn, D.

    1993-01-05

    Aromatic compounds are alkylated in a combination reactor/distillation column comprising a vessel suitable for operating between 70 C and 500 C and from 0.5 to 20 atmospheres pressure; an inert distillation packing in the lower one-third of said vessel; solid acidic catalytic material such as zeolites or an acidic cation exchange resin supported in the middle one-third of said vessel; and inert distillation packing in the upper one-third of said vessel. A benzene inlet is located near the upper end of the vessel; an olefin inlet is juxtaposed with said solid acidic catalytic material; a bottoms outlet is positioned near the bottom of said vessel for removing said cumene and ethyl benzene; and an overhead outlet is placed at the top of said vessel for removing any unreacted benzene and olefin.

  4. Alkylation of organic aromatic compounds

    DOEpatents

    Smith, L.A. Jr.; Arganbright, R.P.; Hearn, D.

    1993-09-07

    Aromatic compounds are alkylated in a catalytic distillation, wherein the catalyst structure also serves as a distillation component by contacting the aromatic compound with a C[sub 2] to C[sub 10] olefin in the catalyst bed under 0.25 to 50 atmospheres of pressure and at temperatures in the range of 80 C to 500 C, using as the catalyst a molecular sieve characterized as acidic or an acidic cation exchange resin. For example, ethyl benzene is produced by feeding ethylene to about the mid point of the catalyst bed while benzene is conveniently added through the reflux in molar excess to that required to react with ethylene, thereby reacting substantially all of the ethylene and recovering benzene as the principal overhead and ethyl benzene in the bottoms. 1 figures.

  5. Alkylation of organic aromatic compounds

    DOEpatents

    Smith, Jr., Lawrence A.; Arganbright, Robert P.; Hearn, Dennis

    1994-01-01

    Aromatic compounds are alkylated in a catalytic distillation, wherein the catalyst structure also serves as a distillation component by contacting the aromatic compound with a C.sub.2 to C.sub.10 olefin in the catalyst bed under 0.25 to 50 atmospheres of pressure and at temperatures in the range of 80.degree. C. to 500.degree. C., using as the catalyst a mole sieve characterized as acidic or an acidic cation exchange resin. For example, ethyl benzene is produced by feeding ethylene below the catalyst bed while benzene is conveniently added through the reflux in molar excess to that required to react with ethylene, thereby reacting substantially all of the ethylene and recovering benzene as the principal overhead and ethyl benzene in the bottoms.

  6. Alkylation of organic aromatic compounds

    DOEpatents

    Smith, L.A. Jr.; Arganbright, R.P.; Hearn, D.

    1994-06-14

    Aromatic compounds are alkylated in a catalytic distillation, wherein the catalyst structure also serves as a distillation component by contacting the aromatic compound with a C[sub 2] to C[sub 10] olefin in the catalyst bed under 0.25 to 50 atmospheres of pressure and at temperatures in the range of 80 C to 500 C, using as the catalyst a molecular sieve characterized as acidic or an acidic cation exchange resin. For example, ethyl benzene is produced by feeding ethylene below the catalyst bed while benzene is conveniently added through the reflux in molar excess to that required to react with ethylene, thereby reacting substantially all of the ethylene and recovering benzene as the principal overhead and ethyl benzene in the bottoms. 1 fig.

  7. Alkylation of organic aromatic compounds

    DOEpatents

    Smith, Jr., Lawrence A.

    1989-01-01

    Aromatic compounds are alkylated in a catalytic distillation, wherein the catalyst structure also serves as a distillation component by contacting the aromatic compound with a C.sub.2 to C.sub.10 olefin in the catalyst bed under 0.25 to 50 atmospheres of pressure and at temperatures in the range of 80.degree. C. to 500.degree. C., using as the catalyst a mole sieve characterized as acidic or an acidic cation exchange resin. For example, ethyl benzene is produced by feeding ethylene below the catalyst bed while benzene is conveniently added through the reflux in molar excess to that required to react with ethylene, thereby reacting substantially all of the ethylene and recovering benzene as the principal overhead and ethyl benzene in the bottoms.

  8. Alkylation of organic aromatic compounds

    DOEpatents

    Smith, Jr., Lawrence A.; Arganbright, Robert P.; Hearn, Dennis

    1993-01-01

    Aromatic compounds are alkylated in a combination reactor/distillation column comprising a vessel suitable for operating between 70.degree. C. and 500.degree. C. and from 0.5 to 20 atmospheres pressure; an inert distillation packing in the lower one-third of said vessel; solid acidic catalytic material such as zeolites or an acidic cation exchange resin supported in the middle one-third of said vessel; and inert distillation packing in the upper one-third of said vessel. A benzene inlet is located near the upper end of the vessel; an olefin inlet is juxtaposed with said solid acidic catalytic material; a bottoms outlet is positioned near the bottom of said vessel for removing said cumene and ethyl benzene; and an overhead outlet is placed at the top of said vessel for removing any unreacted benzene and olefin.

  9. Alkylation of organic aromatic compounds

    DOEpatents

    Smith, Jr., Lawrence A.; Arganbright, Robert P.; Hearn, Dennis

    1993-01-01

    Aromatic compounds are alkylated in a catalytic distillation, wherein the catalyst structure also serves as a distillation component by contacting the aromatic compound with a C.sub.2 to C.sub.10 olefin in the catalyst bed under 0.25 to 50 atmospheres of pressure and at temperatures in the range of 80.degree. C. to 500.degree. C., using as the catalyst a mole sieve characterized as acidic or an acidic cation exchange resin. For example, ethyl benzene is produced by feeding ethylene to about the mid point of the catalyst bed while benzene is conveniently added through the reflux in molar excess to that required to react with ethylene, thereby reacting substantially all of the ethylene and recovering benzene as the principal overhead and ethyl benzene in the bottoms.

  10. Alkylation of organic aromatic compounds

    DOEpatents

    Smith, L.A. Jr.

    1989-07-18

    Aromatic compounds are alkylated in a catalytic distillation, wherein the catalyst structure also serves as a distillation component by contacting the aromatic compound with a C[sub 2] to C[sub 10] olefin in the catalyst bed under 0.25 to 50 atmospheres of pressure and at temperatures in the range of 80 C to 500 C, using as the catalyst a mole sieve characterized as acidic or an acidic cation exchange resin. For example, ethyl benzene is produced by feeding ethylene below the catalyst bed while benzene is conveniently added through the reflux in molar excess to that required to react with ethylene, thereby reacting substantially all of the ethylene and recovering benzene as the principal overhead and ethyl benzene in the bottoms. 1 fig.

  11. Sequence-selective single-molecule alkylation with a pyrrole-imidazole polyamide visualized in a DNA nanoscaffold.

    PubMed

    Yoshidome, Tomofumi; Endo, Masayuki; Kashiwazaki, Gengo; Hidaka, Kumi; Bando, Toshikazu; Sugiyama, Hiroshi

    2012-03-14

    We demonstrate a novel strategy for visualizing sequence-selective alkylation of target double-stranded DNA (dsDNA) using a synthetic pyrrole-imidazole (PI) polyamide in a designed DNA origami scaffold. Doubly functionalized PI polyamide was designed by introduction of an alkylating agent 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) and biotin for sequence-selective alkylation at the target sequence and subsequent streptavidin labeling, respectively. Selective alkylation of the target site in the substrate DNA was observed by analysis using sequencing gel electrophoresis. For the single-molecule observation of the alkylation by functionalized PI polyamide using atomic force microscopy (AFM), the target position in the dsDNA (∼200 base pairs) was alkylated and then visualized by labeling with streptavidin. Newly designed DNA origami scaffold named "five-well DNA frame" carrying five different dsDNA sequences in its cavities was used for the detailed analysis of the sequence-selectivity and alkylation. The 64-mer dsDNAs were introduced to five individual wells, in which target sequence AGTXCCA/TGGYACT (XY = AT, TA, GC, CG) was employed as fully matched (X = G) and one-base mismatched (X = A, T, C) sequences. The fully matched sequence was alkylated with 88% selectivity over other mismatched sequences. In addition, the PI polyamide failed to attach to the target sequence lacking the alkylation site after washing and streptavidin treatment. Therefore, the PI polyamide discriminated the one mismatched nucleotide at the single-molecule level, and alkylation anchored the PI polyamide to the target dsDNA. PMID:22320236

  12. The Interaction of the Chemotherapeutic Drug Chlorambucil with Human Glutathione Transferase A1-1: Kinetic and Structural Analysis

    PubMed Central

    Karpusas, Michael; Axarli, Irine; Chiniadis, Lykourgos; Papakyriakou, Athanasios; Bethanis, Kostas; Scopelitou, Katholiki; Clonis, Yannis D.; Labrou, Nikolaos E.

    2013-01-01

    Glutathione transferases (GSTs) are enzymes that contribute to cellular detoxification by catalysing the nucleophilic attack of glutathione (GSH) on the electrophilic centre of a number of xenobiotic compounds, including several chemotherapeutic drugs. In the present work we investigated the interaction of the chemotherapeutic drug chlorambucil (CBL) with human GSTA1-1 (hGSTA1-1) using kinetic analysis, protein crystallography and molecular dynamics. In the presence of GSH, CBL behaves as an efficient substrate for hGSTA1-1. The rate-limiting step of the catalytic reaction between CBL and GSH is viscosity-dependent and kinetic data suggest that product release is rate-limiting. The crystal structure of the hGSTA1-1/CBL-GSH complex was solved at 2.1 Å resolution by molecular replacement. CBL is bound at the H-site attached to the thiol group of GSH, is partially ordered and exposed to the solvent, making specific interactions with the enzyme. Molecular dynamics simulations based on the crystal structure indicated high mobility of the CBL moiety and stabilization of the C-terminal helix due to the presence of the adduct. In the absence of GSH, CBL is shown to be an alkylating irreversible inhibitor for hGSTA1-1. Inactivation of the enzyme by CBL followed a biphasic pseudo-first-order saturation kinetics with approximately 1 mol of CBL per mol of dimeric enzyme being incorporated. Structural analysis suggested that the modifying residue is Cys112 which is located at the entrance of the H-site. The results are indicative of a structural communication between the subunits on the basis of mutually exclusive modification of Cys112, indicating that the two enzyme active sites are presumably coordinated. PMID:23460799

  13. The efficacy of negative pressure wound therapy on chemotherapeutic extravasation ulcers: An experimental study

    PubMed Central

    Iscı, Evren; Canter, Halil I.; Dadacı, Mehmet; Atılla, Pergin; Cakar, Ayse N.; Kecık, Abdullah

    2014-01-01

    Context: The extravasation of the chemotherapeutic agents is not an unusual phenomenon. Necrosis of the skin and underlying structures has been reported, depending on the cytotoxicity of the extravasating drug. Despite the presence of some antidotes, such wounds tend to enlarge with time and are likely to resist the treatment. Aims: The objective of this study was to investigate the efficacy of negative pressure wound therapy (NPWT) on extravasation ulcers. Settings and Design: Animals were separated into two groups; conventional dressing group and NPWT group. Materials and Methods: Extravasation necrosis was established by intradermal doxorubicin injection. Following the debridement of the necrotic areas, one group of animals was treated with the conventional dressing while NPWT was applied to the other group. The wound areas were measured, and then biopsies were taken on the 3rd, 7th and 14th days after the debridement. Statistical Analysis Used: SPSS 11.5 for Windows was used. Two-way ANOVA test was used to compare wound areas between groups. Willcoxon sign test with Bonferroni correction was used to compare histological scores between groups. Chi-square test with Bonferroni correction was used to compare histological scores within the group between the days. Results: There is no significant difference in terms of inflammatory cell count, neovascularisation, granulation tissue formation between the groups. Contrary to these results wound areas at the end of the treatment were smaller in the NPWT group compared with the dressing group. Conclusion: There is the superiority of NPWT over conventional dressing in chemotherapeutic extravasation wounds as well as the wound area is concerned, but it is not proven histologically. PMID:25593426

  14. Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma

    PubMed Central

    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.

    2013-01-01

    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. PMID:23996800

  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. Combination Chemotherapeutic Dry Powder Aerosols via Controlled Nanoparticle Agglomeration

    PubMed Central

    El-Gendy, Nashwa; Berkland, Cory

    2014-01-01

    Purpose To develop an aerosol system for efficient local lung delivery of chemotherapeutics where nanotechnology holds tremendous potential for developing more valuable cancer therapies. Concurrently, aerosolized chemotherapy is generating interest as a means to treat certain types of lung cancer more effectively with less systemic exposure to the compound. Methods Nanoparticles of the potent anticancer drug, paclitaxel, were controllably assembled to form low density microparticles directly after preparation of the nanoparticle suspension. The amino acid, L-leucine, was used as a colloid destabilizer to drive the assembly of paclitaxel nanoparticles. A combination chemotherapy aerosol was formed by assembling the paclitaxel nanoparticles in the presence of cisplatin in solution. Results Freeze-dried powders of the combination chemotherapy possessed desirable aerodynamic properties for inhalation. In addition, the dissolution rates of dried nanoparticle agglomerate formulations (~60% to 66% after 8 h) were significantly faster than that of micronized paclitaxel powder as received (~18% after 8 h). Interestingly, the presence of the water soluble cisplatin accelerated the dissolution of paclitaxel. Conclusions Nanoparticle agglomerates of paclitaxel alone or in combination with cisplatin may serve as effective chemotherapeutic dry powder aerosols to enable regional treatment of certain lung cancers. PMID:19415471

  17. TIMP3 regulates osteosarcoma cell migration, invasion, and chemotherapeutic resistances.

    PubMed

    Han, Xiu-Guo; Li, Yan; Mo, Hui-Min; Li, Kang; Lin, Du; Zhao, Chang-Qing; Zhao, Jie; Tang, Ting-Ting

    2016-07-01

    Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs) to limit degradation of the extracellular matrix. Low levels of TIMP3 have been demonstrated in cancer tissues at advanced clinical stages, with positive distant metastasis and chemotherapeutic resistance. We examined the role of TIMP3 in osteosarcoma (OS) cell invasiveness and chemoresistance. TIMP3 was overexpressed or knocked down in the human OS cell lines Saos2 and MG63. Cell migration and invasion capacities were then evaluated using Transwell assays, and resistance to cisplatin was assessed by CCK-8 assay and flow cytometry. Real-time PCR and western blotting were used to investigate activation of signaling pathways downstream of TIMP3. Overexpression of TIMP3 inhibited the migration and invasion of Saos2 and MG63 cells, while knockdown of TIMP3 had the opposite effect. Cell survival after exposure to cisplatin was inhibited by TIMP3 overexpression in both Saos2 and MG63 cells. Consistently, downregulation of TIMP3 gene expression significantly decreased the sensitivity of OS cells to cisplatin treatment. MMP1, MMP2, Bcl-2, and Akt1 were all downregulated following TIMP3 overexpression, while Bax and cleaved caspase-3 were upregulated. TIMP3 knockdown had opposite effects on the regulation of these genes. Taken together, our findings suggest TIMP3 as a new target for inhibition of OS progression and chemotherapeutic resistance. PMID:26749283

  18. Methionine depletion with recombinant methioninase: In vitro and in vivo efficacy against neuroblastoma and its synergism with chemotherapeutic drugs

    PubMed Central

    Hu, Jian; Cheung, Nai-Kong V.

    2009-01-01

    Methionine starvation can modulate gene methylation, cell cycle transition, and pathways related to survival following DNA damage. Methionine depletion by recombinant methioninase (rMETase) may have in vitro and in vivo efficacy against neuroblastoma (NB), especially when combined with chemotherapeutic drugs. rMETase from Pseudomonas Putida was produced in E. Coli and purified by ion-exchange chromatography. rMETase alone inhibited the proliferation of 15/15 NB cell lines in vitro. Among these 15 cell lines, only 66N demonstrated rMETase-induced apoptosis. rMETase alone suppressed LAN-1 and NMB-7 xenografts (p<0.01) and no toxicities were noted other than reversible weight loss. In vitro efficacy experiments combining rMETase and chemotherapeutic agents were carried out using SK-N-LD and SK-N-BE(1)N established at diagnosis, as well as LAN-1, SK-N-BE(2)C, and NMB-7 established at relapse. Microtubule depolymerization agents including vincristine, vinorelbine, vinblatine, and mebendazole showed synergism when tested in combination with rMETase in all 5 cell lines. Among DNA damaging agents, synergy with rMETase was observed only in cell lines established at diagnosis, and not at relapse. Cell cycle analysis showed that rMETase arrested G2 phase, and not M phase. In vivo efficacy experiments using LAN-1 and NMB-7 xenografts showed that rMETase rendered vincristine more effective than vincristine alone in tumor growth suppression (p<0.001). In conclusion, methionine depletion inhibited NB proliferation and arrested tumor cells at G2 phase. rMETase synergized with microtubule depolymerization agents. Moreover, synergism between rMETase and DNA damaging agents was dependent on whether cell lines were established at diagnosis or at relapse. PMID:19089915

  19. Process for recovering uranium using an alkyl pyrophosphoric acid and alkaline stripping solution

    SciTech Connect

    Worthington, R.E.; Magdics, A.

    1987-03-24

    A process is described for stripping uranium for a pregnant organic extractant comprising an alkyl pyrophosphoric acid dissolved in a substantially water-immiscible organic diluent. The organic extractant contains tetravalent uranium and an alcohol or phenol modifier in a quantity sufficient to retain substantially all the unhydrolyzed alkyl pyrophosphoric acid in solution in the diluent during stripping. The process comprises adding an oxidizing agent to the organic extractant and thereby oxidizing the tetravalent uranium to the +6 state in the organic extractant, and contacting the organic extractant containing the uranium in the +6 state with a stripping solution comprising an aqueous solution of an alkali metal or ammonium carbonate or hydroxide thereby stripping uranium from the organic extractant into the stripping solution. The resulting barren organic extractant containing substantially all of the unhydrolyzed alkyl pyrophosphoric acid dissolved in the diluent is separated from the stripping solution containing the stripped uranium, the barren extractant being suitable for recycle.

  20. Process for recovering uranium using an alkyl pyrophosphoric acid and alkaline stripping solution

    SciTech Connect

    Worthington, R.E.; Magdics, A.

    1987-03-24

    A process is described for stripping uranium from a pregnant organic extractant comprising an alkyl pyrophosphoric acid dissolved in a substantially water-immiscible organic diluent. The organic extractant contains tetravalent uranium and an alcohol or phenol modifier in a quantity sufficient to retain substantially all the unhydrolyzed alkyl pyrophosphoric acid in solution in the diluent during stripping. The process comprises adding an oxidizing agent to the organic extractant to and thereby oxidizing the tetravalent uranium to the +6 state in the organic extractant, and contacting the organic extractant containing the uranium in the +6 state with a stripping solution comprising an aqueous solution of an alkali metal or ammonium carbonate, nonsaturated in uranium. The uranium is stripped from, the organic extractant into the stripping solution, and the resulting barren organic extractant containing substantially all of the unhydrolyzed alkyl pyrophosphoric acid dissolved in the diluent is separated from the stripping solution containing the stripped uranium, the barren extractant being suitable for recycle.

  1. Thermally induced alkylation of diamond.

    PubMed

    Hoeb, Marco; Auernhammer, Marianne; Schoell, Sebastian J; Brandt, Martin S; Garrido, Jose A; Stutzmann, Martin; Sharp, Ian D

    2010-12-21

    We present an approach for the thermally activated formation of alkene-derived self-assembled monolayers on oxygen-terminated single and polycrystalline diamond surfaces. Chemical modification of the oxygen and hydrogen plasma-treated samples was achieved by heating in 1-octadecene. The resulting layers were characterized using X-ray photoelectron spectroscopy, thermal desorption spectroscopy, atomic force microscopy, Fourier transform infrared spectroscopy, and water contact angle measurements. This investigation reveals that alkenes selectively attach to the oxygen-terminated sites via covalent C-O-C bonds. The hydrophilic oxygen-terminated diamond is rendered strongly hydrophobic following this reaction. The nature of the process limits the organic layer growth to a single monolayer, and FTIR measurements reveal that such monolayers are dense and well ordered. In contrast, hydrogen-terminated diamond sites remain unaffected by this process. This method is thus complementary to the UV-initiated reaction of alkenes with diamond, which exhibits the opposite reactivity contrast. Thermal alkylation increases the range of available diamond functionalization strategies and provides a means of straightforwardly forming single organic layers in order to engineer the surface properties of diamond. PMID:21090790

  2. N-Alkylation by Hydrogen Autotransfer Reactions.

    PubMed

    Ma, Xiantao; Su, Chenliang; Xu, Qing

    2016-06-01

    Owing to the importance of amine/amide derivatives in all fields of chemistry, and also the green and environmentally benign features of using alcohols as alkylating reagents, the relatively high atom economic dehydrative N-alkylation reactions of amines/amides with alcohols through hydrogen autotransfer processes have received much attention and have developed rapidly in recent decades. Various efficient homogeneous and heterogeneous transition metal catalysts, nano materials, electrochemical methods, biomimetic methods, asymmetric N-alkylation reactions, aerobic oxidative methods, and even certain transition metal-free, catalyst-free, or autocatalyzed methods, have also been developed in recent years. With a brief introduction to the background and developments in this area of research, this chapter focuses mainly on recent progress and technical and conceptual advances contributing to the development of this research in the last decade. In addition to mainstream research on homogeneous and heterogeneous transition metal-catalyzed reactions, possible mechanistic routes for hydrogen transfer and alcohol activation, which are key processes in N-alkylation reactions but seldom discussed in the past, the recent reports on computational mechanistic studies of the N-alkylation reactions, and the newly emerged N-alkylation methods based on novel alcohol activation protocols such as air-promoted reactions and transition metal-free methods, are also reviewed in this chapter. Problems and bottlenecks that remained to be solved in the field, and promising new research that deserves greater future attention and effort, are also reviewed and discussed. PMID:27573267

  3. Effect of alkyl glycerophosphate on the activation of peroxisome proliferator-activated receptor gamma and glucose uptake in C2C12 cells

    SciTech Connect

    Tsukahara, Tamotsu; Haniu, Hisao; Matsuda, Yoshikazu

    2013-04-12

    Highlights: •Alkyl-LPA specifically interacts with PPARγ. •Alkyl-LPA treatments induces lipid accumulation in C2C12 cells. •Alkyl-LPA enhanced glucose uptake in C2C12 cells. •Alkyl-LPA-treated C2C12 cells express increased amounts of GLUT4 mRNA. •Alkyl-LPA is a novel therapeutic agent that can be used for the treatment of obesity and diabetes. -- Abstract: Studies on the effects of lipids on skeletal muscle cells rarely examine the effects of lysophospholipids. Through our recent studies, we identified select forms of phospholipids, such as alkyl-LPA, as ligands for the intracellular receptor peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ is a nuclear hormone receptor implicated in many human diseases, including diabetes and obesity. We previously showed that alkyl-LPA is a specific agonist of PPARγ. However, the mechanism by which the alkyl-LPA–PPARγ axis affects skeletal muscle cells is poorly defined. Our objective in the present study was to determine whether alkyl-LPA and PPARγ activation promotes glucose uptake in skeletal muscle cells. Our findings indicate that PPARγ1 mRNA is more abundant than PPARγ2 mRNA in C2C12 cells. We showed that alkyl-LPA (3 μM) significantly activated PPARγ and increased intracellular glucose levels in skeletal muscle cells. We also showed that incubation of C2C12 cells with alkyl-LPA led to lipid accumulation in the cells. These findings suggest that alkyl-LPA activates PPARγ and stimulates glucose uptake in the absence of insulin in C2C12 cells. This may contribute to the plasma glucose-lowering effect in the treatment of insulin resistance.

  4. In vitro testing to a panel of potential chemotherapeutics and current concepts of chemotherapy in benign meningiomas.

    PubMed

    Balik, Vladimir; Sulla, Igor; Park, Hun Ho; Sarissky, Marek

    2015-09-01

    Treatment of benign meningiomas remains a challenge, especially when they involve the skull-base or when surgery and radiation fail. Moreover, a recent in vitro MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) study testing hydroxyurea, temozolomide and other targeting agents failed to identify drugs effective in their treatment; therefore the search for further more effective agents continues. We performed a thorough review of in vitro investigations, animal studies and human clinical trials and endeavoured to integrate our results of MTT assay into current concepts of chemotherapy in benign meningiomas. Our results demonstrated that other chemotherapeutics with various mechanisms of action have the potential to be incorporated into second line therapy. Our study shows for the first time that chemosensitivity/resistance may be associated with histopathological variants of benign meningiomas. PMID:26099192

  5. Alkyl rearrangement processes in organozirconium complexes. Observation of internal alkyl complexes during hydrozirconation

    SciTech Connect

    Chirik, P.J.; Day, M.W.; Labinger, J.A.; Bercaw, J.E.

    1999-11-10

    Isotopically labeled alkyl zirconocene complexes of the form (CpR{sub n}){sub 2}Zr(CH{sub 2}CDR{sub 2}{prime})(X) (CpR{sub n} = alkyl-substituted cyclopentadienyl; R{prime} = H, alkyl group; X = H, D, Me) undergo isomerization of the alkyl ligand as well as exchange with free olefin in solution under ambient conditions. Increasing the substitution on the Cp ring results in slower isomerization reactions, but these steric effects are small. In contrast, changing X has a very large effect on the rate of isomerization. Pure {sigma}-bonding ligands such as methyl and hydride promote rapid isomerization, whereas {pi}-donor ligands inhibit {beta}-H elimination and hence alkyl isomerization. For ({eta}{sup 5}-C{sub 5}H{sub 5}){sub 2}Zr(R)(Cl), internal alkyl complexes have been observed for the first time. The rate of isomerization depends on the length of the alkyl group: longer alkyl chains (heptyl, hexyl) isomerize faster than shorter chains (butyl). The transient intermediate species have been identified by a combination of isotopic labeling and {sup 1}H, {sup 2}H, and {sup 13}C NMR experiments. The solid-state structure of the zirconocene cyclopentyl chloride complex, Cp{sub 2}Zr(cyclo-C{sub 5}H{sub 9})(Cl), has been determined by X-ray diffraction.

  6. Blend of alkyl phenol ethoxylates and alkyl phenol glycoxylates and their use as surfactants

    SciTech Connect

    Grolitzer, M. A.

    1985-11-12

    Nonionic surfactant compositions useful in forming stable emulsions with oil in saline solutions comprising a blend of: at least one alkyl phenol ethoxylate and at least one alkyl phenol glycoxylate. These surfactant compositions may be employed in enhanced oil recovery processes and other applications where good emulsification and high salinity tolerances are required such as textiles, leather, dairy, concrete grinding aids and drilling muds.

  7. Cisplatin@US-tube Carbon Nanocapsules For Enhanced Chemotherapeutic Delivery

    PubMed Central

    Guven, Adem; Rusakova, Irene A.; Lewis, Michael T.; Wilson, Lon J.

    2012-01-01

    The use of chemotherapeutic drugs in cancer therapy is often limited by problems with administration such as insolubility, inefficient biodistribution, lack of selectivity, and inability of the drug to cross cellular barriers. To overcome these limitations, various types of drug delivery systems have been explored, and recently, carbon nanotube (CNT) materials have also garnered attention in the area of drug delivery. In this study, we describe the preparation, characterization, and in vitro testing of a new ultra-short single-walled carbon nanotube (US-tube)-based drug delivery system for the treatment of cancer. In particular, the encapsulation of cisplatin (CDDP), a widely-used anticancer drug, within US-tubes has been achieved, and the resulting CDDP@US-tube material characterized by high-resolution transmission electron microscopy (HR-TEM), energy-dispersive spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), and inductively-coupled optical emission spectrometry (ICP-OES). Dialysis studies performed in phosphate-buffered saline (PBS) at 37 °C have demonstrated that CDDP release from CDDP@US-tubes can be controlled (retarded) by wrapping the CDDP@US-tubes with Pluronic-F108 surfactant. Finally, the anticancer activity of pluronic-wrapped CDDP@US-tubes has been evaluated against two different breast cancer cell lines, MCF-7 and MDA-MB-231, and found to exhibit enhanced cytotoxicity over free CDDP after 24 hours. These studies have laid the foundation for developing US-tube-based delivery of chemotherapeutics, with drug release mainly limited to within cancer cells only. PMID:22078812

  8. Alkylation of isobutane with light olefins: Yields of alkylates for different olefins

    SciTech Connect

    Albright, L.F.; Kranz, K.E.; Masters, K.R.

    1993-12-01

    For alkylation of isobutane with C{sub 3}-C{sub 5} olefins using sulfuric acid as the catalyst, the yields of alkylates with different olefins are compared as the operating conditions are changed. The results of recent pilot plant experiments with propylene, C{sub 4} olefins, and C{sub 5} olefins permit such comparisons. The yields expressed as weight of alkylate produced per 100 wt of olefin consumed varied from about 201:100 to 220:100. Weight ratios of the isobutane consumed per olefin consumed vary from about 101:100 to 120:100. differences of yield values are explained by the changes in the overall chemistry. The procedure employed to calculate yields with good accuracy is based on the analysis of the alkylate and the amount of conjunct polymers produced. Based on literature data, yields are also reported for alkylations using HF as the catalyst.

  9. Structure and DNA binding of alkylation response protein AidB

    SciTech Connect

    Bowles, Timothy; Metz, Audrey H.; O'Quin, Jami; Wawrzak, Zdzislaw; Eichman, Brandt F.

    2009-01-12

    Exposure of Escherichia coli to alkylating agents activates expression of AidB in addition to DNA repair proteins Ada, AlkA, and AlkB. AidB was recently shown to possess a flavin adenine dinucleotide (FAD) cofactor and to bind to dsDNA, implicating it as a flavin-dependent DNA repair enzyme. However, the molecular mechanism by which AidB acts to reduce the mutagenic effects of specific DNA alkylators is unknown. We present a 1.7-{angstrom} crystal structure of AidB, which bears superficial resemblance to the acyl-CoA dehydrogenase superfamily of flavoproteins. The structure reveals a unique quaternary organization and a distinctive FAD active site that provides a rationale for AidB's limited dehydrogenase activity. A highly electropositive C-terminal domain not present in structural homologs was identified by mutational analysis as the DNA binding site. Structural analysis of the DNA and FAD binding sites provides evidence against AidB-catalyzed DNA repair and supports a model in which AidB acts to prevent alkylation damage by protecting DNA and destroying alkylating agents that have yet to reach their DNA target.

  10. 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. PMID:1518040

  11. Acquisition of anoikis resistance in human osteosarcoma cells does not alter sensitivity to chemotherapeutic agents

    PubMed Central

    Díaz-Montero, C Marcela; McIntyre, Bradley W

    2005-01-01

    Background Chemotherapy-induced cell death can involve the induction of apoptosis. Thus, aberrant function of the pathways involved might result in chemoresistance. Since cell adhesion to the extracellular matrix acts as a survival factor that homeostatically maintains normal tissue architecture, it was tested whether acquisition of resistance to deadhesion-induced apoptosis (anoikis) in human osteosarcoma would result in resistance to chemotherapy. Methods Osteosarcoma cell lines (SAOS-2 and TE-85) obtained from ATCC and were maintained in complete Eagle's MEM medium. Suspension culture was established by placing cells in tissue culture wells coated with poly-HEMA. Cell cytotoxicity was determined using a live/dead cytotoxicity assay. Cell cycle/apoptosis analyses were performed using propidium iodide (PI) staining with subsequent FACS analysis. Apoptosis was also assayed by Annexin-FITC/PI staining. Results Etoposide, adriamycin, vinblastine, cisplatin and paclitaxel were able to induce apoptosis in human osteosarcoma cells SAOS-2 regardless of their anoikis resistance phenotype or the culture conditions (adhered vs. suspended). Moreover, suspended anoikis resistant TE-85 cells (TE-85ar) retained their sensitivity to chemotherapy as well. Conclusion Acquisition of anoikis resistance in human osteosarcoma cells does not result in a generalized resistance to all apoptotic stimuli, including chemotherapy. Moreover, our results suggest that the pathways regulating anoikis resistance and chemotherapy resistance might involve the action of different mediators. PMID:15829011

  12. 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

  13. MULTIDRUG RESISTANT TRANSPORT ACTIVITY PROTECTS OOCYTES FROM CHEMOTHERAPEUTIC AGENTS AND CHANGES DURING OOCYTE MATURATION

    PubMed Central

    Brayboy, Lynae M.; Oulhen, Nathalie; Witmyer, Jeannine; Robins, Jared; Carson, Sandra; Wessel, Gary M.

    2013-01-01

    Objective To determine the multidrug resistant (MDR) transporter activity in oocytes and their potential role in oocyte susceptibility to chemotherapy. Design Experimental laboratory study Setting University and Academic Center for reproductive medicine. Patients/Animals Women with eggs retrieved for ICSI cycles and adult female FVBN and B6C3F1 mouse strains. Intervention Inhibition of MDR activity in oocytes. Main Outcome measure(s) Efflux activity of MDRs using quantitative fluorescent dye efflux and oocyte cell death when exposed to chemotherapy. Results Oocytes effluxed fluorescent reporters and this activity was significantly reduced in the presence of the MDR inhibitor PSC 833. GV oocytes are more efficient at efflux compared to M2 oocytes. Human oocytes exposed to cyclophosphamide and PSC 833 showed cell death using two different viability assays compared to controls and those exposed to cyclophosphamide alone. Immunoblots detected MDR-1 in all oocytes with the greatest accumulation in the GV stage. Conclusions Oocytes have a vast repertoire of active MDRs. The implications of this study are that these protective mechanisms are important during oogenesis, and these activities change with maturation, increasing susceptibility to toxicants. Future directions may exploit the up regulation of these transporters during gonadotoxic therapy. PMID:23953328

  14. 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

  15. 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

  16. A systematic review of pentacyclic triterpenes and their derivatives as chemotherapeutic agents against tropical parasitic diseases.

    PubMed

    Isah, Murtala Bindawa; Ibrahim, Mohammed Auwal; Mohammed, Aminu; Aliyu, Abubakar Babando; Masola, Bubuya; Coetzer, Theresa H T

    2016-09-01

    Parasitic infections are among the leading global public health problems with very high economic and mortality burdens. Unfortunately, the available treatment drugs are beset with side effects and continuous parasite drug resistance is being reported. However, new findings reveal more promising compounds especially of plant origin. Among the promising leads are the pentacyclic triterpenes (PTs) made up of the oleanane, ursane, taraxastane, lupane and hopane types. This paper reviews the literature published from 1985 to date on the in vitro and in vivo anti-parasitic potency of this class of phytochemicals. Of the 191 natural and synthetic PT reported, 85 have shown high anti-parasitic activity against various species belonging to the genera of Plasmodium, Leishmania, Trypanosoma, as well as various genera of Nematoda. Moreover, structural modification especially at carbon 3 (C3) and C27 of the parent backbone of PT has led to improved anti-parasitic activity in some cases and loss of activity in others. The potential of this group of compounds as future alternatives in the treatment of parasitic diseases is discussed. It is hoped that the information presented herein will contribute to the full exploration of this promising group of compounds as possible drugs for parasitic diseases. PMID:27240847

  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

    2016-01-01

    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

  18. KAP1 dictates p53 response induced by chemotherapeutic agents via Mdm2 interaction

    SciTech Connect

    Okamoto, Koji . E-mail: kojokamo@gan2.res.ncc.go.jp; Kitabayashi, Issay; Taya, Yoichi . E-mail: ytaya@gan2.res.ncc.go.jp

    2006-12-08

    KAP1 recruits many proteins involved in gene silencing and functions as an integral part of co-repressor complex. KAP1 was identified as Mdm2-binding protein and shown to form a complex with Mdm2 and p53 in vivo. We examined the role of KAP1 in p53 activation after the treatment of cells with different types of external stresses. KAP1 reduction markedly enhanced the induction of p21, a product of the p53 target gene, after treatment with actinomycin D or {gamma}-irradiation, but not with camptothecin. Treatment with actinomycin D, but not with camptothecin, augmented the interaction of p53 with Mdm2 and KAP1. Further, KAP1 reduction in actinomycin D-treated cells facilitated cell cycle arrest and negatively affected clonal cell growth. Thus, the reduction of KAP1 levels promotes p53-dependent p21 induction and inhibits cell proliferation in actinomycin D-treated cells. KAP1 may serve as a therapeutic target against cancer in combination with actinomycin D.

  19. Mycophenolic Acid and Its Derivatives as Potential Chemotherapeutic Agents Targeting Inosine Monophosphate Dehydrogenase in Trypanosoma congolense.

    PubMed

    Suganuma, Keisuke; Sarwono, Albertus Eka Yudistira; Mitsuhashi, Shinya; Jąkalski, Marcin; Okada, Tadashi; Nthatisi, Molefe; Yamagishi, Junya; Ubukata, Makoto; Inoue, Noboru

    2016-07-01

    This study aimed to evaluate the trypanocidal activity of mycophenolic acid (MPA) and its derivatives for Trypanosoma congolense The proliferation of T. congolense was completely inhibited by adding <1 μM MPA and its derivatives. In addition, the IMP dehydrogenase in T. congolense was molecularly characterized as the target of these compounds. The results suggest that MPA and its derivatives have the potential to be new candidates as novel trypanocidal drugs. PMID:27139487

  20. Chemotherapeutic response to cisplatin-like drugs in human breast cancer cells probed by vibrational microspectroscopy.

    PubMed

    Batista de Carvalho, A L M; Pilling, M; Gardner, P; Doherty, J; Cinque, G; Wehbe, K; Kelley, C; Batista de Carvalho, L A E; Marques, M P M

    2016-06-23

    Studies of drug-cell interactions in cancer model systems are essential in the preclinical stage of rational drug design, which relies on a thorough understanding of the mechanisms underlying cytotoxic activity and biological effects, at a molecular level. This study aimed at applying complementary vibrational spectroscopy methods to evaluate the cellular impact of two Pt(ii) and Pd(ii) dinuclear chelates with spermine (Pt2Spm and Pd2Spm), using cisplatin (cis-Pt(NH3)2Cl2) as a reference compound. Their effects on cellular metabolism were monitored in a human triple-negative metastatic breast cancer cell line (MDA-MB-231) by Raman and synchrotron-radiation infrared microspectroscopies, for different drug concentrations (2-8 μM) at 48 h exposure. Multivariate data analysis was applied (unsupervised PCA), unveiling drug- and concentration-dependent effects: apart from discrimination between control and drug-treated cells, a clear separation was obtained for the different agents studied - mononuclear vs. polynuclear, and Pt(ii) vs. Pd(ii). Spectral biomarkers of drug action were identified, as well as the cellular response to the chemotherapeutic insult. The main effect of the tested compounds was found to be on DNA, lipids and proteins, the Pd(ii) agent having a more significant impact on proteins while its Pt(ii) homologue affected the cellular lipid content at lower concentrations, which suggests the occurrence of distinct and unconventional pathways of cytotoxicity for these dinuclear polyamine complexes. Raman and FTIR microspectroscopies were confirmed as powerful non-invasive techniques to obtain unique spectral signatures of the biochemical impact and physiological reaction of cells to anticancer agents. PMID:27063935

  1. Molecular mechanisms of alkylation sensitivity in Indian muntjac cell lines.

    PubMed

    Musk, S R; Hatton, D H; Bouffler, S D; Margison, G P; Johnson, R T

    1989-07-01

    The responses of two Indian muntjac cell lines to two monofunctional alkylating agents were investigated. An SV40-transformed line (SVM) had an increased sensitivity to cell killing when compared to the other, euploid line (DM) after exposure both to methyl nitrosourea (MNU) and to dimethylsulphate (DMS) and also exhibited higher frequencies of sister chromatid exchanges (SCEs) following alkylation. The hypersensitivity of SVM to DMS correlates with the defective repair of single-strand breaks that results in the generation of long-lived breaks in the DNA following exposure, leading eventually to the formation of chromosome aberrations. In contrast no difference is seen in the formation of long-lived breaks in the DNA of SVM and DM after treatment with biologically relevant doses of MNU; in this case hypersensitivity may be due to the loss of O6-alkylguanine-DNA-alkyltransferase activity. The conclusion that the hypersensitivites of SVM to MNU and to DMS have different molecular bases is supported by transfection of SVM with plasmids containing the protein coding region of the Escherichia coli ada+ gene; subsequent expression within the cell corrects its hypersensitivity to the cytotoxic and SCE-inducing effects of MNU but has very little influence upon the lethality, SCE induction or the repair of long-lived DNA strand breaks after exposure to DMS. PMID:2544312

  2. Antibacterial Activity of Alkyl Gallates against Xanthomonas citri subsp. citri

    PubMed Central

    Silva, I. C.; Regasini, L. O.; Petrônio, M. S.; Silva, D. H. S.; Bolzani, V. S.; Belasque, J.; Sacramento, L. V. S.

    2013-01-01

    The plant-pathogenic bacterium Xanthomonas citri subsp. citri is the causal agent of Asiatic citrus canker, a serious disease that affects all the cultivars of citrus in subtropical citrus-producing areas worldwide. There is no curative treatment for citrus canker; thus, the eradication of infected plants constitutes the only effective control of the spread of X. citri subsp. citri. Since the eradication program in the state of São Paulo, Brazil, is under threat, there is a clear risk of X. citri subsp. citri becoming endemic in the main orange-producing area in the world. Here we evaluated the potential use of alkyl gallates to prevent X. citri subsp. citri growth. These esters displayed a potent anti-X. citri subsp. citri activity similar to that of kanamycin (positive control), as evaluated by the resazurin microtiter assay (REMA). The treatment of X. citri subsp. citri cells with these compounds induced altered cell morphology, and investigations of the possible intracellular targets using X. citri subsp. citri strains labeled for the septum and centromere pointed to a common target involved in chromosome segregation and cell division. Finally, the artificial inoculation of citrus with X. citri subsp. citri cells pretreated with alkyl gallates showed that the bacterium loses the ability to colonize its host, which indicates the potential of these esters to protect citrus plants against X. citri subsp. citri infection. PMID:23104804

  3. Alkyl phosphonic acids and sulfonic acids in the Murchison meteorite

    NASA Technical Reports Server (NTRS)

    Cooper, George W.; Onwo, Wilfred M.; Cronin, John R.

    1992-01-01

    Homologous series of alkyl phosphonic acids and alkyl sulfonic acids, along with inorganic orthophosphate and sulfate, are identified in water extracts of the Murchison meteorite after conversion to their t-butyl dimethylsilyl derivatives. The methyl, ethyl, propyl, and butyl compounds are observed in both series. Five of the eight possible alkyl phosphonic acids and seven of the eight possible alkyl sulfonic acids through C4 are identified. Abundances decrease with increasing carbon number as observed of other homologous series indigenous to Murchison. Concentrations range downward from approximately 380 nmol/gram in the alkyl sulfonic acid series, and from 9 nmol/gram in the alkyl phosphonic acid series.

  4. Co-administration of epithelial junction opener JO-1 improves the efficacy and safety of chemotherapeutic drugs

    PubMed Central

    Beyer, Ines; Cao, Hua; Persson, Jonas; Song, Hui; Richter, Maximilian; Feng, Qinghua; Yumul, Roma; van Rensburg, Ruan; Li, Zongyi; Berenson, Ronald; Carter, Darrick; Roffler, Steve; Drescher, Charles; Lieber, André

    2013-01-01

    Purpose Epithelial junctions between tumor cells inhibit the penetration of anti-cancer drugs into tumors. We previously reported on recombinant adenovirus serotype 3 derived protein (JO-1), which triggers transient opening of intercellular junctions in epithelial tumors through binding to desmoglein 2 (DSG2), and enhances the anti-tumor effects of several therapeutic monoclonal antibodies. The goal of this study was to evaluate whether JO-1 co-therapy can also improve the efficacy of chemotherapeutic drugs. Experimental Design The effect of intravenous application of JO-1 in combination with several chemotherapy drugs including paclitaxel/Taxol™, nanoparticle albumin bound paclitaxel/Abraxane™, liposomal doxorubicin/Doxil™ and irinotecan/Camptosar™, was tested in xenograft models for breast, colon, ovarian, gastric and lung cancer. Because JO-1 does not bind to mouse cells, for safety studies with JO-1, we also used human DSG2 (hDSG2) transgenic mice with tumors that overexpressed human DSG2. Results JO-1 increased the efficacy of chemotherapeutic drugs, and in several models overcame drug resistance. JO-1 treatment also allowed for the reduction of drug doses required to achieve anti-tumor effects. Importantly, JO-1 co-admininstration protected normal tissues, including bone marrow and intestinal epithelium, against toxic effects that are normally associated with chemotherapeutic agents. Using the hDSG2 transgenic mouse model, we demonstrated that JO-1 predominantly accumulates in tumors. Except for a mild, transient diarrhea, intravenous injection of JO-1 (2mg/kg) had no critical side effects on other tissues or hematological parameters in hDSG2-transgenic mice. Conclusions Our preliminary data suggest that JO-1 co-therapy has the potential to improve the therapeutic outcome of cancer chemotherapy. PMID:22535153

  5. Synthesis of Norbornane Bisether Antibiotics via Silver-mediated Alkylation

    PubMed Central

    Hickey, Shane M.; Ashton, Trent D.; White, Jonathan M.; Li, Jian; Nation, Roger L.; Yu, Heidi Y.; Elliott, Alysha G.; Butler, Mark S.; Huang, Johnny X.; Cooper, Matthew A.

    2015-01-01

    A small series of norbornane bisether diguanidines have been synthesized and evaluated as antibacterial agents. The key transformation—bisalkylation of norbornane diol 6—was not successful using Williamson methodology but has been accomplished using Ag2O mediated alkylation. Further functionalization to incorporate two guanidinium groups gave rise to a series of structurally rigid cationic amphiphiles; several of which (16d, 16g and 16h) exhibited antibiotic activity. For example, compound 16d was active against a broad range of bacteria including Pseudomonas aeruginosa (MIC = 8 µg/mL), Escherichia coli (MIC = 8 µg/mL) and methicillin-resistant Staphylococcus aureus (MIC = 8 µg/mL). PMID:26251697

  6. Palladium-Catalyzed, Ring-Forming Aromatic C–H Alkylations with Unactivated Alkyl Halides

    PubMed Central

    Venning, Alexander R. O.; Bohan, Patrick T.; Alexanian, Erik J.

    2015-01-01

    A catalytic C–H alkylation using unactivated alkyl halides and a variety of arenes and heteroarenes is described. This ring-forming process is successful with a variety of unactivated primary and secondary alkyl halides, including those with β-hydrogens. In contrast to standard polar or radical cyclizations of aromatic systems, electronic activation of the substrate is not required. The mild, catalytic reaction conditions are highly functional group tolerant and facilitate access to a diverse range of synthetically and medicinally important carbocyclic and heterocyclic systems. PMID:25746442

  7. Pharmacokinetics of Chemotherapeutic Drugs in Pediatric Patients With Down Syndrome and Leukemia.

    PubMed

    Hefti, Erik; Blanco, Javier G

    2016-05-01

    Children with Down syndrome (DS) have a 10- to 30-fold increased risk of developing acute myeloid leukemia or acute lymphoblastic leukemia. Patients with DS and leukemia are treated with the same chemotherapeutic agents as patients without DS. Treatment regimens for pediatric leukemia comprise multiple cytotoxic drugs including methotrexate, doxorubicin, vincristine, cytarabine, and etoposide. There have been reports of increased toxicity, as well as altered therapeutic outcomes in pediatric patients with DS and leukemia. This review is focused on the pharmacokinetics of cytotoxic drugs in pediatric patients with leukemia and DS. The available literature suggests that methotrexate and thioguanine display altered pharmacokinetic parameters in pediatric patients with DS. It has been hypothesized that the variable pharmacokinetics of these drugs may contribute to the increased incidence of treatment-related toxicities seen in DS. Data from a small number of studies suggest that the pharmacokinetics of vincristine, etoposide, doxorubicin, and busulfan are similar between patients with and without DS. Definitive conclusions regarding the pharmacokinetics of cytotoxic drugs in pediatric patients with leukemia and DS are difficult to reach due to limitations in the available studies. PMID:26907658

  8. The structure-activity relationships of the antiviral chemotherapeutic activity of isatin β-thiosemicarbazone

    PubMed Central

    Bauer, D. J.; Sadler, P. W.

    1960-01-01

    As part of an investigation devoted to the development of new antiviral agents a compound of established antiviral activity has been subjected to systematic structural modification. The structure-activity data so obtained have been used in the design of new compounds, some of which are described. The compound chosen was isatin β-thiosemicarbazone, which has high activity against neurovaccinia infection in mice, and a 4-point parallel-line assay of in vivo chemotherapeutic activity has been developed, which has enabled the activity of the derivatives to be determined against isatin β-thiosemicarbazone as a standard. The overall dimensions of the isatin β-thiosemicarbazone molecule appear to be nearly maximal for the retention of high activity, as all substituents in the aromatic ring decrease the activity irrespective of their nature or position. The projection of the -CS.NH2 group in relation to the ring nitrogen was found to be critical, as the α-thiosemicarbazone was inactive. A number of modifications of the side-chain were investigated:all led to reduction or loss of antiviral activity. The antiviral activity showed a positive correlation with chloroform solubility over a considerable range. The most active compound encountered was 1-ethylisatin β-thiosemicarbazone, with an activity of 286 (isatin β-thiosemicarbazone≡100). Isatin β-thiosemicarbazone showed no activity against 15 other viruses, and 20 related compounds showed on activity against ectromelia. PMID:13797622

  9. Assessment of the chemotherapeutic potential of a new camptothecin derivative, ZBH-1205.

    PubMed

    Wu, Di; Shi, Weiguo; Zhao, Jing; Wei, Zhengren; Chen, Zhijia; Zhao, Dawei; Lan, Shijie; Tai, Jiandong; Zhong, Bohua; Yu, Hong

    2016-08-15

    CPT-11 (irinotecan) is a derivative of camptothecin which is a natural product derived from the Chinese tree Camptotheca acuminta and widely used in antitumor therapy. Here, the in vitro anti-tumor activity and associated mechanisms of a novel derivative of camptothecin, ZBH-1205, were investigated in a panel of 9 human tumor cell lines, as well as in HEK 293 and SK-OV-3/DPP, a multi-drug resistant (MDR) cell line, and compared to CPT-11 and 7-ethyl-10-hydroxy-camptothecin (SN38). Comparisons between the different compounds were made on the basis of IC50 values as determined by the MTT assay, and flow cytometry was used to evaluate cell cycle progression, apoptosis, and the levels of pro- and active caspase-3 among different treatment groups. Interaction between the molecules and topoisomerase-1 (Topo-1)-DNA complexes was detected by a DNA relaxation assay. Our results demonstrated that IC50 values for ZBH-1205 ranged from 0.0009 μmol/L to 2.5671 μmol/L, which were consistently lower than IC50 values of CPT-11 or SN38 in the panel of cell lines, including SK-OV-3/DPP. Furthermore, ZBH-1205 was more effective than CPT-11 or SN38 at stabilizing Topo-1-DNA complexes and inducing tumor cell apoptosis. Therefore, ZBH-1205 is a promising chemotherapeutic agent to be further assessed in large-scale clinical trials. PMID:27302903

  10. 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

  11. Enhancement of alkylation catalysts for improved supercritical fluid regeneration

    DOEpatents

    Ginosar, Daniel M.; Petkovic, Lucia

    2009-09-22

    A method of modifying an alkylation catalyst to reduce the formation of condensed hydrocarbon species thereon. The method comprises providing an alkylation catalyst comprising a plurality of active sites. The plurality of active sites on the alkylation catalyst may include a plurality of weakly acidic active sites, intermediate acidity active sites, and strongly acidic active sites. A base is adsorbed to a portion of the plurality of active sites, such as the strongly acidic active sites, selectively poisoning the strongly acidic active sites. A method of modifying the alkylation catalyst by providing an alkylation catalyst comprising a pore size distribution that sterically constrains formation of the condensed hydrocarbon species on the alkylation catalyst or by synthesizing the alkylation catalyst to comprise a decreased number of strongly acidic active sites is also disclosed, as is a method of improving a regeneration efficiency of the alkylation catalyst.

  12. Enhancement of alkylation catalysts for improved supercritical fluid regeneration

    DOEpatents

    Ginosar, Daniel M.; Petkovic, Lucia M.

    2010-12-28

    A method of modifying an alkylation catalyst to reduce the formation of condensed hydrocarbon species thereon. The method comprises providing an alkylation catalyst comprising a plurality of active sites. The plurality of active sites on the alkylation catalyst may include a plurality of weakly acidic active sites, intermediate acidity active sites, and strongly acidic active sites. A base is adsorbed to a portion of the plurality of active sites, such as the strongly acidic active sites, selectively poisoning the strongly acidic active sites. A method of modifying the alkylation catalyst by providing an alkylation catalyst comprising a pore size distribution that sterically constrains formation of the condensed hydrocarbon species on the alkylation catalyst or by synthesizing the alkylation catalyst to comprise a decreased number of strongly acidic active sites is also disclosed, as is a method of improving a regeneration efficiency of the alkylation catalyst.

  13. Interleukin 6 augments lung cancer chemotherapeutic resistance via ataxia-telangiectasia mutated/NF-kappaB pathway activation

    PubMed Central

    Yan, Hong Qiong; Huang, Xiao Bo; Ke, Shi Zhong; Jiang, Yi Na; Zhang, Yue Hua; Wang, Yi Nan; Li, Juan; Gao, Feng Guang

    2014-01-01

    Although it is known that ataxia-telangiectasia mutated (ATM) and interleukin 6 (IL-6) contribute to multiple drug resistance (MDR) in tumor chemotherapy, the exact role of ATM activation in MDR resulting from increased IL-6 expression is still unclear. In the present study, we demonstrate that the activation of the ATM-NF-kappaB pathway, resulting from increased IL-6 expression, plays a central role in augmented chemoresistance in lung cancer cell lines. This result was supported by the increased expressions of Bcl-2, Mcl-1, Bcl-xl, and the upregulation of MDR-associated protein ABCG2. The higher level of IL-6 reveals not only higher ATM/NF-kappaB activity but also increased expressions of ABCG2, Bcl-2, Mcl-1 and Bcl-xl. Most importantly, lung cancer cells themselves upregulated IL-6 secretion by activating the p38/NF-kappaB pathway through treatment with cisplatin and camptothecin. Taken together, these findings demonstrate that chemotherapeutic agents increase IL-6 expression, hence activating the ATM/NF-kappaB pathway, augmenting anti-apoptotic protein expression and contributing to MDR. This indicates that both IL-6 and ATM are potential targets for the treatment of chemotherapeutic resistance in lung cancer. PMID:24988892

  14. Interleukin 6 augments lung cancer chemotherapeutic resistance via ataxia-telangiectasia mutated/NF-kappaB pathway activation.

    PubMed

    Yan, Hong Qiong; Huang, Xiao Bo; Ke, Shi Zhong; Jiang, Yi Na; Zhang, Yue Hua; Wang, Yi Nan; Li, Juan; Gao, Feng Guang

    2014-09-01

    Although it is known that ataxia-telangiectasia mutated (ATM) and interleukin 6 (IL-6) contribute to multiple drug resistance (MDR) in tumor chemotherapy, the exact role of ATM activation in MDR resulting from increased IL-6 expression is still unclear. In the present study, we demonstrate that the activation of the ATM-NF-kappaB pathway, resulting from increased IL-6 expression, plays a central role in augmented chemoresistance in lung cancer cell lines. This result was supported by the increased expressions of Bcl-2, Mcl-1, Bcl-xl, and the upregulation of MDR-associated protein ABCG2. The higher level of IL-6 reveals not only higher ATM/NF-kappaB activity but also increased expressions of ABCG2, Bcl-2, Mcl-1 and Bcl-xl. Most importantly, lung cancer cells themselves upregulated IL-6 secretion by activating the p38/NF-kappaB pathway through treatment with cisplatin and camptothecin. Taken together, these findings demonstrate that chemotherapeutic agents increase IL-6 expression, hence activating the ATM/NF-kappaB pathway, augmenting anti-apoptotic protein expression and contributing to MDR. This indicates that both IL-6 and ATM are potential targets for the treatment of chemotherapeutic resistance in lung cancer. PMID:24988892

  15. Aurora B kinase inhibitor AZD1152: determinants of action and ability to enhance chemotherapeutics effectiveness in pancreatic and colon cancer

    PubMed Central

    Azzariti, A; Bocci, G; Porcelli, L; Fioravanti, A; Sini, P; Simone, G M; Quatrale, A E; Chiarappa, P; Mangia, A; Sebastian, S; Del Bufalo, D; Del Tacca, M; Paradiso, A

    2011-01-01

    Background: AZD1152, the prodrug for AZD1152-hydroxyquinazoline pyrazol anilide (HQPA), is a selective inhibitor of Aurora B kinase activity. Preclinical evaluation of AZD1152 has been reported in several human cancer models. The potentiality of this compound in combination therapy warrants further investigation in solid tumours. Experimental design: This study explored the effects of AZD1152-HQPA in colon and pancreatic tumour cells. The antitumour properties of AZD1152, either as single agent or in combination with chemotherapeutics, were evaluated in each study model. The efficacy and the toxicity of AZD1152 alone and in combination with gemcitabine were validated in pancreatic tumour xenograft model. Results: AZD1152-HQPA treatment resulted in a dramatic increase of chromosome number, modification of cell cycle and induction of apoptosis. The most effective combination was that with chemotherapeutics given soon after AZD1152 in both tumour cell types. The effectiveness of the sequential schedule of AZD1152 with gemcitabine was confirmed in nude mice bearing MiaPaCa-2 tumours, showing inhibition of tumour volumes and delaying of tumour growth after the interruption of the treatments. Conclusion: Here we show that AZD1152-HQPA enhances oxaliplatin and gemcitabine effectiveness in colon and pancreatic cancer, respectively. First, we provide advances into administration schedules and dosing regimens for the combination treatment in in vivo pancreatic tumour. PMID:21304529

  16. Enhancing glioblastoma cell sensitivity to chemotherapeutics: A strategy involving survivin gene silencing mediated by gemini surfactant-based complexes.

    PubMed

    Cruz, Rita Q; Morais, Catarina M; Cardoso, Ana M; Silva, Sandra G; Vale, Maria L; Marques, Eduardo F; Pedroso de Lima, Maria C; Jurado, Amália S

    2016-07-01

    Glioblastoma (GBM), the highest grade astrocytoma, is one of the most aggressive and challenging cancers to treat. The standard treatment is usually limited due to the intrinsic resistance of GBM to chemotherapy and drug non-specific effects. Therefore, new therapeutic strategies need to be developed to target tumor cells, sparing healthy tissues. In this context, the inhibitor-of-apoptosis protein (IAP) survivin emerges as an ideal target for a gene silencing approach, since it is sharply differentially expressed in cancer tissues. In this work, two different families of cationic gemini surfactants (bis-quat conventional and serine-derived) were tested regarding their efficiency to deliver small interfering RNAs (siRNAs) in a human GBM cell line (U87), in order to select an effective siRNA anti-survivin carrier. Importantly, survivin downregulation combined with administration of the chemotherapeutic agents temozolomide or etoposide resulted in a synergistic cytotoxic effect, thus revealing to be a promising strategy to reduce the chemotherapeutic doses for GBM treatment. PMID:27106606

  17. Role of alkyl alcohol on viscosity of silica-based chemical gels for decontamination of highly radioactive nuclear facilities

    SciTech Connect

    Choi, B. S.; Yoon, S. B.; Jung, C. H.; Lee, K. W.; Moon, J. K.

    2012-07-01

    Silica-based chemical gel for the decontamination of nuclear facilities was prepared by using fumed silica as a viscosifier, a 0.5 M Ce (IV) solution dissolved in concentrated nitric acid as a chemical decontamination agent, and tripropylene glycol butyl ether (TPGBE) as a co-viscosifier. A new effective strategy for the preparation of the chemical gel was investigated by introducing the alkyl alcohols as organic solvents to effectively dissolve the co-viscosifier. The mixture solution of the co-viscosifier and alkyl alcohols was more effective in the control of viscosity than that of the co-viscosifier only in gel. Here, the alkyl alcohols played a key role as an effective dissolution solvent for the co-viscosifier in the preparation of the chemical gel, resulting in a reducing of the amount of the co-viscosifier and gel time compared with that of the chemical gel prepared without the alkyl alcohols. It was considered that the alkyl alcohols contributed to the effective dissolution of the co-viscosifier as well as the homogeneous mixing in the formation of the gel, while the co-viscosifier in an aqueous media of the chemical decontamination agent solution showed a lower solubility. The decontamination efficiency of the chemical gels prepared in this work using a multi-channel analyzer (MCA) showed a high decontamination efficiency of over ca. 94% and ca. 92% for Co-60 and Cs-137 contaminated on surface of the stainless steel 304, respectively. (authors)

  18. Ikaros expression sensitizes leukemic cells to the chemotherapeutic drug doxorubicin

    PubMed Central

    He, Licai; Gao, Shenmeng; Zhu, Zhenfeng; Chen, Shang; Gu, Haihua

    2016-01-01

    Ikaros is an important transcription factor involved in the development and differentiation of hematopoietic cells. However, its role in the treatment of hematopoietic malignancies such as leukemia is less well understood. In the present study, it was observed by data mining of the Oncomine database that high expression levels of full-length Ikaros (IK1) is correlated with increased sensitivity of cancer cells to treatments with chemotherapeutic drugs, including doxorubicin (DOX). To examine the functional significance of this observation, the expression of IK1 in a leukemia cell line was altered, and the response of leukemic cells to DOX treatment was analyzed. It was observed that overexpression of IK1 could enhance DOX-induced apoptosis, while knockdown of IK1 attenuated DOX-induced apoptosis in leukemic cells. Further experiments demonstrated that IK1 sensitized leukemic cells to DOX-induced apoptosis, probably through upregulation of caspase-9. These data suggest that high expression levels of IK1 may be a potential biomarker to predict responses of leukemia patients to treatment with chemotherapy.

  19. Effective delivery of chemotherapeutic nanoparticles by depleting host Kupffer cells.

    PubMed

    Ohara, Yusuke; Oda, Tatsuya; Yamada, Keiichi; Hashimoto, Shinji; Akashi, Yoshimasa; Miyamoto, Ryoichi; Kobayashi, Akihiko; Fukunaga, Kiyoshi; Sasaki, Ryoko; Ohkohchi, Nobuhiro

    2012-11-15

    Although chemotherapeutic nanoparticles would confer various advantages, the majority of administrated nanoparticles are known to be spoiled by the reticuloendothelial system (RES). Intending to more effectively deliver therapeutic nanoparticles to target regions in vivo, host RES, especially Kupffer cells in the liver, have been depleted ahead of drug administration. To demonstrate this hypothesis, clodronate liposomes were preinjected into BALB/c nude mice for depletion of Kupffer cells 2 days before, and pegylated liposomal doxorubicin (Doxil) at the doses of 1.25, 2.5 and 5.0 mg/kg was administered. As a result, doxorubicin accumulation in the liver was decreased from 36 to 26% injected dose/organ by the Kupffer cells depletion, and consequently, the plasma concentration of doxorubicin was significantly enhanced threefold (from 11 to 33 μg/mL) on day 1 at 1.25 mg/kg-dose group. Doxorubicin accumulation in the tumor was increased from 0.78 to 3.0 μg/g-tissue on day 3, and tumor growth inhibition by Doxil was significantly boosted (tumor volumes from 751 to 482 mm(3) on day 24) by the Kupffer cells depletion. In conclusion, Kupffer cells depletion by clodronate liposomes enhanced the plasma concentration and antitumor effects of Doxil, and would be widely applicable for various clinical cancer chemotherapies using nanoparticles. PMID:22362271

  20. 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

  1. Nanostructured Lipid Carriers: A Novel Platform for Chemotherapeutics.

    PubMed

    Rizwanullah, Md; Ahmad, Javed; Amin, Saima

    2016-01-01

    Cancer is a disease manifested as abnormal cells division without control. If it is not detected and cured very timely, it can invade other healthy tissues resulting in metastasis. Chemotherapy is the first line treatment for cancer, but due to lack of specificity of most of the anticancer drugs, is associated with side effects that affect the quality of life. Nanostructured lipid carriers (NLC) are one of the promising nano-carriers for the development of effective targeted therapies for cancer chemotherapeutics. These bio-compatible and/or bio-degradable lipids based nanoparticles are composed of solid and liquid lipids as a core matrix dispersed in surfactant solution. NLC improve the aqueous solubility of most of the hydrophobic cancer therapeutics. Their surface modification can be used for overcoming drug resistance in cancer chemotherapy, to achieve site specific targeting for better efficacy and reduced dose related toxicity. The present review is an attempt to contemplate their pharmaceutical, biopharmaceutical aspects and application in cell targeting, gene delivery and in theranostics. PMID:26279117

  2. 40 CFR 721.2420 - Alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., alkyl sulfate salt. 721.2420 Section 721.2420 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.2420 Alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt. (a... generically as an alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt (PMN P-91-288) is subject...

  3. 40 CFR 721.2420 - Alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., alkyl sulfate salt. 721.2420 Section 721.2420 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.2420 Alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt. (a... generically as an alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt (PMN P-91-288) is subject...

  4. 40 CFR 721.575 - Substituted alkyl halide.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Substituted alkyl halide. 721.575... Substances § 721.575 Substituted alkyl halide. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as substituted alkyl halide (PMN P-83-1222)...

  5. 40 CFR 721.1878 - Alkali metal alkyl borohydride (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Alkali metal alkyl borohydride... Specific Chemical Substances § 721.1878 Alkali metal alkyl borohydride (generic). (a) Chemical substance... alkali metal alkyl borohydride (PMN P-00-1089) is subject to reporting under this section for...

  6. 40 CFR 721.1878 - Alkali metal alkyl borohydride (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Alkali metal alkyl borohydride... Specific Chemical Substances § 721.1878 Alkali metal alkyl borohydride (generic). (a) Chemical substance... alkali metal alkyl borohydride (PMN P-00-1089) is subject to reporting under this section for...

  7. 40 CFR 721.1878 - Alkali metal alkyl borohydride (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Alkali metal alkyl borohydride... Specific Chemical Substances § 721.1878 Alkali metal alkyl borohydride (generic). (a) Chemical substance... alkali metal alkyl borohydride (PMN P-00-1089) is subject to reporting under this section for...

  8. 40 CFR 721.1878 - Alkali metal alkyl borohydride (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Alkali metal alkyl borohydride... Specific Chemical Substances § 721.1878 Alkali metal alkyl borohydride (generic). (a) Chemical substance... alkali metal alkyl borohydride (PMN P-00-1089) is subject to reporting under this section for...

  9. 40 CFR 721.555 - Alkyl amino nitriles (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Substances § 721.555 Alkyl amino nitriles (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substances identified generically as alkyl amino nitriles (PMNs P-96... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkyl amino nitriles (generic)....

  10. 40 CFR 721.3485 - Hydrofluorocarbon alkyl ether.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Hydrofluorocarbon alkyl ether. 721... Substances § 721.3485 Hydrofluorocarbon alkyl ether. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as a hydrofluorocarbon alkyl...

  11. 40 CFR 721.3485 - Hydrofluorocarbon alkyl ether.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Hydrofluorocarbon alkyl ether. 721... Substances § 721.3485 Hydrofluorocarbon alkyl ether. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as a hydrofluorocarbon alkyl...

  12. 40 CFR 721.10053 - Alkyl silane methacrylate (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Alkyl silane methacrylate (generic... Specific Chemical Substances § 721.10053 Alkyl silane methacrylate (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as alkyl...

  13. 40 CFR 721.10053 - Alkyl silane methacrylate (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Alkyl silane methacrylate (generic... Specific Chemical Substances § 721.10053 Alkyl silane methacrylate (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as alkyl...

  14. 40 CFR 721.10053 - Alkyl silane methacrylate (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Alkyl silane methacrylate (generic... Specific Chemical Substances § 721.10053 Alkyl silane methacrylate (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as alkyl...

  15. 40 CFR 721.10053 - Alkyl silane methacrylate (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Alkyl silane methacrylate (generic... Specific Chemical Substances § 721.10053 Alkyl silane methacrylate (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as alkyl...

  16. 40 CFR 721.10053 - Alkyl silane methacrylate (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkyl silane methacrylate (generic... Specific Chemical Substances § 721.10053 Alkyl silane methacrylate (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as alkyl...

  17. 40 CFR 721.555 - Alkyl amino nitriles (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Substances § 721.555 Alkyl amino nitriles (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substances identified generically as alkyl amino nitriles (PMNs P-96... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Alkyl amino nitriles (generic)....

  18. IONIC LIQUID-CATALYZED ALKYLATION OF ISOBUTANE WITH 2-BUTENE

    EPA Science Inventory

    A detailed study of the alkylation of isobutane with 2-butene in ionic liquid media has been conducted using 1-alkyl-3-methylimidazolium halides?aluminum chloride encompassing various alkyl groups (butyl-, hexyl-, and octyl-) and halides (Cl, Br, and I) on its cations and anions,...

  19. 40 CFR 721.1852 - Di-alkyl borane (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Di-alkyl borane (generic). 721.1852... Substances § 721.1852 Di-alkyl borane (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as di-alkyl borane (PMN P-00-1087) is...

  20. 40 CFR 721.10087 - Substituted alkyl phosphine oxide (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Substituted alkyl phosphine oxide... Specific Chemical Substances § 721.10087 Substituted alkyl phosphine oxide (generic). (a) Chemical... as substituted alkyl phosphine oxide (PMN P-06-332) is subject to reporting under this section...

  1. 40 CFR 721.10087 - Substituted alkyl phosphine oxide (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Substituted alkyl phosphine oxide... Specific Chemical Substances § 721.10087 Substituted alkyl phosphine oxide (generic). (a) Chemical... as substituted alkyl phosphine oxide (PMN P-06-332) is subject to reporting under this section...

  2. 40 CFR 721.9720 - Disubstituted alkyl triazines (generic name).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Disubstituted alkyl triazines (generic... Specific Chemical Substances § 721.9720 Disubstituted alkyl triazines (generic name). (a) Chemical... as disubstituted alkyl triazines (PMNs P-85-932 and P-85-933) are subject to reporting under...

  3. 40 CFR 721.10506 - Alkylated phenols (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Alkylated phenols (generic). 721.10506... Substances § 721.10506 Alkylated phenols (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substances identified generically as alkylated phenols (PMNs...

  4. 40 CFR 721.5769 - Mixture of nitrated alkylated phenols.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Mixture of nitrated alkylated phenols... Substances § 721.5769 Mixture of nitrated alkylated phenols. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as a mixture of nitrated alkylated...

  5. 40 CFR 721.5769 - Mixture of nitrated alkylated phenols.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Mixture of nitrated alkylated phenols... Substances § 721.5769 Mixture of nitrated alkylated phenols. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as a mixture of nitrated alkylated...

  6. 40 CFR 721.5769 - Mixture of nitrated alkylated phenols.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Mixture of nitrated alkylated phenols... Substances § 721.5769 Mixture of nitrated alkylated phenols. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as a mixture of nitrated alkylated...

  7. 40 CFR 721.5769 - Mixture of nitrated alkylated phenols.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Mixture of nitrated alkylated phenols... Substances § 721.5769 Mixture of nitrated alkylated phenols. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as a mixture of nitrated alkylated...

  8. 40 CFR 721.5769 - Mixture of nitrated alkylated phenols.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Mixture of nitrated alkylated phenols... Substances § 721.5769 Mixture of nitrated alkylated phenols. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as a mixture of nitrated alkylated...

  9. 40 CFR 721.10506 - Alkylated phenols (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Alkylated phenols (generic). 721.10506... Substances § 721.10506 Alkylated phenols (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substances identified generically as alkylated phenols (PMNs...

  10. 40 CFR 721.2410 - Alkoxylated alkyldiethylenetriamine, alkyl sulfate salts.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., alkyl sulfate salts. 721.2410 Section 721.2410 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.2410 Alkoxylated alkyldiethylenetriamine, alkyl sulfate salts. (a... generically as alkoxylated dialkyldiethylenetriamine, alkyl sulfate salts (PMN P-94-325, 326, and 327)...

  11. 40 CFR 721.2420 - Alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., alkyl sulfate salt. 721.2420 Section 721.2420 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.2420 Alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt. (a... generically as an alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt (PMN P-91-288) is subject...

  12. 40 CFR 721.2410 - Alkoxylated alkyldiethylenetriamine, alkyl sulfate salts.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., alkyl sulfate salts. 721.2410 Section 721.2410 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.2410 Alkoxylated alkyldiethylenetriamine, alkyl sulfate salts. (a... generically as alkoxylated dialkyldiethylenetriamine, alkyl sulfate salts (PMN P-94-325, 326, and 327)...

  13. 40 CFR 721.2410 - Alkoxylated alkyldiethylenetriamine, alkyl sulfate salts.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., alkyl sulfate salts. 721.2410 Section 721.2410 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.2410 Alkoxylated alkyldiethylenetriamine, alkyl sulfate salts. (a... generically as alkoxylated dialkyldiethylenetriamine, alkyl sulfate salts (PMN P-94-325, 326, and 327)...

  14. 40 CFR 721.2410 - Alkoxylated alkyldiethylenetriamine, alkyl sulfate salts.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., alkyl sulfate salts. 721.2410 Section 721.2410 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.2410 Alkoxylated alkyldiethylenetriamine, alkyl sulfate salts. (a... generically as alkoxylated dialkyldiethylenetriamine, alkyl sulfate salts (PMN P-94-325, 326, and 327)...

  15. 40 CFR 721.2410 - Alkoxylated alkyldiethylenetriamine, alkyl sulfate salts.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., alkyl sulfate salts. 721.2410 Section 721.2410 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.2410 Alkoxylated alkyldiethylenetriamine, alkyl sulfate salts. (a... generically as alkoxylated dialkyldiethylenetriamine, alkyl sulfate salts (PMN P-94-325, 326, and 327)...

  16. 40 CFR 721.2420 - Alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., alkyl sulfate salt. 721.2420 Section 721.2420 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.2420 Alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt. (a... generically as an alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt (PMN P-91-288) is subject...

  17. 40 CFR 721.2420 - Alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., alkyl sulfate salt. 721.2420 Section 721.2420 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.2420 Alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt. (a... generically as an alkoxylated dialkyldiethylenetriamine, alkyl sulfate salt (PMN P-91-288) is subject...

  18. 40 CFR 721.2825 - Alkyl ester (generic name).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Alkyl ester (generic name). 721.2825... Substances § 721.2825 Alkyl ester (generic name). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance alkyl ester (PMN P-84-968) is subject to reporting under this...

  19. 40 CFR 721.2825 - Alkyl ester (generic name).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkyl ester (generic name). 721.2825... Substances § 721.2825 Alkyl ester (generic name). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance alkyl ester (PMN P-84-968) is subject to reporting under this...

  20. 40 CFR 721.4136 - Alkyl heteropolycyclic-aniline (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Alkyl heteropolycyclic-aniline... Specific Chemical Substances § 721.4136 Alkyl heteropolycyclic-aniline (generic). (a) Chemical substance... alkyl heteropolycyclic-aniline (PMN P-00-0067) is subject to reporting under this section for...

  1. 40 CFR 721.4136 - Alkyl heteropolycyclic-aniline (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Alkyl heteropolycyclic-aniline... Specific Chemical Substances § 721.4136 Alkyl heteropolycyclic-aniline (generic). (a) Chemical substance... alkyl heteropolycyclic-aniline (PMN P-00-0067) is subject to reporting under this section for...

  2. 40 CFR 721.4136 - Alkyl heteropolycyclic-aniline (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Alkyl heteropolycyclic-aniline... Specific Chemical Substances § 721.4136 Alkyl heteropolycyclic-aniline (generic). (a) Chemical substance... alkyl heteropolycyclic-aniline (PMN P-00-0067) is subject to reporting under this section for...

  3. 40 CFR 721.4136 - Alkyl heteropolycyclic-aniline (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkyl heteropolycyclic-aniline... Specific Chemical Substances § 721.4136 Alkyl heteropolycyclic-aniline (generic). (a) Chemical substance... alkyl heteropolycyclic-aniline (PMN P-00-0067) is subject to reporting under this section for...

  4. 40 CFR 721.4136 - Alkyl heteropolycyclic-aniline (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Alkyl heteropolycyclic-aniline... Specific Chemical Substances § 721.4136 Alkyl heteropolycyclic-aniline (generic). (a) Chemical substance... alkyl heteropolycyclic-aniline (PMN P-00-0067) is subject to reporting under this section for...

  5. Synthesis and characterization of chitosan alkyl urea.

    PubMed

    Wang, Jing; Jiang, Ji-Zhou; Chen, Wei; Bai, Zheng-Wu

    2016-07-10

    Chitosan is a versatile material employed for various purposes in many fields including the development of chiral stationary phases for enantioseparation. Chitosan alkyl urea is a kind of intermediate used to prepare enantioseparation materials. In order to synthesize the intermediates, in the present work, a new way to prepare chitosan alkyl urea has been established: chitosan was first reacted with methyl chloroformate yielding N-methoxyformylated chitosan, which was then converted to chitosan alkyl urea through amine-ester exchange reaction. With a large excess of methyl chloroformate and primary amine of low stereohindrance, the amino group in chitosan could be almost completely converted to ureido group. The as-prepared chitosan alkyl urea derivatives were characterized by IR, (1)H NMR, (13)C NMR,(1)H-(1)H COSY and (1)H-(13)C HSQC NMR spectra. The chemical shifts of hydrogen and carbon atoms of glucose unit were assigned. It was found that the degree of substitution was obviously lower if cyclopropyl amine, aniline, tert-butyl amine and diethyl amine were used as reactants for the amine-ester exchange reaction. The reason was explained with the aid of theoretical calculations. PMID:27106154

  6. Poly(ethyleneoxide) functionalization through alkylation

    SciTech Connect

    Sivanandan, Kulandaivelu; Eitouni, Hany Basam; Li, Yan; Pratt, Russell Clayton

    2015-04-21

    A new and efficient method of functionalizing high molecular weight polymers through alkylation using a metal amide base is described. This novel procedure can also be used to synthesize polymer-based macro-initiators containing radical initiating groups at the chain-ends for synthesis of block copolymers.

  7. Polygas spells relief from alkylation ills

    SciTech Connect

    Weismantel, G.E.

    1980-06-16

    Tight supplies and soaring prices of isobutane (for olefin alkylation), are causing renewed interest in the olefin ''polymerization'' (i.e., dimerization), route to high-octane gasoline-blending components. Modern polymerization processes, intended to supplement rather than replace alkylation offer considerable energy and capital savings, compared with alkylation-only schemes. In addition to the Institut Francais du Petrole's Dimersol ''polymerization'' tecnique which is already being used or will be used by 1981 in at least five U.S. refineries, with six more units in the planning stage, a low-cost process to ''polymerize'' excess refinery olefins, developed by International Energy Consultants Inc., is nearing commercialization. A third route to process C/sub 3//C/sub 4/ refinery streams with high conversion rates has been proposed by UOP Inc. The low motor octane number (MON) of the product gasoline (approx. 13 numbers lower than a typical alkylate), was recently confirmed in Total Petroleum Inc.'s studies, but Good Hope Refineries Inc. plans to increase its polymer gasoline MON by adding methyl tert.-butyl ether.

  8. Separate olefin processing in sulfuric acid alkylation

    SciTech Connect

    Imhoff, S.A.; Graves, D.C.

    1995-09-01

    This paper will discuss the effects of alkylating propylene, butylenes and amylenes together and suggest alternative processing schemes which will minimize the negative synergies, improve octane and/or minimize acid consumption. The first option will show the impact of segregating the propylene and amylenes. In the second option, the benefit of alkylating the individual olefins at their optimal acid strengths will be presented. Additionally, each olefin`s optimal reaction conditions will be examined. Unfortunately, many refiners may not have the existing flexibility to take advantage of separate olefin processing. First, the majority of the propylene, butylenes and amylenes must be separate upon entry to the alkylation unit. If the olefins cannot be segregated upstream, separate olefin processing will not be as beneficial. If this is the case, then the benefits of separate olefin processing will have to be weighed versus the capital and energy costs required to separate them. In addition, small units may not have sufficient numbers of Contactors and settlers to achieve adequate segregation. Later in this paper, the modifications required in the alkylation unit for separate olefin processing will be discussed.

  9. Diaryl sulfide analogs of combretastatin A-4: Toxicogenetic, immunomodulatory and apoptotic evaluations and prospects for use as a new chemotherapeutic drug.

    PubMed

    Carvalho, Pamela Castilho; Santos, Edson Anjos; Schneider, Beatriz Ursinos Catelán; Matuo, Renata; Pesarini, João Renato; Cunha-Laura, Andréa Luiza; Monreal, Antônio Carlos Duenhas; Lima, Dênis Pires; Antoniolli, Andréia Conceição Milan Brochado; Oliveira, Rodrigo Juliano

    2015-11-01

    Combretastatin A-4 exhibits efficient anti-cancer potential in human tumors, including multidrug-resistant tumors. We evaluated the mutagenic, apoptotic and immunomodulatory potential of two diaryl sulfide analogs of combretastatin A-4, 1,2,3-trimethoxy-5-([4-methoxy-3-nitrophenyl]thio)benzene (analog 1) and 1,2,3-trimethoxy-5-([3-amino-4-methoxyphenyl]thio)benzene (analog 2), as well as their association with the anti-tumor agent cyclophosphamide, in Swiss mice. Such evaluation was achieved using the comet assay, peripheral blood micronucleus test, splenic phagocytosis assay, and apoptosis assay. Both analogs were found to be genotoxic, mutagenic and to induce apoptosis. They also increased splenic phagocytosis, although this increase was more pronounced for analog 2. When combined with cyclophosphamide, analog 1 enhanced the mutagenic and apoptotic effects of this anti-tumor agent. In contrast, analog 2 did not enhance the effects of cyclophosphamide and prevented apoptosis at lower doses. These data suggest that analog 1 could be an adjuvant chemotherapeutic agent and possibly improve the anti-neoplastic effect of cyclophosphamide. Additionally, this compound could be a candidate chemotherapeutic agent and/or an adjuvant for use in combined anti-cancer therapy. PMID:26410090

  10. Masked N-Heterocyclic Carbene-Catalyzed Alkylation of Phenols with Organic Carbonates.

    PubMed

    Lui, Matthew Y; Yuen, Alexander K L; Masters, Anthony F; Maschmeyer, Thomas

    2016-09-01

    An easily prepared masked N-heterocyclic carbene, 1,3-dimethylimidazolium-2-carboxylate (DMI-CO2 ), was investigated as a "green" and inexpensive organocatalyst for the alkylation of phenols. The process made use of various low-toxicity and renewable alkylating agents, such as dimethyl- and diethyl carbonate, in a focused microwave reactor. DMI-CO2 was found to be a very active catalyst and excellent yields of a range of aryl alkyl ethers were obtained under relatively benign conditions. The observed difference in the conversion behavior of phenol methylation, in the presence of either the carbene or 1,8-diazabicycloundec-7-ene (DBU) catalyst, was rationalized on the basis of mechanistic investigations. The primary mode of action for the N-heterocyclic carbene is nucleophilic catalysis. Activation of the dialkyl carbonate electrophile results in concomitant evolution of an organo-soluble alkoxide, which deprotonates the phenolic starting material. In contrast, DBU is initially protonated by the phenol and thus consumed. Subsequent regeneration and participation in nucleophilic catalysis only becomes significant after some phenolate alkylation occurs. PMID:27528488

  11. A role for Saccharomyces cerevisiae Tpa1 protein in direct alkylation repair.

    PubMed

    Shivange, Gururaj; Kodipelli, Naveena; Monisha, Mohan; Anindya, Roy

    2014-12-26

    Alkylating agents induce cytotoxic DNA base adducts. In this work, we provide evidence to suggest, for the first time, that Saccharomyces cerevisiae Tpa1 protein is involved in DNA alkylation repair. Little is known about Tpa1 as a repair protein beyond the initial observation from a high-throughput analysis indicating that deletion of TPA1 causes methyl methane sulfonate sensitivity in S. cerevisiae. Using purified Tpa1, we demonstrate that Tpa1 repairs both single- and double-stranded methylated DNA. Tpa1 is a member of the Fe(II) and 2-oxoglutarate-dependent dioxygenase family, and we show that mutation of the amino acid residues involved in cofactor binding abolishes the Tpa1 DNA repair activity. Deletion of TPA1 along with the base excision repair pathway DNA glycosylase MAG1 renders the tpa1Δmag1Δ double mutant highly susceptible to methylation-induced toxicity. We further demonstrate that the trans-lesion synthesis DNA polymerase Polζ (REV3) plays a key role in tolerating DNA methyl-base lesions and that tpa1Δmag1revΔ3 triple mutant is extremely susceptible to methylation-induced toxicity. Our results indicate a synergism between the base excision repair pathway and direct alkylation repair by Tpa1 in S. cerevisiae. We conclude that Tpa1 is a hitherto unidentified DNA repair protein in yeast and that it plays a crucial role in reverting alkylated DNA base lesions and cytotoxicity. PMID:25381260

  12. A Role for Saccharomyces cerevisiae Tpa1 Protein in Direct Alkylation Repair*

    PubMed Central

    Shivange, Gururaj; Kodipelli, Naveena; Monisha, Mohan; Anindya, Roy

    2014-01-01

    Alkylating agents induce cytotoxic DNA base adducts. In this work, we provide evidence to suggest, for the first time, that Saccharomyces cerevisiae Tpa1 protein is involved in DNA alkylation repair. Little is known about Tpa1 as a repair protein beyond the initial observation from a high-throughput analysis indicating that deletion of TPA1 causes methyl methane sulfonate sensitivity in S. cerevisiae. Using purified Tpa1, we demonstrate that Tpa1 repairs both single- and double-stranded methylated DNA. Tpa1 is a member of the Fe(II) and 2-oxoglutarate-dependent dioxygenase family, and we show that mutation of the amino acid residues involved in cofactor binding abolishes the Tpa1 DNA repair activity. Deletion of TPA1 along with the base excision repair pathway DNA glycosylase MAG1 renders the tpa1Δmag1Δ double mutant highly susceptible to methylation-induced toxicity. We further demonstrate that the trans-lesion synthesis DNA polymerase Polζ (REV3) plays a key role in tolerating DNA methyl-base lesions and that tpa1Δmag1revΔ3 triple mutant is extremely susceptible to methylation-induced toxicity. Our results indicate a synergism between the base excision repair pathway and direct alkylation repair by Tpa1 in S. cerevisiae. We conclude that Tpa1 is a hitherto unidentified DNA repair protein in yeast and that it plays a crucial role in reverting alkylated DNA base lesions and cytotoxicity. PMID:25381260

  13. Dichloromethyl alkyl ethers and sulfides in the Reformatskii reaction

    SciTech Connect

    Lapkin, I.I.; Fotin, V.V.

    1986-09-10

    A study was carried out on the reaction of dichloromethyl alkyl ethers and sulfides with ..cap alpha..-brominated esters in the presence of zinc resulting in the formation of either ..cap alpha..-alkyl-..beta..-alkoxyacrylates (or ..cap alpha..-alkyl-..beta..-alkylthioacrylates) or ..cap alpha..,..cap alpha..,..cap alpha..',..cap alpha..'-tetramethyl-..beta..-alkoxyglutaric acid (or ..cap alpha..,..cap alpha..,..cap alpha..',..cap alpha..'-tetramethyl-..beta..-alkylthioglutaric acid) depending on the structure of the starting bromoester. PMR and IR spectroscopy indicates the geometry of the ..cap alpha..-alkyl-..beta..-alkoxyacrylates and ..cap alpha..-alkyl-..beta..-alkylthioacrylates.

  14. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics

    PubMed Central

    Whitnall, Megan; Howard, Jonathan; Ponka, Prem; Richardson, Des R.

    2006-01-01

    Novel chemotherapeutics with marked and selective antitumor activity are essential to develop, particularly those that can overcome resistance to established therapies. Iron (Fe) is critical for cell-cycle progression and DNA synthesis and potentially represents a novel molecular target for the design of new anticancer agents. The aim of this study was to evaluate the antitumor activity and Fe chelation efficacy of a new class of Fe chelators using human tumors. In this investigation, the ligands showed broad antitumor activity and could overcome resistance to established antitumor agents. The in vivo efficacy of the most effective chelator identified, di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT), was assessed by using a panel of human xenografts in nude mice. After 7 weeks, net growth of a melanoma xenograft in Dp44mT-treated mice was only 8% of that in mice treated with vehicle. In addition, no differences in these latter animals were found in hematological indices between Dp44mT-treated mice and controls. No marked systemic Fe depletion was observed comparing Dp44mT- and vehicle-treated mice, probably because of the very low doses required to induce anticancer activity. Dp44mT caused up-regulation of the Fe-responsive tumor growth and metastasis suppressor Ndrg1 in the tumor but not in the liver, indicating a potential mechanism of selective anticancer activity. These results indicate that the novel Fe chelators have potent and broad antitumor activity and can overcome resistance to established chemotherapeutics because of their unique mechanism of action. PMID:17003122

  15. Ultra-bright alkylated graphene quantum dots

    NASA Astrophysics Data System (ADS)

    Feng, Lan; Tang, Xing-Yan; Zhong, Yun-Xin; Liu, Yue-Wen; Song, Xue-Huan; Deng, Shun-Liu; Xie, Su-Yuan; Yan, Jia-Wei; Zheng, Lan-Sun

    2014-10-01

    Highly efficient and stable photoluminescence (PL) are urgently desired for graphene quantum dots (GQDs) to facilitate their prospective applications as optical materials. Here, we report the facile and straightforward synthesis of alkylated graphene quantum dots (AGQDs) via the solvothermal reaction of propagatively alkylated graphene sheets (PAGenes). In contrast to most GQDs reported so far, the synthesized AGQDs process pH-independent and ultra-bright PL with a relative quantum yield of up to 65%. Structural and chemical composition characterization demonstrated that the synthesized AGQDs are nearly oxygen-defect-free with alkyl groups decorated on edges and basal plane, which may contribute to their greatly improved pH tolerance and high quantum efficiency. The photocatalytic performance of AGQDs-P25 nanocomposites was evaluated by the degradation of Rhodamine B under visible light. The photocatalytic rate is ca. 5.9 times higher than that of pure P25, indicating that AGQDs could harness the visible spectrum of sunlight for energy conversion or environmental therapy.Highly efficient and stable photoluminescence (PL) are urgently desired for graphene quantum dots (GQDs) to facilitate their prospective applications as optical materials. Here, we report the facile and straightforward synthesis of alkylated graphene quantum dots (AGQDs) via the solvothermal reaction of propagatively alkylated graphene sheets (PAGenes). In contrast to most GQDs reported so far, the synthesized AGQDs process pH-independent and ultra-bright PL with a relative quantum yield of up to 65%. Structural and chemical composition characterization demonstrated that the synthesized AGQDs are nearly oxygen-defect-free with alkyl groups decorated on edges and basal plane, which may contribute to their greatly improved pH tolerance and high quantum efficiency. The photocatalytic performance of AGQDs-P25 nanocomposites was evaluated by the degradation of Rhodamine B under visible light. The

  16. The Hepatoprotective Effect of Haoqin Qingdan Decoction against Liver Injury Induced by a Chemotherapeutic Drug Cyclophosphamide

    PubMed Central

    Li, Xiaojiang; Li, Baole; Jia, Yingjie

    2015-01-01

    Haoqin Qingdan decoction (HQQD), a modern Chinese formula, has been widely used in Eastern Asia. Our study focuses on the hepatoprotective effect of HQQD against cyclophosphamide-induced hepatotoxicity. S180, a kind of ascites tumor cells, was used to establish S180-bearing mice, followed by the injection of cyclophosphamide (CP, 80 mg/kg) every other day for 5 times. HQQD was used intragastrically at the dose of 80 g/kg, 40 g/kg, and 20 g/kg twice a day for 12 days. HL-7702 hepatic cell line was incubated with HQQD-medicated serum. Then we detected the effects of HQQD on (i) tumor suppression; (ii) morphological examination; (iii) SOD, MDA, GSH, ALT, and AST; (iv) cleaved caspase-3 expression and (v) cellular viability. CP caused dramatic elevations of AST, ALT, and MDA, while HQQD notably attenuated these elevations. SOD and GSH were notably increased, which were efficiently attenuated by HQQD. CP injection significantly increased apoptosis by increasing cleaved caspase-3 expression, which was obviously inhibited by HQQD, accompanied by the improvement of cells viability. Histopathological examinations supported the above findings. Therefore, HQQD may protect liver tissue through attenuating oxidative stress and the caspase-3-dependent intrinsic apoptosis induced by CP, which suggests the potentially therapeutic effect of HQQD in the use of alkylating agent for cancer chemotherapy. PMID:26101538

  17. PROCESS FOR PRODUCING ALKYL ORTHOPHOSPHORIC ACID EXTRACTANTS

    DOEpatents

    Grinstead, R.R.

    1962-01-23

    A process is given for producing superior alkyl orthophosphoric acid extractants for use in solvent extraction methods to recover and purify various metals such as uranium and vanadium. The process comprises slurrying P/sub 2/O/ sub 5/ in a solvent diluent such as kerosene, benzene, isopropyl ether, and the like. An alipbatic alcohol having from nine to seventeen carbon atoms, and w- hcrein ihc OH group is situated inward of the terminal carbon atoms, is added to the slurry while the reaction temperature is mainiained below 60 deg C. The alcohol is added in the mole ratio of about 2 to l, alcohol to P/sub 2/O/sub 5/. A pyrophosphate reaotion product is formed in the slurry-alcohol mixture. Subsequently, the pyrophosphate reaction product is hydrolyzed with dilute mineral acid to produce the desired alkyl orthophosphoric aeid extractant. The extraetant may then be separated and utilized in metal-recovery, solvent- extraction processes. (AEC)

  18. Synthesis, characterization and chemoprotective activity of polyoxovanadates against DNA alkylation.

    PubMed

    Nunes, Giovana G; Bonatto, Ana C; de Albuquerque, Carla G; Barison, Andersson; Ribeiro, Ronny R; Back, Davi F; Andrade, André Vitor C; de Sá, Eduardo L; Pedrosa, Fábio de O; Soares, Jaísa F; de Souza, Emanuel M

    2012-03-01

    The alkylation of pUC19 plasmid DNA has been employed as a model reaction for the first studies on chemoprotective action by a mixed-valence (+IV/+V) polyoxovanadate. A new, non-hydrothermal route for the high yield preparation of the test compound is described. The deep green, microcrystalline solid A was isolated after a three-day reaction in water at 80°C and 1 atm, while the reaction at 100°C gave green crystals of B. Both solids were structurally characterized by X-ray diffractometry and FTIR, EPR, NMR and Raman spectroscopies. Product A was identified as (NH(4))(2)V(3)O(8), while B corresponds to the spherical polyoxoanion [V(15)O(36)(Cl)](6-), isolated as the NMe(4)(+) salt. The lack of solubility of A in water and buffers prevented its use in DNA interaction studies, which were then carried out with B. Complex B was also tested for its ability to react with DNA alkylating agents by incubation with diethylsulphate (DES) and dimethylsulphate (DMS) in both the absence and presence of pUC19. For DMS, the best results were obtained with 10 mM of B (48% protection); with DES, this percentage increased to 70%. The direct reaction of B with increasing amounts of DMS in both buffered (PIPES 50 mM) and non-buffered aqueous solutions revealed the sequential formation of several vanadium(IV), vanadium(V) and mixed-valence aggregates of different nuclearities, whose relevance to the DNA-protecting activity is discussed. PMID:22265837

  19. Chemotherapy and Dietary Phytochemical Agents

    PubMed Central

    Sak, Katrin

    2012-01-01

    Chemotherapy has been used for cancer treatment already for almost 70 years by targeting the proliferation potential and metastasising ability of tumour cells. Despite the progress made in the development of potent chemotherapy drugs, their toxicity to normal tissues and adverse side effects in multiple organ systems as well as drug resistance have remained the major obstacles for the successful clinical use. Cytotoxic agents decrease considerably the quality of life of cancer patients manifesting as acute complaints and impacting the life of survivors also for years after the treatment. Toxicity often limits the usefulness of anticancer agents being also the reason why many patients discontinue the treatment. The nutritional approach may be the means of helping to raise cancer therapy to a new level of success as supplementing or supporting the body with natural phytochemicals cannot only reduce adverse side effects but improve also the effectiveness of chemotherapeutics. Various plant-derived compounds improve the efficiency of cytotoxic agents, decrease their resistance, lower and alleviate toxic side effects, reduce the risk of tumour lysis syndrome, and detoxify the body of chemotherapeutics. The personalised approach using various phytochemicals provides thus a new dimension to the standard cancer therapy for improving its outcome in a complex and complementary way. PMID:23320169

  20. In pursuit of homoleptic actinide alkyl complexes.

    PubMed

    Seaman, Lani A; Walensky, Justin R; Wu, Guang; Hayton, Trevor W

    2013-04-01

    This Forum Article describes the pursuit of isolable homoleptic actinide alkyl complexes, starting with the pioneering work of Gilman during the Manhattan project. The initial reports in this area suggested that homoleptic uranium alkyls were too unstable to be isolated, but Wilkinson demonstrated that tractable uranium alkyls could be generated by purposeful "ate" complex formation, which serves to saturate the uranium coordination sphere and provide the complexes with greater kinetic stability. More recently, we reported the solid-state molecular structures of several homoleptic uranium alkyl complexes, including [Li(THF)4][U(CH2(t)Bu)5], [Li(TMEDA)]2[UMe6], [K(THF)]3[K(THF)2][U(CH2Ph)6]2, and [Li(THF)4][U(CH2SiMe3)6], by employing Wilkinson's strategy. Herein, we describe our attempts to extend this chemistry to thorium. The treatment of ThCl4(DME)2 with 5 equiv of LiCH2(t)Bu or LiCH2SiMe3 at -25 °C in THF affords [Th(CH2(t)Bu)5] (1) and [Li(DME)2][Th(CH2SiMe3)5 (2), respectively, in moderate yields. Similarly, the treatment of ThCl4(DME)2 with 6 equiv of K(CH2Ph) produces [K(THF)]2[Th(CH2Ph)6] (3), in good yield. Complexes 1-3 have been fully characterized, while the structures of 1 and 3 were confirmed by X-ray crystallography. Additionally, the electronic properties of 1 and 3 were explored by density functional theory. PMID:22716022

  1. 1,2-bis(arylsulfonyl)hydrazines. 2. The influence of arylsulfonyl and aralkylsulfonyl substituents on antitumor and alkylating activity.

    PubMed

    Shyam, K; Furubayashi, R; Hrubiec, R T; Cosby, L A; Sartorelli, A C

    1986-07-01

    Several 1,2-bis(arylsulfonyl)-1-methylhydrazines were synthesized and evaluated for antineoplastic activity against the L1210 leukemia. The most active compound to emerge from this study, 2-[(4-chlorophenyl)sulfonyl]-1-methyl-1-(4-tolylsulfonyl)hydrazine , increased the survival time of tumor-bearing mice by 88%. The alkylating activity of the synthesized analogues and several compounds reported earlier was determined by measuring the absorbance at 540 nm of the alkylated product of 4-(4-nitrobenzyl)pyridine. The results obtained support the concept that the ability to alkylate is a necessary but not a sufficient condition for the expression of antitumor activity by agents of this class. PMID:3806585

  2. Chemotherapeutic implications in microsatellite unstable colorectal cancer1

    PubMed Central

    Jo, Won-Seok; Carethers, John M.

    2016-01-01

    alternative chemotherapeutic regimens for patients with MSI-H tumors to improve survival. PMID:17192059

  3. Ultra-bright alkylated graphene quantum dots.

    PubMed

    Feng, Lan; Tang, Xing-Yan; Zhong, Yun-Xin; Liu, Yue-Wen; Song, Xue-Huan; Deng, Shun-Liu; Xie, Su-Yuan; Yan, Jia-Wei; Zheng, Lan-Sun

    2014-11-01

    Highly efficient and stable photoluminescence (PL) are urgently desired for graphene quantum dots (GQDs) to facilitate their prospective applications as optical materials. Here, we report the facile and straightforward synthesis of alkylated graphene quantum dots (AGQDs) via the solvothermal reaction of propagatively alkylated graphene sheets (PAGenes). In contrast to most GQDs reported so far, the synthesized AGQDs process pH-independent and ultra-bright PL with a relative quantum yield of up to 65%. Structural and chemical composition characterization demonstrated that the synthesized AGQDs are nearly oxygen-defect-free with alkyl groups decorated on edges and basal plane, which may contribute to their greatly improved pH tolerance and high quantum efficiency. The photocatalytic performance of AGQDs-P25 nanocomposites was evaluated by the degradation of Rhodamine B under visible light. The photocatalytic rate is ca. 5.9 times higher than that of pure P25, indicating that AGQDs could harness the visible spectrum of sunlight for energy conversion or environmental therapy. PMID:25192187

  4. Hydrophilic interaction liquid chromatography-tandem mass spectrometry methylphosponic and alkyl methylphosphonic acids determination in environmental samples after pre-column derivatization with p-bromophenacyl bromide.

    PubMed

    Baygildiev, T M; Rodin, I A; Stavrianidi, A N; Braun, A V; Lebedev, A T; Rybalchenko, I V; Shpigun, O A

    2016-04-15

    Once exposed to the environment organophosphate nerve agents readily degrade by rapid hydrolysis to the corresponding alkyl methylphosphonic acids which do not exist in nature. These alkyl methylphosphonic acids are finally slowly hydrolyzed to methylphosphonic acid. Methylphosphonic acid is the most stable hydrolysis product of organophosphate nerve agents, persisting in environment for a long time. A highly sensitive method of methylphosphonic acid and alkyl methylphosphonic acids detection in dust and ground mixed samples has been developed and validated. The fact that alkyl methylphosphonic acids unlike methylphosphonic acid did not react with p-bromophenacyl bromide under chosen conditions was discovered. This allowed simultaneous chromatographic separation and mass spectrometric detection of derivatized methylphosphonic acid and underivatized alkyl methylphosphonic acids using HILIC-MS/MS method. Very simple sample pretreatment with high recoveries for each analyte was developed. Methylphosphonic acid pre-column derivate and alkyl methylphosphonic acids were detected using tandem mass spectrometry with electrospray ionization after hydrophilic interaction liquid chromatography separation. The developed approach allows achieving ultra-low detection limits: 200 pg mL(-1) for methylphosphonic acid, 70 pg mL(-1) for ethyl methylphosphonic acid, 8 pg mL(-1) for i-propyl methylphosphonic acid, 8 pg mL(-1) for i-butyl methylphosphonic acid, 5 pg mL(-1) for pinacolyl methylphosphonic acid in the extracts of dust and ground mixed samples. This approach was successfully applied to the dust and ground mixed samples from decommissioned plant for the production of chemical weapons. PMID:26965649

  5. 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

  6. Interaction between p53 and estradiol pathways in transcriptional responses to chemotherapeutics.

    PubMed

    Lion, Mattia; Bisio, Alessandra; Tebaldi, Toma; De Sanctis, Veronica; Menendez, Daniel; Resnick, Michael A; Ciribilli, Yari; Inga, Alberto

    2013-04-15

    Estrogen receptors (ERs) and p53 can interact via cis-elements to regulate the angiogenesis-related VEGFR-1 (FLT1) gene, as we reported previously. Here, we address cooperation between these transcription factors on a global scale. Human breast adenocarcinoma MCF7 cells were exposed to single or combinatorial treatments with the chemotherapeutic agent doxorubicin and the ER ligand 17β-estradiol (E2). Whole-genome transcriptome changes were measured by expression microarrays. Nearly 200 differentially expressed genes were identified that showed limited responsiveness to either doxorubicin treatment or ER ligand alone but were upregulated in a greater than additive manner following combined treatment. Based on exposure to 5-fuorouracil and nutlin-3a, the combined responses were treatment-specific. Among 16 genes chosen for validation using quantitative real-time PCR, seven (INPP5D, TLR5, KRT15, EPHA2, GDNF, NOTCH1, SOX9) were confirmed to be novel direct targets of p53, based on responses in MCF7 cells silenced for p53 or cooperative targets of p53 and ER. Promoter pattern searches and chromatin IP experiments for the INPP5D, TLR5, KRT15 genes supported direct, cis-mediated p53 and/or ER regulation through canonical and noncanonical p53 and ER response elements. Collectively, we establish that combinatorial activation of p53 and ER can induce novel gene expression programs that have implications for cell-cell communications, adhesion, cell differentiation, development and inflammatory responses as well as cancer treatments. PMID:23518503

  7. Interaction between p53 and estradiol pathways in transcriptional responses to chemotherapeutics

    PubMed Central

    Lion, Mattia; Bisio, Alessandra; Tebaldi, Toma; De Sanctis, Veronica; Menendez, Daniel; Resnick, Michael A.; Ciribilli, Yari; Inga, Alberto

    2013-01-01

    Estrogen receptors (ERs) and p53 can interact via cis-elements to regulate the angiogenesis-related VEGFR-1 (FLT1) gene, as we reported previously. Here, we address cooperation between these transcription factors on a global scale. Human breast adenocarcinoma MCF7 cells were exposed to single or combinatorial treatments with the chemotherapeutic agent doxorubicin and the ER ligand 17β-estradiol (E2). Whole-genome transcriptome changes were measured by expression microarrays. Nearly 200 differentially expressed genes were identified that showed limited responsiveness to either doxorubicin treatment or ER ligand alone but were upregulated in a greater than additive manner following combined treatment. Based on exposure to 5-fuorouracil and nutlin-3a, the combined responses were treatment-specific. Among 16 genes chosen for validation using quantitative real-time PCR, seven (INPP5D, TLR5, KRT15, EPHA2, GDNF, NOTCH1, SOX9) were confirmed to be novel direct targets of p53, based on responses in MCF7 cells silenced for p53 or cooperative targets of p53 and ER. Promoter pattern searches and chromatin IP experiments for the INPP5D, TLR5, KRT15 genes supported direct, cis-mediated p53 and/or ER regulation through canonical and noncanonical p53 and ER response elements. Collectively, we establish that combinatorial activation of p53 and ER can induce novel gene expression programs that have implications for cell-cell communications, adhesion, cell differentiation, development and inflammatory responses as well as cancer treatments. PMID:23518503

  8. Monitoring Chemotherapeutic Response by Hyperpolarized 13C-Fumarate MRS and Diffusion MRI

    PubMed Central

    Mignion, Lionel; Dutta, Prasanta; Martinez, Gary V.; Foroutan, Parastou; Gillies, Robert J.; Jordan, Bénédicte F.

    2015-01-01

    Targeted chemotherapeutic agents often do not result in tumor shrinkage, so new biomarkers that correlate with clinical efficacy are needed. In this study, we investigated noninvasive imaging protocols to monitor responses to sorafenib, a multikinase inhibitor approved for treatment of renal cell and hepatocellular carcinoma. Healthy cells are impermeable to fumarate, so conversion of this metabolite to malate as detected by 13C-magnetic resonance spectroscopy (MRS) has been suggested as one marker for cell death and treatment response in tumors. Diffusion MRI also has been suggested as a measure of therapy-induced cytotoxic edema because viable cells act as a diffusion barrier in tissue. For these reasons, we assessed sorafenib responses using hyperpolarized 13C-fumarate, diffusion-weighted MRI (DW-MRI) in a xenograft model of human breast cancer in which daily administration of sorafenib was sufficient to stabilize tumor growth. We detected signals from fumarate and malate following intravenous administration of hyperpolarized fumarate with a progressive increase in the malate-to-fumarate (MA/FA) ratio at days 2 to 5 after sorafenib infusion. The apparent diffusion coefficient (ADC) measured by DW-MRI increased in the treated group consistent with cytotoxic edema. However, the MA/FA ratio was a more sensitive marker of therapeutic response than ADC, with 2.8-fold versus 1.3-fold changes, respectively, by day 5 of drug treatment. Histologic analyses confirmed cell death in the sorafenib-treated cohort. Notably, 13C-pyruvate-to-lactate conversion was not affected by sorafenib in the breast cancer model examined. Our results illustrate how combining hyperpolarized substrates with DW-MRI can allow noninvasive monitoring of targeted therapeutic responses at relatively early times after drug administration. PMID:24285723

  9. Monitoring chemotherapeutic response by hyperpolarized 13C-fumarate MRS and diffusion MRI.

    PubMed

    Mignion, Lionel; Dutta, Prasanta; Martinez, Gary V; Foroutan, Parastou; Gillies, Robert J; Jordan, Bénédicte F

    2014-02-01

    Targeted chemotherapeutic agents often do not result in tumor shrinkage, so new biomarkers that correlate with clinical efficacy are needed. In this study, we investigated noninvasive imaging protocols to monitor responses to sorafenib, a multikinase inhibitor approved for treatment of renal cell and hepatocellular carcinoma. Healthy cells are impermeable to fumarate, so conversion of this metabolite to malate as detected by (13)C-magnetic resonance spectroscopy (MRS) has been suggested as one marker for cell death and treatment response in tumors. Diffusion MRI also has been suggested as a measure of therapy-induced cytotoxic edema because viable cells act as a diffusion barrier in tissue. For these reasons, we assessed sorafenib responses using hyperpolarized (13)C-fumarate, diffusion-weighted MRI (DW-MRI) in a xenograft model of human breast cancer in which daily administration of sorafenib was sufficient to stabilize tumor growth. We detected signals from fumarate and malate following intravenous administration of hyperpolarized fumarate with a progressive increase in the malate-to-fumarate (MA/FA) ratio at days 2 to 5 after sorafenib infusion. The apparent diffusion coefficient (ADC) measured by DW-MRI increased in the treated group consistent with cytotoxic edema. However, the MA/FA ratio was a more sensitive marker of therapeutic response than ADC, with 2.8-fold versus 1.3-fold changes, respectively, by day 5 of drug treatment. Histologic analyses confirmed cell death in the sorafenib-treated cohort. Notably, (13)C-pyruvate-to-lactate conversion was not affected by sorafenib in the breast cancer model examined. Our results illustrate how combining hyperpolarized substrates with DW-MRI can allow noninvasive monitoring of targeted therapeutic responses at relatively early times after drug administration. PMID:24285723

  10. Predictive imaging of chemotherapeutic response in a transgenic mouse model of pancreatic cancer.

    PubMed

    Wang, Ping; Yoo, Byunghee; Sherman, Sarah; Mukherjee, Pinku; Ross, Alana; Pantazopoulos, Pamela; Petkova, Victoria; Farrar, Christian; Medarova, Zdravka; Moore, Anna

    2016-08-01

    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

  11. Enhanced delivery of the RAPTA-C macromolecular chemotherapeutic by conjugation to degradable polymeric micelles.

    PubMed

    Blunden, Bianca M; Lu, Hongxu; Stenzel, Martina H

    2013-12-01

    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. PMID:24266669

  12. Beneficiation of coal and metallic and non-metallic ores by froth flotation process using polyhydroxy alkyl xanthate depressants

    SciTech Connect

    Petrovich, V.

    1980-07-08

    In the concentration of metallic and non-metallic minerals by froth flotation with a high content of pyrite and the like iron sulfides, which includes the subjecting of such ores when finely ground and sized to substantially liberate particles of pyrite, to froth flotation process in the presence of any suitabl E and adeuqate collector and frother for desired metallic and non-metallic mineral for the recovery of the same, and in the presence of a polyhydroxy alkyl xanthate wetting and depressing agent for pyrite, the step of adding to a pulp of mineral slurry an amount of the order of 0.01 to 0.10 kg per metric ton of a non-collecting polyhydroxy alkyl xanthate, of which hydroxyl groups of said polyhydroxy alkyl xanthates contain from 3 to 4, and having the following general formula: HOCH/sub 2/(CHOH)mcH(CHO)OCSSK wherein M is an integer from 2 to 3; said polyhydroxy alkyl xanthates, react with pyrite and said iron sulfides of the pulp of mineral slurry to yield a water soluble or insoluble hydrophilic coating depressing the pyrite and said iron sulfides, said polyhydroxy alkyl xanthates being selected from the group consisting of potassium pentose, and potassium hexose xanthates, such as potassium arabinose xanthate, potassium xylose xanthate, potassium glucose xanthate, potassium fructose xanthate.

  13. Principles and major agents in clinical oncology chemotherapy

    SciTech Connect

    Weller, R.E.

    1991-10-01

    This paper provides a brief classification of drugs available for veterinary chemotherapy, as well as justifications for their use. Some common neoplasia and the drugs of choice for their treatment are described. A listing by class of systemic chemotherapeutic agents, their mode of action, tumors responsive to the drugs, precautions and common adverse effects and mode of administration is provided. 2 tabs. (MHB)

  14. Survey of small antifungal peptides with chemotherapeutic potential.

    PubMed

    Desbois, Andrew P; Tschörner, David; Coote, Peter J

    2011-08-01

    Many cationic peptides with antimicrobial properties have been isolated from bacteria, fungi, plants, and animals. These peptides vary in molecular size, potency and spectra of activities. This report surveyed the literature to highlight the peptides that have antifungal activity and greatest potential for development as new therapeutic agents. Thus, to be included in the evaluation, each peptide had to fulfil the following criteria: (i) potent antifungal activity, (ii) no, or minimal, mammalian cell toxicity, (iii) of ≤25 amino acids in length, which minimises the costs of synthesis, reduces immunogenicity and enhances bioavailability and stability in vivo, (iv) minimal post-translational modifications (also reduces the production costs). The ~80 peptides that satisfied these criteria are discussed with respect to their structures, mechanisms of antimicrobial action and in vitro and in vivo toxicities. Certainly, some of these small peptides warrant further study and have potential for future exploitation as new antifungal agents. PMID:21470150

  15. New agents for prostate cancer.

    PubMed

    Agarwal, N; Di Lorenzo, G; Sonpavde, G; Bellmunt, J

    2014-09-01

    The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years. Immunotherapy in the form of sipuleucel-T, androgen axis inhibitors, including abiraterone acetate and enzalutamide, a chemotherapeutic agent, cabazitaxel, and a radiopharmaceutical, radium-223, have all yielded incremental extensions of survival and have been recently approved. A number of other agents appear promising in early studies, suggesting that the armamentarium against castrate-resistant prostate cancer is likely to continue to expand. Emerging androgen pathway inhibitors include androgen synthesis inhibitors (TAK700), androgen receptor inhibitors (ARN-509, ODM-201), AR DNA binding domain inhibitors (EPI-001), selective AR downregulators or SARDs (AZD-3514), and agents that inhibit both androgen synthesis and receptor binding (TOK-001/galeterone). Promising immunotherapeutic agents include poxvirus vaccines and CTLA-4 inhibitor (ipilimumab). Biologic agents targeting the molecular drivers of disease are also being investigated as single agents, including cabozantinib (Met and VEGFR2 inhibitor) and tasquinimod (angiogenesis and immune modulatory agent). Despite the disappointing results seen from studies evaluating docetaxel in combination with other agents, including GVAX, anti-angiogentic agents (bevacizumab, aflibercept, lenalinomide), a SRC kinase inhibitor (dasatinib), endothelin receptor antagonists (atrasentan, zibotentan), and high-dose calcitriol (DN-101), the results from the trial evaluating docetaxel in combination with the clusterin antagonist, custirsen, are eagerly awaited. New therapeutic hurdles consist of discovering new targets, understanding resistance mechanisms, the optimal sequencing and combinations of available agents, as well as biomarkers predictive for benefit. Novel agents targeting bone metastases are being developed following the success of zoledronic acid

  16. 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

  17. Lithium perchlorate-nitromethane-promoted alkylation of anilines with arylmethanols.

    PubMed

    Zhou, Jun; Mao, Hai-Feng; Wang, Lu; Zou, Jian-Ping; Zhang, Wei

    2011-11-01

    A new application of lithium perchlorate-nitromethane (LPNM) for the formation of aromatic C-N and C-C bonds is introduced. LPNM-promoted reactions of anilines with diarylmethanols selectively generate N-alkylated anilines or mono and double Friedel-Crafts alkylation products under different conditions by changing the reaction time, reaction temperature, and the ratio of the reactants. This method does not require the use of transition metal catalysts to prepare alkylated aniline derivatives. PMID:21547437

  18. Correlation between radioactivity and chemotherapeutics of the 111In-VNB-liposome in pharmacokinetics and biodistribution in rats

    PubMed Central

    Lee, Wen-Chuan; Chang, Chih-Hsien; Huang, Chih-Min; Wu, Yu-Tse; Chen, Liang-Cheng; Ho, Chung-Li; Chang, Tsui-Jung; Lee, Te-Wei; Tsai, Tung-Hu

    2012-01-01

    Background The combination of a radioisotope with a chemotherapeutic agent in a liposomal carrier (ie, Indium-111-labeled polyethylene glycol pegylated liposomal vinorelbine, [111In-VNB-liposome]) has been reported to show better therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this therapeutic effect is attributable to the combination of a radioisotope with chemotherapeutics. The goal of this study was to investigate the pharmacokinetics, biodistribution, and correlation of Indium-111 radioactivity and vinorelbine concentration in the 111In-VNB-liposome. Methods The VNB-liposome and 111In-VNB-liposome were administered to rats. Blood, liver, and spleen tissue were collected to determine the distribution profile of the 111In-VNB-liposome. A liquid chromatography tandem mass spectrometry system and gamma counter were used to analyze the concentration of vinorelbine and radioactivity of Indium-111. Results High uptake of the 111In-VNB-liposome in the liver and spleen demonstrated the properties of a nanosized drug delivery system. Linear regression showed a good correlation (r = 0.97) between Indium-111 radioactivity and vinorelbine concentration in the plasma of rats administered the 111In-VNB-liposome. Conclusion A significant positive correlation between the pharmacokinetics and biodistribution of 111Indium radioactivity and vinorelbine in blood, spleen, and liver was found following administration of the 111In-VNB-liposome. The liposome efficiently encapsulated both vinorelbine and Indium-111, and showed a similar concentration-radioactivity time profile, indicating the correlation between chemotherapy and radiotherapy could be identical in the liposomal formulation. PMID:22359447

  19. Multi-layered polymeric nanoparticles for pH-responsive and sequenced release of theranostic agents.

    PubMed

    Wang, Hai; Zhao, Shuting; Agarwal, Pranay; Dumbleton, Jenna; Yu, Jianhua; Lu, Xiongbin; He, Xiaoming

    2015-05-01

    In this study, multi-layered pH-responsive polymeric nanoparticles (NPs) are prepared by multiple (up to 4) emulsifications to encapsulate multiple hydrophilic and hydrophobic theranostic agents for controlled and sequenced release. It is found that the sequence of release of multiple chemotherapeutic agents from the NPs significantly affects their efficacy against cancer cells. PMID:25850616

  20. Determining cysteine oxidation status using differential alkylation

    NASA Astrophysics Data System (ADS)

    Schilling, Birgit; Yoo, Chris B.; Collins, Christopher J.; Gibson, Bradford W.

    2004-08-01

    Oxidative damage to proteins plays a major role in aging and in the pathology of many degenerative diseases. Under conditions of oxidative stress, reactive oxygen and nitrogen species can modify key redox sensitive amino acid side chains leading to altered biological activities or structures of the targeted proteins. This in turn can affect signaling or regulatory control pathways as well as protein turnover and degradation efficiency in the proteasome. Cysteine residues are particularly susceptible to oxidation, primarily through reversible modifications (e.g., thiolation and nitrosylation), although irreversible oxidation can lead to products that cannot be repaired in vivo such as sulfonic acid. This report describes a strategy to determine the overall level of reversible cysteine oxidation using a stable isotope differential alkylation approach in combination with mass spectrometric analysis. This method employs 13C-labeled alkylating reagents, such as N-ethyl-[1,4-13C2]-maleimide, bromo-[1,2-13C2]-acetic acid and their non-labeled counterparts to quantitatively assess the level of cysteine oxidation at specific sites in oxidized proteins. The differential alkylation protocol was evaluated using standard peptides and proteins, and then applied to monitor and determine the level of oxidative damage induced by diamide, a mild oxidant. The formation and mass spectrometric analysis of irreversible cysteine acid modification will also be discussed as several such modifications have been identified in subunits of the mitochondrial electron transport chain complexes. This strategy will hopefully contribute to our understanding of the role that cysteine oxidation plays in such chronic diseases such as Parkinson's disease, where studies in animal and cell models have shown oxidative damage to mitochondrial Complex I to be a specific and early target.

  1. Possible involvement of the Sigma-1 receptor chaperone in chemotherapeutic-induced neuropathic pain.

    PubMed

    Tomohisa, Mori; Junpei, Ohya; Aki, Masumoto; Masato, Harumiya; Mika, Fukase; Kazumi, Yoshizawa; Teruo, Hayashi; Tsutomu, Suzuki

    2015-11-01

    Previous studies have shown that ligands of the sigma-1 receptor chaperone (Sig-1R) regulate pain-related behaviors. Clinical use of chemotherapeutics is often compromised due to their adverse side effects, particularly those related to neuropathy. Previous studies have shown that repeated administration of oxaliplatin and paclitaxel produces neuropathy in rodents. Therefore, the aim of the present study was to clarify the involvement of the Sig-1R in chemotherapeutic-induced neuropathy by examining the effects of oxaliplatin and paclitaxel on the Sig-1R levels in the spinal cord, and by examining the effects of Sig-1R agonist and antagonist on oxaliplatin- and paclitaxel-induced neuropathy in rats. Chemotherapeutic-induced neuropathic pain was accompanied by a significant reduction of the Sig-1R level in the spinal cord. Furthermore, the administration of paclitaxel to CHO cells that stably overexpressed Sig-1Rs induced the clustering of Sig-1Rs. We also found that the Sig-1R agonist SA4503 potently inhibited the neuropathy induced by oxaliplatin- and paclitaxel, whereas this action was abolished by the Sig-1R antagonist NE-100. These results suggest that the reduction of Sig-1R activity is involved in chemotherapeutic-induced neuropathy, and the Sig-1R agonist SA4503 could serve as a potential candidate for the treatment of chemotherapeutic-induced neuropathy. PMID:26234785

  2. Alkyl Chlorides as Hydrogen Bond Acceptors

    SciTech Connect

    Nadas, Janos I; Vukovic, Sinisa; Hay, Benjamin

    2012-01-01

    To gain an understanding of the role of an alkyl chloride as a hydrogen bond acceptor, geometries and interaction energies were calculated at the MP2/aug-cc-pVDZ level of theory for complexes between ethyl chloride and representative hydrogen donor groups. The results establish that these donors, which include hydrogen cyanide, methanol, nitrobenzene, pyrrole, acetamide, and N-methylurea, form X-H {hor_ellipsis} Cl hydrogen bonds (X = C, N, O) of weak to moderate strength, with {Delta}E values ranging from -2.8 to -5.3 kcal/mol.

  3. Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics.

    PubMed

    Sociali, Giovanna; Galeno, Lauretta; Parenti, Marco Daniele; Grozio, Alessia; Bauer, Inga; Passalacqua, Mario; Boero, Silvia; Donadini, Alessandra; Millo, Enrico; Bellotti, Marta; Sturla, Laura; Damonte, Patrizia; Puddu, Alessandra; Ferroni, Claudia; Varchi, Greta; Franceschi, Claudio; Ballestrero, Alberto; Poggi, Alessandro; Bruzzone, Santina; Nencioni, Alessio; Del Rio, Alberto

    2015-09-18

    The NAD(+)-dependent sirtuin SIRT6 is highly expressed in human breast, prostate, and skin cancer where it mediates resistance to cytotoxic agents and prevents differentiation. Thus, SIRT6 is an attractive target for the development of new anticancer agents to be used alone or in combination with chemo- or radiotherapy. Here we report on the identification of novel quinazolinedione compounds with inhibitory activity on SIRT6. As predicted based on SIRT6's biological functions, the identified new SIRT6 inhibitors increase histone H3 lysine 9 acetylation, reduce TNF-α production and increase glucose uptake in cultured cells. In addition, these compounds exacerbate DNA damage and cell death in response to the PARP inhibitor olaparib in BRCA2-deficient Capan-1 cells and cooperate with gemcitabine to the killing of pancreatic cancer cells. In conclusion, new SIRT6 inhibitors with a quinazolinedione-based structure have been identified which are active in cells and could potentially find applications in cancer treatment. PMID:26310895

  4. Saikosaponin-d: A potential chemotherapeutics in castration resistant prostate cancer by suppressing cancer metastases and cancer stem cell phenotypes.

    PubMed

    Zhong, Di; Zhang, Hui-Jian; Jiang, Yao-Dong; Wu, Peng; Qi, Huan; Cai, Chao; Zheng, Shao-Bin; Dang, Qiang

    2016-06-10

    Androgen deprivation therapy is the gold standard regimen for advanced Prostate cancer (PCa) patients, nevertheless, patients eventually develop into castration-resistant prostate cancer (CRPC). Currently only a few chemotherapeutics are available for CRPC. Therefore, it is critical for identifying a new drug. In this study, we will explore a new agent, Saikosaponin-d (SSd), for CRPC therapy based on its mechanism of action. DU145 and CWR22Rv1 cells representing CRPC were employed in this study. A series of cell, biochemical, and molecular biologic assays such as Immunofluorescence, Zymography, Sphere formation, Colony formation, and MTT were used. Finally, we find SSd can significantly inhibit the growth of PCa cells in both dose- and time-dependent and suppress the colony formation during a long-term drug administration, it also can inhibit their migration and invasion abilities, which was accompanied by reverse the epithelial-mesenchymal transition (EMT) and suppress MMP2/9 expression as well as activities. Furthermore, SSd can suppress cancer stem cell (CSC) phenotypes such as self-renewal ability. Mechanistically, SSd blocks Wnt/β-catenin signaling pathway by decreasing GSK3β phosphorylation to affect EMT and CSC. These findings demonstrate the mechanism of anti-cancer activity of SSd in targeting EMT and CSC, suggesting SSd can be a potent agent for CRPC therapy. PMID:27155154

  5. Drilling fluid containing a copolymer filtration control agent

    SciTech Connect

    Enright, D.P.; Lucas, J.M.; Perricone, A.C.

    1981-10-06

    The invention relates to an aqueous drilling fluid composition, a filtration control agent for utilization in said aqueous drilling fluid, and a method of forming a filter cake on the wall of a well for the reduction of filtrate from said drilling fluid, by utilization of a copolymer of: (1) a (Meth) acrylamido alkyl sulfonic acid or alkali metal salt thereof; and (2) a (Meth) acrylamide or n-alkyl (Meth) acrylamide. The copolymer may be cross-linked with a quaternary ammonium salt cross-linking agent.

  6. 40 CFR 721.10218 - 2-Propenoic acid, 2-mehtyl-, C12-15-branched and linear alkyl esters, telomers with alkyl 2...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...-branched and linear alkyl esters, telomers with alkyl 2- thio]-2-alkanoate, aminoalkyl methacrylate and alkyl methacrylate, tert-Bu 2-ethylhexanoperoxoate-initiated (generic). 721.10218 Section 721.10218...-alkanoate, aminoalkyl methacrylate and alkyl methacrylate, tert-Bu 2-ethylhexanoperoxoate-initiated...

  7. 40 CFR 721.10218 - 2-Propenoic acid, 2-mehtyl-, C12-15-branched and linear alkyl esters, telomers with alkyl 2...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...-branched and linear alkyl esters, telomers with alkyl 2- thio]-2-alkanoate, aminoalkyl methacrylate and alkyl methacrylate, tert-Bu 2-ethylhexanoperoxoate-initiated (generic). 721.10218 Section 721.10218...-alkanoate, aminoalkyl methacrylate and alkyl methacrylate, tert-Bu 2-ethylhexanoperoxoate-initiated...

  8. 40 CFR 721.10218 - 2-Propenoic acid, 2-mehtyl-, C12-15-branched and linear alkyl esters, telomers with alkyl 2...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...-branched and linear alkyl esters, telomers with alkyl 2- thio]-2-alkanoate, aminoalkyl methacrylate and alkyl methacrylate, tert-Bu 2-ethylhexanoperoxoate-initiated (generic). 721.10218 Section 721.10218...-alkanoate, aminoalkyl methacrylate and alkyl methacrylate, tert-Bu 2-ethylhexanoperoxoate-initiated...

  9. 40 CFR 721.10218 - 2-Propenoic acid, 2-mehtyl-, C12-15-branched and linear alkyl esters, telomers with alkyl 2...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...-branched and linear alkyl esters, telomers with alkyl 2- thio]-2-alkanoate, aminoalkyl methacrylate and alkyl methacrylate, tert-Bu 2-ethylhexanoperoxoate-initiated (generic). 721.10218 Section 721.10218...-alkanoate, aminoalkyl methacrylate and alkyl methacrylate, tert-Bu 2-ethylhexanoperoxoate-initiated...

  10. Old drugs, novel ways out: Drug resistance toward cytotoxic chemotherapeutics.

    PubMed

    Wijdeven, Ruud H; Pang, Baoxu; Assaraf, Yehuda G; Neefjes, Jacques

    2016-09-01

    Efficacy of chemotherapy in the treatment of distinct malignancies is often hampered by drug resistance arising in the tumor. Understanding the molecular basis of drug resistance and translating this knowledge into personalized treatment decisions can enhance therapeutic efficacy and even curative outcome. Over the years, multiple drug resistance mechanisms have been identified that enable tumors to cope with the damage instigated by a specific drug or group of anti-tumor agents. Here we provide an overview of the molecular pathways leading to resistance against conventional anti-cancer drugs, with emphasis on the utility of these pathways for rational selection of treatments for individual cancer patients. We further complement the review by discussing the pitfalls and difficulties in translating these findings into novel treatment strategies for cancer patients. PMID:27620955

  11. Pharmacokinetic interactions of breast cancer chemotherapeutics with human doxorubicin reductases.

    PubMed

    Hofman, Jakub; Skarka, Adam; Havrankova, Jana; Wsol, Vladimir

    2015-08-01

    Paclitaxel (PTX), docetaxel (DTX), 5-fluorouracil (5-FU), cyclophosphamide (CYC) or tamoxifen (TMX) are combined with doxorubicin (DOX) in first-line chemotherapy regimens that are indicated for breast cancer patients. Although the efficacies of these drugs in combination treatments have been demonstrated in clinical practice, their possible interference with DOX metabolism has not been described in detail to date. In the present study, we investigated the possible interactions of human carbonyl reducing enzymes with 5-FU, PTX, DTX, CYC and TMX. First, the reducing activities of carbonyl reducing enzymes toward DOX were tested using incubations with purified recombinant enzymes. In the subsequent studies, we investigated the possible effects of the tested anticancer agents on the DOX-reducing activities of the most potent enzymes (AKR1C3, CBR1 and AKR1A1) and on the DOX metabolism driven by MCF7, HepG2 and human liver cytosols. In both of these assays, we observed that CYC and its active metabolites inhibited DOX metabolism. In the final study, we tracked the changes in AKR1C3, CBR1 and AKR1A1 expression levels following exposure to the tested cytostatics in MCF7 and HepG2 cells. Consequently, no significant changes in the expression levels of tested enzymes were detected in either cell line. Based on these findings, it is feasible to presume that inhibition rather than induction plays a role in the interactions of the tested anticancer agents with DOX-reducing enzymes. In conclusion, our results describe important molecular events that occur during combination breast cancer therapies and might modulate pharmacokinetic DOX resistance and/or behaviour. PMID:25986883

  12. The photodissociation dynamics of alkyl radicals

    NASA Astrophysics Data System (ADS)

    Giegerich, Jens; Fischer, Ingo

    2015-01-01

    The photodisscociation dynamics of the alkyl radicals i-propyl (CH(CH3)2) and t-butyl (C(CH3)3) are investigated by H-atom photofragment imaging. While i-propyl is excited at 250 nm, the photodynamics of t-butyl are explored over a large energy range using excitation wavelengths between 347 nm and 233 nm. The results are compared to those obtained previously for ethyl, CH3CH2, and to those reported for t-butyl using 248 nm excitation. The translational energy (ET) distribution of the H-atom photofragments is bimodal and appears rather similar for all three radicals. The low ET part of the distribution shows an isotropic photofragment angular distribution, while the high ET part is associated with a considerable anisotropy. Thus, for t-butyl, two H-atom loss channels of roughly equal importance have been identified in addition to the CH3-loss channel reported previously. A mechanism for the photodissociation of alkyl radicals is suggested that is based on interactions between Rydberg- and valence states.

  13. The photodissociation dynamics of alkyl radicals

    SciTech Connect

    Giegerich, Jens; Fischer, Ingo

    2015-01-28

    The photodisscociation dynamics of the alkyl radicals i-propyl (CH(CH{sub 3}){sub 2}) and t-butyl (C(CH{sub 3}){sub 3}) are investigated by H-atom photofragment imaging. While i-propyl is excited at 250 nm, the photodynamics of t-butyl are explored over a large energy range using excitation wavelengths between 347 nm and 233 nm. The results are compared to those obtained previously for ethyl, CH{sub 3}CH{sub 2}, and to those reported for t-butyl using 248 nm excitation. The translational energy (E{sub T}) distribution of the H-atom photofragments is bimodal and appears rather similar for all three radicals. The low E{sub T} part of the distribution shows an isotropic photofragment angular distribution, while the high E{sub T} part is associated with a considerable anisotropy. Thus, for t-butyl, two H-atom loss channels of roughly equal importance have been identified in addition to the CH{sub 3}-loss channel reported previously. A mechanism for the photodissociation of alkyl radicals is suggested that is based on interactions between Rydberg- and valence states.

  14. Bacteriocins as Potential Anticancer Agents

    PubMed Central

    Kaur, Sumanpreet; Kaur, Sukhraj

    2015-01-01

    Cancer remains one of the leading causes of deaths worldwide, despite advances in its treatment and detection. The conventional chemotherapeutic agents used for the treatment of cancer have non-specific toxicity toward normal body cells that cause various side effects. Secondly, cancer cells are known to develop chemotherapy resistance in due course of treatment. Thus, the demand for novel anti-cancer agents is increasing day by day. Some of the experimental studies have reported the therapeutic potential of bacteriocins against various types of cancer cell lines. Bacteriocins are ribosomally-synthesized cationic peptides secreted by almost all groups of bacteria. Some bacteriocins have shown selective cytotoxicity toward cancer cells as compared to normal cells. This makes them promising candidates for further investigation and clinical trials. In this review article, we present the overview of the various cancer cell-specific cytotoxic bacteriocins, their mode of action and efficacies. PMID:26617524

  15. 40 CFR 721.10038 - Trimellitic anhydride, polymer with substituted glycol, alkyl phenols and ethoxylated nonylphenol...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... substituted glycol, alkyl phenols and ethoxylated nonylphenol (generic). 721.10038 Section 721.10038... Trimellitic anhydride, polymer with substituted glycol, alkyl phenols and ethoxylated nonylphenol (generic... identified generically as trimellitic anhydride, polymer with substituted glycol, alkyl phenols...

  16. 40 CFR 721.10038 - Trimellitic anhydride, polymer with substituted glycol, alkyl phenols and ethoxylated nonylphenol...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... substituted glycol, alkyl phenols and ethoxylated nonylphenol (generic). 721.10038 Section 721.10038... Trimellitic anhydride, polymer with substituted glycol, alkyl phenols and ethoxylated nonylphenol (generic... identified generically as trimellitic anhydride, polymer with substituted glycol, alkyl phenols...

  17. 40 CFR 721.10038 - Trimellitic anhydride, polymer with substituted glycol, alkyl phenols and ethoxylated nonylphenol...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... substituted glycol, alkyl phenols and ethoxylated nonylphenol (generic). 721.10038 Section 721.10038... Trimellitic anhydride, polymer with substituted glycol, alkyl phenols and ethoxylated nonylphenol (generic... identified generically as trimellitic anhydride, polymer with substituted glycol, alkyl phenols...

  18. Design and in vitro activities of N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, novel small molecule Hypoxia Inducible Factor-1 (HIF-1) pathway inhibitors and anti-cancer agents

    PubMed Central

    Mun, Jiyoung; Jabbar, Adnan Abdul; Devi, Narra Sarojini; Yin, Shaoman; Wang, Yingzhe; Tan, Chalet; Culver, Deborah; Snyder, James P.; Van Meir, Erwin G.; Goodman, Mark M.

    2013-01-01

    The Hypoxia Inducible Factor (HIF) pathway is an attractive target for cancer as it controls tumor adaptation to growth under hypoxia and mediates chemo- and radiation resistance. We previously discovered 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, as a novel small molecule HIF-1 pathway inhibitor in a high-throughput cell-based assay, but its in vivo delivery is hampered by poor aqueous solubility (0.009 μM in water; logP7.4: 3.7). Here we describe the synthesis of twelve N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, which were designed to possess optimal lipophilicities and aqueous solubilities by in silico calculations. Experimental logP7.4 values of 8 of the 12 new analogs ranged from 1.2 ∼ 3.1. Aqueous solubilities of 3 analogs were measured, among which the most soluble N-[(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide had an aqueous solubility of 80 μM, e.g. a solubility improvement of ∼9,000-fold. The pharmacological optimization had minimal impact on drug efficacy as the compounds retained IC50 values at or below 5 μM in our HIF-dependent reporter assay. PMID:22746274

  19. 5-Alkyl-6-benzyl-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones, a series of anti-HIV-1 agents of the dihydro-alkoxy-benzyl-oxopyrimidine family with peculiar structure-activity relationship profile.

    PubMed

    Nawrozkij, Maxim B; Rotili, Dante; Tarantino, Domenico; Botta, Giorgia; Eremiychuk, Alexandre S; Musmuca, Ira; Ragno, Rino; Samuele, Alberta; Zanoli, Samantha; Armand-Ugón, Mercedes; Clotet-Codina, Imma; Novakov, Ivan A; Orlinson, Boris S; Maga, Giovanni; Esté, José A; Artico, Marino; Mai, Antonello

    2008-08-14

    A series of dihydro-alkylthio-benzyl-oxopyrimidines (S-DABOs) bearing a 2-aryl-2-oxoethylsulfanyl chain at pyrimidine C2, an alkyl group at C5, and a 2,6-dichloro-, 2-chloro-6-fluoro-, and 2,6-difluoro-benzyl substitution at C6 (oxophenethyl- S-DABOs, 6-8) is here described. The new compounds showed low micromolar to low nanomolar (in one case subnanomolar) inhibitory activity against wt HIV-1. Against clinically relevant HIV-1 mutants (K103N, Y181C, and Y188L) as well as in enzyme (wt and K103N, Y181I, and L100I mutated RTs) assays, compounds carrying an ethyl/ iso-propyl group at C5 and a 2,6-dichloro-/2-chloro-6-fluoro-benzyl moiety at C6 were the most potent derivatives, also characterized by low fold resistance ratio. Interestingly, the structure-activity relationship (SAR) data drawn from this DABO series are more related to HEPT than to DABO derivatives. These findings were at least in part rationalized by the description of a fair superimposition between the 6-8 and TNK-651 (a HEPT analogue) binding modes in both WT and Y181C RTs. PMID:18630898

  20. Agent Orange

    MedlinePlus

    ... Index Agent Orange Agent Orange Home Facts about Herbicides Veterans' Diseases Birth Defects Benefits Exposure Locations Provider ... millions of gallons of Agent Orange and other herbicides on trees and vegetation during the Vietnam War. ...