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Sample records for alkylating chemotherapeutic agents

  1. [Chemotherapeutic agents under study].

    PubMed

    Kawahara, S

    1998-12-01

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

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

    PubMed Central

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

    1981-01-01

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

  3. 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.

  4. Current Research and Development of Chemotherapeutic Agents for Melanoma

    PubMed Central

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

    2010-01-01

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

  5. Alterations in repair of alkylating agent-induced DNA damage in polyamine-depleted human cells.

    PubMed

    Snyder, R D; Bhatt, S

    1993-08-16

    Treatment of HeLa cells with the polyamine biosynthesis inhibitors difluoromethylornithine (DFMO) and/or methylglyoxal bis(guanylhydrazone) (MGBG) results in marked depression in levels of the cellular polyamines putrescine, spermidine and spermine. Cells in this polyamine-depleted state exhibited increased sensitivity to monofunctional alkylating agents, manifested as decreased cloning ability and retardation of the DNA excision repair process. DFMO treatment did not alter the initial level of interaction of radiolabeled alkylating agent with cellular DNA, but combined treatment with DFMO and MGBG reduced covalent binding, probably through effects on cell cycling. Polyamine supplementation had no effects on initial yield of DNA single-strand breaks in drug-treated cells. The repair defect appeared similar to that observed previously in polyamine-depleted cells following X-irradiation and UV irradiation, namely retarded sealing of DNA strand breaks. It was not possible to reverse the effects of these inhibitors by short periods of polyamine loading, despite the fact that all three polyamines could be restored to near-normal levels. These findings provide the first demonstration of altered response of polyamine-depleted cells to monofunctional alkylating agents and contribute to our understanding of altered responses of polyamine-depleted cancer cells to a variety of DNA-reactive chemotherapeutic drugs.

  6. The Scarlet Letter of Alkylation: A Mini Review of Selective Alkylating Agents

    PubMed Central

    Oronsky, Bryan T; Reid, Tony; Knox, Susan J; Scicinski, Jan J

    2012-01-01

    If there were a stigma scale for chemotherapy, alkylating agents would be ranked at the top of the list. The chemical term alkylation is associated with nonselective toxicity, an association that dates back to the use of nitrogen mustards during World War I as chemical warfare agents. That this stigma persists and extends to compounds that, through selectivity, attempt to “tame” the indiscriminate destructive potential of alkylation is the subject of this review. Selective alkylation, as it is referred to herein, constitutes an extremely nascent and dynamic field in oncology. The pharmacodynamic response to this selective strategy depends on a delicate kinetic balance between specificity and the rate and extent of binding. Three representative compounds are presented: RRx-001, 3-bromopyruvate, and TH-302. The main impetus for the development of these compounds has been the avoidance of the serious complications of traditional alkylating agents; therefore, it is the thesis of this review that they should not experience stigma by association. PMID:22937173

  7. 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

  8. 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

  9. 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.

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

    PubMed

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

    2017-01-01

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

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

    PubMed Central

    2013-01-01

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

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

    DTIC Science & Technology

    2002-05-01

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

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

    PubMed

    Wüst, J; Hardegger, U

    1991-12-27

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

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

    PubMed

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

    2014-02-01

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

  15. Determination of reaction rate constants for alkylation of 4-(p-nitrobenzyl) pyridine by different alkylating agents.

    PubMed

    Walles, S A

    1980-02-01

    The rate constants have been determined for the reaction between some different alkylating agents and 4-(p-nitrobenzyl) pyridine (NBP) in methanol. These constants have been compared with those for alkylation of aniline in water. All the constants were lower in methanol than in water but in different degrees. The rate constants of the different alkylating agents have been calculated at a nucleophilic strength n=2. The genetic risk defined as the degree of alkylation of a nucleophile (n=2) is equivalent to the rate constant kn=2 and the target dose. The dependence of the genetic risk on the rate constant (kn=2) is discussed.

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

    PubMed

    Begleiter, A; Leith, M K

    1990-05-15

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

  17. 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.

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

    PubMed

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

    2017-03-28

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

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

    DTIC Science & Technology

    2006-08-01

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

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

    DTIC Science & Technology

    2007-08-01

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

  1. Carcinogenic potency of alkylating agents in rodents and humans.

    PubMed

    Dedrick, R L; Morrison, P F

    1992-05-01

    Alkylating agents are known to produce second tumors in cancer patients treated for their primary cancer. Since therapeutic doses are high and the pharmacokinetics of the drugs are thoroughly studied, these agents provide a unique opportunity to compare intrinsic carcinogenic potency between experimental animals and humans. We have examined the carcinogenicity of melphalan, chlorambucil, and cyclophosphamide in causing leukemia in patients treated for cancer or polycythemia vera and lymphosarcoma in rats and mice. A good correlation among species is observed when the carcinogenic potency is based on the total lifetime exposure to active species derived from these drugs.

  2. Cu(I)-Catalyzed Enantioselective Friedel-Crafts Alkylation of Indoles with 2-Aryl-N-sulfonylaziridines as Alkylating Agents.

    PubMed

    Ge, Chen; Liu, Ren-Rong; Gao, Jian-Rong; Jia, Yi-Xia

    2016-07-01

    A highly enantioselective Friedel-Crafts alkylation of indoles with N-sulfonylaziridines as alkylating agents has been developed by utilizing the complex of Cu(CH3CN)4BF4/(S)-Segphos as a catalyst. A range of optically active tryptamine derivatives are obtained in good to excellent yields and enantioselectivities (up to >99% ee) via a kinetic resolution process.

  3. 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.

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

    PubMed

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

    2015-11-12

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

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

    PubMed

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

    2005-08-01

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

  6. 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.

  7. 2,3-DIPHENYL-1,4-NAPHTHOQUINONE: A POTENTIAL CHEMOTHERAPEUTIC AGENT AGAINST TRYPANOSOMA CRUZI

    PubMed Central

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

    2010-01-01

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

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

    PubMed

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

    2017-03-01

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

  9. Nicotinamide Inhibits Alkylating Agent-Induced Apoptotic Neurodegeneration in the Developing Rat Brain

    PubMed Central

    Naseer, Muhammad Imran; Ullah, Ikram; Suh, Joo Won; Kim, Myeong Ok

    2011-01-01

    Background Exposure to the chemotherapeutic alkylating agent thiotepa during brain development leads to neurological complications arising from neurodegeneration and irreversible damage to the developing central nerve system (CNS). Administration of single dose of thiotepa in 7-d postnatal (P7) rat triggers activation of apoptotic cascade and widespread neuronal death. The present study was aimed to elucidate whether nicotinamide may prevent thiotepa-induced neurodegeneration in the developing rat brain. Methodology/Principal Findings Neuronal cell death induced by thiotepa was associated with the induction of Bax, release of cytochrome-c from mitochondria into the cytosol, activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP-1). Post-treatment of developing rats with nicotinamide suppressed thiotepa-induced upregulation of Bax, reduced cytochrome-c release into the cytosol and reduced expression of activated caspase-3 and cleavage of PARP-1. Cresyl violet staining showed numerous dead cells in the cortex hippocampus and thalamus; post-treatment with nicotinamide reduced the number of dead cells in these brain regions. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) and immunohistochemical analysis of caspase-3 show that thiotepa-induced cell death is apoptotic and that it is inhibited by nicotinamide treatment. Conclusion Nicotinamide (Nic) treatment with thiotepa significantly improved neuronal survival and alleviated neuronal cell death in the developing rat. These data demonstrate that nicotinamide shows promise as a therapeutic and neuroprotective agent for the treatment of neurodegenerative disorders in newborns and infants. PMID:22164206

  10. The effect of alkylating agents on male rat fertility

    PubMed Central

    Jackson, H.; Fox, B. W.; Craig, A. W.

    1959-01-01

    The effects of tumour inhibitory doses of tretamine (triethylenemelamine), busulphan, and melphalan on the fertility of male rats have been examined. The aromatic nitrogen mustard, melphalan, was inactive, but busulphan has a highly selective action on spermatogenesis which contrasts strikingly with that of tretamine. The main action of tretamine was exerted upon spermatocytes or spermatids, but, with increasing dose, the effects spread to involve a wide range of spermatogenic cells including mature sperm, so that infertility could be induced very rapidly. Busulphan, however, interfered with the development of spermatogonia for several weeks, although other germinal cells were unaffected and continued to develop into mature spermatozoa. This accounted for the continuation of normal fertility for 7 weeks after a dose, before sterility suddenly developed. The antifertility activity of tretamine could be simulated by a variety of other ethyleneimino compounds, potency being greatest in trifunctional and least in monofunctional compounds. The latter were, however, very destructive to the seminiferous epithelium with increasing dose. In the rat, there appeared to be no definite relationship between the ability of alkylating substances to interfere with the activity of normal and pathological proliferating tissues, as represented by the germinal epithelium, haematopoietic, and tumour tissue. Although carcinogenicity was a biological property of alkylating agents, other chemical types of carcinogen did not interfere with fertility. ImagesFIG. 2aFIG. 2bFIG. 2c PMID:13662565

  11. 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

  12. 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.

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

    PubMed

    Lee, Kuo-Hsiung

    2010-03-26

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

  14. DNA minor groove targeted alkylating agents based on bisbenzimidazole carriers: synthesis, cytotoxicity and sequence-specificity of DNA alkylation.

    PubMed

    Smaill, J B; Fan, J Y; Denny, W A

    1998-12-01

    A series of bisbenzimidazoles bearing a variety of alkylating agents [ortho- and meta-mustards, imidazolebis(hydroxymethyl), imidazolebis(methylcarbamate) and pyrrolebis(hydroxymethyl)], appended by a propyl linker chain, were prepared and investigated for sequence-specificity of DNA alkylation and their cytotoxicity. Previous work has shown that, for para-aniline mustards, a propyl linker is optimal for cytotoxicity. Alkaline cleavage assays using a variety of different labelled oligonucleotides showed that the preferred sequences for adenine alkylation were 5'-TTTANANAANN and 5'-ATTANANAANN (underlined bases show the drug alkylation sites), with AT-rich sequences required on both the 5' and 3' sides of the alkylated adenine. The different aniline mustards showed little variation in alkylation pattern and similar efficiencies of DNA cross-link formation despite the changes in orientation and positioning of the mustard, suggesting that the propyl linker has some flexibility. The imidazole- and pyrrolebis(hydroxymethyl) alkylators showed no DNA strand cleavage following base treatment, indicating that no guanine or adenine N3 or N7 adducts were formed. Using the PCR-based polymerase stop assay, these alkylators showed PCR blocks at 5'-C*G sites (the * nucleotide indicates the blocked site), particularly at 5'-TAC*GA 5'-AGC*GGA, and 5'-AGCC*GGT sequences, caused by guanine 2-NH2 lesions on the opposite strand. Only the (more reactive) imidazolebis(methylcarbamoyl) and pyrrolebis(hydroxymethyl) alkylators demonstrated interstrand cross-linking ability. All of the bifunctional mustards showed large (approximately 100-fold) increases in cytotoxicity over chlorambucil, with the corresponding monofunctional mustards being 20- to 60-fold less cytotoxic. These results suggest that in the mustards the propyl linker provides sufficient flexibility to achieve delivery of the alkylator to favoured (adenine N3) sites in the minor groove, regardless of its exact geometry with

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

    PubMed

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

    2016-08-01

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

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

    PubMed

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

    2002-05-01

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

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

    PubMed

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

    1993-12-01

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

  18. 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.

  19. Bifunctional rhodium intercalator conjugates as mismatch-directing DNA alkylating agents.

    PubMed

    Schatzschneider, Ulrich; Barton, Jacqueline K

    2004-07-21

    A conjugate of a DNA mismatch-specific rhodium intercalator, containing the bulky chrysenediimine ligand, and an aniline mustard has been prepared, and targeting of mismatches in DNA by this conjugate has been examined. The preferential alkylation of mismatched over fully matched DNA is found by a mobility shift assay at concentrations where untethered organic mustards show little reaction. The binding site of the Rh intercalator was determined by DNA photocleavage, and the position of covalent modification was established on the basis of the enhanced depurination associated with N-alkylation. The site-selective alkylation at mismatched DNA renders these conjugates useful tools for the covalent tagging of DNA base pair mismatches and new chemotherapeutic design.

  20. Alkyl and Aromatic Amines as Digestive Ripening/Size Focusing Agents for Gold Nanoparticles

    PubMed Central

    Sun, Yijun; Jose, Deepa; Sorensen, Christopher; Klabunde, Kenneth J.

    2013-01-01

    Both long chain alkyl thiols and alkyl amines behave as size focusing agents for gold nanoparticles, a process that is under thermodynamic control. However, amines do not oxidize surface gold atoms while thiols do oxidize surface gold to gold(I) with evolution of hydrogen gas. Therefore, alkyl amines participate in digestive ripening by a different mechanism. The efficiency of alkyl amines for this process is described and compared, and ultimate gold particle size differences are discussed. Reported herein is a detailed investigation of alkyl chain lengths for alkyl amines, aromatic amines (aniline), and unusually reactive amines (2-phenylethyl amine). Also, two methods of preparation of the crude gold nanoparticles were employed: gold ion reduction/inverse micelle vs. metal vaporization (Solvated Metal Atom Dispersion—SMAD).

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

    PubMed

    Fujiwara, Toshiyoshi; Kagawa, Shunsuke; Tazawa, Hiroshi

    2012-07-01

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

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

    PubMed

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

    2013-02-01

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

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

    PubMed

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

    1988-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  5. 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

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

    PubMed

    Torchilin, Vladimir P

    2010-08-01

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

  7. 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.

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

    PubMed

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

    1999-01-01

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

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

    PubMed

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

    2016-02-01

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

  10. 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

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

    PubMed

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

    2017-03-13

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

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

    PubMed Central

    2011-01-01

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

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

    SciTech Connect

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

    1987-12-01

    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 preferences was observed with both methyl and ethyl donors where the predicted common ultimate alkylating species in the alkyl diazonium ion. In contrast, this preferences 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.

  14. S - and N-alkylating agents diminish the fluorescence of fluorescent dye-stained DNA.

    PubMed

    Giesche, Robert; John, Harald; Kehe, Kai; Schmidt, Annette; Popp, Tanja; Balzuweit, Frank; Thiermann, Horst; Gudermann, Thomas; Steinritz, Dirk

    2017-01-25

    Sulfur mustard (SM), a chemical warfare agent, causes DNA alkylation, which is believed to be the main cause of its toxicity. SM DNA adducts are commonly used to verify exposure to this vesicant. However, the required analytical state-of-the-art mass-spectrometry methods are complex, use delicate instruments, are not mobile, and require laboratory infrastructure that is most likely not available in conflict zones. Attempts have thus been made to develop rapid detection methods that can be used in the field. The analysis of SM DNA adducts (HETE-G) by immunodetection is a convenient and suitable method. For a diagnostic assessment, HETE-G levels must be determined in relation to the total DNA in the sample. Total DNA can be easily visualized by the use of fluorescent DNA dyes. This study examines whether SM and related compounds affect total DNA staining, an issue that has not been investigated before. After pure DNA was extracted from human keratinocytes (HaCaT cells), DNA was exposed to different S- and N-alkylating agents. Our experiments revealed a significant, dose-dependent decrease in the fluorescence signal of fluorescent dye-stained DNA after exposure to alkylating agents. After mass spectrometry and additional fluorescence measurements ruled out covalent modifications of ethidium bromide (EthBr) by SM, we assumed that DNA crosslinks caused DNA condensation and thereby impaired access of the fluorescent dyes to the DNA. DNA digestion by restriction enzymes restored fluorescence, a fact that strengthened our hypothesis. However, monofunctional agents, which are unable to crosslink DNA, also decreased the fluorescence signal. In subsequent experiments, we demonstrated that protons produced during DNA alkylation caused a pH decrease that was found responsible for the reduction in fluorescence. The use of an appropriate buffer system eliminated the adverse effect of alkylating agents on DNA staining with fluorescent dyes. An appropriate buffer system is thus

  15. Alkylating agents and immunotoxins exert synergistic cytotoxic activity against ovarian cancer cells. Mechanism of action.

    PubMed Central

    Lidor, Y J; O'Briant, K C; Xu, F J; Hamilton, T C; Ozols, R F; Bast, R C

    1993-01-01

    Alkylating agents can be administered in high dosage to patients with ovarian cancer using autologous bone marrow support, but drug-resistant tumor cells can still persist. Immunotoxins provide reagents that might eliminate drug resistant cells. In the present study, concurrent treatment with alkylators and immunotoxins proved superior to treatment with each agent alone. Toxin immunoconjugates prepared from different monoclonal antibodies and recombinant ricin A chain (rRTA) inhibited clonogenic growth of ovarian cancer cell lines in limiting dilution assays. When alkylating agents and toxin conjugates were used in combination, the addition of the immunotoxins to cisplatin, or to cisplatin and thiotepa, produced synergistic cytotoxic activity against the OVCA 432 and OVCAR III cell lines. Studies performed to clarify the mechanism of action showed that cisplatin and thiotepa had no influence on internalization and binding of the 317G5-rRTA immunotoxin. Intracellular uptake of [195m]Pt-cisplatin was not affected by the immunoconjugate and thiotepa. The combination of the 317G5-rRTA and thiotepa, as well as 317G5-rRTA alone, increased [195m]Pt cisplatin-DNA adduct levels. The immunotoxin alone and in combination with the alkylators decreased intracellular glutathione levels and reduced glutathione-S-transferase activity. Repair of DNA damage induced by the combination of alkylators and 317G5-rRTA was significantly reduced when compared to repair after damage with alkylators alone. These findings suggest that immunotoxins affect levels and activity of enzymes required for the prevention and repair of alkylator damage. Images PMID:8227359

  16. N-alkylated aminopyrazines for use as hydrophilic optical agents

    NASA Astrophysics Data System (ADS)

    Poreddy, Amruta R.; Asmelash, Bethel; Galen, Karen P.; Fitch, Richard M.; Shieh, Jeng-Jong; Wilcox, James M.; Schoenstein, Tasha M.; Wojdyla, Jolette K.; Gaston, Kimberly R.; Freskos, John N.; Neumann, William L.; Rajagopalan, Raghavan; Ahn, Hyo-Yang; Kostelc, James G.; Debreczeny, Martin P.; Belfield, Kevin D.; Dorshow, Richard B.

    2009-02-01

    Rapid assessment of glomerular filtration rate (GFR), which measures the amount of plasma filtered through the kidney within a given time, would greatly facilitate monitoring of renal function for patients at the bedside in the clinic. In our pursuit to develop exogenous fluorescent tracers for real-time monitoring of renal function by optical methods, N-alkylated aminopyrazine dyes and their hydrophilic conjugates based on poly (ethylene glycol) (PEG) were synthesized via reductive amination as the key step. Photophysical properties indicated a bathochromic shift on the order of 50 nm in both absorption and emission compared to naked aminopyrazines which could be very useful in enhancing both tissue penetration as well as easier detection methods. Structure-activity relationship (SAR) and pharmacokinetic (PK) studies, and the correlation of in vivo optical data with plasma PK for measurement of clearance (and hence GFR) are focus of the current investigation.

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed

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

    2016-10-01

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

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

    PubMed

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

    2016-04-29

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

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

    PubMed

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

    2013-12-01

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

  1. DNA-directed alkylating ligands as potential antitumor agents: sequence specificity of alkylation by intercalating aniline mustards.

    PubMed

    Prakash, A S; Denny, W A; Gourdie, T A; Valu, K K; Woodgate, P D; Wakelin, L P

    1990-10-23

    The sequence preferences for alkylation of a series of novel parasubstituted aniline mustards linked to the DNA-intercalating chromophore 9-aminoacridine by an alkyl chain of variable length were studied by using procedures analogous to Maxam-Gilbert reactions. The compounds alkylate DNA at both guanine and adenine sites. For mustards linked to the acridine by a short alkyl chain through a para O- or S-link group, 5'-GT sequences are the most preferred sites at which N7-guanine alkylation occurs. For analogues with longer chain lengths, the preference of 5'-GT sequences diminishes in favor of N7-adenine alkylation at the complementary 5'-AC sequence. Magnesium ions are shown to selectively inhibit alkylation at the N7 of adenine (in the major groove) by these compounds but not the alkylation at the N3 of adenine (in the minor groove) by the antitumor antibiotic CC-1065. Effects of chromophore variation were also studied by using aniline mustards linked to quinazoline and sterically hindered tert-butyl-9-aminoacridine chromophores. The results demonstrate that in this series of DNA-directed mustards the noncovalent interactions of the carrier chromophores with DNA significantly modify the sequence selectivity of alkylation by the mustard. Relationships between the DNA alkylation patterns of these compounds and their biological activities are discussed.

  2. Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition.

    PubMed

    Tse, Anfernee Kai-Wing; Chen, Ying-Jie; Fu, Xiu-Qiong; Su, Tao; Li, Ting; Guo, Hui; Zhu, Pei-Li; Kwan, Hiu-Yee; Cheng, Brian Chi-Yan; Cao, Hui-Hui; Lee, Sally Kin-Wah; Fong, Wang-Fun; Yu, Zhi-Ling

    2017-04-01

    Nitrosourea represents one of the most active classes of chemotherapeutic alkylating agents for metastatic melanoma. Treatment with nitrosoureas caused severe systemic side effects which hamper its clinical use. Here, we provide pharmacological evidence that reactive oxygen species (ROS) induction and IKKβ inhibition cooperatively enhance nitrosourea-induced cytotoxicity in melanoma cells. We identified SC-514 as a ROS-inducing IKKβ inhibitor which enhanced the function of nitrosoureas. Elevated ROS level results in increased DNA crosslink efficiency triggered by nitrosoureas and IKKβ inhibition enhances DNA damage signals and sensitizes nitrosourea-induced cell death. Using xenograft mouse model, we confirm that ROS-inducing IKKβ inhibitor cooperates with nitrosourea to reduce tumor size and malignancy in vivo. Taken together, our results illustrate a new direction in nitrosourea treatment, and reveal that the combination of ROS-inducing IKKβ inhibitors with nitrosoureas can be potentially exploited for melanoma therapy.

  3. 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.

  4. 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.

  5. Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents.

    PubMed Central

    Knebel, A; Rahmsdorf, H J; Ullrich, A; Herrlich, P

    1996-01-01

    Several non-physiologic agents such as radiation, oxidants and alkylating agents induce ligand-independent activation of numerous receptor tyrosine kinases (RTKs) and of protein tyrosine kinases at the inner side of the plasma membrane (e.g. Dévary et al., 1992; Sachsenmaier et al., 1994; Schieven et al., 1994; Coffer et al., 1995). Here we show additional evidence for the activation of epidermal growth factor receptor (EGFR), and we show activation of v-ErbB, ErbB2 and platelet-derived growth factor receptor. As a common principle of action the inducing agents such as UVC, UVB, UVA, hydrogen peroxide and iodoacetamide inhibit receptor tyrosine dephosphorylation in a thiol-sensitive and, with the exception of the SH-alkylating agent, reversible manner. EGFR dephosphorylation can also be modulated by these non-physiologic agents in isolated plasma membranes in the presence of Triton X-100. Further, substrate (EGFR) and phosphatase have been separated: a membrane preparation of cells that have been treated with epidermal growth factor (EGF) and whose dephosphorylating enzymes have been permanently destroyed by iodoacetamide can be mixed with a membrane preparation from untreated cells which re-establishes EGFR dephosphorylation. This dephosphorylation can be modulated in vitro by UV and thiol agents. We conclude that RTKs exhibit significant spontaneous protein kinase activity; several adverse agents target (an) essential SH-group(s) carried by (a) membrane-bound protein tyrosine phosphatase(s). Images PMID:8895576

  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. 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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  10. HTB140 melanoma cells under proton irradiation and/or alkylating agents

    NASA Astrophysics Data System (ADS)

    Korićanac, L.; Petrović, I.; Privitera, G.; Cuttone, G.; Ristić-Fira, A.

    2007-09-01

    Chemoresistance is a major problem in the treatment of malignant melanoma. The mainstay of treatment for melanoma is the DNA-alkylating agent dacarbazine (DTIC). Fotemustine (FM), a member of the chloroethylnitrosourea group of alkylating agents, has also demonstrated significant antitumor effects in malignant melanoma. However, the intrinsic and acquired resistance of melanoma limits the clinical application of these drugs. Melanomas are also extremely radioresistant. With the objective of enhancing growth inhibition of melanoma cells, combined treatments of FM or DTIC with proton irradiation have been investigated. These effects were studied on HTB140 melanoma cell viability and proliferation. Cells exposed to treatment with FM and protons have shown inhibition of cell growth and significant reduction of proliferation capacity compared to single irradiation or drug treatment. Treatment with DTIC and protons has shown improved growth inhibition compared to appropriate single drug treatment, while the effects of single proton irradiation have been the most pronounced.

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

    PubMed Central

    Bierman, Howard R.

    1953-01-01

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

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

    PubMed

    Bartzatt, Ronald L

    2004-01-01

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

  13. 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

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

    PubMed

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

    1983-01-01

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

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

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

    PubMed Central

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

    2014-01-01

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

  1. Photo-triggered fluorescent theranostic prodrugs as DNA alkylating agents for mechlorethamine release and spatiotemporal monitoring.

    PubMed

    Cao, Yanting; Pan, Rong; Xuan, Weimin; Wei, Yongyi; Liu, Kejian; Zhou, Jiahong; Wang, Wei

    2015-06-28

    We describe a new theranostic strategy for selective delivery and spatiotemporal monitoring of mechlorethamine, a DNA alkylating agent. A photo-responsive prodrug is designed and composed of a photolabile o-nitrophenylethyl group, a DNA alkylating mechlorethamine drug and a coumarin fluorophore. Masking of the "N" in mechlorethamine in a positively charged state in the prodrug renders it inactive, non-toxic, selective and non-fluorescent. Indeed, the stable prodrug shows negligible cytotoxicity towards normal cells with and without UV activation and is completely non-fluorescent. However, upon photo-irradiation, the active mechlorethamine is released and induces efficient DNA cross-links, accompanied by a strong fluorescence enhancement (152 fold). Furthermore, DNA cross-linking activity from the release can be transformed into anticancer activity observed in in vitro studies of tumor cells. Importantly, the drug release progress and the movement can be conveniently monitored by fluorescence spectroscopy. The mechanistic study proves that the DNA cross-linking activity is mainly due to the release of DNA alkylating mechlorethamine. Altogether, the studies show the power of the theranostic strategy for efficient therapy in cancer treatment.

  2. Cytotoxic and apoptotic effects of bortezomib and gefitinib compared to alkylating agents on human glioblastoma cells.

    PubMed

    Pédeboscq, Stéphane; L'Azou, Béatrice; Passagne, Isabelle; De Giorgi, Francesca; Ichas, François; Pometan, Jean-Paul; Cambar, Jean

    2008-01-01

    Glioblastoma is a malignant astrocytic tumor with a median survival of about 12 months for which new therapeutic strategies are required. We therefore examined the cytotoxicity of anticancer drugs with different mechanisms of action on two human glioblastoma cell lines expressing various levels of EGFR (epidermal growth factor receptor). Apoptosis induced by these anticancer agents was evaluated by flow cytometry. The cytotoxicity of alkylating drugs followed a dose-effect curve and cytotoxicity index values were lower with carboplatin than with BCNU and temozolomide. Anti-EGFR gefitinib (10 microM) cytotoxicity on DBTRG.05-MG expressing high levels of EGFR was significantly higher than on U87-MG expressing low levels of EGFR. Carboplatin and temozolomide cytotoxicity was potentiated with the addition of gefitinib on DBTRG.05-MG. Among the anticancer agents tested, the proteasome inhibitor bortezomib was the most cytotoxic with very low IC50 on the two cell lines. Moreover, all anticancer drugs tested induced apoptosis in a concentration-dependent manner. Bortezomib proved to be a more potent inductor of apoptosis than gefitinib and alkylating agents. These results show the efficacy of bortezomib and of the association between conventional chemotherapy and gefitinib on glioblastoma cells and therefore suggest the interest of these molecules in the treatment of glioblastoma.

  3. 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.

  4. DNA stretching in the nucleosome facilitates alkylation by an intercalating antitumour agent

    PubMed Central

    Dong, Yuancai; Surana, Uttam; Davey, Curt A.

    2010-01-01

    DNA stretching in the nucleosome core can cause dramatic structural distortions, which may influence compaction and factor recognition in chromatin. We find that the base pair unstacking arising from stretching-induced extreme minor groove kinking near the nucleosome centre creates a hot spot for intercalation and alkylation by a novel anticancer compound. This may have far reaching implications for how chromatin structure can influence binding of intercalator species and indicates potential for the development of site selective DNA-binding agents that target unique conformational features of the nucleosome. PMID:20026584

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

    SciTech Connect

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

    1986-08-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2015-09-01

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

  8. 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

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

    PubMed

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

    2008-12-01

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

  10. 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.

  11. 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.

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

    PubMed

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

    2016-04-01

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

  13. 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

  14. 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.

  15. Directing alkyl chain ordering of functional phosphorus coupling agents on ZrO2.

    PubMed

    Lomoschitz, Christoph J; Feichtenschlager, Bernhard; Moszner, Norbert; Puchberger, Michael; Müller, Klaus; Abele, Matthias; Kickelbick, Guido

    2011-04-05

    ZrO(2) powder (6.6 m(2)/g) was modified using polymerizable phosphorus-based coupling agents (P-CAs) (i.e., phosphonic acid, phosphoric acid, and bis-phosphonic acid), resulting in densely grafted layers as determined by thermogravimetry and elemental analysis (up to 4.2 molecules/nm(2)). The applied P-CAs contained a methacrylate group, which led to the covalent incorporation of a polymerizable moiety into the grafted layer. To direct the ordering of the alkyl chains in the layer, three different approaches were evaluated with respect to their structure-directing ability by means of FT-IR and nitrogen sorption at 77 K: (i) variation of the chain length, (ii) variation of the anchoring group and (iii) comodification with a defined amount of a nonfunctional phosphonic acid (variation of the functional/nonfunctional acid ratio). It was shown that the chain length and anchoring group size have significant effects on the alkyl chain ordering and morphology of the layer.

  16. 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells

    PubMed Central

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

    2016-01-01

    The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53’s oncogenic mutants are just destabilized and rapidly aggregate, and are targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity in several cell lines, especially those with mutationally compromised p53. PK11007 acted by two routes: p53 dependent and p53 independent. PK11007 stabilized p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. Unstable p53 was reactivated by PK11007 in some cancer cell lines, leading to up-regulation of p53 target genes such as p21 and PUMA. More generally, there was cell death that was independent of p53 but dependent on glutathione depletion and associated with highly elevated levels of reactive oxygen species and induction of endoplasmic reticulum (ER) stress, as also found for the anticancer agent PRIMA-1MET(APR-246). PK11007 may be a lead for anticancer drugs that target cells with nonfunctional p53 or impaired reactive oxygen species (ROS) detoxification in a wide variety of mutant p53 cells. PMID:27551077

  17. Synergistic cytotoxicity of the DNA alkylating agent busulfan, nucleoside analogs and SAHA in lymphoma cell lines

    PubMed Central

    Valdez, Benigno C.; Murray, David; Nieto, Yago; Li, Yang; Wang, Guiyun; Champlin, Richard E.; Andersson, Borje S.

    2013-01-01

    Hematopoietic stem cell transplantation (HSCT) is a promising treatment for lymphomas. Its success depends on effective pre-transplant conditioning regimens. We previously reported on the efficacy of DNA alkylating agent-nucleoside analog (NA) combinations for conditioning in AML. We hypothesized that a similar combinatory approach can be used for lymphomas. A combination of busulfan (Bu) with two NAs – clofarabine (Clo), fludarabine (Flu) or gemcitabine (Gem) – resulted in synergistic cytotoxicity in lymphoma cell lines. We demonstrated that the [2 NAs+Bu] combination activates a DNA damage response through the ATM-CHK2 and ATM-CHK1 pathways, leading to cell cycle checkpoint activation and apoptosis. Histone modifications and KAP1 phosphorylation are indicative of chromatin relaxation mediated by the nucleoside analogs which sequentially increase Bu alkylation. Addition of suberoylanilide hydroxamic acid (SAHA) enhanced chromatin relaxation through increased histone acetylation and further augmented the cytotoxicity of [2 NAs+Bu]. Our results provide a preclinical basis for a clinical trial on using [2 NAs+Bu±SAHA] combinations as conditioning therapy for chemotherapy-refractory lymphoma patients undergoing HSCT. PMID:22023523

  18. 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells.

    PubMed

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

    2016-09-06

    The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53's oncogenic mutants are just destabilized and rapidly aggregate, and are targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity in several cell lines, especially those with mutationally compromised p53. PK11007 acted by two routes: p53 dependent and p53 independent. PK11007 stabilized p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. Unstable p53 was reactivated by PK11007 in some cancer cell lines, leading to up-regulation of p53 target genes such as p21 and PUMA. More generally, there was cell death that was independent of p53 but dependent on glutathione depletion and associated with highly elevated levels of reactive oxygen species and induction of endoplasmic reticulum (ER) stress, as also found for the anticancer agent PRIMA-1(MET)(APR-246). PK11007 may be a lead for anticancer drugs that target cells with nonfunctional p53 or impaired reactive oxygen species (ROS) detoxification in a wide variety of mutant p53 cells.

  19. Liposomal chemotherapeutics.

    PubMed

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

    2013-12-01

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

  20. Nucleophilic selectivity of alkylating agents and their hypermutability in Drosophila as predictors of carcinogenic potency in rodents.

    PubMed

    Vogel, E W; Barbin, A; Nivard, M J; Bartsch, H

    1990-12-01

    The nucleophilic selectivity (Swain-Scott s constant or initial 7-alkylguanine/O6-alkylguanine ratio in DNA) of 60 alkylating agents, mostly monofunctional or cross-linking was compared to their carcinogenic potency in rodents (median TD50 estimates) and to two genotoxicity indices in Drosophila: (i) hypermutability, measured by the increased frequency of induced sex-linked recessive lethal mutations (SLRL) in a strain defective in DNA excision repair (exr-), as compared to the wild-type (exr+); (ii) relative clastogenic efficiency, expressed by the ratio of chromosomal aberrations (ring-X loss) to SLRL determined in the exr+ strain. For a subset of direct-acting, monofunctional alkylating agents, nucleophilic selectivity and TD50 values or hypermutability indices were linearly correlated. In addition, the hypermutability indices in Drosophila by methylating or ethylating procarcinogens were similar to the corresponding values of their ultimate metabolites. In contrast, cross-linking agents, including antitumour drugs, did not show these positive correlations. The relative clastogenic efficiencies in Drosophila of 26 direct-acting, alkylating carcinogens increased with both their cross-linking activity and nucleophilic selectivity. By analyzing mutational spectra in Drosophila induced in the vermilion gene by four monofunctional alkylating agents with contrasting s values, critical DNA lesions, i.e. type of base pair substitution mutations, deletions, insertions, involved in genotoxicity were pinpointed. Thus, these multi-endpoint analyses should, as a new approach, assist in the quantitative risk evaluation of genotoxic agents.

  1. 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.

  2. 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.

  3. 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

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

    PubMed Central

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

    2007-01-01

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

  5. Gene expression caused by alkylating agents and cis-diamminedichloroplatinum(II) in Escherichia coli.

    PubMed

    Fram, R J; Crockett, J; Volkert, M R

    1988-09-01

    Previous work has demonstrated heterogeneous effects of methylating agents on induction of DNA damage inducible genes in Escherichia coli. These studies employed E. coli mutants that have fusions of the lac operon to genes induced by treatment with sublethal levels of alkylating agents. These mutants were selected from random insertions of the Mu-dl (Apr lac) phage by screening for induction of beta-galactosidase activity in the presence of methylmethanesulfonate or N-methyl-N'-nitro-N-nitrosoguanidine. The current report extends these findings by analyzing gene expression caused by mechlorethamine, chloroethylnitrosoureas and cis-diamminedichloroplatinum(II) (cis-DDP). The results demonstrate heterogeneous effects by these agents on gene expression. While 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea induces alkA, other nitrosoureas, mechlorethamine, and cis-DDP do not cause expression of this gene. Further, while all nitrosoureas caused expression of aidC, mechlorethamine and cis-DDP did not. Lastly, cis-DDP caused marked expression of a sulA fusion mutant while not inducing any of the other E. coli fusion mutants.

  6. 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.

  7. 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

  8. 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

  9. Abnormal sensitivity of skin fibroblasts from familial polyposis patients to DNA alkylating agents

    SciTech Connect

    Barfknecht, T.R.; Little, J.B.

    1982-04-01

    Fibroblast cell strains derived from different patients all afflicted with genetic predisposing to the development of intestinal polyposis and cancer were tested for their sensitivity to the lethal effects of the DNA alkylating agents methylmethanesulfonate (MMS), ethyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, and 4-nitroquinoline 1-oxide. The genetic syndromes studied were: (a) adenomatosis of the colon and rectum only, an autosomal dominant trait; (b) Turcot's syndrome, a rare autosomal recessive polyposis syndrome also characterized by central nervous system tumors; and (c) Gardner's syndrome, an autosomal dominant syndrome which, in addition to intestinal polyposis, is also clinically characterized by osteomas and soft tissue tumors. Fibroblasts from a patient with Turcot's syndrome were hypersensitive to MMS, having a D0 value of 0.24 mM (p less than 0.01) versus the normal average D0 of 0.36 mM and a D10 value of 0.95 mM (p less than 0.01) compared with the normal average value of 1.3 mM. Fibroblasts from the Gardner's syndrome proband were moderately sensitive to MMS, ethyl methanesulfonate, and N-methyl-N'-nitro-N-nitrosoguanidine due to significant differences of D10 values of 0.60 mM (p less than 0.01), 15 mM (p less than 0.01), and 4.8 microM (p less than 0.025), respectively, versus the normal average values of 1.3 mM, 28 mM, and 9.4 microM. Fibroblasts from the clinically affected Gardner's syndrome daughter of the proband were significantly more sensitive to MMS treatment, D0 of 0.22 mM (p less than 0.01) versus the normal average D0 of 0.36 mM and a D10 of 0.97 mM (p less than 0.01) versus the normal average. This differential sensitivity to the several DNA alkylating agents suggests that different mechanisms of hypersensitivity to these chemicals may be associated with fibroblasts from the various forms of familial polyposis.

  10. Mutagenicity of bleomycin and cross-adaptation with alkylating agents in Crepis capillaris

    SciTech Connect

    Dubinina, L.G.

    1995-05-01

    The radiomimetic effect of bleomycin (BLM) at concentrations of 5 and 10 mg/l on root meristem cells was studied. The roots of germinating seeds of Crepis capillaris were exposed to BLM 16 h after the seeds were soaked. At this time, the root meristem cells were at the S or late G{sub 1} phase of the cell cycle. The mutagenic effect of BLM was found when the cells were fixed at the 29th, 32nd, 39th, 42nd, or 45th hour (i.e., the early germinating fraction). The aberrations induced included chromosome and chromatid rearrangements. At late fixations cells were observed which had, in addition to definite double-hit aberrations, multiple chromosomal breaks and pronounced chromosomal fragmentation. A hypothesis is advanced that BLM causes inducible repair that is similar to SOS-repair. This repair is prone to DNA synthesis errors, which account for the increase in the number of aberrations at late fixation times. Pretreatment with 1 {mu}g/ml of mitomycin C, an alkylating agent, before the exposure to 10 mg/l BLM, resulted in cross-adaptation, which drastically reduced the number of BLM-induced aberrations. This was especially evident for the number of aberrations and the number of cells affected at late fixations. 36 refs., 5 figs.

  11. In vitro susceptibilities in lymphocytes from mothers and cord blood to the monofunctional alkylating agent EMS.

    PubMed

    Wyatt, N P; Falque-Gonzalez, C; Farrar, D; Tuffnell, D; Whitelaw, D; Knudsen, L E; Anderson, D

    2007-03-01

    It has been reported that children may experience different levels of chemical exposures than adults and that their sensitivities to chemical toxins may be increased or decreased when compared to adults. The perinatal period is one period in which these susceptibilities may be examined. Midwives at the Bradford Royal Infirmary collected venous blood samples from mothers at the time of birth and venous cord blood post-delivery. Lymphocytes were isolated from both blood types and examined in the alkaline comet assay using the monofunctional alkylating agent ethyl methanesulphonate (EMS). There were no biologically significant differences when subjects were categorized into subgroups based on lifestyle habits and physical characteristics, and overall there were no statistically significant differences in levels of DNA damage in mothers (n=22) and babies (n=22), except at the basal level (P<0.05), but mean values in babies were always lower over the EMS dose range. Whole blood was used in the micronucleus (MN) assay, and there was a significantly (P<0.05) higher rate of MN in mothers (n=17), per 1000 binucleates, as compared with lymphocytes from their offspring (n=17) at the basal level. This may be accounted for by age and endogenous factors. Overall, this current study cannot provide statistically significant evidence that children have either increased or decreased levels of susceptibility to a chemical toxin in comparison to adults when EMS is examined in vitro.

  12. 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

  13. [Quasi-adaptive response to alkylating agents in Escherichia coli and Ada-protein functions].

    PubMed

    Vasil'eva, S V; Moshkovskaia, E Iu; Terekhov, A S; Mikoian, V D; Vanin, A F

    2008-01-01

    In 2005 we have described in exponentially growing E. coli cells a new fundamental genetic phenomenon,--quasi-adaptive response to alkylating compounds (quasi-Ada). Phenotypic expression of quasi-Ada is similar to the true Ada response. However, in contrast to the letter, it develops in the course of pretreatment of the cells by a sublethal dose of nonalkylating agent, an NO-containing dinitrosyl iron complex with glutathione (DNICglu). To reveal the mechanisms of quasi-adaptation and its association with the function of the Ada regulatory protein, here we used a unique property of dual gene expression regulation of aidB1 gene, a part of the Ada-regulon, namely its relative independence from Ada protein in anaerobic conditions. Based on the results of aidB1 gene expression analysis an EPR spectra of E. coli MV2176 cells (aidB1::lacZ) in aerobic and anaerobic conditions after the corresponding treatments, we conclude that the function and the spatial structure of meAda and [(Cys-)2Fe+(NO+)2]Ada are identical and thus the nitrosylated protein represents a regulator of the Ada regulon gene expression during quasi-adaptation development.

  14. Oxidants and not alkylating agents induce rapid mtDNA loss and mitochondrial dysfunction

    PubMed Central

    Furda, Amy M.; Marrangoni, Adele M.; Lokshin, Anna; Van Houten, Bennett

    2013-01-01

    Mitochondrial DNA (mtDNA) is essential for proper mitochondrial function and encodes 22 tRNAs, 2 rRNAs and 13 polypeptides that make up subunits of complex I, III, IV, in the electron transport chain and complex V, the ATP synthase. Although mitochondrial dysfunction has been implicated in processes such as premature aging, neurodegeneration, and cancer, it has not been shown whether persistent mtDNA damage causes a loss of oxidative phosphorylation. We addressed this question by treating mouse embryonic fibroblasts with either hydrogen peroxide (H2O2) or the alkylating agent methyl methanesulfonate (MMS) and measuring several endpoints, including mtDNA damage and repair rates using QPCR, levels of mitochondrial- and nuclear-encoded proteins using antibody analysis, and a pharmacologic profile of mitochondria using the Seahorse Extracellular Flux Analyzer. We show that a 60 min treatment with H2O2 causes persistent mtDNA lesions, mtDNA loss, decreased levels of a nuclear-encoded mitochondrial subunit, a loss of ATP-linked oxidative phosphorylation and a loss of total reserve capacity. Conversely, a 60 min treatment with 2 mM MMS causes persistent mtDNA lesions but no mtDNA loss, no decrease in levels of a nuclear-encoded mitochondrial subunit, and no mitochondrial dysfunction. These results suggest that persistent mtDNA damage is not sufficient to cause mitochondrial dysfunction. PMID:22766155

  15. 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

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

    PubMed

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

    2012-09-01

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

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

    PubMed

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

    2010-04-15

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

  18. 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

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

    PubMed Central

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

    2001-01-01

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

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

    PubMed

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

    2016-12-01

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

  1. Transfection of a human glioblastoma cell line with liver-type glutaminase (LGA) down-regulates the expression of DNA-repair gene MGMT and sensitizes the cells to alkylating agents.

    PubMed

    Szeliga, Monika; Zgrzywa, Agata; Obara-Michlewska, Marta; Albrecht, Jan

    2012-11-01

    O(6)-methylguanine-DNA methyltransferase (MGMT) is a DNA-repair protein promoting resistance of tumor cells to alkylating chemotherapeutic agents. Glioma cells are particularly resistant to this class of drugs which include temozolomide (TMZ) and carmustine (BCNU). A previous study using the RNA microarray technique showed that decrease of MGMT mRNA stands out among the alterations in gene expression caused by the cell growth-depressing transfection of a T98G glioma cell line with liver-type glutaminase (LGA) [Szeliga et al. (2009) Glia, 57, 1014]. Here, we show that stably LGA-transfected cells (TLGA) exhibit decreased MGMT protein expression and activity as compared with non-transfected or mock transfected cells (controls). However, the decrease of expression occurs in the absence of changes in the methylation of the promoter region, indicating that LGA circumvents, by an as yet unknown route, the most common mechanism of MGMT silencing. TLGA turned out to be significantly more sensitive to treatment with 100-1000 μM of TMZ and BCNU in the acute cell growth inhibition assay (MTT). In the clonogenic survival assay, TLGA cells displayed increased sensitivity even to 10 μM TMZ and BCNU. Our results indicate that enrichment with LGA, in addition to inhibiting glioma growth, may facilitate chemotherapeutic intervention.

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

    PubMed Central

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

    2016-01-01

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

  3. 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.

  4. Quinolone antimicrobial agents. 1. Versatile new synthesis of 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids.

    PubMed

    Mitscher, L A; Gracey, H E; Clark, G W; Suzuki, T

    1978-05-01

    A flexible reaction sequence has been developed which starts with readily available anthranilic acids or isatoic anhydrides and leads regiospecifically to 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids after reaction with 1,3-dicarbonyl compounds. The sequence is superior to earlier published methods by allowing electron-releasing and -withdrawing groups in any position on the aro;atic ring, by allowing convenient substitution at C2, and better overall yield. A number of new and known antimicrobial agents were prepared and tested in vitro, demonstrating, inter alia, that substitution of the H at C2 abolished antibacterial activity.

  5. 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.

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

    PubMed

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

    2014-08-15

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

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

    PubMed Central

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

    2014-01-01

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

  8. Transcriptional blockages in a cell-free system by sequence-selective DNA alkylating agents.

    PubMed

    Ferguson, L R; Liu, A P; Denny, W A; Cullinane, C; Talarico, T; Phillips, D R

    2000-04-14

    There is considerable interest in DNA sequence-selective DNA-binding drugs as potential inhibitors of gene expression. Five compounds with distinctly different base pair specificities were compared in their effects on the formation and elongation of the transcription complex from the lac UV5 promoter in a cell-free system. All were tested at drug levels which killed 90% of cells in a clonogenic survival assay. Cisplatin, a selective alkylator at purine residues, inhibited transcription, decreasing the full-length transcript, and causing blockage at a number of GG or AG sequences, making it probable that intrastrand crosslinks are the blocking lesions. A cyclopropylindoline known to be an A-specific alkylator also inhibited transcription, with blocks at adenines. The aniline mustard chlorambucil, that targets primarily G but also A sequences, was also effective in blocking the formation of full-length transcripts. It produced transcription blocks either at, or one base prior to, AA or GG sequences, suggesting that intrastrand crosslinks could again be involved. The non-alkylating DNA minor groove binder Hoechst 33342 (a bisbenzimidazole) blocked formation of the full-length transcript, but without creating specific blockage sites. A bisbenzimidazole-linked aniline mustard analogue was a more effective transcription inhibitor than either chlorambucil or Hoechst 33342, with different blockage sites occurring immediately as compared with 2 h after incubation. The blockages were either immediately prior to AA or GG residues, or four to five base pairs prior to such sites, a pattern not predicted from in vitro DNA-binding studies. Minor groove DNA-binding ligands are of particular interest as inhibitors of gene expression, since they have the potential ability to bind selectively to long sequences of DNA. The results suggest that the bisbenzimidazole-linked mustard does cause alkylation and transcription blockage at novel DNA sites. in addition to sites characteristic of

  9. High-performance liquid chromatographic method for sensitive determination of the alkylating agent CB1954 in human plasma.

    PubMed

    Anderson, D; Ferry, D R; Knox, R J; Andrews, S J; Downes, A J; Kerr, D J; Seymour, L W

    1999-08-20

    A high-performance liquid chromatography (HPLC) method is described for the measurement of the weak alkylating agent CB1954 in human plasma. CB1954 can be used as an innocuous prodrug designed for activation by bacterial nitroreductases in strategies of gene-directed enzyme-prodrug therapy, and becomes activated to a potent bifunctional alkylating agent. The HPLC method involves precipitation and solvent extraction and uses Mitomycin C (MMC) as an internal standard, with a retention time for MMC of 5.85 +/- 0.015 min, and for CB1954 of 10.72 +/- 0.063 min. The limit of detection for CB1954 is 2.9 ng/ml, and this compares favourably with systems involving direct analysis of plasma (limit of detection 600 ng/ml, approximately). The method is now being used for pharmacokinetic measurements in plasma samples from cancer patients entering phase I clinical trials of CB1954. Results using serial plasma samples from one patient are presented. The patient was treated intravenously with CB1954 (6 mg/m2), and plasma clearance of the drug showed biphasic kinetics with alpha half-life 14.6 min, and beta half-life 170.5 min.

  10. The effect of alkylating agents on the reproductive and hormonal testicular function in patients with rheumatoid arthritis.

    PubMed

    Lazowski, Z; Janczewski, Z; Polowiec, Z

    1982-01-01

    An evaluation of testicular function was undertaken in 11 boys and young men aged 14-26 years suffering from rheumatoid arthritis complicated by amyloidosis and treated with cyclophosphamide and chlorambucil. 7 cases were studied during life and 4 at autopsy. Semen analysis showed azoospermia in 4 cases; in one, cryptozoospermia; in one, oligoasthenotheratozoospermia; and in one, asthenoteratozoospermia. In 4 patients with azoospermia and in one with cryptozoospermia, testicular biopsy was done for histo-pathological examination. In patients with azoospermia, only Sertoli cells were present in the seminiferous tubules. In one patient with cryptozoospermia, normal spermato- and spermiogenesis was found only in occasional seminiferous tubules. Microscopic examination of the testis failed to show any changes in the structure of the interstitial gland in any of the patients. Amyloid deposits were found in the vascular walls of the interstitial gland in one patient only. The serum testosterone level was depressed in 3 patients of the 9 examined. The LH level was elevated in 2 patients. The mean value of testosterone-LH ratio was significantly lower in patients treated with alkylating agents as compared with patients not so treated. Serum FSH level was elevated in 6 patients. Post-mortem examination of the testis in 4 patients showed complete absence of the germinal epithelium and only the presence of Sertoli cells. In 2 cases, amyloid deposits were found in the vascular walls in the rete testis. It was concluded that alkylating agents, besides damaging the testicular germinal epithelium, also affect the function of Leydig cells.

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

    PubMed

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

    2008-06-01

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

  12. 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.

  13. 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

  14. Aag DNA glycosylase promotes alkylation-induced tissue damage mediated by Parp1.

    PubMed

    Calvo, Jennifer A; Moroski-Erkul, Catherine A; Lake, Annabelle; Eichinger, Lindsey W; Shah, Dharini; Jhun, Iny; Limsirichai, Prajit; Bronson, Roderick T; Christiani, David C; Meira, Lisiane B; Samson, Leona D

    2013-04-01

    Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic β-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag⁻/⁻ mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage.

  15. 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.

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

    PubMed

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

    2011-03-31

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

  17. 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.

  18. Nitrosation of glycine ethyl ester and ethyl diazoacetate to give the alkylating agent and mutagen ethyl chloro(hydroximino)acetate.

    PubMed

    Zhou, Lin; Haorah, James; Chen, Sheng C; Wang, Xiaojie; Kolar, Carol; Lawson, Terence A; Mirvish, Sidney S

    2004-03-01

    Whereas nitrosation of secondary amines produces nitrosamines, amino acids with primary amino groups and glycine ethyl ester were reported to react with nitrite to give unidentified agents that alkylated 4-(p-nitrobenzyl)pyridine to produce purple dyes and be direct mutagens in the Ames test. We report here that treatment of glycine ethyl ester at 37 degrees C with excess nitrite acidified with HCl, followed by ether extraction, gave 30-40% yields of a product identified as ethyl chloro(hydroximino)acetate [ClC(=NOH)COOEt, ECHA] and a 9% yield of ethyl chloroacetate. The ECHA was identical to that synthesized by a known method from ethyl acetoacetate, strongly alkylated nitrobenzylpyridine, and may have arisen by N-nitrosation of glycine ethyl ester to give ethyl diazoacetate, which was C-nitrosated and reacted with chloride to give ECHA. Nitrosation of ethyl diazoacetate also yielded ECHA. Ethyl nitroacetate was not an intermediate as its nitrosation did not produce ECHA. ECHA reacted with aniline to give ethyl (hydroxamino)(phenylimino)acetate [PhN=C(NHOH)CO2Et]. This product was different from ethyl [(phenylamino)carbonyl]carbamate [PhNHC(=O)NHCO2Et], which was synthesized by reacting ethyl isocyanatoformate (OCN.CO2Et) with aniline. ECHA reacted with guanosine to give a derivative, which may have been a guanine-C(=NOH)CO2Et derivative. ECHA showed moderate toxicity and weak but significant mutagenicity without activation in Salmonella typhimurium TA-100 (mean, 1.31 x control value for 12-18 microg/plats) and for V79 mammalian cells (1.5-1.7 x control value for 60-100 microM). In conclusion, gastric nitrosation of glycine derivatives such as peptides with a N-terminal glycine might produce ECHA analogues that alkylate bases of gastric mucosal DNA and thereby initiate gastric cancer.

  19. 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.

  20. Determination of methyl-, 2-hydroxyethyl- and 2-cyanoethylmercapturic acids as biomarkers of exposure to alkylating agents in cigarette smoke.

    PubMed

    Scherer, Gerhard; Urban, Michael; Hagedorn, Heinz-Werner; Serafin, Richard; Feng, Shixia; Kapur, Sunil; Muhammad, Raheema; Jin, Yan; Sarkar, Mohamadi; Roethig, Hans-Juergen

    2010-10-01

    Alkylating agents occur in the environment and are formed endogenously. Tobacco smoke contains a variety of alkylating agents or precursors including, among others, N-nitrosodimethylamine (NDMA), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), acrylonitrile and ethylene oxide. We developed and validated a method for the simultaneous determination of methylmercapturic acid (MMA, biomarker for methylating agents such as NDMA and NNK), 2-hydroxyethylmercapturic acid (HEMA, biomarker for ethylene oxide) and 2-cyanoethylmercapturic acid (CEMA, biomarker for acrylonitrile) in human urine using deuterated internal standards of each compound. The method involves liquid/liquid extraction of the urine sample, solid phase extraction on anion exchange cartridges, derivatization with pentafluorobenzyl bromide (PFBBr), liquid/liquid extraction of the reaction mixture and LC-MS/MS analysis with positive electrospray ionization. The method was linear in the ranges of 5.00-600, 1.00-50.0 and 1.50-900 ng/ml for MMA, HEMA and CEMA, respectively. The method was applied to two clinical studies in adult smokers of conventional cigarettes who either continued smoking conventional cigarettes, were switched to test cigarettes consisting of either an electrically heated cigarette smoking system (EHCSS) or having a highly activated carbon granule filter that were shown to have reduced exposure to specific smoke constituents, or stopped smoking. Urinary excretion of MMA was found to be unaffected by switching to the test cigarettes or stop smoking. Urinary HEMA excretion decreased by 46 to 54% after switching to test cigarettes and by approximately 74% when stopping smoking. Urinary CEMA excretion decreased by 74-77% when switching to test cigarettes and by approximately 90% when stopping smoking. This validated method for urinary alkylmercapturic acids is suitable to distinguish differences in exposure not only between smokers and nonsmokers but also between smoking of conventional and

  1. Targeting neddylation induces DNA damage and checkpoint activation and sensitizes chronic lymphocytic leukemia B cells to alkylating agents.

    PubMed

    Paiva, C; Godbersen, J C; Berger, A; Brown, J R; Danilov, A V

    2015-07-09

    Microenvironment-mediated upregulation of the B-cell receptor (BCR) and nuclear factor-κB (NF-κB) signaling in CLL cells resident in the lymph node and bone marrow promotes apoptosis evasion and clonal expansion. We recently reported that MLN4924 (pevonedistat), an investigational agent that inhibits the NEDD8-activating enzyme (NAE), abrogates stromal-mediated NF-κB pathway activity and CLL cell survival. However, the NAE pathway also assists degradation of multiple other substrates. MLN4924 has been shown to induce DNA damage and cell cycle arrest, but the importance of this mechanism in primary neoplastic B cells has not been studied. Here we mimicked the lymph node microenvironment using CD40 ligand (CD40L)-expressing stroma and interleukin-21 (IL-21) to find that inducing proliferation of the primary CLL cells conferred enhanced sensitivity to NAE inhibition. Treatment of the CD40-stimulated CLL cells with MLN4924 resulted in deregulation of Cdt1, a DNA replication licensing factor, and cell cycle inhibitors p21 and p27. This led to DNA damage, checkpoint activation and G2 arrest. Alkylating agents bendamustine and chlorambucil enhanced MLN4924-mediated DNA damage and apoptosis. These events were more prominent in cells stimulated with IL-21 compared with CD40L alone, indicating that, following NAE inhibition, the culture conditions were able to direct CLL cell fate from an NF-κB inhibition to a Cdt1 induction program. Our data provide insight into the biological consequences of targeting NAE in CLL and serves as further rationale for studying the clinical activity of MLN4924 in CLL, particularly in combination with alkylating agents.

  2. 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.

  3. Use of 3,4-dichlorobenzenethiol as a trapping agent for alkylating intermediates during in vitro metabolism of nitrosamines

    SciTech Connect

    Kroeger-Koepke, M.B.; Michejda, C.J.; Roller, P.P.; Keefer, L.K.

    1985-07-01

    Studies using 3,4-dichlorobenzenethiol as a probe for methylating agent production during exposure of N-nitrosodimethylamine to rat liver S-9 preparations produced results different from those of an investigation reported in the literature. Methyl-3,4-dichlorophenyl thioether was detected, but the quantities found were not significantly different from the background levels of methylation product detected in the absence of nitrosamine. Only about 10% of the thioether isolated after incubating N-nitrosodi(/sup 14/C)methylamine as substrate was radioactive. The results indicate that the majority of the methyl groups transferred to the sulfur nucleophile in these experiments came from components of the incubation mixture other than the nitrosamine. Some artifactual methylation was also associated with the analytical procedure. The authors conclude that 3,4-dichlorobenzenethiol should be used with caution in studies of alkylation during the in vitro metabolism of carcinogenic nitrosamines.

  4. DRDE-07 and its analogues as promising cytoprotectants to nitrogen mustard (HN-2)--an alkylating anticancer and chemical warfare agent.

    PubMed

    Sharma, Manoj; Vijayaraghavan, R; Gautam, Anshoo

    2009-08-10

    Nitrogen mustard (HN-2), also known as mechlorethamine, is an alkylating anticancer agent as well as blister inducing chemical warfare agent. We evaluated the cytoprotective efficacy of amifostine, DRDE-07 and their analogues, and other antidotes of mustard agents against HN-2. Administration of 1 LD(50) of HN-2 (20mg/kg) percutaneously, decreased WBC count from 24h onwards. Liver glutathione (GSH) level decreased prominently and the maximum depletion was observed on 7th day post-HN-2 administration. Oxidised glutathione (GSSG) level increased significantly at 24h post-administration and subsequently showed a progressive decrease. Hepatic malondialdehyde (MDA) level and percent DNA damage increased progressively following HN-2 administration. The spleen weight decreased progressively and reached a minimum on 3-4 days with subsequent increase. The antidotes were administered repeatedly for 4 and 8 days after percutaneous administration of single sublethal dose (0.5 and 0.25 LD(50)) of HN-2. Treatment with DRDE-07, DRDE-30 and DRDE-35 significantly protected the changes in spleen weight, WBC count, GSH, GSSG, MDA and DNA damage following HN-2 administration (0.5 and 0.25 LD(50)). There was no alteration in the transaminases (AST and ALT), and alkaline phosphatase (ALP) activities, neither with HN-2 nor with antidotes. The present study shows that HN-2 is highly toxic by percutaneous route and DRDE-07, DRDE-30 and DRDE-35 can partially protect it.

  5. Nanospheric Chemotherapeutic and Chemoprotective Agents

    DTIC Science & Technology

    2008-09-01

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

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

    PubMed

    Ni Nyoman, Ayu Dewi; Lüder, Carsten G K

    2013-06-01

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

  7. Preparation and evaluation of radioiodinated 1-methyl-1-(alkyl or hydroxyalkyl)-4-phenylpiperazinium salts as myocardial imaging agents

    SciTech Connect

    Hanson, R.N.; Hassan, M.A.

    1985-05-01

    In this study the authors evaluate the effect of various substituents upon the myocardial uptake and selectivity of radioiodinated phenylpiperazinium derivatives. A series of 1-methyl-1-(alkyl or hydroxyalkyl)-4-(substituted phenyl) piperazinium salts were synthesized, characterized, radioiodinated at the no-carrier-added level with Na/sup 125/I and chloroamine-T, and isolated in 50-85% radiochemical yields using HPLC. The tissue distribution of the radiochemicals was determined in rats at 0.25 - 4 hr following i.v. administration. The compounds where R/sub 2/=CH/sub 2/CH/sub 2/OH had the highest myocardial uptake and selectivity. The radioactivity in the heart did not diminish during the time period evaluation but also was not displaced by tetraethylammonium, or other quaternary amines. Scintigraphic imaging in the dog with (I-131) 1-methyl-1-(2-hydroxyethyl)-4-(2-methylphenyl)piperazine clearly visualized the heart. Following sacrifice at 2 hrs and tissue dissection, the heart uptake was 4.5-6.5% ID with H/B1=25 and H/lung=l.5. In summary, the initial data suggest that this agent which can be readily labeled with radioiodide possesses substantial potential as a myocardial perfusion agent.

  8. Nucleophilic selectivity as a determinant of carcinogenic potency (TD50) in rodents: a comparison of mono- and bi-functional alkylating agents and vinyl chloride metabolites.

    PubMed

    Barbin, A; Bartsch, H

    1989-11-01

    Using published data, the carcinogenic potency (TD50) in rodents of a series of monofunctional alkylating agents, bifunctional antitumor drugs and the vinyl chloride (VC) metabolites chloroethylene oxide (CEO) and chloroacetaldehyde (CAA) was compared to their nucleophilic selectivity (Swain and Scott's constant s or initial ratio of 7-/O6-alkylguanine in DNA). A positive correlation between the log of TD50 estimates and the s values for a series of 14, mostly monofunctional, alkylating agents was observed. This linear relationship also included 2 bifunctional chloroethylnitrosoureas, although their carcinogenic potency was compared to their initial 7-/O6-alkylguanine ratio rather than their s values (n = 16, r = 0.91, p less than 0.005). In addition, the carcinogenic potency of 2 alkyl sulfates, which is not yet known accurately, may correlate with their nucleophilic selectivity through the same relationship. By contrast, 2 methyl halides and 5 bifunctional antitumor drugs (nitrogen mustards and azyridinyl derivatives) did not follow this linear relationship: at similar nucleophilic selectivity, they were more potent carcinogens than the above 18 alkylating agents; this may hold true for CEO and CAA too, although further carcinogenicity experiments are needed to calculate their precise TD50 values. The possible molecular mechanisms involved in tumor induction by these agents are discussed on the basis of these findings. Comparison of the estimated TD50 for CEO, CAA and VC in rodents confirms that CEO is the ultimate carcinogenic metabolite of VC and suggests that only a very small proportion of metabolically generated CEO is available for DNA alkylation in vivo.

  9. Monoalkyl sulfates as alkylating agents in water, alkylsulfatase rate enhancements, and the “energy-rich” nature of sulfate half-esters

    PubMed Central

    Wolfenden, Richard; Yuan, Yang

    2007-01-01

    Alkyl sulfate monoesters are involved in cell signaling and structure. Alkyl sulfates are also present in many commercial detergents. Here, we show that monomethyl sulfate acts as an efficient alkylating agent in water, reacting spontaneously with oxygen nucleophiles >100-fold more rapidly than do alkylsulfonium ions, the usual methyl donors in living organisms. These reactions of methyl sulfate, which are much more rapid than its hydrolysis, are insensitive to the nature of the attacking nucleophile, with a Brønsted βnuc value of −0.01. Experiments at elevated temperatures indicate a rate constant of 2 × 10−11 s−1 for the uncatalyzed hydrolysis of methyl sulfate at 25°C (t1/2 = 1,100 y), corresponding to a rate enhancement of ≈1011-fold by a human alkylsulfatase. Equilibria of formation of methyl sulfate from methanol and sodium hydrogen sulfate indicate a group transfer potential (ΔG′pH7) of −8.9 kcal/mol for sulfate ester hydrolysis. The magnitude of that value, involving release of the strong acid HSO4−, helps to explain the need for harnessing the free energy of hydrolysis of two ATP molecules in activating sulfate for the biosynthesis of sulfate monoesters. The “energy-rich” nature of monoalkyl sulfate esters, coupled with their marked resistance to hydrolysis, renders them capable of acting as sulfating or alkylating agents under relatively mild conditions. These findings raise the possibility that, under appropriate circumstances, alkyl groups may undergo transfer from alkyl sulfate monoesters to biological target molecules. PMID:17182738

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

    PubMed Central

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

    2012-01-01

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

  11. 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.

  12. Expression of mammalian O6-alkylguanine-DNA alkyltransferase in a cell line sensitive to alkylating agents.

    PubMed

    Dolan, M E; Norbeck, L; Clyde, C; Hora, N K; Erickson, L C; Pegg, A E

    1989-09-01

    Chinese hamster ovary cells (CHO) were co-transfected with pSV2neo and sheared DNA from either a human cell line (HT29) expressing high levels of O6-alkylguanine-DNA alkyltransferase (AGT) or from a cell line (BE) deficient in this activity. Cells expressing the selectable marker were obtained by exposure to G418 and colonies resistant to alkylation damage isolated by growth in the presence of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). The number of colonies of cells expressing AGT activity arising after transfection with DNA from BE cells was similar to the number arising from cells exposed to HT29 DNA. Although the amount of AGT repair protein expressed in the transfectant colonies from this experiment was relatively low, these results indicate that repair of alkylation damage can be restored in AGT-deficient cells by transfection of human DNA from both repair-deficient and proficient cells. A separate transfection of CHOMG cells [a mutant of CHO cells resistant to the drug, methylglyoxal bis(guanylhydrazone) (MGBG)] with HT29 DNA and pSV2neo followed by selection of G418 and 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) resulted in three colonies with high AGT levels. These transfectants had different growth rates and expressed levels of the AGT protein between 230 and 300 fmol/mg protein. The transfectants were as resistant to the cytotoxic effects of BCNU, Clomesone, methylnitrosourea (MNU) and 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) as HT29 cells which were much more resistant than the parental CHOMG cells. Pretreatment of transfectant cells with 0.4 mM O6-methylguanine for 24 h reduced AGT activity to 14% basal levels, which upon removal of the base increased to approximately 74% basal level within 8 h. The sensitivity to the cytotoxic effects of both the chloroethylating and methylating agents was enhanced by treatment with O6-methylguanine. In the same manner, the number of BCNU-induced DNA interstrand cross-links increased in transfectant

  13. DNA-directed alkylating agents. 4. 4-anilinoquinoline-based minor groove directed aniline mustards.

    PubMed

    Gravatt, G L; Baguley, B C; Wilson, W R; Denny, W A

    1991-05-01

    A series of 4-anilinoquinoline-linked aniline mustards of widely varying mustard reactivity were prepared and evaluated for their antitumor activity. The compounds were designed as minor grove binding agents, where the aniline mustard ring is itself part of the DNA-binding ligand. While there was a general trend for cytotoxicity to correlate with mustard reactivity, this was much less pronounced than with untargeted mustards. The compounds were much more cytotoxic than the parent diols, and were also at least 10-fold more cytotoxic than the corresponding aniline mustards themselves. Comparative cell line studies suggested that the mechanism of cytotoxicity varied with mustard reactivity. The most reactive mustards cross-linked DNA, while cell killing by the less reactive compounds appeared to be by the formation of bulky monoadducts. The compounds were active but not particularly dose-potent against P388 leukemia in vivo. The modest potency may be related to their poor aqueous solubility, since the more soluble methyl quaternary salts were equally active at much lower doses.

  14. Synthesis and evaluation of DNA-targeted spatially separated bis(aniline mustards) as potential alkylating agents with enhanced DNA cross-linking capability.

    PubMed

    Gourdie, T A; Prakash, A S; Wakelin, L P; Woodgate, P D; Denny, W A

    1991-01-01

    DNA-targeted separated bis-mustards were synthesized by attaching aniline mono-mustards at the 4- and 9-positions of the DNA-intercalating ligand 9-aminoacridine-4-carboxamide, with the intention of improving the low cross-link to monoadduct ratio found with most alkylating agents. The geometry of these compounds requires that, when the acridine binds to DNA by intercalation, one alkylating moiety is delivered to each DNA groove. Gel electrophoretic studies show that only one arm of these compounds (probably that attached to the 9-position) alkylates DNA, such alkylation occurring specifically in the major groove at the N7 of guanines. Cell-line studies confirm that the mode of cytotoxicity of these compounds (unlike that of untargeted aniline bis-mustards of comparable reactivity) is due to bulky DNA monoadduct formation. It is concluded that more information is required about the exact orientation of the initial monoadducts before ligands with specific DNA cross-linking ability can be designed.

  15. Depletion of a discrete nuclear glutathione pool by oxidative stress, but not by buthionine sulfoximine. Correlation with enhanced alkylating agent cytotoxicity to human melanoma cells in vitro.

    PubMed

    Jevtović-Todorović, V; Guenthner, T M

    1992-10-06

    The existence of a distinct pool of glutathione in the nucleus of cultured human melanoma cells was demonstrated. Melanoma cell nuclei contained 13-35 pmol of glutathione/10(6) nuclei, or approximately 0.4-1.3% of the total cellular glutathione. This nuclear glutathione pool resisted depletion by buthionine sulfoximine, an agent that inhibits glutathione synthesis, but was rapidly and reversibly depleted by subtoxic concentrations of Adriamycin plus carmustine, two agents that promote oxidation of glutathione without permitting its regeneration through enzymatic reduction of glutathione disulfide. The ability of Adriamycin plus carmustine to deplete this small but significant pool of glutathione in the cell nucleus may explain why these agents potentiate the cytotoxic effects of the DNA-alkylating agent melphalan to a much higher degree than does buthionine sulfoximine at concentrations that are equipotent in depleting cytosolic glutathione.

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

    PubMed Central

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

    2016-01-01

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

  17. DNA-directed alkylating agents. 1. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the reactivity of the mustard.

    PubMed

    Gourdie, T A; Valu, K K; Gravatt, G L; Boritzki, T J; Baguley, B C; Wakelin, L P; Wilson, W R; Woodgate, P D; Denny, W A

    1990-04-01

    A series of DNA-targeted aniline mustards have been prepared, and their chemical reactivity and in vitro and in vivo cytotoxicity have been evaluated and compared with that of the corresponding simple aniline mustards. The alkylating groups were anchored to the DNA-intercalating 9-aminoacridine chromophore by an alkyl chain of fixed length attached at the mustard 4-position through a link group X, while the corresponding simple mustards possessed an electronically identical small group at this position. The link group was varied to provide a series of compounds of similar geometry but widely differing mustard reactivity. Variation in biological activity should then largely be a consequence of this varying reactivity. Rates of mustard hydrolysis in the two series related only to the electronic properties of the link group, with attachment of the intercalating chromophore having no effect. The cytotoxicities of the simple mustards correlated well with group electronic properties (with a 200-300-fold range in IC50S). The corresponding DNA-targeted mustards were much more potent (up to 100-fold), but their IC50 values varied much less with linker group electronic properties. Most of the DNA-targeted mustards showed in vivo antitumor activity, being both more active and more dose-potent than either the corresponding untargeted mustards and chlorambucil. These results show that targeting alkylating agents to DNA by attachment to DNA-affinic units may be a useful strategy.

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

    PubMed

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

    2013-09-01

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

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

    PubMed

    Yousuf, Imtiyaz; Arjmand, Farukh

    2016-11-01

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

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

    PubMed

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

    2015-05-26

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

  1. Synthesis, Characterization and Cytotoxicity of Alkylated Quercetin Derivatives.

    PubMed

    Bao, Xin-Ran; Liao, Han; Qu, Jiao; Sun, Yong; Guo, Xin; Wang, En-Xia; Zhen, Yu-Hong

    2016-01-01

    Quercetin, a ubiquitous flavonol, represents a promising leading drug for development of new chemotherapeutic agents. However, its limited cytotoxicity to cancer cells hampers its clinical use. In order to obtain novel quercetin derivatives with superior cytotoxicity, seven alkylated quercetin derivatives were synthesized. Solubility of these derivatives was determined by turbidimetry. Cytotoxicity of the high-soluble derivatives against MCF-7 cells and caco-2 cells was determined using MTT assay. Among these seven products, 7-O-butylquercetin had the highest solubility in DMEM medium and 7-O-geranylquercetin had the most potent cytotoxicity. Further study on cytotoxicity of 7-O-geranylquercetin on NCI-H446, A549, MGC-803 and SGC-7901 cell lines revealed potential antiproliferative effects. The 7-O-geranylquercetin is a broad spectrum cytotoxic agent and it may be a promising leading drug for cancer chemotherapy.

  2. Synthesis, Characterization and Cytotoxicity of Alkylated Quercetin Derivatives

    PubMed Central

    Bao, Xin-Ran; Liao, Han; Qu, Jiao; Sun, Yong; Guo, Xin; Wang, En-Xia; Zhen, Yu-Hong

    2016-01-01

    Quercetin, a ubiquitous flavonol, represents a promising leading drug for development of new chemotherapeutic agents. However, its limited cytotoxicity to cancer cells hampers its clinical use. In order to obtain novel quercetin derivatives with superior cytotoxicity, seven alkylated quercetin derivatives were synthesized. Solubility of these derivatives was determined by turbidimetry. Cytotoxicity of the high-soluble derivatives against MCF-7 cells and caco-2 cells was determined using MTT assay. Among these seven products, 7-O-butylquercetin had the highest solubility in DMEM medium and 7-O-geranylquercetin had the most potent cytotoxicity. Further study on cytotoxicity of 7-O-geranylquercetin on NCI-H446, A549, MGC-803 and SGC-7901 cell lines revealed potential antiproliferative effects. The 7-O-geranylquercetin is a broad spectrum cytotoxic agent and it may be a promising leading drug for cancer chemotherapy. PMID:27980567

  3. Phosphine-catalyzed reductions of alkyl silyl peroxides by titanium hydride reducing agents: development of the method and mechanistic investigations.

    PubMed

    Harris, Jason R; Haynes, M Taylor; Thomas, Andrew M; Woerpel, K A

    2010-08-06

    A method that allows for the reduction of protected hydroperoxides by employing catalytic amounts of phosphine is presented. The combination of a titanium(IV) alkoxide and a siloxane allowed for the chemoselective reduction of phosphine oxides in the presence of alkyl silyl peroxides. Subsequent reduction of the peroxide moiety by phosphine provided the corresponding silylated alcohols in useful yields. Mechanistic experiments, including crossover experiments, support a mechanism in which the peroxide group was reduced and the silyl group was transferred in a concerted step. Labeling studies with (17)O-labeled peroxides demonstrate that the oxygen atom adjacent to the silicon atom is removed from the silyl peroxide.

  4. DNA-directed alkylating agents. 6. Synthesis and antitumor activity of DNA minor groove-targeted aniline mustard analogues of pibenzimol (Hoechst 33258)

    PubMed

    Gravatt, G L; Baguley, B C; Wilson, W R; Denny, W A

    1994-12-09

    A series of nitrogen mustard analogues of the DNA minor groove binding fluorophore pibenzimol (Hoechst 33258) have been synthesized and evaluated for antitumor activity. Conventional construction of the bisbenzimidazole ring system from the piperazinyl terminus, via two consecutive Pinner-type reactions, gave low yields of products contaminated with the 2-methyl analogue which proved difficult to separate. An alternative synthesis was developed, involving construction of the bisbenzimidazole from the mustard terminus, via Cu(2+)-promoted oxidative coupling of the mustard aldehydes with 3,4-diaminobenzonitrile to form the monobenzimidazoles, followed by a Pinner-type reaction and condensation with 4-(1-methyl-4-piperazinyl)-o-phenylenediamine. This process gives higher yields and pure products. The mustard analogues showed high hypersensitivity factors (IC50AA8/IC50 UV4), typical of DNA alkylating agents. There was a large increase in cytotoxicity (85-fold) across the homologous series which cannot be explained entirely by changes in mustard reactivity and may be related to altering orientation of the mustard with respect to the DNA resulting in different patterns of alkylation. Pibenzimol itself (which has been evaluated clinically as an anticancer drug) was inactive against P388 in vivo using a single-dose protocol, but the short-chain mustard homologues were highly effective, eliciting a proportion of long-term survivors.

  5. Synthesis of 5-alkylated barbituric acids and 3-alkylated indoles via microwave-assisted three-component reactions in solvent-free conditions using Hantzsch 1,4-dihydropyridines as reducing agents.

    PubMed

    Baruah, Biswajita; Seetham Naidu, P; Borah, Pallabi; Bhuyan, Pulak J

    2012-05-01

    Reaction of barbituric acids with aldehydes and dihydropyridines in one pot under microwave (MW) irradiation in the absence of solvent, affords 55–82% of the 5-benzylated barbituric acids. Use of alkyl nitriles or barbituric acids with indole-3-aldehyde and dihydropyridine (DHP) afforded 3-alkylated indoles in 57–76 % yield. In each case DHPs are converted to pyridines.

  6. 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.

  7. 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

  8. Effect of the salting-out agent anion nature on the phase separation of a potassium salt-potassium bis(alkyl polyoxyethylene)phosphate-water systems

    NASA Astrophysics Data System (ADS)

    Elokhov, A. M.; Lesnov, A. E.; Kudryashova, O. S.

    2016-10-01

    The effect the salting-out agent anion nature has on the temperature and concentration intervals of the existence of the separation area is established by analyzing the phase diagrams of pseudoternary KCl (KBr, KI, KNO3, K2SO4, K4P2O7)-potassium bis(alkyl polyoxyethylene)phosphate (oxyphos B)-water systems. It is concluded that the anionic salting-out capability is reduced in the order P2O 7 4- > SO 4 2- > Cl- > Br‒> NO 7 4- > SO 3 - > I-. The thermodynamic parameters of phase separation used to interpret the results are calculated. The observed pattern of a change in the salting-out ability of the investigated salts relative to aqueous solutions of the surfactants is in good agreement with the lyotropic (Hofmeister) series.

  9. Antigenotoxic effects of Citrus aurentium L. fruit peel oil on mutagenicity of two alkylating agents and two metals in the Drosophila wing spot test.

    PubMed

    Demir, Eşref; Kocaoğlu, Serap; Cetin, Huseyin; Kaya, Bülent

    2009-07-01

    Antigenotoxic effects of Citrus aurentium L. (Rutaceae) fruit peel oil (CPO) in combination with mutagenic metals and alkylating agents were studied using the wing spot test of D. melanogaster. The four reference mutagens, potassium dichromate (K2Cr2O7), cobalt chloride (CoCl2), ethylmethanesulfonate (EMS), and N-ethyl-N-nitrosourea (ENU) were clearly genotoxic. CPO alone at doses from 0.1 to 0.5% in Tween 80 was not mutagenic and did not enhance the mutagenic effect of the reference mutagens. However, antigenotoxic effects of CPO were clearly demonstrated in chronic cotreatments with mutagens and oil, by a significant decrease in wing spots induced by all four mutagens. The D. melanogaster wing spot test was found to be a suitable assay for detecting antigenotoxic effects in vivo.

  10. Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner

    PubMed Central

    Fake, Kimberly R.; Muthupalani, Sureshkumar; Corrigan, Joshua J.; Bronson, Roderick T.; Samson, Leona D.

    2016-01-01

    Nephrotoxicity is a common toxic side-effect of chemotherapeutic alkylating agents. Although the base excision repair (BER) pathway is essential in repairing DNA alkylation damage, under certain conditions the initiation of BER produces toxic repair intermediates that damage healthy tissues. We have shown that the alkyladenine DNA glycosylase, Aag (a.k.a. Mpg), an enzyme that initiates BER, mediates alkylation-induced whole-animal lethality and cytotoxicity in the pancreas, spleen, retina, and cerebellum, but not in the kidney. Cytotoxicity in both wild-type and Aag-transgenic mice (AagTg) was abrogated in the absence of Poly(ADP-ribose) polymerase-1 (Parp1). Here we report that Parp1-deficient mice expressing increased Aag (AagTg/Parp1−/−) develop sex-dependent kidney failure upon exposure to the alkylating agent, methyl methanesulfonate (MMS), and suffer increased whole-animal lethality compared to AagTg and wild-type mice. Macroscopic, histological, electron microscopic and immunohistochemical analyses revealed morphological kidney damage including dilated tubules, proteinaceous casts, vacuolation, collapse of the glomerular tuft, and deterioration of podocyte structure. Moreover, mice exhibited clinical signs of kidney disease indicating functional damage, including elevated blood nitrogen urea and creatinine, hypoproteinemia and proteinuria. Pharmacological Parp inhibition in AagTg mice also resulted in sensitivity to MMS-induced nephrotoxicity. These findings provide in vivo evidence that Parp1 modulates Aag-dependent MMS-induced nephrotoxicity in a sex-dependent manner and highlight the critical roles that Aag-initiated BER and Parp1 may play in determining the side-effects of chemotherapeutic alkylating agents. PMID:27391435

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

    PubMed Central

    Kodela, Ravinder; Chattopadhyay, Mitali; Kashfi, Khosrow

    2013-01-01

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

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

    PubMed

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

    2014-01-01

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

  13. Effect of ionic strength and cationic DNA affinity binders on the DNA sequence selective alkylation of guanine N7-positions by nitrogen mustards

    SciTech Connect

    Hartley, J.A.; Forrow, S.M.; Souhami, R.L. )

    1990-03-27

    Large variations in alkylation intensities exist among guanines in a DNA sequence following treatment with chemotherapeutic alkylating agents such as nitrogen mustards, and the substituent attached to the reactive group can impose a distinct sequence preference for reaction. In order to understand further the structural and electrostatic factors which determine the sequence selectivity of alkylation reactions, the effect of increase ionic strength, the intercalator ethidium bromide, AT-specific minor groove binders distamycin A and netropsin, and the polyamine spermine on guanine N7-alkylation by L-phenylalanine mustard (L-Pam), uracil mustard (UM), and quinacrine mustard (QM) was investigated with a modification of the guanine-specific chemical cleavage technique for DNA sequencing. The result differed with both the nitrogen mustard and the cationic agent used. The effect, which resulted in both enhancement and suppression of alkylation sites, was most striking in the case of netropsin and distamycin A, which differed from each other. DNA footprinting indicated that selective binding to AT sequences in the minor groove of DNA can have long-range effects on the alkylation pattern of DNA in the major groove.

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

    PubMed

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

    2016-09-07

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

  15. 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

  16. Optimization of alkylating agent prodrugs derived from phenol and aniline mustards: a new clinical candidate prodrug (ZD2767) for antibody-directed enzyme prodrug therapy (ADEPT).

    PubMed

    Springer, C J; Dowell, R; Burke, P J; Hadley, E; Davis, D H; Blakey, D C; Melton, R G; Niculescu-Duvaz, I

    1995-12-22

    Sixteen novel potential prodrugs derived from phenol or aniline mustards and their 16 corresponding drugs with ring substitution and/or different alkylating functionalities were designed. The [[[4-]bis(2-bromoethyl)-(1a), [[[4-[bis(2-iodoethyl)-(1b), and [[[4-[(2-chloroethyl)-[2-(mesyloxy)ethyl]amino]phenyl]oxy] carbonyl]-L-glutamic acids (1c), their [[[2- and 3-substituted-4-[bis(2-chloroethyl)amino]phenyl]oxy]carbonyl]-L- glutamic acids (1e-1), and the [[3-substituted-4-[bis(2-chloroethyl)amino]phenyl]carbamoyl]-L- glutamic acids (1o-r) were synthesized. They are bifunctional alkylating agents in which the activating effect of the phenolic hydroxyl or amino function is masked through an oxycarbonyl or a carbamoyl bond to a glutamic acid. These prodrugs were designed to be activated to their corresponding phenol and aniline nitrogen mustard drugs at a tumor site by prior administration of a monoclonal antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2) in antibody-directed enzyme prodrug therapy (ADEPT). The synthesis of the analogous novel parent drugs (2a-r) is also described. The viability of a colorectal cell line (LoVo) was monitored with the potential prodrugs and the parent drugs. The differential in the cytotoxicity between the potential prodrugs and their corresponding active drugs ranged between 12 and > 195 fold. Compounds 1b-d,f,o exhibited substantial prodrug activity, since a cytotoxicity differential of > 100 was achieved compared to 2b-d,f,o respectively. The ability of the potential prodrugs to act as substrates for CPG2 was determined (kinetic parameters KM and kcat), and the chemical stability was measured for all the compounds. The unsubstituted phenols with different alkylating functionalities (1a-c) proved to have the highest ratio of the substrates kcat:KM. From these studies [[[4-[bis(2-iodoethyl)amino]phenyl]oxy]carbonyl]-L-glutamic acid (1b) emerges as a new ADEPT clinical trial candidate due to its physicochemical and

  17. Α-aryl-N-alkyl nitrones, as potential agents for stroke treatment: synthesis, theoretical calculations, antioxidant, anti-inflammatory, neuroprotective, and brain-blood barrier permeability properties.

    PubMed

    Chioua, Mourad; Sucunza, David; Soriano, Elena; Hadjipavlou-Litina, Dimitra; Alcázar, Alberto; Ayuso, Irene; Oset-Gasque, María Jesús; González, María Pilar; Monjas, Leticia; Rodríguez-Franco, María Isabel; Marco-Contelles, José; Samadi, Abdelouahid

    2012-01-12

    We report the synthesis, theoretical calculations, the antioxidant, anti-inflammatory, and neuroprotective properties, and the ability to cross the blood-brain barrier (BBB) of (Z)-α-aryl and heteroaryl-N-alkyl nitrones as potential agents for stroke treatment. The majority of nitrones compete with DMSO for hydroxyl radicals, and most of them are potent lipoxygenase inhibitors. Cell viability-related (MTT assay) studies clearly showed that nitrones 1-3 and 10 give rise to significant neuroprotection. When compounds 1-11 were tested for necrotic cell death (LDH release test) nitrones 1-3, 6, 7, and 9 proved to be neuroprotective agents. In vitro evaluation of the BBB penetration of selected nitrones 1, 2, 10, and 11 using the PAMPA-BBB assay showed that all of them cross the BBB. Permeable quinoline nitrones 2 and 3 show potent combined antioxidant and neuroprotective properties and, therefore, can be considered as new lead compounds for further development in specific tests for potential stroke treatment.

  18. 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.

  19. 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

    Johnson, Kevin M; Parsons, Zachary D; Barnes, Charles L; Gates, Kent S

    2014-08-15

    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.

  20. 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

  1. (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.

  2. Development and validation of a sensitive GC-MS method for the determination of alkylating agent, 4-chloro-1-butanol, in active pharmaceutical ingredients.

    PubMed

    Harigaya, Koki; Yamada, Hiroyuki; Yaku, Koji; Nishi, Hiroyuki; Haginaka, Jun

    2014-01-01

    The analysis of genotoxic impurities (GTIs) in active pharmaceutical ingredients (APIs) is a challenging task. The target detection limit (DL) in an API is typically around 1 ppm (1 µg/g API). Therefore, a sensitive and selective analytical method is required for their analysis. 4-Chloro-1-butanol, an alkylating agent, is one of the GTIs. It is generated when tetrahydrofuran and hydrochloric acid are used during the synthesis of the APIs. In this study, a sensitive and robust gas chromatography-mass spectrometry (GC-MS) method was developed and validated for the identification of 4-chloro-1-butanol in APIs. In the GC-MS method, 3-chloro-1-butanol was employed as an internal standard to ensure accuracy and precision. Linearity was observed over the range 0.08 to 40 ppm (µg/g API), with a R(2) value of 0.9999. The DL and quantitation limit (QL) obtained were 0.05 ppm and 0.08 ppm (0.13 ng/mL and 0.20 ng/mL as the 4-chloro-1-butanol concentration), respectively. These DL and QL values are well over the threshold specified in the guidelines. The accuracy (recovery) of detection ranged from 90.5 to 108.7% between 0.4 ppm and 20 ppm of 4-chloro-1-butanol. The relative standard deviation in the repeatability of the spiked recovery test was 6.0%. These results indicate the validity of the GC-MS method developed in this study. The GC-MS method was applied for the determination of 4-chloro-1-butanol in the API (Compound A), which is under clinical trials. No 4-chloro-1-butanol was found in Compound A (below QL, 0.08 ppm).

  3. A combined DNA-affinic molecule and N-mustard alkylating agent has an anti-cancer effect and induces autophagy in oral cancer cells.

    PubMed

    Lo, Wen-Liang; Chu, Pen-Yuan; Lee, Tsung-Heng; Su, Tsann-Long; Chien, Yueh; Chen, Yi-Wei; Huang, Pin-I; Tseng, Ling-Ming; Tu, Pang-Hsien; Kao, Shou-Yen; Lo, Jeng-Fan

    2012-01-01

    Although surgery or the combination of chemotherapy and radiation are reported to improve the quality of life and reduce symptoms in patients with oral cancer, the prognosis of oral cancer remains generally poor. DNA alkylating agents, such as N-mustard, play an important role in cancer drug development. BO-1051 is a new 9-anilinoacridine N-mustard-derivative anti-cancer drug that can effectively target a variety of cancer cell lines and inhibit tumorigenesis in vivo. However, the underlying mechanism of BO-1051-mediated tumor suppression remains undetermined. In the present study, BO-1051 suppressed cell viability with a low IC(50) in oral cancer cells, but not in normal gingival fibroblasts. Cell cycle analysis revealed that the tumor suppression by BO-1051 was accompanied by cell cycle arrest and downregulation of stemness genes. The enhanced conversion of LC3-I to LC3-II and the formation of acidic vesicular organelles indicated that BO-1501 induced autophagy. The expression of checkpoint kinases was upregulated as demonstrated with Western blot analysis, showing that BO-1051 could induce DNA damage and participate in DNA repair mechanisms. Furthermore, BO-1051 treatment alone exhibited a moderate tumor suppressive effect against xenograft tumor growth in immunocompromised mice. Importantly, the combination of BO-1051 and radiation led to a potent inhibition on xenograft tumorigenesis. Collectively, our findings demonstrated that BO-1051 exhibited a cytotoxic effect via cell cycle arrest and the induction of autophagy. Thus, the combination of BO-1051 and radiotherapy may be a feasible therapeutic strategy against oral cancer in the future.

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

    PubMed

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

    2015-12-01

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

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

    PubMed

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

    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.

  6. Increased frequency of dicentric chromosomes in therapy-related MDS and AML compared to de novo disease is significantly related to previous treatment with alkylating agents and suggests a specific susceptibility to chromosome breakage at the centromere.

    PubMed

    Andersen, M K; Pedersen-Bjergaard, J

    2000-01-01

    Dicentric chromosomes are observed in many malignant diseases including myelodysplasia (MDS) and acute myeloid leukemia (AML) and have often been observed in a subset of these diseases, namely therapy-related MDS (t-MDS) and AML (t-AML). Using fluorescence in situ hybridization (FISH) with centromere-specific probes, we investigated the frequency and type of dicentric chromosomes in 180 consecutive patients with t-MDS and t-AML and in 231 consecutive patients with de novo MDS and AML, whose karyotypes had been studied previously by conventional G-banding. Twenty-seven out of 180 patients with t-MDS or t-AML presented dicentric chromosomes compared to only seven out of 231 patients with de novo disease (P = 0.00003). A dic(1q;7p) was observed in 10 cases, a dic(5p;17q) was observed in six cases, whereas various isodicentric chromosomes were observed in six cases. Excluding these six cases with isodicentrics, all 25 patients with dicentric chromosomes had involvement of at least one of the chromosome arms 1q, 5p, or 7p resulting in monosomy for 5q or 7q, and/or trisomy for 1q. Patients with dicentric chromosomes presented significantly more often as t-MDS compared to patients without dicentrics (P = 0.046), and the presence of a dicentric chromosome was significantly related to previous therapy with alkylating agents (P = 0.026). Thus, only one out of 27 patients with a dicentric chromosome had not previously received an alkylating agent. A specific susceptibility to breakage at the centromere after exposure to alkylating agents is suggested and may explain the frequent loss of whole chromosomes, in particular chromosomes 5 and 7 in t-MDS and t-AML, if the breaks are not followed by rejoining. Leukemia (2000) 14, 105-111.

  7. γ-Hydroxyethyl piperidine iminosugar and N-alkylated derivatives: a study of their activity as glycosidase inhibitors and as immunosuppressive agents.

    PubMed

    Markad, Pramod R; Sonawane, Dhiraj P; Ghosh, Sougata; Chopade, Balu A; Kumbhar, Navnath; Louat, Thierry; Herman, Jean; Waer, Mark; Herdewijn, Piet; Dhavale, Dilip D

    2014-11-01

    An efficient and practical strategy for the synthesis of (3R,4s,5S)-4-(2-hydroxyethyl) piperidine-3,4,5-triol and its N-alkyl derivatives 8a-f, starting from the D-glucose, is reported. The chiral pool methodology involves preparation of the C-3-allyl-α-D-ribofuranodialdose 10, which was converted to the C-5-amino derivative 11 by reductive amination. The presence of C-3-allyl group gives an easy access to the requisite hydroxyethyl substituted compound 13. Intramolecular reductive aminocyclization of C-5 amino group with C-1 aldehyde provided the γ-hydroxyethyl substituted piperidine iminosugar 8a that was N-alkylated to get N-alkyl derivatives 8b-f. Iminosugars 8a-f were screened against glycosidase enzymes. Amongst synthetic N-alkylated iminosugars, 8b and 8c were found to be α-galactosidase inhibitors while 8d and 8e were selective and moderate α-mannosidase inhibitors. In addition, immunomodulatory activity of compounds 8a-f was examined. These results were substantiated by molecular docking studies using AUTODOCK 4.2 programme.

  8. Stereospecific nickel-catalyzed cross-coupling reactions of alkyl Grignard reagents and identification of selective anti-breast-cancer agents.

    PubMed

    Yonova, Ivelina M; Johnson, A George; Osborne, Charlotte A; Moore, Curtis E; Morrissette, Naomi S; Jarvo, Elizabeth R

    2014-02-24

    Alkyl Grignard reagents that contain β-hydrogen atoms were used in a stereospecific nickel-catalyzed cross-coupling reaction to form C(sp(3))-C(sp(3)) bonds. Aryl Grignard reagents were also utilized to synthesize 1,1-diarylalkanes. Several compounds synthesized by this method exhibited selective inhibition of proliferation of MCF-7 breast cancer cells.

  9. DNA-directed alkylating agents. 3. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the length of the linker chain.

    PubMed

    Valu, K K; Gourdie, T A; Boritzki, T J; Gravatt, G L; Baguley, B C; Wilson, W R; Wakelin, L P; Woodgate, P D; Denny, W A

    1990-11-01

    Four series of acridine-linked aniline mustards have been prepared and evaluated for in vitro cytotoxicity, in vivo antitumor activity, and DNA cross-linking ability. The anilines were attached to the DNA-intercalating acridine chromophores by link groups (-O-, -CH2-, -S-, and -SO2-) of widely varying electronic properties, providing four series of widely differing mustard reactivity where the alkyl chain linking the acridine and mustard moieties was varied from two to five carbons. Relationships were sought between chain length and biological properties. Within each series, increasing the chain length did not alter the reactivity of the alkylating moiety but did appear to position it differently on the DNA, since cross-linking ability (measured by agarose gel assay) altered with chain length, being maximal with the C4 analogue. The in vivo antitumor activities of the compounds depended to some extent on the reactivity of the mustard, with the least reactive SO2 compounds being inactive. However, DNA-targeting did appear to allow the use of less reactive mustards, since the S-linked acridine mustards showed significant activity whereas the parent S-mustard did not. Within each active series, the most active compound was the C4 homologue, suggesting some relationship between activity and extent of DNA alkylation.

  10. The DinB•RecA complex of Escherichia coli mediates an efficient and high-fidelity response to ubiquitous alkylation lesions.

    PubMed

    Cafarelli, Tiziana M; Rands, Thomas J; Godoy, Veronica G

    2014-03-01

    Alkylation DNA lesions are ubiquitous, and result from normal cellular metabolism as well as from treatment with methylating agents and chemotherapeutics. DNA damage tolerance by translesion synthesis DNA polymerases has an important role in cellular resistance to alkylating agents. However, it is not yet known whether Escherichia coli (E. coli) DNA Pol IV (DinB) alkylation lesion bypass efficiency and fidelity in vitro are similar to those inferred by genetic analyses. We hypothesized that DinB-mediated bypass of 3-deaza-3-methyladenine, a stable analog of 3-methyladenine, the primary replication fork-stalling alkylation lesion, would be of high fidelity. We performed here the first kinetic analyses of E. coli DinB•RecA binary complexes. Whether alone or in a binary complex, DinB inserted the correct deoxyribonucleoside triphosphate (dNTP) opposite either lesion-containing or undamaged template; the incorporation of other dNTPs was largely inefficient. DinB prefers undamaged DNA, but the DinB•RecA binary complex increases its catalytic efficiency on lesion-containing template, perhaps as part of a regulatory mechanism to better respond to alkylation damage. Notably, we find that a DinB derivative with enhanced affinity for RecA, either alone or in a binary complex, is less efficient and has a lower fidelity than DinB or DinB•RecA. This finding contrasts our previous genetic analyses. Therefore, mutagenesis resulting from alkylation lesions is likely limited in cells by the activity of DinB•RecA. These two highly conserved proteins play an important role in maintaining genomic stability when cells are faced with ubiquitous DNA damage. Kinetic analyses are important to gain insights into the mechanism(s) regulating TLS DNA polymerases.

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

    PubMed Central

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

    1990-01-01

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

  12. 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

  13. 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.

  14. The Escherichia coli AlkB protein protects human cells against alkylation-induced toxicity.

    PubMed Central

    Chen, B J; Carroll, P; Samson, L

    1994-01-01

    Escherichia coli can ameliorate the toxic effects of alkylating agents either by preventing DNA alkylation or by repairing DNA alkylation damage. The alkylation-sensitive phenotype of E. coli alkB mutants marks the alkB pathway as an extremely effective defense mechanism against the cytotoxic effects of the SN2, but not the SN1, alkylating agents. Although it is clear that AlkB helps cells to better handle alkylated DNA, no DNA alkylation repair function could be assigned to the purified AlkB protein, suggesting that AlkB either acts as part of a complex or acts to regulate the expression of other genes whose products are directly responsible for alkylation resistance. However, here we present evidence that the provision of alkylation resistance is an intrinsic function of the AlkB protein per se. We expressed the E. coli AlkB protein in two human cell lines and found that it confers the same characteristic alkylation-resistant phenotype in this foreign environment as it does in E. coli. AlkB expression rendered human cells extremely resistant to cell killing by the SN2 but not the SN1 alkylating agents but did not affect the ability of dimethyl sulfate (an SN2 agent) to alkylate the genome. We infer that SN2 agents produce a class of DNA damage that is not efficiently produced by SN1 agents and that AlkB somehow prevents this damage from killing the cell. Images PMID:7928996

  15. Mitochondria and redox homoeostasis as chemotherapeutic targets.

    PubMed

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

    2014-08-01

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

  16. 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.

  17. 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

  18. 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.

  19. 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.

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

    DTIC Science & Technology

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

  1. Co-electroosmotic capillary electrophoresis of basic proteins with 1-alkyl-3-methylimidazolium tetrafluoroborate ionic liquids as non-covalent coating agents of the fused-silica capillary and additives of the electrolyte solution.

    PubMed

    Corradini, Danilo; Nicoletti, Isabella; Bonn, Günther K

    2009-06-01

    The paper reports the results of a study carried out to evaluate the use of three 1-alkyl-3-methylimidazolium-based ionic liquids as non-covalent coating agents for bare fused-silica capillaries and additives of the electrolyte solutions (BGE) for CE of basic proteins in the co-EOF separation mode. The three ionic liquids are differentiated from each other by the length of the alkyl group on the imidazolium cation, consisting of either an ethyl, butyl or octyl substituent, whereas tetrafluoroborate is the common anionic component of the ionic liquids. Coating the capillary with the ionic liquid resulted in improved peak shape and protein separation, while the EOF was maintained cathodic. This indicates that each ionic liquid is effective at masking the protein interaction sites on the inner surface of the capillary, also when its adsorption onto the capillary wall has not completely neutralized all the negative charges arising from the ionization of the silanol groups and the ionic liquid is not incorporated into the BGE employed for separation. Using the coated capillaries with BGE containing the ionic liquid employed for the coating, at concentration low enough to maintaining the EOF cathodic, both peak shape and protein separation varied to different extents, based on the particular ionic liquid used and its concentration. Fast and efficient separation of the model basic protein mixture in co-electroosmotic CE is obtained with the 1-butyl-3-methylimidazolium tetrafluoroborate coated capillary and 100 mM acetate buffer (pH 4.0) containing 4.4 mM 1-butyl-3-methylimidazolium tetrafluoroborate as the BGE.

  2. Synthesis, structure, theoretical and experimental in vitro antioxidant/pharmacological properties of α-aryl, N-alkyl nitrones, as potential agents for the treatment of cerebral ischemia.

    PubMed

    Samadi, Abdelouahid; Soriano, Elena; Revuelta, Julia; Valderas, Carolina; Chioua, Mourad; Garrido, Ignacio; Bartolomé, Begoña; Tomassolli, Isabelle; Ismaili, Lhassane; González-Lafuente, Laura; Villarroya, Mercedes; García, Antonio G; Oset-Gasque, María J; Marco-Contelles, José

    2011-01-15

    The synthesis, structure, theoretical and experimental in vitro antioxidant properties using the DPPH, ORAC, and benzoic acid, as well as preliminary in vitro pharmacological activities of (Z)-α-aryl and heteroaryl N-alkyl-nitrones 6-15, 18, 19, 21, and 23, is reported. In the in vitro antioxidant activity, for the DPPH radical test, only nitrones bearing free phenol groups gave the best RSA (%) values, nitrones 13 and 14 showing the highest values in this assay. In the ORAC analysis, the most potent radical scavenger was nitrone indole 21, followed by the N-benzyl benzene-type nitrones 10 and 15. Interestingly enough, the archetypal nitrone 7 (PBN) gave a low RSA value (1.4%) in the DPPH test, or was inactive in the ORAC assay. Concerning the ability to scavenge the hydroxyl radical, all the nitrones studied proved active in this experiment, showing high values in the 94-97% range, the most potent being nitrone 14. The theoretical calculations for the prediction of the antioxidant power, and the potential of ionization confirm that nitrones 9 and 10 are among the best compounds in electron transfer processes, a result that is also in good agreement with the experimental values in the DPPH assay. The calculated energy values for the reaction of ROS (hydroxyl, peroxyl) with the nitrones predict that the most favourable adduct-spin will take place between nitrones 9, 10, and 21, a fact that would be in agreement with their experimentally observed scavenger ability. The in vitro pharmacological analysis showed that the neuroprotective profile of the target molecules was in general low, with values ranging from 0% to 18.7%, in human neuroblastoma cells stressed with a mixture of rotenone/oligomycin-A, being nitrones 18, and 6-8 the most potent, as they show values in the range 24-18.4%.

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

    PubMed

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

    2010-10-28

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

  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. Synthesis and anticancer effects evaluation of 1-alkyl-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-yl)benzo[d]thiazol-2-yl)urea as anticancer agents with low toxicity.

    PubMed

    Xie, Xiao-Xiao; Li, Huan; Wang, Juan; Mao, Shuai; Xin, Min-Hang; Lu, She-Min; Mei, Qi-Bing; Zhang, San-Qi

    2015-10-01

    As a PI3K and mTOR dual inhibitor, N-(2-chloro-5-(2-acetylaminobenzo[d]thiazol-6-yl)pyridin-3-yl)-4-fluorophenylsulfonamide displays toxicity when orally administrated. In the present study, alkylurea moiety replaced the acetamide group in the compound and a series of 1-alkyl-3-(6-(2,3-disubstituted pyridin-5-yl)benzo[d]thiazol-2-yl)urea derivatives were synthesized. The antiproliferative activities of the synthesized compounds in vitro were evaluated against HCT116, MCF-7, U87 MG and A549 cell lines. The compounds with potent antiproliferative activity were tested for their acute oral toxicity and inhibitory activity against PI3Ks and mTORC1. The results indicate that the compound attached a 2-(dialkylamino)ethylurea moiety at the 2-positeion of benzothiazole can retain the antiproliferative activity and inhibitory activity against PI3K and mTOR. In addition, their acute oral toxicity reduced dramatically. Moreover, compound 2f can effectively inhibit tumor growth in a mice S180 homograft model. These findings suggest that 1-(2-dialkylaminoethyl)-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-yl)benzo[d]thiazol-2-yl)urea derivatives can serve as potent PI3K inhibitors and anticancer agents with low toxicity.

  6. Hypoxia-activated prodrugs: substituent effects on the properties of nitro seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (nitroCBI) prodrugs of DNA minor groove alkylating agents.

    PubMed

    Tercel, Moana; Atwell, Graham J; Yang, Shangjin; Stevenson, Ralph J; Botting, K Jane; Boyd, Maruta; Smith, Eileen; Anderson, Robert F; Denny, William A; Wilson, William R; Pruijn, Frederik B

    2009-11-26

    Nitrochloromethylbenzindolines (nitroCBIs) are a new class of hypoxia-activated prodrugs for antitumor therapy. The recently reported prototypes undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents and are selectively toxic to some but not all hypoxic tumor cell lines. Here we report a series of 31 analogues that bear an extra electron-withdrawing substituent that serves to raise the one-electron reduction potential of the nitroCBI. We identify a subset of compounds, those with a basic side chain and sulfonamide or carboxamide substituent, that have consistently high hypoxic selectivity. The best of these, with a 7-sulfonamide substituent, displays hypoxic cytotoxicity ratios of 275 and 330 in Skov3 and HT29 human tumor cell lines, respectively. This compound (28) is efficiently and selectively metabolized to the corresponding aminoCBI, is selectively cytotoxic under hypoxia in all 11 cell lines examined, and demonstrates activity against hypoxic tumor cells in a human tumor xenograft in vivo.

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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.

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

    DTIC Science & Technology

    2008-05-01

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

  13. 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-.

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

    PubMed

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

    1981-01-01

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

  15. Synthesis of Taxol-Like Prostate Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2006-11-01

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

  16. Design and Sythesis of New Breast Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2000-08-01

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

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

    PubMed

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

    2016-01-01

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

  18. The Effect of Chemotherapeutic Agents on Immune Reactions.

    DTIC Science & Technology

    1982-08-01

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

  19. Synthesis Of Alkyl Hydroperoxides Via Alkylation Of gem-Dihydroperoxides

    PubMed Central

    Kyasa, ShivaKumar; Puffer, Benjamin W.

    2013-01-01

    Two-fold alkylation of 1,1-dihydroperoxides, followed by hydrolysis of the resulting bisperoxyacetals, provides a convenient method for synthesis of primary and secondary alkyl hydroperoxides. PMID:23469994

  20. Agents.

    PubMed

    Chambers, David W

    2002-01-01

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

  1. Safety assessment of alkyl benzoates as used in cosmetics.

    PubMed

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

    2012-01-01

    The functions of alkyl benzoates in cosmetics include fragrance ingredients, skin-conditioning agents--emollient, skin-conditioning agents--miscellaneous, preservatives, solvents, and plasticizers. The Cosmetic Ingredient Review Expert Panel reviewed the relevant animal and human data and noted gaps in the available safety data for some of the alkyl benzoates. Similar structure activity relationships, biologic functions, and cosmetic product usage allowed the available data of many of the alkyl benzoates to be extended to the entire group. Carcinogenicity data were not available, but available data indicated that these alkyl benzoate cosmetic ingredients are not genotoxic. Also benzoic acid and tested component alcohols were not reproductive or developmental toxicants, are not genotoxic in almost all assays, and are not carcinogenic. These ingredients were determined to be safe in the present practices of use and concentration.

  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. 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

  4. 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

  5. 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

  6. Bifunctional alkylating agent-induced p53 and nonclassical nuclear factor kappaB responses and cell death are altered by caffeic acid phenethyl ester: a potential role for antioxidant/electrophilic response-element signaling.

    PubMed

    Minsavage, Gary D; Dillman, James F

    2007-04-01

    Bifunctional alkylating agents (BFA) such as mechlorethamine (nitrogen mustard) and bis-(2-chloroethyl) sulfide (sulfur mustard; SM) covalently modify DNA and protein. The roles of nuclear factor kappaB (NF-kappaB) and p53, transcription factors involved in inflammatory and cell death signaling, were examined in normal human epidermal keratinocytes (NHEK) and immortalized HaCaT keratinocytes, a p53-mutated cell line, to delineate molecular mechanisms of action of BFA. NHEK and HaCaT cells exhibited classical NF-kappaB signaling as degradation of inhibitor protein of NF-kappaBalpha (IkappaBalpha) occurred within 5 min after exposure to tumor necrosis factor-alpha. However, exposure to BFA induced nonclassical NF-kappaB signaling as loss of IkappaBalpha was not observed until 2 or 6 h in NHEK or HaCaT cells, respectively. Exposure of an NF-kappaB reporter gene-expressing HaCaT cell line to 12.5, 50, or 100 muM SM activated the reporter gene within 9 h. Pretreatment with caffeic acid phenethyl ester (CAPE), a known inhibitor of NF-kappaB signaling, significantly decreased BFA-induced reporter gene activity. A 1.5-h pretreatment or 30-min postexposure treatment with CAPE prevented BFA-induced loss of membrane integrity by 24 h in HaCaT cells but not in NHEK. CAPE disrupted BFA-induced phosphorylation of p53 and p90 ribosomal S6 kinase (p90RSK) in both cell lines. CAPE also increased nuclear factor E2-related factor 2 and decreased aryl hydrocarbon receptor protein expression, both of which are involved in antioxidant/electrophilic response element (ARE/EpRE) signaling. Thus, disruption of p53/p90RSK-mediated NF-kappaB signaling and activation of ARE/EpRE pathways may be effective strategies to delineate mechanisms of action of BFA-induced inflammation and cell death signaling in immortalized versus normal skin systems.

  7. 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.

  8. 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.

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

    PubMed

    Błaszczak-Świątkiewicz, Katarzyna; Mikiciuk-Olasik, Elżbieta

    2015-03-01

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

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

    PubMed

    Urbina, J A

    1997-01-01

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

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  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

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

    2011-10-13

    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 (MIC(90) = 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.

  17. Chemotherapeutic trial to control enterobiasis in schoolchildren.

    PubMed

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

    1997-12-01

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

  18. 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

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

    PubMed

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

    2015-06-12

    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.

  20. 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.

  1. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy.

    PubMed

    Hunter, Chris; Smith, Raffaella; Cahill, Daniel P; Stephens, Philip; Stevens, Claire; Teague, Jon; Greenman, Chris; Edkins, Sarah; Bignell, Graham; Davies, Helen; O'Meara, Sarah; Parker, Adrian; Avis, Tim; Barthorpe, Syd; Brackenbury, Lisa; Buck, Gemma; Butler, Adam; Clements, Jody; Cole, Jennifer; Dicks, Ed; Forbes, Simon; Gorton, Matthew; Gray, Kristian; Halliday, Kelly; Harrison, Rachel; Hills, Katy; Hinton, Jonathon; Jenkinson, Andy; Jones, David; Kosmidou, Vivienne; Laman, Ross; Lugg, Richard; Menzies, Andrew; Perry, Janet; Petty, Robert; Raine, Keiran; Richardson, David; Shepherd, Rebecca; Small, Alexandra; Solomon, Helen; Tofts, Calli; Varian, Jennifer; West, Sofie; Widaa, Sara; Yates, Andy; Easton, Douglas F; Riggins, Gregory; Roy, Jennifer E; Levine, Kymberly K; Mueller, Wolf; Batchelor, Tracy T; Louis, David N; Stratton, Michael R; Futreal, P Andrew; Wooster, Richard

    2006-04-15

    Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statistically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We sequenced 500 kb of genomic DNA corresponding to the kinase domains of 518 protein kinases in each of nine gliomas. Large numbers of somatic mutations were observed in two gliomas recurrent after alkylating agent treatment. The pattern of mutations in these cases showed strong similarity to that induced by alkylating agents in experimental systems. Further investigation revealed inactivating somatic mutations of the mismatch repair gene MSH6 in each case. We propose that inactivating somatic mutations of MSH6 confer resistance to alkylating agents in gliomas in vivo and concurrently unleash accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. The evidence therefore suggests that when MSH6 is inactivated in gliomas, alkylating agents convert from induction of tumor cell death to promotion of neoplastic progression. These observations highlight the potential of large scale sequencing for revealing and elucidating mutagenic processes operative in individual human cancers.

  2. 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

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

    PubMed

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

    2014-10-01

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

  4. 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

  5. Escherichia coli gene induction by alkylation treatment.

    PubMed

    Volkert, M R; Nguyen, D C; Beard, K C

    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 beta-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.

  6. Isolation and identification of products from alkylation of nucleic acids: ethyl- and isopropyl-purines.

    PubMed Central

    Lawley, P D; Orr, D J; Jarman, M

    1975-01-01

    Ethylation and isopropylation of guanine in alkaline solution, or of adenine in formic acid, by alkyl methanesulphonates gave the following products: 1-, N2-, 3-, O6-, 7- and 9-alkylguanines; 1-, 3-, 7- and 9-alkyladenines. The products were identified from their characteristic u.v-absorption spectra, by comparison with either known ethyladenines or with the corresponding known methyladenines, and were also characterized by mass spectrometry. Their chromatographic properties on paper, t.l.c. and various columns were determined. DNA was alkylated in neutral solution with 14C-labelled alkyl methanesulphonates and the ratios of the alkylpurines formed were obtained, and compared for alkylation by methyl, ethyl and isopropyl methanesulphonates and by N-methyl-N-nitrosourea. The extents of alkylation at O-6 of guanine relative to those at N-7 of guanine varied with the reactivity of the methylating agents according to the predictions of Swain & Scott (1953) relating nucleophilicity of the groups alkylated with the substrate constants of the alkylating agents. The relative extents of alkylation at N-3 of adenine did not follow this correlation. PMID:172066

  7. Differences in sequence selectivity of DNA alkylation by isomeric intercalating aniline mustards.

    PubMed

    Prakash, A S; Denny, W A; Wakelin, L P

    1990-01-01

    Two DNA-targeted mustard derivatives, N,N-bis(2-chloroethyl)-4-(5-[9-acridinylamino]-pentamido)aniline and 4-(9-[acridinylamino]butyl 4-(N,N-bis[2-chloroethyl]-aminobenzamide, which are isomeric compounds where the mustard is linked to the DNA-binding 9-aminoacridine moiety by either a -CONH- or a -NHCO- group, show significant differences in the sequence selectivity of their alkylation of DNA. The CONH isomer is a more efficient alxylating agent than the NHCO compound by an order of magnitude, consistent with the larger electron release of the CONH group to the aniline ring. However, the pattern of alkylation by the two compounds is also very different, with the CONH isomer preferring alkylation of guanines adjacent to 3'- or 5'-adenines and cytosines (for example those in sequences 5'-CGC, 5'-AGC, 5'-CGG and 5'-AGA) while the isomeric NHCO compound shows preference for guanines in runs of Gs. In addition, both isomers alkylate 3'-adenines in runs of adenines. Both compounds also show completely different patterns of alkylation to their untargeted mustard counterparts, since 4-MeCONH-aniline mustard alkylates all guanines and adenines in runs of adenines, while 4-Me2NCO-aniline mustard fails to alkylate DNA at all. These differences in alkylation patterns between the CONH- and its isomeric NHCO- compounds and their relationships between the alkylation patterns of the isomers and their biological activities are discussed.

  8. 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.

  9. 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.

  10. 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.

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

    PubMed

    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

    2014-01-07

    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 O(6)-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.

  12. 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

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

    PubMed Central

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

    2014-01-01

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

  14. Alkylating potential of styrene oxide: reactions and factors involved in the alkylation process.

    PubMed

    González-Pérez, Marina; Gómez-Bombarelli, Rafael; Pérez-Prior, M Teresa; Arenas-Valgañón, Jorge; García-Santos, M Pilar; Calle, Emilio; Casado, Julio

    2014-10-20

    The chemical reactivity of styrene-7,8-oxide (SO), an alkylating agent with high affinity for the guanine–N7 position and a probable carcinogen for humans, with 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to those of DNA bases, was investigated kinetically in water/dioxane media. UV–vis spectrophotometry and ultrafast liquid chromatography were used to monitor the reactions involved. It was found that in the alkylation process four reactions occur simultaneously: (a) the formation of a β-NBP–SO adduct through an SN2 mechanism; (b) the acid-catalyzed formation of the stable α-NBP–SO adduct through an SN2′ mechanism; (c) the base-catalyzed hydrolysis of the β-adduct, and (d) the acid-catalyzed hydrolysis of SO. At 37.5 °C and pH = 7.0 (in 7:3 water/dioxane medium), the values of the respective reaction rate constants were as follows: kalkβ = (2.1 ± 0.3) × 10–4 M–1 s–1, kalkα = (1.0 ± 0.1) × 10–4 M–1 s–1, khydAD = (3.06 ± 0.09) × 10–6 s–1, and khyd = (4.2 ± 0.9) × 10–6 s–1. These values show that, in order to determine the alkylating potential of SO, none of the four reactions involved can be neglected. Temperature and pH were found to exert a strong influence on the values of some parameters that may be useful to investigate possible chemicobiological correlations (e.g., in the pH 5.81–7.69 range, the fraction of total adducts formed increased from 24% to 90% of the initial SO, whereas the adduct lifetime of the unstable β-adduct, which gives an idea of the permanence of the adduct over time, decreased from 32358 to 13313 min). A consequence of these results is that the conclusions drawn in studies addressing alkylation reactions at temperatures and/or pH far from those of biological conditions should be considered with some reserve.

  15. 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

  16. 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

  17. Alkylation of benzene or toluene with MeOH or C{sub 2}H{sub 4} over ZSM-5 or {beta} zeolite: Effect of the zeolite pore openings and of the hydrocarbons involved on the mechanism of alkylation

    SciTech Connect

    Smirniotis, P.G.; Ruckenstein, E.

    1995-05-01

    A comparative study of the alkylation of benzene or toluene with MeOH or C{sub 2}H{sub 4} over a medium (ZSM-5) and a large pore ({beta}) zeolite of comparable acidities was carried out. It was observed that the reaction temperature in combination with the structure of the zeolite plays an important role in the reactions that take place. The maximum yield of either the primary or secondary alkylation products may occur at an intermediate temperature, which is lower over {beta} zeolite. Due to its pore structure, {beta} zeolite favors secondary alkylation reactions and also disproportionation reactions of the generated alkylaromatics to a higher extent than ZSM-5 does. MeOH generates both primary and secondary alkylation products, while C{sub 2}H{sub 4} favors oligomerization reactions, primary alkylation reactions, and particularly, disproportionation reactions. Toluene is more reactive than benzene. The aromatic/alkylating agent molar ratio plays an important role in the relative importance of the reactions that take place. The size of the pores of the zeolite in combination with the sizes of the aromatic hydrocarbons and the alkylating agents employed determines whether the alkylation occurs via a Langmuir-Henshelwood (LH) or Rideal-Eley (RE) mechanism. When a LH mechanism occurs, the alkylation rate passes through a maximum with respect to the concentration of the aromatic hydrocarbon employed; no such maximum occurs for the RE mechanism.

  18. Outlook for the U. S. alkylation industry

    SciTech Connect

    Felten, J.R.; Bradshaw, T.; McCarthy, K. )

    1994-01-01

    Alkylation has long been recognized in the refining industry as one of the best options to convert refinery olefins into valuable, clean, high octane blending components. In fact, refinery alkylation is a preferred source of blending stocks for reformulated gasoline. However, the hydrofluoric acid (HF) alkylation process and, to a lesser extent, the sulfuric acid (SA) process have come under increasing pressure in the US due to safety and environmental concerns. This paper examines the current outlook for the US alkylation industry including: key trends and driving forces in the industry, the impact of environmental issues on both HF and SA alkylation, US alkylation supply/demand forecast including the outlook for oxygenates, how US refines will respond to the increased demand and restricted supply for alkylates, and the outlook for new solid acid alkylation (SAC) technology.

  19. Total synthesis of alkyl citrate natural products.

    PubMed

    Rizzacasa, Mark A; Sturgess, Dayna

    2014-03-07

    This review highlights the synthesis of members of the alkyl citrate family of natural products. The focus is on the stereoselective construction of the alkyl citrate moiety common to these compounds.

  20. 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.

  1. Chichibabin-type direct alkylation of pyridyl alcohols with alkyl lithium reagents.

    PubMed

    Jeffrey, Jenna L; Sarpong, Richmond

    2012-11-02

    Direct C(6) alkylation of pyridyl alcohols can be achieved following an initial deprotonation of the hydroxy group. This transformation, which is believed to occur by a Chichibabin-type alkylation, avoids lateral deprotonation prior to pyridine ring alkylation and gives increased regioselectivity for C(6) over C(4) alkylation.

  2. Refiners discuss HF alkylation process and issues

    SciTech Connect

    Not Available

    1992-04-06

    Safety and oxygenate operations made HF alkylation a hot topic of discussion at the most recent National Petroleum Refiners Association annual question and answer session on refining and petrochemical technology. This paper provides answers to a variety of questions regarding the mechanical, process, and safety aspects of the HF alkylation process. Among the issues discussed were mitigation techniques, removal of oxygenates from alkylation unit feed, and amylene alkylation.

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

    PubMed Central

    Pickard, Amanda J.

    2013-01-01

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

  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.

  5. 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...

  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. Alkylation of human hair keratin for tunable hydrogel erosion and drug delivery in tissue engineering applications.

    PubMed

    Han, Sangheon; Ham, Trevor R; Haque, Salma; Sparks, Jessica L; Saul, Justin M

    2015-09-01

    Polymeric biomaterials that provide a matrix for cell attachment and proliferation while achieving delivery of therapeutic agents are an important component of tissue engineering and regenerative medicine strategies. Keratins are a class of proteins that have received attention for numerous tissue engineering applications because, like other natural polymers, they promote favorable cell interactions and have non-toxic degradation products. Keratins can be extracted from various sources including human hair, and they are characterized by a high percentage of cysteine residues. Thiol groups on reductively extracted keratin (kerateine) form disulfide bonds, providing a more stable cross-linked hydrogel network than oxidatively extracted keratin (keratose) that cannot form disulfide crosslinks. We hypothesized that an iodoacetamide alkylation (or "capping") of cysteine thiol groups on the kerateine form of keratin could be used as a simple method to modulate the levels of disulfide crosslinking in keratin hydrogels, providing tunable rates of gel erosion and therapeutic agent release. After alkylation, the alkylated kerateines still formed hydrogels and the alkylation led to changes in the mechanical and visco-elastic properties of the materials consistent with loss of disulfide crosslinking. The alkylated kerateines did not lead to toxicity in MC3T3-E1 pre-osteoblasts. These cells adhered to keratin at levels comparable to fibronectin and greater than collagen. Alkylated kerateine gels eroded more rapidly than non-alkylated kerateine and this control over erosion led to tunable rates of delivery of rhBMP-2, rhIGF-1, and ciprofloxacin. These results demonstrate that alkylation of kerateine cysteine residues provides a cell-compatible approach to tune rates of hydrogel erosion and therapeutic agent release within the context of a naturally-derived polymeric system.

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

    DTIC Science & Technology

    2005-04-01

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

  10. 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.

  11. 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.

  12. Iron-Catalyzed Decarboxylative Alkyl Etherification of Vinylarenes with Aliphatic Acids as the Alkyl Source.

    PubMed

    Jian, Wujun; Ge, Liang; Jiao, Yihang; Qian, Bo; Bao, Hongli

    2017-03-20

    Because of the lack of effective alkylating reagents, alkyl etherification of olefins with general alkyl groups has not been previously reported. In this work, a variety of alkyl diacyl peroxides and peresters generated from aliphatic acids have been found to enable the first iron-catalyzed alkyl etherification of olefins with general alkyl groups. Primary, secondary and tertiary aliphatic acids are suitable for this reaction, delivering products with yields up to 97 %. Primary and secondary alcohols react well, affording products in up to 91 % yield.

  13. 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.

  14. 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.

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

    PubMed

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

    2017-04-01

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

  16. 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

  17. Bimetallic oxidative addition involving radical intermediates in nickel-catalyzed alkyl-alkyl Kumada coupling reactions.

    PubMed

    Breitenfeld, Jan; Ruiz, Jesus; Wodrich, Matthew D; Hu, Xile

    2013-08-14

    Many nickel-based catalysts have been reported for cross-coupling reactions of nonactivated alkyl halides. The mechanistic understanding of these reactions is still primitive. Here we report a mechanistic study of alkyl-alkyl Kumada coupling catalyzed by a preformed nickel(II) pincer complex ([(N2N)Ni-Cl]). The coupling proceeds through a radical process, involving two nickel centers for the oxidative addition of alkyl halide. The catalysis is second-order in Grignard reagent, first-order in catalyst, and zero-order in alkyl halide. A transient species, [(N2N)Ni-alkyl(2)](alkyl(2)-MgCl), is identified as the key intermediate responsible for the activation of alkyl halide, the formation of which is the turnover-determining step of the catalysis.

  18. Reactions of Tributylstannyl Anioniods with Alkyl Bromides.

    DTIC Science & Technology

    1981-09-28

    g (12 mmol) of cesium tert-butoxide was added to the reaction vessel before the addition of n-butyllithium. Alkylation of Tributylstannyl Anionoids...Dry reaction vessels were purged with argon. The desired alkyl halide (1.0 mmol unless noted) and any desired additive were added to the reaction ...OFFICE OF NAVAL RESEARCH Contract N00014-79-C-0584 Task No. NR 053-714 TECHNICAL REPORT No. 2 Reactions of Tributylstannyl Anionoids with Alkyl

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

    Kevin Baird, J.

    2012-01-01

    The endemic malarias threaten the several billion people residing where transmission occurs. Chemotherapeutic strategy pitted against these threats hinges upon species- and stage-specific treatments guided by diagnosis and screening against sometime dangerous contraindications. This approach suits malaria as it occurs among travelers in the developed, non-endemic world. However, limiting treatment to that which diagnosis affirms may not be rational in endemic zones. Most of the endemic malarias remain out of diagnostic reach, either by inaccessibility of the parasite stage, insensitivity of the technology, or unavailability of diagnostic services. The partial and fragmented chemotherapeutic attack of malaria guided by confirmed diagnostics leaves most of the endemic malarias unchallenged. Development of elimination therapy, a single course of treatment aimed at all species and stages, would significantly advance progress against the major killers known collectively as malaria. PMID:24533286

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

    PubMed Central

    Khan, M. Omar F.

    2007-01-01

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

  2. 40 CFR 721.1875 - Boric acid, alkyl and substituted alkyl esters (generic name).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... alkyl esters (generic name). 721.1875 Section 721.1875 Protection of Environment ENVIRONMENTAL... esters (generic name). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance boric acid, alkyl and substituted alkyl esters (PMN P-86-1252) is subject to...

  3. 40 CFR 721.1875 - Boric acid, alkyl and substituted alkyl esters (generic name).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... alkyl esters (generic name). 721.1875 Section 721.1875 Protection of Environment ENVIRONMENTAL... esters (generic name). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance boric acid, alkyl and substituted alkyl esters (PMN P-86-1252) is subject to...

  4. 40 CFR 721.1875 - Boric acid, alkyl and substituted alkyl esters (generic name).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... alkyl esters (generic name). 721.1875 Section 721.1875 Protection of Environment ENVIRONMENTAL... esters (generic name). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance boric acid, alkyl and substituted alkyl esters (PMN P-86-1252) is subject to...

  5. 40 CFR 721.1875 - Boric acid, alkyl and substituted alkyl esters (generic name).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... alkyl esters (generic name). 721.1875 Section 721.1875 Protection of Environment ENVIRONMENTAL... esters (generic name). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance boric acid, alkyl and substituted alkyl esters (PMN P-86-1252) is subject to...

  6. 40 CFR 721.1875 - Boric acid, alkyl and substituted alkyl esters (generic name).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... alkyl esters (generic name). 721.1875 Section 721.1875 Protection of Environment ENVIRONMENTAL... esters (generic name). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance boric acid, alkyl and substituted alkyl esters (PMN P-86-1252) is subject to...

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

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

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

    PubMed

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

    2014-07-01

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

  10. Repair of O6-G-alkyl-O6-G interstrand cross-links by human O6-alkylguanine-DNA alkyltransferase†

    PubMed Central

    Fang, Qingming; Noronha, Anne M.; Murphy, Sebastian P.; Wilds, Christopher J.; Tubbs, Julie L.; Tainer, John A.; Chowdhury, Goutam; Guengerich, F. Peter; Pegg, Anthony E.

    2008-01-01

    O6-Alkylguanine-DNA alkyltransferase (AGT) plays an important role protecting cells from alkylating agents. This reduces carcinogenesis and mutagenesis initiated by such agents but AGT also provides a major resistance mechanism to some chemotherapeutic drugs. In order to improve understanding of the AGT-mediated repair reaction and to increase understanding of the spectrum of repairable damage, we have studied the ability of AGT to repair interstrand cross-link DNA damage where the two DNA strands are joined via the guanine-O6 in each strand. An oligodeoxyribonucleotide containing a heptane cross-link was repaired with initial formation of an AGT-oligo complex and further reaction of a second AGT molecule yielding a hAGT dimer and free oligo. However, an oligodeoxyribonucleotide with a butane cross-link was a very poor substrate for AGT-mediated repair and only the first reaction to form an AGT-oligo complex could be detected. Models of the reaction of these substrates in the AGT active site show that the DNA duplex is forced apart locally to repair the first guanine. This reaction is greatly hindered with the butane cross-link, which is mostly buried in the active site pocket and limited in conformational flexibility. This limitation also prevents the adoption of a conformation for the second reaction to repair the AGT-oligo complex. These results are consistent with the postulated mechanism of AGT repair that involves DNA binding and flipping of the substrate nucleotide and indicate that hAGT can repair some types of interstrand cross-link damages. PMID:18803403

  11. S-alkylation of soft scorpionates.

    PubMed

    Rajasekharan-Nair, Rajeev; Moore, Dean; Chalmers, Kirsten; Wallace, Dawn; Diamond, Louise M; Darby, Lisa; Armstrong, David R; Reglinski, John; Spicer, Mark D

    2013-02-11

    The alkylation reactions of soft scorpionates are reported. The hydrotris(S-alkyl-methimazolyl)borate dications (alkyl = methyl, allyl, benzyl), which were prepared by the reaction of Tm(Me) anion and primary alkyl halides, have been isolated and structurally characterised. The reaction is, however, not universally successful. DFT analysis of these alkylation reactions (C=S versus B-H alkylation) indicates that the observed outcome is driven by kinetic factors. Extending the study to incorporate alternative imine thiones (mercaptobenzothiazole, bz; thiazoline, tz) led to the structural characterisation of di[aquo-μ-aquohydrotris(mercaptobenzothiazolyl)boratosodium], which contains sodium atoms in the κ(3)-S,S,S coordination mode. Alkylation of Na[Tbz] and Na[tzTtz] leads to decomposition resulting in the formation of the simple S-alkylated heterocycles. The analysis of the species involved in these reactions shows an inherent weakness in the B-N bond in soft scorpionates, which has implications for their use in more advanced chemistry.

  12. 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.

  13. 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

  14. 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.

  15. Optical resolution of 5-alkyl-delta-valerolactones and synthesis of optically active 5-fluoroalkanols.

    PubMed

    Riswoko, Asep; Aoki, Yoshio; Hirose, Takuji; Nohira, Hiroyuki

    2002-01-01

    Optical resolutions of 5-alkyl-delta-valerolactones were carried out by derivatization to the diastereomeric amides, in which (R)-(+)-1-(1-naphthyl)ethylamine or (S)-(-)-1-phenylethylamine were used as resolving agents. Optically active 5-fluoroalkanols, useful intermediates for fluorinated ferroelectric liquid crystals, were derived from the resolved lactones in four steps without racemization.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

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

    PubMed

    Tsen, Andrew R; Long, Patrick M; Driscoll, Heather E; Davies, Matthew T; Teasdale, Benjamin A; Penar, Paul L; Pendlebury, William W; Spees, Jeffrey L; Lawler, Sean E; Viapiano, Mariano S; Jaworski, Diane M

    2014-03-15

    Cancer is associated with epigenetic (i.e., histone hypoacetylation) and metabolic (i.e., aerobic glycolysis) alterations. Levels of N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate, are reduced in glioma; yet, few studies have investigated acetate as a potential therapeutic agent. This preclinical study sought to test the efficacy of the food additive Triacetin (glyceryl triacetate, GTA) as a novel therapy to increase acetate bioavailability in glioma cells. The growth-inhibitory effects of GTA, compared to the histone deacetylase inhibitor Vorinostat (SAHA), were assessed in established human glioma cell lines (HOG and Hs683 oligodendroglioma, U87 and U251 glioblastoma) and primary tumor-derived glioma stem-like cells (GSCs), relative to an oligodendrocyte progenitor line (Oli-Neu), normal astrocytes, and neural stem cells (NSCs) in vitro. GTA was also tested as a chemotherapeutic adjuvant with temozolomide (TMZ) in orthotopically grafted GSCs. GTA-induced cytostatic growth arrest in vitro comparable to Vorinostat, but, unlike Vorinostat, GTA did not alter astrocyte growth and promoted NSC expansion. GTA alone increased survival of mice engrafted with glioblastoma GSCs and potentiated TMZ to extend survival longer than TMZ alone. GTA was most effective on GSCs with a mesenchymal cell phenotype. Given that GTA has been chronically administered safely to infants with Canavan disease, a leukodystrophy due to ASPA mutation, GTA-mediated acetate supplementation may provide a novel, safe chemotherapeutic adjuvant to reduce the growth of glioma tumors, most notably the more rapidly proliferating, glycolytic and hypoacetylated mesenchymal glioma tumors.

  6. 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

  7. Regioselectivity of Birch reductive alkylation of biaryls.

    PubMed

    Lebeuf, Raphaël; Robert, Frédéric; Landais, Yannick

    2005-10-13

    [reaction: see text] The regioselectivity of the Birch reductive alkylation of polysubstituted biaryls has been investigated. Results indicate that regioselectivity is affected by the electronic nature of substituents on both aromatic rings. The electron-rich 3,5-dimethoxyphenyl moiety is selectively reduced and then alkylated, while phenols and aniline are not dearomatized under these conditions. Biaryls possessing a phenol moiety are alkylated on the second ring, providing that the acidic proton has been removed prior to the Li/NH3 reduction.

  8. 21 CFR 176.120 - Alkyl ketene dimers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Alkyl ketene dimers. 176.120 Section 176.120 Food... Use Only as Components of Paper and Paperboard § 176.120 Alkyl ketene dimers. Alkyl ketene dimers may... section. (a) The alkyl ketene dimers are manufactured by the dehydrohalogenation of the acyl...

  9. 21 CFR 176.120 - Alkyl ketene dimers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Alkyl ketene dimers. 176.120 Section 176.120 Food... Use Only as Components of Paper and Paperboard § 176.120 Alkyl ketene dimers. Alkyl ketene dimers may... section. (a) The alkyl ketene dimers are manufactured by the dehydrohalogenation of the acyl...

  10. Ruthenium-catalyzed meta/ortho-selective C-H alkylation of azoarenes using alkyl bromides.

    PubMed

    Li, Gang; Ma, Xingxing; Jia, Chunqi; Han, Qingqing; Wang, Ya; Wang, Junjie; Yu, Liuyang; Yang, Suling

    2017-01-19

    meta/ortho-Selective CAr-H (di)alkylation reactions of azoarenes have been achieved via [Ru(p-cymene)Cl2]2 catalyzed ortho-metalation using various types of alkyl bromides. Particularly, dual meta-alkylation of azoarene and reduction offer an attractive strategy for the synthesis of meta-alkylanilines, which are difficult to access via traditional aniline functionalization methods.

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

    PubMed

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

    2015-01-01

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

  12. Induction of the alkylation-inducible aidB gene of Escherichia coli by anaerobiosis.

    PubMed Central

    Volkert, M R; Hajec, L I; Nguyen, D C

    1989-01-01

    Induction of the adaptive response to alkylation damage results in the expression of four genes arranged in three transcriptional units: the ada-alkB operon and the alkA and aidB genes. Adaptive-response induction requires the ada gene product and occurs when cells are treated with methylating agents. In previous studies we noted that aidB, but not alkA or ada-alkB, was induced in the absence of alkylation damage as cells were grown to stationary phase. In this note we present evidence that aidB is induced by anaerobiosis. Thus, aidB is subject to dual regulation by ada-dependent alkylation induction and ada-independent anaerobic induction. PMID:2492508

  13. 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.

  14. 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.

  15. 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.

  16. 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.

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

    PubMed

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

    2017-03-01

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

  18. 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.

  19. Evaluation of Chemotherapeutic Agents Against Malaria, Drugs, Diet, and Biological Response Modifiers.

    DTIC Science & Technology

    1991-10-29

    In experiment 76 the antioxidant Coenzyme Q10 (ubiquinone 50) was tested to see if it would replace vitamin E as an antioxidant and influence the...low whether started at 3 weeks of age or 4 weeks of age. 49 In experiment 76 the antioxidant coenzyme Q10 (ubiquinone 50) administered PO at 100, 36 or...line has remained stable under drug pressure for this year. Co-enzyme Q10 did not act as an antioxidant like vitamin E during a malarial infection

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

    DTIC Science & Technology

    2006-02-01

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

  1. Monitoring of Breast Tumor Response to Local Chemotherapeutic Agent Delivered by Biodegradable Fibers

    DTIC Science & Technology

    2005-05-01

    16) gives 00 00 ft.[HbO2]0 .(-K)-e-"t .dt 1 J(i().Ie-’ .d(xt) 0" 0=_. (17) f[HbO 2 10. (-K).e-l .dt fe -lt .d(ta) 0 0 Equation (17) indicates that the...Zhao, D., Constantinescu, A., and Mason, R. P., (2004), "Comparison of BOLD contrast and Gd -DTPA dynamic contrast enhanced imaging in rat prostate tumor...I. Chau, and Z. Grossman, "Functional magnetic resonance ( fMR ) imaging of a rat brain tumor model: implications for evaluation of tumor

  2. 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

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

    DTIC Science & Technology

    2003-05-01

    pharmacokinetics of doxorubicin related to dietary intake of vitamin E or St . John’s wort . Rats ingesting St . John’s wort had similar survival at each...doxorubicin. Our studies indicate that vitamin E and St . John’s wort neither increase nor protect against the toxicity of doxorubicin or docetaxel in rats.

  4. 1-Alpha Hydroxyvitamin D(5) as a Chemotherapeutic and Possibly Chemopreventive Agent

    DTIC Science & Technology

    2007-03-01

    any underlying conditions that would contraindicate therapy with study treatment (or allergies to D5 used in this study). 6.2.5 Patients with prior...D2. Arch Biochem Biophys. 197:119-25. [10] Norman AW. (1998) Sunlight, season , skin pigmentation, vitamin D, and 25-hydroxyvitamin D: integral...cases of breast, colon, and prostate cancer diagnosed in the summer and fall—the seasons when serum levels of vitamin Dj are expected to be the highest

  5. How to Use a Chemotherapeutic Agent When Resistance to It Threatens the Patient.

    PubMed

    Hansen, Elsa; Woods, Robert J; Read, Andrew F

    2017-02-01

    When resistance to anticancer or antimicrobial drugs evolves in a patient, highly effective chemotherapy can fail, threatening patient health and lifespan. Standard practice is to treat aggressively, effectively eliminating drug-sensitive target cells as quickly as possible. This prevents sensitive cells from acquiring resistance de novo but also eliminates populations that can competitively suppress resistant populations. Here we analyse that evolutionary trade-off and consider recent suggestions that treatment regimens aimed at containing rather than eliminating tumours or infections might more effectively delay the emergence of resistance. Our general mathematical analysis shows that there are situations in which regimens aimed at containment will outperform standard practice even if there is no fitness cost of resistance, and, in those cases, the time to treatment failure can be more than doubled. But, there are also situations in which containment will make a bad prognosis worse. Our analysis identifies thresholds that define these situations and thus can guide treatment decisions. The analysis also suggests a variety of interventions that could be used in conjunction with cytotoxic drugs to inhibit the emergence of resistance. Fundamental principles determine, across a wide range of disease settings, the circumstances under which standard practice best delays resistance emergence-and when it can be bettered.

  6. Effects of Saint John’s Wort and Vitamin E on Breast Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2005-05-01

    standard diet and those supplemented with vitamin E (Table 1). None of the treatment means were significantly different from the control means. Table 1...different from the standard diet group (Figure 3). There was no effect of vitamin E supplementation on Hct or Hctfall after docetaxel treatment (data not...E [ High E 5000- •4000- •SEM 8 3000-2000- -1i 1000- 12 15 18 20 Docetaxel Dose (mg/kg) Figure 2. Nadir WBC counts measured 4 days after treatment of

  7. 1 ALPHA-Hydroxyvitamin D5 as a Chemotherapeutic and Possibly Chemopreventive Agent

    DTIC Science & Technology

    2004-09-01

    size 0; Apothecary Products, Inc.) 4. Preparation of 10 jig dosage: a. Weigh 3 gm of cornstarch, NF b. Using a syringe, measure 0.5 mL D5 solution...cornstarch d. Weigh 150 mg of D5/cornstarch mixture to fill each of 52 capsules (size 0; Apothecary Products, Inc.) 5. Preparation of 15 jig dosage: a...capsules (size 0; Apothecary Products, Inc.) lchydroxyvitamin D5 Phase 1/11 Trial Protocol (Version #10 (06/30/04) - Page 32 of 33 6. Preparation of 20

  8. How to Use a Chemotherapeutic Agent When Resistance to It Threatens the Patient

    PubMed Central

    Hansen, Elsa; Woods, Robert J.

    2017-01-01

    When resistance to anticancer or antimicrobial drugs evolves in a patient, highly effective chemotherapy can fail, threatening patient health and lifespan. Standard practice is to treat aggressively, effectively eliminating drug-sensitive target cells as quickly as possible. This prevents sensitive cells from acquiring resistance de novo but also eliminates populations that can competitively suppress resistant populations. Here we analyse that evolutionary trade-off and consider recent suggestions that treatment regimens aimed at containing rather than eliminating tumours or infections might more effectively delay the emergence of resistance. Our general mathematical analysis shows that there are situations in which regimens aimed at containment will outperform standard practice even if there is no fitness cost of resistance, and, in those cases, the time to treatment failure can be more than doubled. But, there are also situations in which containment will make a bad prognosis worse. Our analysis identifies thresholds that define these situations and thus can guide treatment decisions. The analysis also suggests a variety of interventions that could be used in conjunction with cytotoxic drugs to inhibit the emergence of resistance. Fundamental principles determine, across a wide range of disease settings, the circumstances under which standard practice best delays resistance emergence—and when it can be bettered. PMID:28182734

  9. 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

  10. Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma.

    PubMed

    Veytsman, Irina; Nieman, Lynnette; Fojo, Tito

    2009-09-20

    Adrenal cortical carcinoma (ACC) is a rare malignancy in which patients have poor overall 5-year survival. Patients with ACC can present with symptoms of hormone excess, including Cushing's syndrome, virilization, feminization, or--less frequently--hypertension with hypokalemia. In many patients with ACC, advanced disease at presentation precludes surgery or is followed by local relapse or distant metastatic disease that cannot be managed surgically. In these instances, chemotherapy is often tried, but its limited efficacy all too often leaves the problem of persistent hormonal excess. Physicians who treat patients with ACC and severe hypercortisolism should recognize that uncontrolled hormone production is a malignant disease, which has severe consequences that require aggressive management. Because chemotherapy benefits only a small percentage of patients, steroidogenesis inhibitors, including mitotane, ketoconazole, metyrapone, and etomidate, should be used singly or in combination even as chemotherapy is administered. Diligent management with frequent adjustments is required, especially in patients with chemotherapy-refractory tumors that continue to grow. In the absence of randomized, controlled trials, adjuvant use of mitotane remains controversial, although the authors of a recent case-control study argue for its use. Despite difficulty administering effective doses, most clinicians agree that mitotane should be used if the tumor cannot be removed surgically or should be used as adjuvant therapy if there is a high likelihood of recurrence. The option of long-term monotherapy is restricted to patients who tolerate mitotane and either experience a clinical response or are at high risk for recurrence. Recommendations are provided to help manage patients with this difficult disease and to improve the quality of their lives.

  11. Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents

    PubMed Central

    Chatelut, E; White-Koning, M L; Mathijssen, R HJ; Puisset, F; Baker, S D; Sparreboom, A

    2012-01-01

    Background: Dose banding is a recently suggested dosing method that uses predefined ranges (bands) of body surface area (BSA) to calculate each patient's dose by using a single BSA-value per band. Thus, drugs with sufficient long-term stability can be prepared in advance. The main advantages of dose banding are to reduce patient waiting time and improve pharmacy capacity planning; additional benefits include reduced medication errors, reduced drug wastage, and prospective quality control. This study compares dose banding with individual BSA dosing and fixed dose according to pharmacokinetic criteria. Methods: Three BSA bands were defined: BSA<1.7 m2, 1.7 m2⩽BSA<1.9 m2, BSA⩾1.9 m2 and each patient dose was calculated based on a unique BSA-value per band (1.55, 1.80, and 2.05 m2, respectively). By using individual clearance values of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, and topotecan) from 1012 adult cancer patients in total, the AUCs corresponding to three dosing methods (BSA dosing, dose banding, and fixed dose) were compared with a target AUC for each drug. Results: For all six drugs, the per cent variation in individual dose obtained with dose banding compared with BSA dosing ranged between −14% and +22%, and distribution of AUC values was very similar with both dosing methods. In terms of reaching the target AUC, there was no significant difference in precision between dose banding and BSA dosing, except for paclitaxel (32.0% vs 30.7%, respectively; P<0.05). However, precision was significantly better for BSA dosing compared with fixed dose for four out of six drugs. Conclusion: For the studied drugs, implementation of dose banding should be considered as it entails no significant increase in interindividual plasma exposure. PMID:22929884

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

    PubMed

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

    2016-08-30

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

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

    PubMed

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

    2017-03-15

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

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

    DTIC Science & Technology

    2007-12-01

    to the AR without decreasing AR levels. Strategic targeting of the AR with ribozymes , antisense oligomers, and small interfering RNAs has been shown... ribozyme . Mol Endrocrinol 1998;12:1558-1566. 20 10. Ko YJ, Devi GR, London CA, et al. Androgen receptor down-regulation in prostate cancer with

  15. Combining chemotherapeutic agents and netrin-1 interference potentiates cancer cell death

    PubMed Central

    Paradisi, Andrea; Creveaux, Marion; Gibert, Benjamin; Devailly, Guillaume; Redoulez, Emeline; Neves, David; Cleyssac, Elsa; Treilleux, Isabelle; Klein, Christian; Niederfellner, Gerhard; Cassier, Philippe A; Bernet, Agnès; Mehlen, Patrick

    2013-01-01

    The secreted factor netrin-1 is upregulated in a fraction of human cancers as a mechanism to block apoptosis induced by netrin-1 dependence receptors DCC and UNC5H. Targeted therapies aiming to trigger tumour cell death via netrin-1/receptors interaction interference are under preclinical evaluation. We show here that Doxorubicin, 5-Fluorouracil, Paclitaxel and Cisplatin treatments trigger, in various human cancer cell lines, an increase of netrin-1 expression which is accompanied by netrin-1 receptors increase. This netrin-1 upregulation which appears to be p53-dependent is a survival mechanism as netrin-1 silencing by siRNA is associated with a potentiation of cancer cell death upon Doxorubicin treatment. We show that candidate drugs interfering with netrin-1/netrin-1 receptors interactions potentiate Doxorubicin, Cisplatin or 5-Fluorouracil-induced cancer cell death in vitro. Moreover, in a model of xenografted nude mice, we show that systemic Doxorubicin treatment triggers netrin-1 upregulation in the tumour but not in normal organs, enhancing and prolonging tumour growth inhibiting effect of a netrin-1 interfering drug. Together these data suggest that combining conventional chemotherapies with netrin-1 interference could be a promising therapeutic approach. PMID:24293316

  16. Monitoring of Breast Tumor Response to Local Chemotherapeutic Agent Delivered by Biodegradable Fibers

    DTIC Science & Technology

    2006-05-01

    Sausalito: University science books) 73-77 (1997) 46. H. Liu, A. H. Hielscher , F. K. Tittel, S. L. Jacques, and B. Chance, “Influence of blood...Reson. Imaging, 15, 41-57 (2004). 92. A. Y. Bluestone, M. Stewart, J. Lasker, G.S. Absoulaev, and A. H. Hielscher , “Three-dimensional optical...during forearm ischemia J. Appl. Physiol. 64 2449–57 [44] Liu H, Hielscher A H, Tittel F K, Jacques S L and Chance B 1995 Influence of blood vessels on

  17. 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

  18. Ligand-Accelerated ortho-C–H Alkylation of Arylcarboxylic Acids Using Alkyl Boron Reagents

    PubMed Central

    Thuy-Boun, Peter S.; Villa, Giorgio; Dang, Devin; Richardson, Paul; Su, Shun; Yu, Jin-Quan

    2013-01-01

    A protocol for the Pd(II)-catalyzed ortho-C–H alkylation of phenylacetic and benzoic acids using alkylboron reagents is disclosed. Mono-protected amino acid ligands (MPAA) were found to significantly promote reactivity. Both potassium alkyltrifluoroborates and alkylboronic acids were compatible coupling partners. The possibility of a radical alkyl transfer to Pd(II) was also investigated. PMID:24124892

  19. 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.

  20. Palladium-Catalyzed Arylation of Alkyl Sulfenate Anions.

    PubMed

    Jia, Tiezheng; Zhang, Mengnan; Jiang, Hui; Wang, Carol Y; Walsh, Patrick J

    2015-11-04

    A unique palladium-catalyzed arylation of alkyl sulfenate anions is introduced that affords aryl alkyl sulfoxides in high yields. Due to the base sensitivity of the starting sulfoxides, sulfenate anion intermediates, and alkyl aryl sulfoxide products, the use of a mild method to generate alkyl sulfenate anions was crucial to the success of this process. Thus, a fluoride triggered elimination strategy was employed with alkyl 2-(trimethylsilyl)ethyl sulfoxides to liberate the requisite alkyl sulfenate anion intermediates. In the presence of palladium catalysts with bulky monodentate phosphines (SPhos and Cy-CarPhos) and aryl bromides or chlorides, alkyl sulfenate anions were readily arylated. Moreover, the thermal fragmentation and the base promoted elimination of alkyl sulfoxides was overridden. The alkyl sulfenate anion arylation exhibited excellent chemoselectivity in the presence of functional groups, such as anilines and phenols, which are also known to undergo palladium catalyzed arylation reactions.

  1. 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.

  2. DNA Alkylating Therapy Induces Tumor Regression through an HMGB1-Mediated Activation of Innate Immunity

    PubMed Central

    Guerriero, Jennifer L.; Ditsworth, Dara; Catanzaro, Joseph M.; Sabino, Gregory; Furie, Martha B.; Kew, Richard R.; Crawford, Howard C.; Zong, Wei-Xing

    2011-01-01

    Dysregulation of apoptosis is associated with the development of human cancer and resistance to anticancer therapy. We have previously shown in tumor xenografts that DNA alkylating agents induce sporadic cell necrosis and regression of apoptosis-deficient tumors. Sporadic tumor cell necrosis is associated with extracellular release of cellular content such as the high mobility group box 1 (HMGB1) protein and subsequent recruitment of innate immune cells into the tumor tissue. It remained unclear whether HMGB1 and the activation of innate immunity played a role in tumor response to chemotherapy. In this study, we show that whereas DNA alkylating therapy leads to a complete tumor regression in an athymic mouse tumor xenograft model, it fails to do so in tumors deficient in HMGB1. The HMGB1-deficient tumors have an impaired ability to recruit innate immune cells including macrophages, neutrophils, and NK cells into the treated tumor tissue. Cytokine array analysis reveals that whereas DNA alkylating treatment leads to suppression of protumor cytokines such as IL-4, IL-10, and IL-13, loss of HMGB1 leads to elevated levels of these cytokines upon treatment. Suppression of innate immunity and HMGB1 using depleting Abs leads to a failure in tumor regression. Taken together, these results indicate that HMGB1 plays an essential role in activation of innate immunity and tumor clearance in response to DNA alkylating agents. PMID:21300822

  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. 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

  5. Loss of Cytoplasmic CDK1 Predicts Poor Survival in Human Lung Cancer and Confers Chemotherapeutic Resistance

    PubMed Central

    Zhang, Chunyu; Elkahloun, Abdel G.; Robertson, Matthew; Gills, Joell J.; Tsurutani, Junji; Shih, Joanna H.; Fukuoka, Junya; Hollander, M. Christine; Harris, Curtis C.; Travis, William D.; Jen, Jin; Dennis, Phillip A.

    2011-01-01

    The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early stage patients and individualizing therapeutic choices. We hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery. PMID:21887332

  6. 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

  7. Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma.

    PubMed

    Munson, Jennifer M; Fried, Levi; Rowson, Sydney A; Bonner, Michael Y; Karumbaiah, Lohitash; Diaz, Begoña; Courtneidge, Sara A; Knaus, Ulla G; Brat, Daniel J; Arbiser, Jack L; Bellamkonda, Ravi V

    2012-03-28

    The invasive nature of glioblastoma (GBM) represents a major clinical challenge contributing to poor outcomes. Invasion of GBM into healthy tissue restricts chemotherapeutic access and complicates surgical resection. Here, we test the hypothesis that an effective anti-invasive agent can "contain" GBM and increase the efficacy of chemotherapy. We report a new anti-invasive small molecule, Imipramine Blue (IB), which inhibits invasion of glioma in vitro when tested against several models. IB inhibits NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase-mediated reactive oxygen species generation and alters expression of actin regulatory elements. In vivo, liposomal IB (nano-IB) halts invasion of glioma, leading to a more compact tumor in an aggressively invasive RT2 syngeneic astrocytoma rodent model. When nano-IB therapy was followed by liposomal doxorubicin (nano-DXR) chemotherapy, the combination therapy prolonged survival compared to nano-IB or nano-DXR alone. Our data demonstrate that nano-IB-mediated containment of diffuse glioma enhanced the efficacy of nano-DXR chemotherapy, demonstrating the promise of an anti-invasive compound as an adjuvant treatment for glioma.

  8. Parasite prolyl oligopeptidases and the challenge of designing chemotherapeuticals for Chagas disease, leishmaniasis and African trypanosomiasis.

    PubMed

    Bastos, I M D; Motta, F N; Grellier, P; Santana, J M

    2013-01-01

    The trypanosomatids Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp. cause Chagas disease, leishmaniasis and human African trypanosomiasis, respectively. It is estimated that over 10 million people worldwide suffer from these neglected diseases, posing enormous social and economic problems in endemic areas. There are no vaccines to prevent these infections and chemotherapies are not adequate. This picture indicates that new chemotherapeutic agents must be developed to treat these illnesses. For this purpose, understanding the biology of the pathogenic trypanosomatid- host cell interface is fundamental for molecular and functional characterization of virulence factors that may be used as targets for the development of inhibitors to be used for effective chemotherapy. In this context, it is well known that proteases have crucial functions for both metabolism and infectivity of pathogens and are thus potential drug targets. In this regard, prolyl oligopeptidase and oligopeptidase B, both members of the S9 serine protease family, have been shown to play important roles in the interactions of pathogenic protozoa with their mammalian hosts and may thus be considered targets for drug design. This review aims to discuss structural and functional properties of these intriguing enzymes and their potential as targets for the development of drugs against Chagas disease, leishmaniasis and African trypanosomiasis.

  9. Chiral Alkyl Halides: Underexplored Motifs in Medicine

    PubMed Central

    Gál, Bálint; Bucher, Cyril; Burns, Noah Z.

    2016-01-01

    While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in comparison. This is likely attributable to the common misconception that these compounds are merely non-specific alkylators in biological systems. A number of chlorinated compounds in the pharmaceutical and food industries, as well as a growing number of halogenated marine natural products showing unique bioactivity, illustrate the role that chiral alkyl halides can play in drug discovery. Through a series of case studies, we demonstrate in this review that these motifs can indeed be stable under physiological conditions, and that halogenation can enhance bioactivity through both steric and electronic effects. Our hope is that, by placing such compounds in the minds of the chemical community, they may gain more traction in drug discovery and inspire more synthetic chemists to develop methods for selective halogenation. PMID:27827902

  10. Identification of novel chemotherapeutic strategies for metastatic uveal melanoma

    PubMed Central

    Fagone, Paolo; Caltabiano, Rosario; Russo, Andrea; Lupo, Gabriella; Anfuso, Carmelina Daniela; Basile, Maria Sofia; Longo, Antonio; Nicoletti, Ferdinando; De Pasquale, Rocco; Libra, Massimo; Reibaldi, Michele

    2017-01-01

    Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS2 web-based utility was used to predict small molecules and drugs targeting the metastatic uveal melanoma gene signature. The most promising drugs were found to be Cinnarizine, an anti-histaminic drug used for motion sickness, Digitoxigenin, a precursor of cardiac glycosides, and Clofazimine, a fat-soluble iminophenazine used in leprosy. In vitro and in vivo validation studies will be needed to confirm the efficacy of these molecules for the prevention and treatment of metastatic uveal melanoma. PMID:28303962

  11. 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

  12. Identification of novel chemotherapeutic strategies for metastatic uveal melanoma.

    PubMed

    Fagone, Paolo; Caltabiano, Rosario; Russo, Andrea; Lupo, Gabriella; Anfuso, Carmelina Daniela; Basile, Maria Sofia; Longo, Antonio; Nicoletti, Ferdinando; De Pasquale, Rocco; Libra, Massimo; Reibaldi, Michele

    2017-03-17

    Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS(2) web-based utility was used to predict small molecules and drugs targeting the metastatic uveal melanoma gene signature. The most promising drugs were found to be Cinnarizine, an anti-histaminic drug used for motion sickness, Digitoxigenin, a precursor of cardiac glycosides, and Clofazimine, a fat-soluble iminophenazine used in leprosy. In vitro and in vivo validation studies will be needed to confirm the efficacy of these molecules for the prevention and treatment of metastatic uveal melanoma.

  13. Transition metal-free decarboxylative alkylation reactions.

    PubMed

    Liu, Ping; Zhang, Guanghui; Sun, Peipei

    2016-11-22

    This review summarizes advances in the decarboxylative alkylation of carboxylic acids and their derivatives under transition metal-free conditions in recent years. Unlike most transition metal-catalyzed decarboxylative coupling reactions which tend to undergo catalytic cycles, the mechanisms of reactions under metal-free conditions are usually diverse and even ambiguous in some cases. This article offers an overview of reaction types and their corresponding mechanisms, highlights some of the advantages and limitations, and focuses on introducing UV and visible light-induced, organocatalyst and peroxide promoted radical processes for decarboxylative alkylation and the formation of C-C bonds.

  14. Alkyl ferulates in wound healing potato tubers.

    PubMed

    Bernards, M A; Lewis, N G

    1992-10-01

    Seven ferulic acid esters of 1-alkanols ranging in carbon length from C16 to C28 were synthesized and an HPLC protocol for their separation developed. Extracts prepared from wound healing potato (Solanum tuberosum) tubers and analysed by HPLC indicated that alkyl ferulate esters begin to accumulate 3-7 days after wound treatment. Of the nine esters identified by EIMS, (including two esters of odd chain length alkanols) hexadecyl and octadecyl ferulates were predominant. Alkyl ferulate esters were restricted to the wound periderm.

  15. 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

  16. 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.

  17. 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.

  18. 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...

  19. 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)...

  20. 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...

  1. 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)...

  2. 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,...

  3. 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...

  4. 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...

  5. 40 CFR 721.2825 - Alkyl ester (generic name).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 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...

  6. 40 CFR 721.2825 - Alkyl ester (generic name).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 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...

  7. 40 CFR 721.2825 - Alkyl ester (generic name).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 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...

  8. 40 CFR 721.10233 - Linear alkyl epoxide (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Linear alkyl epoxide (generic). 721... Substances § 721.10233 Linear alkyl epoxide (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as linear alkyl epoxide (PMN...

  9. 40 CFR 721.10233 - Linear alkyl epoxide (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Linear alkyl epoxide (generic). 721... Substances § 721.10233 Linear alkyl epoxide (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as linear alkyl epoxide (PMN...

  10. 40 CFR 721.10233 - Linear alkyl epoxide (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Linear alkyl epoxide (generic). 721... Substances § 721.10233 Linear alkyl epoxide (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as linear alkyl epoxide (PMN...

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. 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...

  17. 40 CFR 721.10699 - Polyfluorinated alkyl thio acrylamide (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Polyfluorinated alkyl thio acrylamide... Specific Chemical Substances § 721.10699 Polyfluorinated alkyl thio acrylamide (generic). (a) Chemical... as polyfluorinated alkyl thio acrylamide (PMN P-11-529) is subject to reporting under this...

  18. 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)...

  19. 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...

  20. 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)...

  1. 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...

  2. 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...

  3. 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)...

  4. Copper-catalyzed radical carbooxygenation: alkylation and alkoxylation of styrenes.

    PubMed

    Liao, Zhixiong; Yi, Hong; Li, Zheng; Fan, Chao; Zhang, Xu; Liu, Jie; Deng, Zixin; Lei, Aiwen

    2015-01-01

    A simple copper-catalyzed direct radical carbooxygenation of styrenes is developed utilizing alkyl bromides as radical resources. This catalytic radical difunctionalization accomplishes both alkylation and alkoxylation of styrenes in one pot. A broad range of styrenes and alcohols are well tolerated in this transformation. The EPR experiment shows that alkyl halides could oxidize Cu(I) to Cu(II) in this transformation.

  5. 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...

  6. 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...

  7. 40 CFR 721.1878 - Alkali metal alkyl borohydride (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 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 721.1878 - 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...

  10. Inhibition of hydrogen sulfide biosynthesis sensitizes lung adenocarcinoma to chemotherapeutic drugs by inhibiting mitochondrial DNA repair and suppressing cellular bioenergetics

    PubMed Central

    Szczesny, Bartosz; Marcatti, Michela; Zatarain, John R.; Druzhyna, Nadiya; Wiktorowicz, John E.; Nagy, Péter; Hellmich, Mark R.; Szabo, Csaba

    2016-01-01

    Therapeutic manipulation of the gasotransmitter hydrogen sulfide (H2S) has recently been proposed as a novel targeted anticancer approach. Here we show that human lung adenocarcinoma tissue expresses high levels of hydrogen sulfide (H2S) producing enzymes, namely, cystathionine beta-synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), in comparison to adjacent lung tissue. In cultured lung adenocarcinoma but not in normal lung epithelial cells elevated H2S stimulates mitochondrial DNA repair through sulfhydration of EXOG, which, in turn, promotes mitochondrial DNA repair complex assembly, thereby enhancing mitochondrial DNA repair capacity. In addition, inhibition of H2S-producing enzymes suppresses critical bioenergetics parameters in lung adenocarcinoma cells. Together, inhibition of H2S-producing enzymes sensitize lung adenocarcinoma cells to chemotherapeutic agents via induction of mitochondrial dysfunction as shown in in vitro and in vivo models, suggesting a novel mechanism to overcome tumor chemoresistance. PMID:27808278

  11. Poly(ethyleneoxide) functionalization through alkylation

    DOEpatents

    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.

  12. 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.

  13. 77 FR 72747 - Alkyl(C8

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-06

    ... Classification System (NAICS) codes is not intended to be exhaustive, but rather provides a guide to help readers.../reproductive screening test (OECD 422) toxicity study on a representative N- alkyl(C 8 -C 18... in the reproductive or developmental parameters examined. No systemic toxicity was observed in...

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

    PubMed

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

    2006-12-01

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

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

    PubMed Central

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

    2013-01-01

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

  16. Effects of alkyl chain length on properties of 1-alkyl-3-methylimidazolium fluorohydrogenate ionic liquid crystals.

    PubMed

    Xu, Fei; Matsumoto, Kazuhiko; Hagiwara, Rika

    2010-11-15

    A series of 1-alkyl-3-methylimidazolium fluorohydrogenate salts (C(x)MIm(FH)(2)F, x=8, 10, 12, 14, 16, and 18) have been characterized by thermal analysis, polarized optical microscopy, IR spectroscopy, X-ray diffraction, and anisotropic ionic conductivity measurements. Liquid crystalline mesophases with a smectic A interdigitated bilayer structure are observed from C(10) to C(18), showing a fan-like or focal conic texture. The temperature range of the mesophase increases with the increase in the alkyl chain length (from 10.1 °C for C(10)MIm(FH)(2)F to 123.1 °C for C(18)MIm(FH)(2)F). The distance between the two layers in the smectic structure gradually increases with increasing alkyl chain length and decreases with increasing temperature. Conductivity parallel to the smectic layers is around 10 mS cm(-1) regardless of the alkyl chain length, whereas that perpendicular to the smectic layers decreases with increasing alkyl chain length because of the thicker insulating sheet with the longer alkyl chain.

  17. Ada response - a strategy for repair of alkylated DNA in bacteria.

    PubMed

    Mielecki, Damian; Grzesiuk, Elżbieta

    2014-06-01

    Alkylating agents are widespread in the environment and also occur endogenously. They can be cytotoxic or mutagenic to the cells introducing alkylated bases to DNA or RNA. All organisms have evolved multiple DNA repair mechanisms to counteract the effects of DNA alkylation: the most cytotoxic lesion, N(3)-methyladenine (3meA), is excised by AlkA glycosylase initiating base excision repair (BER); toxic N(1)-methyladenine (1meA) and N(3)-methylcytosine (3meC), induced in DNA and RNA, are removed by AlkB dioxygenase; and mutagenic and cytotoxic O(6)-methylguanine (O(6) meG) is repaired by Ada methyltransferase. In Escherichia coli, Ada response involves the expression of four genes, ada, alkA, alkB, and aidB, encoding respective proteins Ada, AlkA, AlkB, and AidB. The Ada response is conserved among many bacterial species; however, it can be organized differently, with diverse substrate specificity of the particular proteins. Here, an overview of the organization of the Ada regulon and function of individual proteins is presented. We put special effort into the characterization of AlkB dioxygenases, their substrate specificity, and function in the repair of alkylation lesions in DNA/RNA.

  18. 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.

  19. Masked N-Heterocyclic Carbene-Catalyzed Alkylation of Phenols with Organic Carbonates.

    PubMed

    Lui, Matthew Y; Yuen, Alexander K L; Masters, Anthony F; Maschmeyer, Thomas

    2016-09-08

    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.

  20. Corrosion abatement in sulfuric acid alkylation unit horizontal contactors

    SciTech Connect

    Schutt, H.U.

    1997-09-01

    The need to increase throughput in alkylation plants has resulted in higher operating temperatures and higher water levels in alkylation acids than projected by design. Combined with higher flow rates, the more severe process environment causes carbon steel to corrode at increased rates. Carbon steel is the main material of construction for horizontal contactors (Stratco reactors). A leak to the atmosphere in the hydraulic end cone of one contactor and the realization that basic corrosion data are not available for high throughput process conditions in alkylation units prompted a laboratory study to develop the lacking expertise. Corrosion in alkylation unit horizontal contactors is successfully mitigated by saturating fresh alkylation acid with ferrous sulfate.

  1. Searches for new alkylation catalysts, processes forge ahead

    SciTech Connect

    Rhodes, A.

    1994-08-22

    As a result of the hazardous properties of hydrofluoric acid (HF), HF alkylation has been the subject of much recent controversy. The safety and environmental requirements associated with the HF alkylation processes continue to drive industry to develop new alkylation technologies. In fact, several major process licensors are well on their ways to bringing these new technologies to market. The new alkylation processes under development center around new, less-harmful catalysts. Although this work is progressing rapidly, an update of the status of some of these new processes will keep refiners abreast of the new options they may soon have for building new alkylation units or retrofitting existing ones. The process development and economics are described for a Topsoe/Kellogg fixed bed alkylation process and the Kerr-McGee homogeneous alkylation technology process.

  2. Enhanced delivery of the RAPTA-C macromolecular chemotherapeutic by conjugation to degradable polymeric micelles.

    PubMed

    Blunden, Bianca M; Lu, Hongxu; Stenzel, Martina H

    2013-12-09

    Macromolecular ruthenium complexes are a promising avenue to better and more selective chemotherapeutics. We have previously shown that RAPTA-C [RuCl2(p-cymene)(PTA)], with the water-soluble 1,3,5-phosphaadamantane (PTA) ligand, could be attached to a polymer moiety via nucleophilic substitution of an available iodide with an amide in the PTA ligand. To increase the cell uptake of this macromolecule, we designed an amphiphilic block copolymer capable of self-assembling into polymeric micelles. The block copolymer was prepared by ring-opening polymerization of d,l-lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) using a RAFT agent with an additional hydroxyl functionality, followed by the RAFT copolymerization of 2-hydroxyethyl acrylate (HEA) and 2-chloroethyl methacrylate (CEMA). The Finkelstein reaction and reaction with PTA led to polymers that can readily react with the dimer of RuCl2(p-cymene) to create a macromolecular RAPTA-C drug. RAPTA-C conjugation, micellization, and subsequent cytotoxicity and cell uptake of these polymeric moieties was tested on ovarian cancer A2780, A2780cis, and Ovcar-3 cell lines. Confocal microscopy images confirmed cell uptake of the micelles into the lysosome of the cells, indicative of an endocytic pathway. On average, a 10-fold increase in toxicity was found for the macromolecular drugs when compared to the RAPTA-C molecule. Furthermore, the cell uptake of ruthenium was analyzed and a significant increase was found for the micelles compared to RAPTA-C. Notably, micelles prepared from the polymer containing fewer HEA units had the highest cytotoxicity, the best cell uptake of ruthenium and were highly effective in suppressing the colony-forming ability of cells.

  3. 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

  4. Predictive imaging of chemotherapeutic response in a transgenic mouse model of pancreatic cancer

    PubMed Central

    Wang, Ping; Yoo, Byunghee; Sherman, Sarah; Mukherjee, Pinku; Ross, Alana; Pantazopoulos, Pamela; Petkova, Victoria; Farrar, Christian; Medarova, Zdravka; Moore, Anna

    2016-01-01

    The underglycosylated mucin 1 tumor antigen (uMUC1) is a biomarker that forecasts the progression of adenocarcinomas. In this study, we evaluated the utility of a dual-modality molecular imaging approach based on targeting uMUC1 for monitoring chemotherapeutic response in a transgenic murine model of pancreatic cancer (KCM triple transgenic mice). An uMUC1-specific contrast agent (MN-EPPT) was synthesized for use with magnetic resonance imaging (MRI) and fluorescence optical imaging. It consisted of dextran-coated iron oxide nanoparticles conjugated to the near infrared fluorescent dye Cy5.5 and to a uMUC1-specific peptide (EPPT). KCM triple transgenic mice were given gemcitabine as chemotherapy while control animals received saline injections following the same schedule. Changes in uMUC1 levels following chemotherapy were monitored using T2-weighted MRI and optical imaging before and 24 hr after injection of the MN-EPPT. uMUC1 expression in tumors from both groups was evaluated by histology and qRT-PCR. We observed that the average delta-T2 in the gemcitabine-treated group was significantly reduced compared to the control group indicating lower accumulation of MN-EPPT, and correspondingly, a lower level of uMUC1 expression. In vivo optical imaging confirmed the MRI findings. Fluorescence microscopy of pancreatic tumor sections showed a lower level of uMUC1 expression in the gemcitabine-treated group compared to the control, which was confirmed by qRT-PCR. Our data proved that changes in uMUC1 expression after gemcitabine chemotherapy could be evaluated using MN-EPPT-enhanced in vivo MR and optical imaging. These results suggest that the uMUC1-targeted imaging approach could provide a useful tool for the predictive assessment of therapeutic response. PMID:26996122

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

    PubMed

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

    2011-09-01

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

  6. 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)

  7. Cardiotoxicity of Molecularly Targeted Agents

    PubMed Central

    Hedhli, Nadia; Russell, Kerry S

    2011-01-01

    Cardiac toxicity of molecularly targeted cancer agents is increasingly recognized as a significant side effect of chemotherapy. These new potent therapies may not only affect the survival of cancer cells, but have the potential to adversely impact normal cardiac and vascular function. Unraveling the mechanisms by which these therapies affect the heart and vasculature is crucial for improving drug design and finding alternative therapies to protect patients predisposed to cardiovascular disease. In this review, we summarize the classification and side effects of currently approved molecularly targeted chemotherapeutics. PMID:22758623

  8. 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.

  9. Soluble Alkyl Substituted Polygermanes. Thermochromic Behavior.

    DTIC Science & Technology

    1986-07-17

    are strongly thermochromic . The effect is attributed to conformational locking of the backbone which is caused by the crystallization of the side groups...are strongly thermochromic . The effect is attributed to the conformational locking of the backbone which is caused by the crystallization of the side...SYMBOL. 02 &m A -- .- h.. .. .. . . . . . . . . ... . . . .. RJ 5008 (52258) 1/24/86 Chemis try SOLUBLE ALKYL SUBSTITUTED POLYGERMANES: THERMOCHROMIC

  10. Tetrahydrofurfuryloxide derivatives of alkyl aluminum species.

    SciTech Connect

    Boyle, Timothy J.; Avilucea, Gabriel; Bunge, Scott D.; Alam, Todd Michael; Rodriguez, Mark Andrew; Cherry, Brian Ray; Tissot, Ralph George, Jr.; Segall, Judith M.

    2004-12-01

    Tetrahydrofurfuryl alcohol (H-OTHF) was successfully reacted with a series of aluminum alkyls (AlR{sub 3}) to yield compounds of the general formula [R{sub 2}Al({mu}-OTHF)]{sub 2} where R = CH{sub 3} (1), CH{sub 2}CH{sub 3} (2), and CH{sub 2}CH(CH{sub 3}){sub 2} (3). Further, reactivity studies showed that the alkyls for 1 were easily exchanged, forming compounds of the general formula [Me(OR)Al({mu}-OTHF)]{sub 2} where OR = OC{sub 6}H{sub 3}(Me){sub 2}-2,6 (4), OC{sub 6}H{sub 3}(CMe{sub 3}){sub 2}-2,6 (5a), and OSi(C{sub 6}H5){sub 3} (6). For 5a, reflux temperatures were required to get the full exchange; otherwise the asymmetric derivative [Me(OR)Al({mu}-OTHF){sub 2}AlMe{sub 2}] (5b) was isolated. The bulk powders of 1-6 were found to be in agreement with the crystal structures on the basis of elemental analyses and multinuclear solid state NMR studies. Multinuclear solution state NMR studies indicate that the alkyl OTHF derivatives have cis/trans isomers due to the chiral proton on the OTHF ligand.

  11. 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)

  12. Rational Choice of Antiemetic Agents during Cancer Chemotherapy

    PubMed Central

    Brigden, Malcolm L.; Wilson, Kenneth S.; Barnett, Jeffrey B.

    1983-01-01

    Nausea and vomiting are major limitations in cancer chemotherapy. Individual susceptibility to nausea varies enormously. There is no ideal antiemetic, but some work with some chemotherapeutic agents, and some are more effective in younger patients. This article describes a flexible, stepped approach using the phenothiazines, metoclopramide, cannabinoids, anticholinergics, antihistamines and others. PMID:21283402

  13. Alkyl ammonium cation stabilized biocidal polyiodides with adaptable high density and low pressure.

    PubMed

    He, Chunlin; Parrish, Damon A; Shreeve, Jean'ne M

    2014-05-26

    The effective application of biocidal species requires building the active moiety into a molecular back bone that can be delivered and decomposed on demand under conditions of low pressure and prolonged high-temperature detonation. The goal is to destroy storage facilities and their contents while utilizing the biocidal products arising from the released energy to destroy any remaining harmful airborne agents. Decomposition of carefully selected iodine-rich compounds can produce large amounts of the very active biocides, hydroiodic acid (HI) and iodine (I2). Polyiodide anions, namely, I3(-), I5(-), which are excellent sources of such biocides, can be stabilized through interactions with large, symmetric cations, such as alkyl ammonium salts. We have designed and synthesized suitable compounds of adaptable high density up to 3.33 g cm(-3) that are low-pressure polyiodides with various alkyl ammonium cations, deliverable iodine contents of which range between 58.0-90.9%.

  14. 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

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

    PubMed

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

    2013-10-11

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

  16. The involvement of hypoxia-inducible factor-1alpha in the susceptibility to gamma-rays and chemotherapeutic drugs of oral squamous cell carcinoma cells.

    PubMed

    Sasabe, Eri; Zhou, Xuan; Li, Dechao; Oku, Naohisa; Yamamoto, Tetsuya; Osaki, Tokio

    2007-01-15

    The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) is the key regulator that controls the hypoxic response of mammalian cells. The overexpression of HIF-1alpha has been demonstrated in many human tumors. However, the role of HIF-1alpha in the therapeutic efficacy of chemotherapy and radiotherapy in cancer cells is poorly understood. In this study, we investigated the influence of HIF-1alpha expression on the susceptibility of oral squamous cell carcinoma (OSCC) cells to chemotherapeutic drugs (cis-diamminedichloroplatinum and 5-fluorouracil) and gamma-rays. Treatment with chemotherapeutic drugs and gamma-rays enhanced the expression and nuclear translocation of HIF-1alpha, and the susceptibility of OSCC cells to the drugs and gamma-rays was negatively correlated with the expression level of HIF-1alpha protein. The overexpression of HIF-1alpha induced OSCC cells to become more resistant to the anticancer agents, and down-regulation of HIF-1alpha expression by small interfering RNA enhanced the susceptibility of OSCC cells to them. In the HIF-1alpha-knockdown OSCC cells, the expression of P-glycoprotein, heme oxygenase-1, manganese-superoxide dismutase and ceruloplasmin were downregulated and the intracellular levels of chemotherapeutic drugs and reactive oxygen species were sustained at higher levels after the treatment with the anticancer agents. These results suggest that enhanced HIF-1alpha expression is related to the resistance of tumor cells to chemo- and radio-therapy and that HIF-1alpha is an effective therapeutic target for cancer treatment.

  17. DNA alkylation lesions and their repair in human cells: modification of the comet assay with 3-methyladenine DNA glycosylase (AlkD).

    PubMed

    Hašplová, Katarína; Hudecová, Alexandra; Magdolénová, Zuzana; Bjøras, Magnar; Gálová, Eliška; Miadoková, Eva; Dušinská, Mária

    2012-01-05

    3-methyladenine DNA glycosylase (AlkD) belongs to a new family of DNA glycosylases; it initiates repair of cytotoxic and promutagenic alkylated bases (its main substrates being 3-methyladenine and 7-methylguanine). The modification of the comet assay (single cell gel electrophoresis) using AlkD enzyme thus allows assessment of specific DNA alkylation lesions. The resulting baseless sugars are alkali-labile, and under the conditions of the alkaline comet assay they appear as DNA strand breaks. The alkylating agent methyl methanesulfonate (MMS) was used to induce alkylation lesions and to optimize conditions for the modified comet assay method with AlkD on human lymphoblastoid (TK6) cells. We also studied cellular and in vitro DNA repair of alkylated bases in DNA in TK6 cells after treatment with MMS. Results from cellular repair indicate that 50% of DNA alkylation is repaired in the first 60 min. The in vitro repair assay shows that while AlkD recognises most alkylation lesions after 60 min, a cell extract from TK6 cells recognises most of the MMS-induced DNA adducts already in the first 15 min of incubation, with maximum detection of lesions after 60 min' incubation. Additionally, we tested the in vitro repair capacity of human lymphocyte extracts from 5 individuals and found them to be able to incise DNA alkylations in the same range as AlkD. The modification of the comet assay with AlkD can be useful for in vitro and in vivo genotoxicity studies to detect alkylation damage and repair and also for human biomonitoring and molecular epidemiology studies.

  18. Effects of alkyl parabens on plant pathogenic fungi.

    PubMed

    Ito, Shinsaku; Yazawa, Satoru; Nakagawa, Yasutaka; Sasaki, Yasuyuki; Yajima, Shunsuke

    2015-04-15

    Alkyl parabens are used as antimicrobial preservatives in cosmetics, food, and pharmaceutical products. However, the mode of action of these chemicals has not been assessed thoroughly. In this study, we determined the effects of alkyl parabens on plant pathogenic fungi. All the fungi tested, were susceptible to parabens. The effect of linear alkyl parabens on plant pathogenic fungi was related to the length of the alkyl chain. In addition, the antifungal activity was correlated with the paraben-induced inhibition of oxygen consumption. The antifungal activity of linear alkyl parabens likely originates, at least in part, from their ability to inhibit the membrane respiratory chain, especially mitochondrial complex II. Additionally, we determined that some alkyl parabens inhibit Alternaria brassicicola infection of cabbage.

  19. Alkylation damage by lipid electrophiles targets functional protein systems.

    PubMed

    Codreanu, Simona G; Ullery, Jody C; Zhu, Jing; Tallman, Keri A; Beavers, William N; Porter, Ned A; Marnett, Lawrence J; Zhang, Bing; Liebler, Daniel C

    2014-03-01

    Protein alkylation by reactive electrophiles contributes to chemical toxicities and oxidative stress, but the functional impact of alkylation damage across proteomes is poorly understood. We used Click chemistry and shotgun proteomics to profile the accumulation of proteome damage in human cells treated with lipid electrophile probes. Protein target profiles revealed three damage susceptibility classes, as well as proteins that were highly resistant to alkylation. Damage occurred selectively across functional protein interaction networks, with the most highly alkylation-susceptible proteins mapping to networks involved in cytoskeletal regulation. Proteins with lower damage susceptibility mapped to networks involved in protein synthesis and turnover and were alkylated only at electrophile concentrations that caused significant toxicity. Hierarchical susceptibility of proteome systems to alkylation may allow cells to survive sublethal damage while protecting critical cell functions.

  20. 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.

  1. Corrosion abatement in sulfuric acid alkylation unit horizontal contactors

    SciTech Connect

    Schutt, H.U.

    1999-03-01

    A leak to the atmosphere in the hydraulic end cone of a horizontal contactor and the realization that basic corrosion data are not available for high-throughput process conditions in alkylation units prompted a laboratory study to develop the lacking expertise. Corrosion in the horizontal contractor of an alkylation unit was mitigated successfully by saturating fresh alkylation acid with ferrous sulfate (FeSO{sub 4}).

  2. Photochemical Production of Alkyl Nitrates in the Tropical Pacific Ocean

    NASA Astrophysics Data System (ADS)

    Dahl, E. E.; Yvon-Lewis, S. A.; Saltzman, E. S.

    2005-12-01

    Alkyl nitrates are important to the tropospheric NOx/ozone cycle because they represent a significant fraction of the reactive nitrogen (NOy). Previous work has shown that there is an oceanic source of alkyl nitrates. A photochemical mechanism for the formation of alkyl nitrates in seawater has been proposed. This mechanism involves the reaction of ROO and NO, where ROO is an alkyl peroxy radical. ROO and NO radicals in seawater are derived from the photolysis of DOM and nitrite, respectively. In this study, the photochemical production of low molecular weight alkyl nitrates (C1-C3) was observed in shipboard incubation experiments in the tropical Pacific during the PHASE 1 cruise. Seawater samples from several regions, including high and low-chlorophyll areas, were collected and incubated. Alkyl nitrate production rates as high as 2 nM/hour were observed. The production rate of alkyl nitrates was clearly dependent upon the initial concentration of nitrite, most likely as the source for NO radicals. While the magnitude of production varied between sample locations, the ratios of the production rates of the various alkyl nitrates remained relatively constant. The observed production ratios of methyl, ethyl, isopropyl, and n-propyl nitrate were 5.9:1.0:0.1:0.2. These ratios presumably reflect the speciation of peroxy radicals formed in seawater, and the yield of alkyl nitrates from the ROO+NO reaction. The observed production rate ratios are similar to the concentration ratios of alkyl nitrates observed in ambient seawater and the overlying atmosphere during the study. A comparison of the measured production rates and the observed concentrations, suggests that photochemically produced alkyl nitrates are a major source of atmospheric alkyl nitrates in the surface ocean and marine atmosphere.

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

    PubMed

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

    2005-09-01

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

  4. Molecular combo of photodynamic therapeutic agent silicon(iv) phthalocyanine and anticancer drug cisplatin.

    PubMed

    Mao, Jiafei; Zhang, Yangmiao; Zhu, Jianhui; Zhang, Changli; Guo, Zijian

    2009-02-28

    The combination of a red light PDT agent and a Pt(ii)-based chemotherapeutic drug at the molecular level maintains the intrinsic functions of each unit; the conjugated complexes exhibit remarkable photocytoxicity and demonstrate potential to serve as agents for DNA-targeting PDT as well as red light photochemotherapy.

  5. 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.

  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, 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...

  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, 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...

  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, 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...

  10. Regioselective alkylation of 1,3,4,5-tetrahydrobenzo[d]azepin-2-one and biological evaluation of the resulting alkylated products as potentially selective [Formula: see text] agonists.

    PubMed

    Prajapati, Navnit; Giridhar, Rajani; Sinha, Anshuman; Kanhed, Ashish M; Yadav, Mange Ram

    2015-11-01

    The benzazepine ring system has offered interesting CNS-active medicinal agents. Taking this privileged structure as the basic scaffold, [Formula: see text] and/or [Formula: see text]-alkylated benzazepin-2-one derivatives and their reduced analogs have been prepared as potential [Formula: see text] receptor agonists. The selective alkylation at the [Formula: see text] and/or [Formula: see text] positions of this seven-membered lactam ring is here reported for the first time under different reaction conditions. The synthesized compounds were evaluated for their biological profile as potential [Formula: see text] agonists using a classic pharmacological approach. Three derivatives (15, 17, and 20) have shown promising [Formula: see text] agonistic activity which can be further optimized as anti-obesity agents for the treatment of male sexual dysfunction. Further, a homology model for [Formula: see text] receptor was generated using MODELLER, and ligand-receptor interactions for these potential molecules were studied.

  11. Radioiodination of Aryl-Alkyl Cyclic Sulfates

    PubMed Central

    Mushti, Chandra; Papisov, Mikhail I.

    2015-01-01

    Among the currently available positron emitters suitable for Positron Emission Tomography (PET), 124I has the longest physical half-life (4.2 days). The long half-life and well-investigated behavior of iodine in vivo makes 124I very attractive for pharmacological studies. In this communication, we describe a simple yet effective method for the synthesis of novel 124I labeled compounds intended for PET imaging of arylsulfatase activity in vivo. Arylsulfatases have important biological functions, and genetic deficiencies of such functions require pharmacological replacement, the efficacy of which must be properly and non-invasively evaluated. These enzymes, even though their natural substrates are mostly of aliphatic nature, hydrolyze phenolic sulfates to phenol and sulfuric acid. The availability of [124I]iodinated substrates is expected to provide a PET-based method for measuring their activity in vivo. The currently available methods of synthesis of iodinated arylsulfates usually require either introducing of a protected sulfate ester early in the synthesis or introduction of sulfate group at the end of synthesis in a separate step. The described method gives the desired product in one step from an aryl-alkyl cyclic sulfate. When treated with iodide, the source cyclic sulfate opens with substitution of iodide at the alkyl center and gives the desired arylsulfate monoester. PMID:23135631

  12. Microstructure of Hydrophobically Modified Alkyl Acrylamide Hydrogels

    NASA Astrophysics Data System (ADS)

    Tian, Jun; Seery, Thomas A. P.; Ho, Derek L.; Weiss, R. A.

    2004-03-01

    Hydrophobically modified water-soluble acrylamide polymers have a variety of applications, including viscosity thickeners, microencapsulation, biosensors and controlled drug delivery systems. The microstructure of copolymer hydrogels of N,N-dimethylacrylamide (DMA) or N-isopropylacrylamide(NIPA) modified with 2-(N-ethylfluorooctanesulfonamido)ethyl acrylate, FOSA, was studied by small angle x-ray (SAXS) and neutron scattering (SANS). Swelling and DSC measurements showed that FOSA/NIPA gels exhibited a volume phase transition (VPT), but that FOSA/DMA gels did not. A modified interacting core-shell model was used to explain the SAXS and SANS data for both gels. The crosslink junctions of the gel consisted of nanophase-separated FOSA domains as the core surrounded by a water-poor layer of the alkyl acrylamide. These nanodomains were dispersed in a matrix of water-swollen alkyl acrylamide that had large scale heterogeneities. The average spherical core radius ranged from 1 to 3 nm and the average shell thickness ranged from 1 to 1.5 nm; the aggregation number ranged from 10 to 200.

  13. Partial Crystallinity in Alkyl Side Chain Polymers.

    NASA Astrophysics Data System (ADS)

    Sahni, Vasav; Prasad, Shishir; Villate, Johanna; Jiang, Zhang; Sinha, Sunil; Dhinojwala, Ali

    2009-03-01

    Surface freezing is the formation of a crystalline monolayer at the free surface of a melt at a temperature Ts, a few degrees above the bulk freezing temperature, Tb. This effect, i.e. Ts> Tb, common to many chain molecules, is in marked contrast with the surface melting effect, i.e. Ts<=Tb, shown by almost all other materials. Various theoretical and experimental studies have been done to characterize the monolayer formed when the surface freezes before the bulk. We have studied the structure of a novel crystalline surface monolayer on top of a disordered melt of the same material (poly(n-alkyl acrylate)s) using grazing incidence x-ray diffraction. The grazing incidence x-ray diffraction, surface tension, and bulk latent heat results show that there is partial side-chain crystallinity. Also, the surface tension results explain the trend of the difference between the surface order-to-disorder transition temperature and the bulk melting temperature (δT) as a function of side chain length. The behavior of the crystal length, crystal spacing and tilt with varying alkyl chain length and temperature was also studied.

  14. 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.

  15. Chemotherapeutic efficiency of drugs in vitro: Comparison of doxorubicin exposure in 3D and 2D culture matrices.

    PubMed

    Casey, A; Gargotti, M; Bonnier, F; Byrne, H J

    2016-06-01

    The interest in the use of 3D matrices for in vitro analysis, with a view to increasing the relevance of in vitro studies and reducing the dependence on in vivo studies, has been growing in recent years. Cells grown in a 3D in vitro matrix environment have been reported to exhibit significantly different properties to those in a conventional 2D culture environment. However, comparison of 2D and 3D cell culture models have recently been noted to result in differing responses of cytotoxic assays, without any associated change in viability. The effect was attributed to differing conversion rates and effective concentrations of the resazurin assay in 2D and 3D environments, rather than differences in cellular metabolism. In this study, the efficacy of a chemotherapeutic agent, doxorubicin, is monitored and compared in conventional 2D and 3D collagen gel exposures of immortalized human cervical cells. Viability was monitored with the aid of the Alamar Blue assay and drug internalisation was verified using confocal microscopy. Drug uptake and retention within the collagen matrix was monitored by absorption spectroscopy. The viability studies showed apparent differences between the 2D and 3D culture systems, the differences attributed in part to the physical transition from 2D to a 3D environment causing alterations to dye resazurin uptake and conversion rates. The use of 3D culture matrices has widely been interpreted to result in "reduced" toxicity or cellular "resistance" to the chemotherapeutic agent. The results of this study show that the reduced efficiency of the drug to cells grown in the 3D environment can be accounted for by a sequential reduction of the effective concentration of the test compound and assay. This is due to absorption within the collagen gel inducing a higher uptake of both drug and assay thereby influencing the toxic impact of the drug and conversion rate of resazurin, and. The increased effective surface area of the cell exposed to the drug

  16. 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

  17. Co-delivery of Doxorubicin Encapsulated PLGA Nanoparticles and Bcl-xL shRNA Using Alkyl-Modified PEI into Breast Cancer Cells.

    PubMed

    Ebrahimian, Mahboubeh; Taghavi, Sahar; Mokhtarzadeh, Ahad; Ramezani, Mohammad; Hashemi, Maryam

    2017-02-24

    In recent years, much effort has been focused on an appropriate combination of chemotherapeutic drugs and nucleic acids to exploit additive or synergistic therapeutic effects and overcome many obstacles such as the reduction of side effects and drug resistance. Short hairpin RNA (shRNA) has designed to allow the production of small interfering RNA (siRNA) within the cells and offer long-lasting silencing of target genes. In this study, alkyl-modified polyethylenimine (PEI 10 kD) was used for co-delivery of doxorubicin (DOX) encapsulated into poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) and Bcl-xL shRNA (one class of molecules that block apoptosis of tumor cells) into breast cancer cells. Our results demonstrated that modification of PEI with alkyl chain could enhance the induction of apoptosis in tumor cells by suppression of Bcl-xL gene using Bcl-xL shRNA more than PEI alone. On the other hand, DOX encapsulated into PLGA had more synergistic effect with shRNA in comparison with DOX alone. In conclusion, combination of PLGA-DOX NPs and alkyl-PEI/shRNA complexes may have promising applications in breast cancer therapy.

  18. Chemotherapeutic strategies for reducing transmission of Plasmodium vivax malaria.

    PubMed

    Douglas, Nicholas M; John, George K; von Seidlein, Lorenz; Anstey, Nicholas M; Price, Ric N

    2012-01-01

    Effective use of anti-malarial drugs is key to reducing the transmission potential of Plasmodium vivax. In patients presenting with symptomatic disease, treatment with potent and relatively slowly eliminated blood schizontocidal regimens administered concurrently with a supervised course of 7 mg/kg primaquine over 7-14 days has potential to exert the greatest transmission-blocking benefit. Given the spread of chloroquine-resistant P. vivax strains, the artemisinin combination therapies dihydroartemisinin + piperaquine and artesunate + mefloquine are currently the most assured means of preventing P. vivax recrudescence. Preliminary evidence suggests that, like chloroquine, these combinations potentiate the hypnozoitocidal effect of primaquine, but further supportive evidence is required. In view of the high rate of P. vivax relapse following falciparum infections in co-endemic regions, there is a strong argument for broadening current radical cure policy to include the administration of hypnozoitocidal doses of primaquine to patients with Plasmodium falciparum malaria. The most important reservoir for P. vivax transmission is likely to be very low-density, asymptomatic infections, the majority of which will arise from liver-stage relapses. Therefore, judicious mass administration of hypnozoitocidal therapy will reduce transmission of P. vivax to a greater extent than strategies focused on treatment of symptomatic patients. An efficacious hypnozoitocidal agent with a short curative treatment course would be particularly useful in mass drug administration campaigns.

  19. Structure-function relationship of substituted bromomethylcoumarins in nucleoside specificity of RNA alkylation.

    PubMed

    Kellner, Stefanie; Kollar, Laura Bettina; Ochel, Antonia; Ghate, Manjunath; Helm, Mark

    2013-01-01

    Selective alkylation of RNA nucleotides is an important field of RNA biochemistry, e.g. in applications of fluorescent labeling or in structural probing experiments, yet detailed structure-function studies of labeling agents are rare. Here, bromomethylcoumarins as reactive compounds for fluorescent labeling of RNA are developed as an attractive scaffold on which electronic properties can be modulated by varying the substituents. Six different 4-bromomethyl-coumarins of various substitution patterns were tested for nucleotide specificity of RNA alkylation using tRNA from Escherichia coli as substrate. Using semi-quantitative LC-MS/MS analysis, reactions at mildly acidic and slightly alkaline pH were compared. For all tested compounds, coumarin conjugates with 4-thiouridine, pseudouridine, guanosine, and uridine were identified, with the latter largely dominating. This data set shows that selectivity of ribonucleotide alkylation depends on the substitution pattern of the reactive dye, and even more strongly on the modulation of the reaction conditions. The latter should be therefore carefully optimized when striving to achieve selectivity. Interestingly, the highest selectivity for labeling of a modified nucleoside, namely of 4-thiouridine, was achieved with a compound whose selectivity was somewhat less dependent on reaction conditions than the other compounds. In summary, bromomethylcoumarin derivatives are a highly interesting class of compounds, since their selectivity for 4-thiouridine can be efficiently tuned by variation of substitution pattern and reaction conditions.

  20. Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole-imidazole polyamide conjugate.

    PubMed

    Hiraoka, Kiriko; Inoue, Takahiro; Taylor, Rhys Dylan; Watanabe, Takayoshi; Koshikawa, Nobuko; Yoda, Hiroyuki; Shinohara, Ken-ichi; Takatori, Atsushi; Sugimoto, Hirokazu; Maru, Yoshiaki; Denda, Tadamichi; Fujiwara, Kyoko; Balmain, Allan; Ozaki, Toshinori; Bando, Toshikazu; Sugiyama, Hiroshi; Nagase, Hiroki

    2015-04-27

    Despite extensive efforts to target mutated RAS proteins, anticancer agents capable of selectively killing tumour cells harbouring KRAS mutations have remained unavailable. Here we demonstrate the direct targeting of KRAS mutant DNA using a synthetic alkylating agent (pyrrole-imidazole polyamide indole-seco-CBI conjugate; KR12) that selectively recognizes oncogenic codon 12 KRAS mutations. KR12 alkylates adenine N3 at the target sequence, causing strand cleavage and growth suppression in human colon cancer cells with G12D or G12V mutations, thus inducing senescence and apoptosis. In xenograft models, KR12 infusions induce significant tumour growth suppression, with low host toxicity in KRAS-mutated but not wild-type tumours. This newly developed approach may be applicable to the targeting of other mutant driver oncogenes in human tumours.

  1. Sulfoalkyl ether-alkyl ether cyclodextrin derivatives, their synthesis, NMR characterization, and binding of 6alpha-methylprednisolone.

    PubMed

    Tongiani, Serena; Velde, David Vander; Ozeki, Tetsuya; Stella, Valentino J

    2005-11-01

    The objective of this study is to see if random alkyl ethers of various sulfoalkyl ether cyclodextrins can be synthesized and characterized. The purpose of the alkylation was to test the hypothesis that an increase in the "height" of a cyclodextrins cavity would help in the binding/complexation of larger more structurally complex molecules. The synthesis of new cyclodextrin derivatives comprising a mixture of sulfoalkyl ether and alkyl ether substituents on the same cyclodextrin ring was performed in aqueous alkaline solutions using various sultones and alkylsulfates. The method presented provided an easy and efficient way to modify cyclodextrins avoiding the use of organic solvents and high quantities of alkylating agents and could be carried out in either a two step or "one pot" single step process. Purification was by neutralization followed by ultrafiltration. The derivatives were characterized by 1D, ((1)H and (13)C), and a 2D NMR technique (HMQC, Heteronuclear Multiple Quantum Coherence). The combination of these techniques allowed an analysis of the degree of substitution and the site of substitution on the cyclodextrin (CD) nucleus. For both beta- and gamma-CD, sulfoakylation was preferred on the 2 > 3 > 6 hydroxyls while alkylation was preferred 6 > 2 > 3. Due to the simultaneous presence of short alkyl ether chains and negatively charged sulfoalkyl ether chains, these mixed water-soluble cyclodextrin derivatives, especially those of gamma-cyclodextrin, should be able to bind more complex drugs. The improved binding capacity of these new modified CDs with the model drug 6alpha-methylprednisolone is reported.

  2. 40 CFR 721.6070 - Alkyl phosphonate ammonium salts.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Alkyl phosphonate ammonium salts. 721... Substances § 721.6070 Alkyl phosphonate ammonium salts. (a) Chemical substances and significant new uses... salts (PMNs P-93-725 and P-93-726) are subject to reporting under this section for the significant...

  3. 40 CFR 721.6070 - Alkyl phosphonate ammonium salts.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkyl phosphonate ammonium salts. 721... Substances § 721.6070 Alkyl phosphonate ammonium salts. (a) Chemical substances and significant new uses... salts (PMNs P-93-725 and P-93-726) are subject to reporting under this section for the significant...

  4. 40 CFR 721.2155 - Alkoxyamino-alkyl-coumarin (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Alkoxyamino-alkyl-coumarin (generic... Substances § 721.2155 Alkoxyamino-alkyl-coumarin (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as...

  5. 40 CFR 721.2155 - Alkoxyamino-alkyl-coumarin (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkoxyamino-alkyl-coumarin (generic... Substances § 721.2155 Alkoxyamino-alkyl-coumarin (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as...

  6. 40 CFR 721.2155 - Alkoxyamino-alkyl-coumarin (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Alkoxyamino-alkyl-coumarin (generic... Substances § 721.2155 Alkoxyamino-alkyl-coumarin (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as...

  7. 40 CFR 721.2155 - Alkoxyamino-alkyl-coumarin (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Alkoxyamino-alkyl-coumarin (generic... Substances § 721.2155 Alkoxyamino-alkyl-coumarin (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as...

  8. 40 CFR 721.2155 - Alkoxyamino-alkyl-coumarin (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Alkoxyamino-alkyl-coumarin (generic... Substances § 721.2155 Alkoxyamino-alkyl-coumarin (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as...

  9. 40 CFR 721.10317 - Alkyl phosphate derivative (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Alkyl phosphate derivative (generic... Specific Chemical Substances § 721.10317 Alkyl phosphate derivative (generic). (a) Chemical substance and... phosphate derivative (PMN P-02-1040) is subject to reporting under this section for the significant new...

  10. 40 CFR 721.10317 - Alkyl phosphate derivative (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Alkyl phosphate derivative (generic... Specific Chemical Substances § 721.10317 Alkyl phosphate derivative (generic). (a) Chemical substance and... phosphate derivative (PMN P-02-1040) is subject to reporting under this section for the significant new...

  11. 40 CFR 721.10317 - Alkyl phosphate derivative (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Alkyl phosphate derivative (generic... Specific Chemical Substances § 721.10317 Alkyl phosphate derivative (generic). (a) Chemical substance and... phosphate derivative (PMN P-02-1040) is subject to reporting under this section for the significant new...

  12. Organocatalytic enantioselective indole alkylations of alpha,beta-unsaturated ketones.

    PubMed

    Chen, Wei; Du, Wei; Yue, Lei; Li, Rui; Wu, Yong; Ding, Li-Sheng; Chen, Ying-Chun

    2007-03-07

    The C3-selective enantioselective Michael-type Friedel-Crafts alkylations of indoles with nonchelating alpha,beta-unsaturated alkyl ketones, catalysed by a chiral primary amine derived from natural cinchonine, were investigated. The reactions, in the presence of 30 mol% catalyst, were smoothly conducted at 0 to -20 degrees C. Moderate to good ee (47-89%) has been achieved.

  13. An overview of the properties of fatty acid alkyl esters

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fatty acid alkyl esters of plant oils, especially in the form of methyl esters, have numerous applications with fuel use having received the most attention in recent times due to the potential high volume. Various properties imparted by neat fatty acid alkyl esters have been shown to influence fuel ...

  14. 40 CFR 721.840 - Alkyl substituted diaromatic hydrocarbons.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... hydrocarbons. 721.840 Section 721.840 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.840 Alkyl substituted diaromatic hydrocarbons. (a) Chemical substance... alkyl substituted di-aro-matic hydrocarbons (PMN P-91-710) is subject to reporting under this...

  15. 40 CFR 721.840 - Alkyl substituted diaromatic hydrocarbons.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... hydrocarbons. 721.840 Section 721.840 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.840 Alkyl substituted diaromatic hydrocarbons. (a) Chemical substance... alkyl substituted di-aro-matic hydrocarbons (PMN P-91-710) is subject to reporting under this...

  16. 40 CFR 721.840 - Alkyl substituted diaromatic hydrocarbons.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... hydrocarbons. 721.840 Section 721.840 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.840 Alkyl substituted diaromatic hydrocarbons. (a) Chemical substance... alkyl substituted di-aro-matic hydrocarbons (PMN P-91-710) is subject to reporting under this...

  17. 40 CFR 721.840 - Alkyl substituted diaromatic hydrocarbons.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... hydrocarbons. 721.840 Section 721.840 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.840 Alkyl substituted diaromatic hydrocarbons. (a) Chemical substance... alkyl substituted di-aro-matic hydrocarbons (PMN P-91-710) is subject to reporting under this...

  18. 40 CFR 721.840 - Alkyl substituted diaromatic hydrocarbons.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... hydrocarbons. 721.840 Section 721.840 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.840 Alkyl substituted diaromatic hydrocarbons. (a) Chemical substance... alkyl substituted di-aro-matic hydrocarbons (PMN P-91-710) is subject to reporting under this...

  19. 40 CFR 721.10073 - Modified alkyl acrylamide (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Modified alkyl acrylamide (generic... Specific Chemical Substances § 721.10073 Modified alkyl acrylamide (generic). (a) Chemical substance and... acrylamide (PMN P-05-536) is subject to reporting under this section for the significant new uses...

  20. 40 CFR 721.10073 - Modified alkyl acrylamide (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Modified alkyl acrylamide (generic... Specific Chemical Substances § 721.10073 Modified alkyl acrylamide (generic). (a) Chemical substance and... acrylamide (PMN P-05-536) is subject to reporting under this section for the significant new uses...

  1. 40 CFR 721.10073 - Modified alkyl acrylamide (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Modified alkyl acrylamide (generic... Specific Chemical Substances § 721.10073 Modified alkyl acrylamide (generic). (a) Chemical substance and... acrylamide (PMN P-05-536) is subject to reporting under this section for the significant new uses...

  2. 40 CFR 721.10073 - Modified alkyl acrylamide (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Modified alkyl acrylamide (generic... Specific Chemical Substances § 721.10073 Modified alkyl acrylamide (generic). (a) Chemical substance and... acrylamide (PMN P-05-536) is subject to reporting under this section for the significant new uses...

  3. 40 CFR 721.10073 - Modified alkyl acrylamide (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Modified alkyl acrylamide (generic... Specific Chemical Substances § 721.10073 Modified alkyl acrylamide (generic). (a) Chemical substance and... acrylamide (PMN P-05-536) is subject to reporting under this section for the significant new uses...

  4. 40 CFR 721.6070 - Alkyl phosphonate ammonium salts.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Alkyl phosphonate ammonium salts. 721... Substances § 721.6070 Alkyl phosphonate ammonium salts. (a) Chemical substances and significant new uses... salts (PMNs P-93-725 and P-93-726) are subject to reporting under this section for the significant...

  5. 40 CFR 721.6070 - Alkyl phosphonate ammonium salts.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Alkyl phosphonate ammonium salts. 721... Substances § 721.6070 Alkyl phosphonate ammonium salts. (a) Chemical substances and significant new uses... salts (PMNs P-93-725 and P-93-726) are subject to reporting under this section for the significant...

  6. 40 CFR 721.6070 - Alkyl phosphonate ammonium salts.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Alkyl phosphonate ammonium salts. 721... Substances § 721.6070 Alkyl phosphonate ammonium salts. (a) Chemical substances and significant new uses... salts (PMNs P-93-725 and P-93-726) are subject to reporting under this section for the significant...

  7. 40 CFR 721.10430 - Tetra alkyl ammonium salt (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Tetra alkyl ammonium salt (generic... Specific Chemical Substances § 721.10430 Tetra alkyl ammonium salt (generic). (a) Chemical substance and... ammonium salt (PMN P-97-823) is subject to reporting under this section for the significant new...

  8. 40 CFR 721.10430 - Tetra alkyl ammonium salt (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Tetra alkyl ammonium salt (generic... Specific Chemical Substances § 721.10430 Tetra alkyl ammonium salt (generic). (a) Chemical substance and... ammonium salt (PMN P-97-823) is subject to reporting under this section for the significant new...

  9. Degradable Polymer Composites Fabricated from Starch and Alkyl Cyanoacrylate Monomer

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Degradable polymer composites are fabricated from alkyl cyanoacrylate monomer and starch without special equipment. Alkyl cyanoacrylate, which is a major component of “super glue”, is a monomer that polymerizes at room temperature in the presence of initiators. During the fabrication of polymer com...

  10. Deaminative and decarboxylative catalytic alkylation of amino acids with ketones.

    PubMed

    Kalutharage, Nishantha; Yi, Chae S

    2013-12-16

    It cuts two ways: The cationic [Ru-H] complex catalyzes selective coupling of α- and β-amino acids with ketones to form α-alkylated ketone products. The reaction involves CC and CN bond cleavage which result in regio- and stereoselective alkylation using amino acids. A broad substrate scope and high functional-group tolerance is demonstrated.

  11. Direct, Regioselective N-Alkylation of 1,3-Azoles.

    PubMed

    Chen, Shuai; Graceffa, Russell F; Boezio, Alessandro A

    2016-01-04

    Regioselective N-alkylation of 1,3-azoles is a valuable transformation. Organomagnesium reagents were discovered to be competent bases to affect regioselective alkylation of various 1,3-azoles. Counterintuitively, substitution selectively occurred at the more sterically hindered nitrogen atom. Numerous examples are provided, on varying 1,3-azole scaffolds, with yields ranging from 25 to 95%.

  12. 40 CFR 721.10677 - Alkyl phosphonate (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... CONTROL ACT SIGNIFICANT NEW USES OF CHEMICAL SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10677 Alkyl phosphonate (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as alkyl phosphonate (PMN...

  13. 40 CFR 721.10711 - Alkyl substituted catechol (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Alkyl substituted catechol (generic... Specific Chemical Substances § 721.10711 Alkyl substituted catechol (generic). (a) Chemical substance and... substituted catechol (PMN P-13-197) is subject to reporting under this section for the significant new...

  14. 40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... compound. 721.655 Section 721.655 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.655 Ethoxylated alkyl quaternary ammonium compound. (a) Chemical... as an ethoxylated alkyl quaternary ammonium compound (PMN P-96-573) is subject to reporting...

  15. 40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... compound. 721.655 Section 721.655 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.655 Ethoxylated alkyl quaternary ammonium compound. (a) Chemical... as an ethoxylated alkyl quaternary ammonium compound (PMN P-96-573) is subject to reporting...

  16. 40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... compound. 721.655 Section 721.655 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.655 Ethoxylated alkyl quaternary ammonium compound. (a) Chemical... as an ethoxylated alkyl quaternary ammonium compound (PMN P-96-573) is subject to reporting...

  17. 40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... compound. 721.655 Section 721.655 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.655 Ethoxylated alkyl quaternary ammonium compound. (a) Chemical... as an ethoxylated alkyl quaternary ammonium compound (PMN P-96-573) is subject to reporting...

  18. 40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... compound. 721.655 Section 721.655 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.655 Ethoxylated alkyl quaternary ammonium compound. (a) Chemical... as an ethoxylated alkyl quaternary ammonium compound (PMN P-96-573) is subject to reporting...

  19. The role of alkyl chain length of monothiol-terminated alkyl carboxylic acid in the synthesis, characterization, and application of gelatin-g-poly(N-isopropylacrylamide) carriers for antiglaucoma drug delivery.

    PubMed

    Luo, Li-Jyuan; Lai, Jui-Yang

    2017-02-01

    To improve ocular bioavailability and extend pharmacological response, this study aims to investigate the role of alkyl chain length of monothiol-terminated alkyl carboxylic acids in the synthesis, characterization, and application of gelatin-g-poly(N-isopropylacrylamide) (GN) biodegradable in situ gelling carriers for antiglaucoma drug delivery. In the presence of mercaptoacetic acid (MAA), mercaptopropionic acid (MPA), mercaptobutyric acid (MBA), or mercaptohexanoic acid (MHA) as a chain transfer agent, the carboxylic end-capped poly(N-isopropylacrylamide) samples were prepared by free radical polymerization technique. Our results showed that with increasing alkyl chain length, the hydrophobicity of thermo-responsive polymer segments significantly increased, mainly due to an increase in CH stretching frequencies. In addition, the greater hydrophobic association favored the decrease in both phase transition temperature and weight loss of GN copolymers, thereby accelerating their temperature-triggered gelation process and retarding the degradation progress under physiological conditions. The benefits from these features allowed the pilocarpine carriers to increase drug payload and extend drug release. Irrespective of carbon number of monothiol-terminated alkyl carboxylic acid, the synthesized GN materials exhibited high tolerance to corneal endothelial cells without any evidence of inhibited proliferation, viability loss, inflammatory stimulation, and functional abnormality, indicating good biocompatibility. Results of clinical observations and histological examinations demonstrated that the therapeutic efficacies in treating glaucomatous damage are in response to in vivo drug release profiles from various intracamerally injected GN carriers. The research findings suggest the influence of alkyl chain length of chain transfer agent-mediated polymer hydrophobicity and degradability on pharmacological bioavailability and action of pilocarpine in a glaucomatous rabbit

  20. Safety of Chemotherapeutic Infusion or Chemoembolization for Hepatocellular Carcinoma Supplied Exclusively by the Cystic Artery

    SciTech Connect

    Kang, Beomsik Kim, Hyo-Cheol Chung, Jin Wook Hur, Saebeom Joo, Seung-Moon Jae, Hwan Jun Park, Jae Hyung

    2013-10-15

    Purpose: This study was designed to evaluate the safety of chemotherapeutic infusion or chemoembolization by way of the cystic artery in patients with hepatocellular carcinoma (HCC) supplied exclusively by the cystic artery. Methods: Between Jan 2002 and Dec 2011, we performed chemotherapeutic infusion or chemoembolization using iodized oil for the treatment of 27 patients with HCC supplied exclusively by the cystic artery. Computed tomography (CT) scans, digital subtraction angiograms, and medical records were retrospectively reviewed by consensus. Results: The cystic artery originated from the main right hepatic artery in 24 (89 %) patients, from the right anterior hepatic artery in 2 (7 %) patients, and from the left hepatic artery in 1 (4 %) patient. Selective catheterization of the cystic artery was achieved in all patients. Superselection of tumor-feeding vessels from the cystic artery was achieved in 7 patients (26 %). Chemotherapeutic infusion was performed in 18 patients (67 %), and chemoembolization was performed in 9 patients (33 %). There were no major complications and only 2 minor complications, including vasovagal syncope and nausea with vomiting. Individual tumor response supplied exclusively by the cystic artery at the follow-up enhanced CT scan were complete response (n = 16), partial response (n = 3), and stable disease (n = 8). Conclusion: HCC supplied exclusively by the cystic artery can be safely treated without severe complications by chemotherapeutic infusion or chemoembolization using iodized oil through the cystic artery.

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

    PubMed Central

    2016-01-01

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

  2. Polyimide characterization studies - Effect of pendant alkyl groups

    NASA Technical Reports Server (NTRS)

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

    1984-01-01

    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.

  3. Effect of polyester blends in hydroentangled raw and bleached cotton nonwoven fabrics on the adsorption of alkyl-dimethyl-benzyl-ammonium chloride

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The adsorption kinetics and isotherms of alkyl-dimethyl-benzyl-ammonium chloride (ADBAC), a cationic surfactant commonly employed as an antimicrobial agent, on hydroentangled nonwoven fabrics (applicable for wipes) including raw cotton, bleached cotton, and their blends with polyester (PES) were stu...

  4. Alkylation of terminal alkynes with transient σ-alkylpalladium(II) complexes: a carboalkynylation route to alkyl-substituted alkynes.

    PubMed

    Zhou, Ming-Bo; Huang, Xiao-Cheng; Liu, Yan-Yun; Song, Ren-Jie; Li, Jin-Heng

    2014-02-10

    A mild and general alkylation of terminal alkynes with transient σ-alkylpalladium(II) complexes for assembling alkyl-substituted alkynes is described. This method represents a new way to the use of transient σ-alkylpalladium(II) complexes in organic synthesis through 1,2-carboalkynylation of alkenes.

  5. New in vitro system to predict chemotherapeutic efficacy of drug combinations in fresh tumor samples

    PubMed Central

    Weidemüller, Paula; Krapfl, Jens; Yassin-Kelepir, Rauaa; Job, Laura; Fraefel, Marius; Braicu, Ioana; Kopp-Schneider, Annette; Sehouli, Jalid; De Wilde, Rudy Leon

    2017-01-01

    Background To find the best individual chemotherapy for cancer patients, the efficacy of different chemotherapeutic drugs can be predicted by pretesting tumor samples in vitro via the chemotherapy-resistance (CTR)-Test®. Although drug combinations are widely used among cancer therapy, so far only single drugs are tested by this and other tests. However, several first line chemotherapies are combining two or more chemotherapeutics, leading to the necessity of drug combination testing methods. Methods We established a system to measure and predict the efficacy of chemotherapeutic drug combinations with the help of the Loewe additivity concept in combination with the CTR-test. A combination is measured by using half of the monotherapy’s concentration of both drugs simultaneously. With this method, the efficacy of a combination can also be calculated based on single drug measurements. Results The established system was tested on a data set of ovarian carcinoma samples using the combination carboplatin and paclitaxel and confirmed by using other tumor species and chemotherapeutics. Comparing the measured and the calculated values of the combination testings revealed a high correlation. Additionally, in 70% of the cases the measured and the calculated values lead to the same chemotherapeutic resistance category of the tumor. Conclusion Our data suggest that the best drug combination consists of the most efficient single drugs and the worst drug combination of the least efficient single drugs. Our results showed that single measurements are sufficient to predict combinations in specific cases but there are exceptions in which it is necessary to measure combinations, which is possible with the presented system. PMID:28265509

  6. A common element involved in transcriptional regulation of two DNA alkylation repair genes (MAG and MGT1) of Saccharomyces cerevisiae.

    PubMed Central

    Xiao, W; Singh, K K; Chen, B; Samson, L

    1993-01-01

    The Saccharomyces cerevisiae MAG gene encodes a 3-methyladenine DNA glycosylase that protects cells from killing by alkylating agents. MAG mRNA levels are induced not only by alkylating agents but also by DNA-damaging agents that do not produce alkylated DNA. We constructed a MAG-lacZ gene fusion to help identify the cis-acting promoter elements involved in regulating MAG expression. Deletion analysis defined the presence of one upstream activating sequence and one upstream repressing sequence (URS) and suggested the presence of a second URS. One of the MAG URS elements matches a decamer consensus sequence present in the promoters of 11 other S. cerevisiae DNA repair and metabolism genes, including the MGT1 gene, which encodes an O6-methylguanine DNA repair methyltransferase. Two proteins of 26 and 39 kDa bind specifically to the MAG and MGT1 URS elements. We suggest that the URS-binding proteins may play an important role in the coordinate regulation of these S. cerevisiae DNA repair genes. Images PMID:8246943

  7. Materials performance in HF-alkylation units

    SciTech Connect

    Forsen, O.; Aromaa, J.; Somervuori, M.; Tavi, M.

    1995-11-01

    Materials selection in HF-alkylation units is mostly based on long time experience. The most widely used material in the Station units is standard carbon steel, because it is capable to form a thick protective FeF{sub 2} layer in concentrated or anhydrous hydrofluoric acid. The corrosion resistance decreases, when the acid is dilute (less than 64% HF) or the temperature is above 160F (70 C). The composition and metallurgical state are also suspected to affect the corrosion resistance of carbon steel. The effect of composition appears more complicated than believed, especially the A-106 specification on the total amount of Cr+Ni+Cu+Mo+V < 1% should be studied more closely from the corrosion point of view. Laboratory tests showed that the uniform corrosion rate may be 100 times higher in galvanic contact of two dissimilar steels. The effect of galvanic contacts can neither be excluded in the process equipment corrosion cases.

  8. Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species

    PubMed Central

    Liang, Wenquan; Cai, Aizhen; Chen, Guozhu; Xi, Hongqing; Wu, Xiaosong; Cui, Jianxin; Zhang, Kecheng; Zhao, Xudong; Yu, Jiyun; Wei, Bo; Chen, Lin

    2016-01-01

    The prognosis of gastric cancer remains poor due to clinical drug resistance. Novel drugs are urgently needed. Shikonin (SHK), a natural naphthoquinone, has been reported to trigger cell death and overcome drug resistance in anti-tumour therapy. In this study, we investigated the effectiveness and molecular mechanisms of SHK in treatment with gastric cancer. In vitro, SHK suppresses proliferation and triggers cell death of gastric cancer cells but leads minor damage to gastric epithelial cells. SHK induces the generation of intracellular reactive oxygen species (ROS), depolarizes the mitochondrial membrane potential (MMP) and ultimately triggers mitochondria-mediated apoptosis. We confirmed that SHK induces apoptosis of gastric cancer cells not only in a caspase-dependent manner which releases Cytochrome C and triggers the caspase cascade, but also in a caspase-independent manner which mediates the nuclear translocation of apoptosis-inducing factor and Endonuclease G. Furthermore, we demonstrated that SHK enhanced the chemotherapeutic sensitivity of 5-fluorouracil and oxaliplatin in vitro and in vivo. Taken together, our data show that SHK may be a novel therapeutic agent in the clinical treatment of gastric cancer. PMID:27905569

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

    PubMed Central

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

    2016-01-01

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

  10. Novel Resveratrol and 5-Fluorouracil Coencapsulated in PEGylated Nanoliposomes Improve Chemotherapeutic Efficacy of Combination against Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Sethuraman, Swaminathan

    2014-01-01

    Increasing consumption of tobacco and alcohol has led to a steady increase in the incidence of head and neck cancers in Asia. The drawbacks associated with the existing chemotherapeutic and surgical interventions have necessitated the development of a safer alternative for therapy of head and neck cancers. In this study we have explored the synergistic therapeutic potential of a phytochemical and chemotherapeutic agent using PEGylated liposomes as a delivery vehicle. Resveratrol and 5-fluorouracil were successfully coencapsulated in a single PEGylated nanoliposome. The thermal analysis and the nuclear magnetic resonance results revealed that resveratrol localized near the glycerol backbone of the liposomal membrane while 5-fluorouracil localized closer to the phosphate moiety, which influenced the release kinetics of both drugs. The nanoformulation was tested in vitro on a head and neck cancer cell line NT8e and was found to exhibit a GI50 similar to that of free 5-fluorouracil. Further, gene expression studies showed that the combination of resveratrol and 5-fluorouracil exhibited different effects on different genes that may influence the net antagonistic effect. The coencapsulation of resveratrol and 5-fluorouracil in a liposomal nanocarrier improved the cytotoxicity in comparison with the free drug combination when tested in vitro. PMID:25114900

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  13. Investigation of Unanticipated Alkylation at the N(π) Position of a Histidyl Residue Under Mitsunobu Conditions and Synthesis of Orthogonally Protected Histidine Analogues

    PubMed Central

    Qian, Wenjian; Liu, Fa; Burke, Terrence R.

    2011-01-01

    We had previously reported that Mitsunobu-based introduction of alkyl substituents onto the imidazole N(π)-position of a key histidine residue in phosphothreonine-containing peptides can impart high binding affinity against the polo box domain of polo like kinase 1. Our current paper investigates the mechanism leading to this N(π)-alkylation and provides synthetic methodologies that permit the facile synthesis of histidine N(π)-modified peptides. These agents represent new and potentially important tools for biological studies. PMID:21950469

  14. Comparative toxicity of mono- and bifunctional alkylating homologues of sulphur mustard in human skin keratinocytes.

    PubMed

    Sawyer, Thomas W; McNeely, Karin; Louis, Kristen; Lecavalier, Pierre; Song, Yanfeng; Villanueva, Mercy; Clewley, Robin

    2017-03-08

    Sulphur mustard (bis(2-chloroethyl) sulphide; agent H) is a vesicant chemical warfare (CW) agent whose mechanism of action is not known with any certainty and for which there are no effective antidotes. It has a pronounced latent period before signs and symptoms of poisoning appear which it shares with the nitrogen mustards, and that differentiates it from other classes of vesicant agents. Sulphur mustard, the sulphur mustard CW agents Q (1,2-bis(2-chloroethylthio) ethane) and T (1,1 bis(2-chloroethylthioethyl) ether), the H partial hydrolysis product hemi-sulphur mustard (2-chloroethyl 2-hydroxyethyl sulphide; HSM), and the commercially available 2-chloroethyl ethyl sulphide (CEES) were characterized with respect to their toxicity in first passage cultures of proliferating human skin keratinocytes, the target cell of H-induced skin vesication. Agents H and T were equitoxic and half as toxic as agent Q. Hemi-sulphur mustard and CEES were approximately six times and seventeen times, respectively less cytotoxic than H. 2-Chloroethyl ethyl sulphide was only slightly less toxic in confluent cultures compared to actively proliferating cells. In contrast, the toxicity of H, Q, T and HSM significantly decreased as the cultures became confluent, paralleling the decreasing sensitivity of skin keratinocytes to H as they leave the basement membrane of the skin. The toxicity of CEES was maximal by 24h. In contrast, the maximal toxicity of the other four agents occurred at 48h, mirroring the latent period observed for these agents in vivo. The markedly different characteristics of toxicity between CEES and the other four test compounds indicate that it is likely that different mechanisms of action are operative between them. Caution should therefore be taken when interpreting the results of studies utilizing CEES as a simulant for the mechanistic study of H, or in the elucidation of medical countermeasures against this CW agent. It is also notable that the toxicity

  15. Antihydrophobic cosolvent effects for alkylation reactions in water solution, particularly oxygen versus carbon alkylations of phenoxide ions.

    PubMed

    Breslow, Ronald; Groves, Kevin; Mayer, M Uljana

    2002-04-10

    Antihydrophobic cosolvents such as ethanol increase the solubility of hydrophobic molecules in water, and they also affect the rates of reactions involving hydrophobic surfaces. In simple reactions of hydrocarbons, such as the Diels-Alder dimerization of 1,3-cyclopentadiene, the rate and solubility data directly reflect the geometry of the transition state, in which some hydrophobic surface becomes hidden. In reactions involving polar groups, such as alkylations of phenoxide ions or S(N)1 ionizations of alkyl halides, cosolvents in water can have other effects as well. However, solvation of hydrophobic surfaces is still important. By the use of structure-reactivity relationships, and comparing the effects of ethanol and DMSO as solvents, it has been possible to sort out these effects. The conclusions are reinforced by an ab initio computer model for hydrophobic solvation. The result is a sensible transition state for phenoxide ion as a nucleophile, using its oxygen n electrons to avoid loss of conjugation. The geometry of alkylation of aniline is very different, involving packing (stacking) of the aniline ring onto the phenyl ring of a benzyl group in the benzylation reaction. The alkylation of phenoxide ions by benzylic chlorides can occur both at the phenoxide oxygen and on ortho and para positions of the ring. Carbon alkylation occurs in water, but not in nonpolar organic solvents, and it is observed only when the phenoxide has at least one methyl substituent ortho, meta, or para. The effects of phenol substituents and of antihydrophobic cosolvents on the rates of the competing alkylation processes indicate that in water the carbon alkylation involves a transition state with hydrophobic packing of the benzyl group onto the phenol ring. The results also support our conclusion that oxygen alkylation uses the n electrons of the phenoxide oxygen as the nucleophile and does not have hydrophobic overlap in the transition state. The mechanisms and explanations for

  16. Succinimide complexes of borated alkyl catechols and lubricating oil compositions containing same

    SciTech Connect

    Liston, T.V.

    1986-12-16

    A composition is described comprising a complex prepared by reacting a borated alkyl catechol and an oil soluble alkyl or alkenyl succinimide wherein the weight percent ratio of the alkyl or alkenyl succinimide to the borated alkyl catechol ranges from 3:1 to 16:1.

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

    PubMed Central

    Popp, Maximilian W.; Maquat, Lynne E.

    2015-01-01

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

  18. Alkaline phosphatase revisited: hydrolysis of alkyl phosphates.

    PubMed

    O'Brien, Patrick J; Herschlag, Daniel

    2002-03-05

    Escherichia coli alkaline phosphatase (AP) is the prototypical two metal ion catalyst with two divalent zinc ions bound approximately 4 A apart in the active site. Studies spanning half a century have elucidated many structural and mechanistic features of this enzyme, rendering it an attractive model for investigating the potent catalytic power of bimetallic centers. Unfortunately, fundamental mechanistic features have been obscured by limitations with the standard assays. These assays generate concentrations of inorganic phosphate (P(i)) in excess of its inhibition constant (K(i) approximately 1 muM). This tight binding by P(i) has affected the majority of published kinetic constants. Furthermore, binding limits k(cat)/K(m) for reaction of p-nitrophenyl phosphate, the most commonly employed substrate. We describe a sensitive (32)P-based assay for hydrolysis of alkyl phosphates that avoids the complication of product inhibition. We have revisited basic mechanistic features of AP with these alkyl phosphate substrates. The results suggest that the chemical step for phosphorylation of the enzyme limits k(cat)/K(m). The pH-rate profile and additional results suggest that the serine nucleophile is active in its anionic form and has a pK(a) of < or = 5.5 in the free enzyme. An inactivating pK(a) of 8.0 is observed for binding of both substrates and inhibitors, and we suggest that this corresponds to ionization of a zinc-coordinated water molecule. Counter to previous suggestions, inorganic phosphate dianion appears to bind to the highly charged AP active site at least as strongly as the trianion. The dependence of k(cat)/K(m) on the pK(a) of the leaving group follows a Brønsted correlation with a slope of beta(lg) = -0.85 +/- 0.1, differing substantially from the previously reported value of -0.2 obtained from data with a less sensitive assay. This steep leaving group dependence is consistent with a largely dissociative transition state for AP-catalyzed hydrolysis of

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

    DTIC Science & Technology

    2009-05-14

    Iqbal O, Kaiser B. Tissue factor pathway inhibitor in thrombosis and beyond. In Methods in Molecular Medicine, vol 93: Anticoagulants , Antiplatelets ...TITLE: “Enhancing the Efficacy of Chemotherapeutic Breast Cancer Treatment with Non- anticoagulant Heparins” PRINCIPAL INVESTIGATOR: Shaker... anticoagulant Heparins" 5b. GRANT NUMBER W81XWH-07-1-0344 5c. PROGRAM ELEMENT NUMBER 5d. PROJECT NUMBER 5e. TASK NUMBER 6. AUTHOR(S

  20. Fluorinated Alkyl Ether Epoxy Resin Compositions and Applications Thereof

    NASA Technical Reports Server (NTRS)

    Wohl, Christopher J. (Inventor); Connell, John W. (Inventor); Smith, Joseph G. (Inventor); Siochi, Emilie J. (Inventor); Gardner, John M. (Inventor); Palmieri, Frank M. (Inventor)

    2017-01-01

    Epoxy resin compositions prepared using amino terminated fluoro alkyl ethers. The epoxy resin compositions exhibit low surface adhesion properties making them useful as coatings, paints, moldings, adhesives, and fiber reinforced composites.