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Sample records for paclitaxel temperature-responsive gel

  1. A mucoadhesive in situ gel delivery system for paclitaxel.

    PubMed

    Jauhari, Saurabh; Dash, Alekha K

    2006-01-01

    MUC1 gene encodes a transmembrane mucin glycoprotein that is overexpressed in human breast cancer and colon cancer. The objective of this study was to develop an in situ gel delivery system containing paclitaxel (PTX) and mucoadhesives for sustained and targeted delivery of anticancer drugs. The delivery system consisted of chitosan and glyceryl monooleate (GMO) in 0.33M citric acid containing PTX. The in vitro release of PTX from the gel was performed in presence and absence of Tween 80 at drug loads of 0.18%, 0.30%, and 0.54% (wt/wt), in Sorensen's phosphate buffer (pH 7.4) at 37 degrees C. Different mucin-producing cell lines (Calu-3>Caco-2) were selected for PTX transport studies. Transport of PTX from solution and gel delivery system was performed in side by side diffusion chambers from apical to basal (A-B) and basal to apical (B-A) directions. In vitro release studies revealed that within 4 hours, only 7.61% +/- 0.19%, 12.0% +/- 0.98%, 31.7% +/- 0.40% of PTX were released from 0.18%, 0.30%, and 0.54% drug-loaded gel formulation, respectively, in absence of Tween 80. However, in presence of surfactant (0.05% wt/vol) in the dissolution medium, percentages of PTX released were 28.1% +/- 4.35%, 44.2% +/- 6.35%, and 97.1% +/- 1.22%, respectively. Paclitaxel has shown a polarized transport in all the cell monolayers with B-A transport 2 to 4 times higher than in the A-B direction. The highest mucin-producing cell line (Calu-3) has shown the lowest percentage of PTX transport from gels as compared with Caco-2 cells. Transport of PTX from mucoadhesive gels was shown to be influenced by the mucin-producing capability of cell.

  2. A rapid temperature-responsive sol-gel reversible poly(N-isopropylacrylamide)-g-methylcellulose copolymer hydrogel.

    PubMed

    Liu, Wenguang; Zhang, Bingqi; Lu, William W; Li, Xiaowei; Zhu, Dunwan; De Yao, Kang; Wang, Qin; Zhao, Chengru; Wang, Chuandong

    2004-07-01

    Poly(N-isopropylacrylamide) (PNIPAAm) was grafted to methylcellulose (MC) with various feeding ratios using ammonium persulfate and N,N,N',N'-tetramethyl ethylene diamine as an initiator. FTIR results confirm the formation of PNIPAAm-g-MC copolymers. The temperature responsiveness of copolymer gels was investigated by turbidimetry, dynamic contact angle (DCA), differential scanning calorimetry and dynamic mechanical analysis (DMA). The results indicate that PNIPAAm-g-MC hydrogels are strongly temperature responsive. At lower contents of MC, the lower critical solution temperature (LCST) is decreased, whereas further increasing MC contents raises the LCSTs. It is observed that the phase transition of the hydrogels occurs reversibly within 1 min, and near body temperature, a rigid gel can be generated in a certain range of MC content. What is more, the incorporation of MC prevents the syneresis of copolymer hydrogel. DMA measurement reveals that the storage moduli (E') of the gels increase upon increasing MC contents, and moreover the values of E' go up markedly above LCST. The copolymer hydrogels hold a promise as a blood vessel barrier by tuning gelation temperature, gelation time and mechanical strength.

  3. Polymer Nanocomposites Based Thermo-Sensitive Gel for Paclitaxel and Temozolomide Co-Delivery to Glioblastoma Cells.

    PubMed

    Xu, Yuanyuan; Shen, Ming; Sun, Ying; Gao, Pei; Duan, Yourong

    2015-12-01

    In this work, we have reported the preparation and optimization of paclitaxel (PTX) and temozolomide (TMZ) loaded monomethoxy (polyethylene glycol)-poly(D, L-lactide-co-glycolide) (mPEG-PLGA) nanocomposite which is a thermo-sensitive gel delivery system to glioblastoma. We utilized the orthogonal design and homogeneous design for the optimal drug-loaded nanoparticles (NPs) and composite gel prescription, respectively. The physicochemical characteristics of NPs and rheological properties of the gel were analyzed. Then the in vitro release of the gel was determined with a membrane-less diffusion system. Finally, the cytotoxic and apoptosis-inducing effects of the gel on the human malignant glioblastoma cell line U87 and C6 rat glioblastoma cell line were evaluated by MTT and flow cytometry apoptosis assay, respectively. The transmission electron microscopy (TEM) analysis revealed the optimized NPs with a relatively uniform diameter and distribution. The homogeneous design and rheological determination showed that the optimized gel prescription was 250 mg/mL Pluronic F127 (F127), 0.5% hydroxy propyl methylcellulose (HPMC-100M), 0.5% Pluronic F68 (F68), 0.5% sodium alginate (SA) and suitable NPs, which possessed the appropriate gelation behaviors: gelation temperature 28.01 degrees C, gelation time 127.1 s and corrosion speed 0.1892 g/cm2 x hr; and rheological properties: suitable elasticity modulus, viscosity modulus and low phase angle. The in vitro results suggested that the PTX and TMZ were sustainedly released from nanoparticles or the composite gel, and the release and elimination time greatly prolonged; and the composite gel possessed much higher growth-inhibiting effect and apoptosis-inducing rate in U87 and C6 cells than other formulations. These findings demonstrated that the optimal gel was a promising delivery system for the interstitial chemotherapy to glioblastoma. PMID:26682412

  4. Delayed onset of paresis in rats with experimental intramedullary spinal cord gliosarcoma following intratumoral administration of the paclitaxel delivery system OncoGel

    PubMed Central

    Tyler, Betty M.; Hdeib, Alia; Caplan, Justin; Legnani, Federico G.; Fowers, Kirk D.; Brem, Henry; Jallo, George; Pradilla, Gustavo

    2014-01-01

    Object Treatment options for anaplastic or malignant intramedullary spinal cord tumors (IMSCTs) remain limited. Paclitaxel has potent cytotoxicity against experimental intracranial gliomas and could be beneficial in the treatment of IMSCTs, but poor CNS penetration and significant toxicity limit its use. Such limitations could be overcome with local intratumoral delivery. Paclitaxel has been previously incorporated into a biodegradable gel depot delivery system (OncoGel) and in this study the authors evaluated the safety of intramedullary injections of OncoGel in rats and its efficacy against an intramedullary rat gliosarcoma. Methods Safety of intramedullary OncoGel was tested in 12 Fischer-344 rats using OncoGel concentrations of 1.5 and 6.0 mg/ml (5 μl); median survival and functional motor scores (Basso-Beattie-Bresnahan [BBB] scale) were compared with those obtained with placebo (ReGel) and medium-only injections. Efficacy of OncoGel was tested in 61 Fischer-344 rats implanted with an intramedullary injection of 9L gliosarcoma containing 100,000 cells in 5 μl of medium, and randomized to receive OncoGel administered on the same day (in 32 rats) or 5 days after tumor implantation (in 29 rats) using either 1.5 mg/ml or 3.0 mg/ml doses of paclitaxel. Median survival and BBB scores were compared with those of ReGel-treated and tumor-only rats. Animals were killed after the onset of deficits for histopathological analysis. Results OncoGel was safe for intramedullary injection in rats in doses up to 5 μl of 3.0 mg/ml of paclitaxel; a dose of 5 μl of 6.0 mg/ml caused rapid deterioration in BBB scores. OncoGel at concentrations of 1.5 mg/ml and 3.0 mg/ml paclitaxel given on both Day 0 and Day 5 prolonged median survival and preserved BBB scores compared with controls. OncoGel 1.5 mg/ml produced 62.5% long-term survivors when delivered on Day 0. A comparison between the 1.5 mg/ml and the 3.0 mg/ml doses showed higher median survival with the 1.5 mg/ml dose on Day 0

  5. Paclitaxel Injection

    MedlinePlus

    ... with other medications. Paclitaxel injection manufactured with polyoxyethylated castor oil is used to treat ovarian cancer (cancer that ... cancer, and lung cancer. Paclitaxel injection with polyoxyethylated castor oil is also used to treat Kaposi's sarcoma (a ...

  6. Temperature responsive hydroxypropyl cellulose for encapsulation

    SciTech Connect

    Heitfeld, Kevin A.; Guo, Tingtai; Yang, George; Schaefer, Dale W.

    2009-08-26

    This work focuses on the use of temperature responsive gels (TRGs) (polymeric hydrogels with a large temperature-dependent change in volume) for flavor retention at cooking temperatures. Specifically, we have studied a gel with a lower critical solution temperature (LCST) that swells at low temperatures and collapses at high temperatures. In the collapsed state, the polymer acts as a transport barrier, keeping the volatile flavors inside. We have successfully synthesized a cellulose gel that exhibits this volume change and have encapsulated an oil phase inside the gel. The flavor-loaded encapsulated oil exhibited an increased release time when compared to similar gelatin capsules.

  7. Temperature responsive transmitter

    NASA Technical Reports Server (NTRS)

    Kleinberg, Leonard L. (Inventor)

    1987-01-01

    A temperature responsive transmitter is provided in which frequency varies linearly with temperature. The transmitter includes two identically biased transistors connected in parallel. A capacitor, which reflects into the common bases to generate negative resistance effectively in parallel with the capacitor, is connected to the common emitters. A crystal is effectively in parallel with the capacitor and the negative resistance. Oscillations occur if the magnitude of the absolute value of the negative resistance is less than the positive resistive impedance of the capacitor and the inductance of the crystal. The crystal has a large linear temperature coefficient and a resonant frequency which is substantially less than the gain-bandwidth product of the transistors to ensure that the crystal primarily determines the frequency of oscillation. A high-Q tank circuit having an inductor and a capacitor is connected to the common collectors to increase the collector current flow which in turn enhances the radiation of the oscillator frequency by the inductor.

  8. Prodrug Strategies for Paclitaxel.

    PubMed

    Meng, Ziyuan; Lv, Quanxia; Lu, Jun; Yao, Houzong; Lv, Xiaoqing; Jiang, Feng; Lu, Aiping; Zhang, Ge

    2016-01-01

    Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective. PMID:27223283

  9. Prodrug Strategies for Paclitaxel

    PubMed Central

    Meng, Ziyuan; Lv, Quanxia; Lu, Jun; Yao, Houzong; Lv, Xiaoqing; Jiang, Feng; Lu, Aiping; Zhang, Ge

    2016-01-01

    Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective. PMID:27223283

  10. Pharmacologic sensitivity of paclitaxel to its delivery vehicles drives distinct clinical outcomes of paclitaxel formulations.

    PubMed

    Li, Yan; Chen, Nianhang; Palmisano, Maria; Zhou, Simon

    2015-04-01

    Paclitaxel, an effective antitumor agent, is formulated in various vehicles serving as carriers to deliver the hydrophobic paclitaxel to tissue. The approved formulations in the U.S. are paclitaxel formulated in Cremophor EL (currently known as Kolliphor EL) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel). Despite having the same active ingredient (paclitaxel), different formulations produce distinct products with unique efficacy and safety profiles. A semimechanistic model was developed to describe the pharmacologic sensitivity of paclitaxel under different formulations. Circulating paclitaxel concentration data from patients treated with nab-paclitaxel or Cremophor EL-paclitaxel were analyzed in NONMEM using a semimechanistic model with simultaneous disposition of paclitaxel-carrier complexes and the total paclitaxel released from the complexes. The key factors driving paclitaxel exposure in circulation and peripheral tissues were explored via sensitivity analysis. The rapid decline of total paclitaxel concentration following intravenous administration of nab-paclitaxel and Cremophor EL-paclitaxel was attributed to rapid tissue distribution of the paclitaxel-carrier complexes, with minor contribution of free and protein-bound paclitaxel. Distribution of nab-paclitaxel to peripheral tissue was 4-fold faster and 10-fold more extensive than that of Cremophor EL-paclitaxel micelles, resulting in distinct tissue paclitaxel profiles. Sensitivity analyses showed the plasma paclitaxel-time profile was insensitive to the rapid rates of tissue distribution and decomposition of paclitaxel-carrier complexes but that the tissue distribution profile of paclitaxel was highly sensitive. Tissue distribution of paclitaxel is carrier complex system-dependent. Different delivery systems result in distinct tissue paclitaxel profiles but similar paclitaxel concentration-time profiles in plasma or blood, rendering the paclitaxel plasma profile a poor surrogate for its

  11. Meth math: modeling temperature responses to methamphetamine.

    PubMed

    Molkov, Yaroslav I; Zaretskaia, Maria V; Zaretsky, Dmitry V

    2014-04-15

    Methamphetamine (Meth) can evoke extreme hyperthermia, which correlates with neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose dependence of temperature responses to Meth by mathematical modeling of the neuronal circuitry. On the basis of previous studies, we composed an artificial neural network with the core comprising three sequentially connected nodes: excitatory, medullary, and sympathetic preganglionic neuronal (SPN). Meth directly stimulated the excitatory node, an inhibitory drive targeted the medullary node, and, in high doses, an additional excitatory drive affected the SPN node. All model parameters (weights of connections, sensitivities, and time constants) were subject to fitting experimental time series of temperature responses to 1, 3, 5, and 10 mg/kg Meth. Modeling suggested that the temperature response to the lowest dose of Meth, which caused an immediate and short hyperthermia, involves neuronal excitation at a supramedullary level. The delay in response after the intermediate doses of Meth is a result of neuronal inhibition at the medullary level. Finally, the rapid and robust increase in body temperature induced by the highest dose of Meth involves activation of high-dose excitatory drive. The impairment in the inhibitory mechanism can provoke a life-threatening temperature rise and makes it a plausible cause of fatal hyperthermia in Meth users. We expect that studying putative neuronal sites of Meth action and the neuromediators involved in a detailed model of this system may lead to more effective strategies for prevention and treatment of hyperthermia induced by amphetamine-like stimulants.

  12. Paclitaxel-incorporated nanoparticles using block copolymers composed of poly(ethylene glycol)/poly(3-hydroxyoctanoate)

    PubMed Central

    2014-01-01

    Block copolymers composed of poly(3-hydroxyoctanoate) (PHO) and methoxy poly(ethylene glycol) (PEG) were synthesized to prepare paclitaxel-incorporated nanoparticle for antitumor drug delivery. In a 1H-NMR study, chemical structures of PHO/PEG block copolymers were confirmed and their molecular weight (M.W.) was analyzed with gel permeation chromatography (GPC). Paclitaxel as a model anticancer drug was incorporated into the nanoparticles of PHO/PEG block copolymer. They have spherical shapes and their particle sizes were less than 100 nm. In a 1H-NMR study in D2O, specific peaks of PEG solely appeared while peaks of PHO disappeared, indicating that nanoparticles have core-shell structures. The higher M.W. of PEG decreased loading efficiency and particle size. The higher drug feeding increased drug contents and average size of nanoparticles. In the drug release study, the higher M.W. of PEG block induced the acceleration of drug release rate. The increase in drug contents induced the slow release rate of drug. In an antitumor activity study in vitro, paclitaxel nanoparticles have practically similar anti-proliferation activity against HCT116 human colon carcinoma cells. In an in vivo animal study using HCT116 colon carcinoma cell-bearing mice, paclitaxel nanoparticles have enhanced antitumor activity compared to paclitaxel itself. Therefore, paclitaxel-incorporated nanoparticles of PHO/PEG block copolymer are a promising vehicle for antitumor drug delivery. PMID:25288916

  13. How Taxol/paclitaxel kills cancer cells.

    PubMed

    Weaver, Beth A

    2014-09-15

    Taxol (generic name paclitaxel) is a microtubule-stabilizing drug that is approved by the Food and Drug Administration for the treatment of ovarian, breast, and lung cancer, as well as Kaposi's sarcoma. It is used off-label to treat gastroesophageal, endometrial, cervical, prostate, and head and neck cancers, in addition to sarcoma, lymphoma, and leukemia. Paclitaxel has long been recognized to induce mitotic arrest, which leads to cell death in a subset of the arrested population. However, recent evidence demonstrates that intratumoral concentrations of paclitaxel are too low to cause mitotic arrest and result in multipolar divisions instead. It is hoped that this insight can now be used to develop a biomarker to identify the ∼50% of patients that will benefit from paclitaxel therapy. Here I discuss the history of paclitaxel and our recently evolved understanding of its mechanism of action.

  14. Characterization of perivascular poly(lactic-co-glycolic acid) films containing paclitaxel.

    PubMed

    Jackson, John K; Smith, Janet; Letchford, Kevin; Babiuk, Kelly Anne; Machan, Lindsay; Signore, Pierre; Hunter, William L; Wang, Kaiyue; Burt, Helen M

    2004-09-28

    The objectives of this study were to investigate the use of poly(lactic-co-glycolic acid) (PLGA) for the formulation of paclitaxel loaded films and to characterize these films for potential application as perivascular "wraps" to prevent restenosis. Films were manufactured from PLGA blended with either methoxypolyethylene glycol (MePEG) or a diblock copolymer composed of poly(D,L-lactic acid)-block-methoxypolyethylene glycol, PDLLA-MePEG (diblock) by solvent evaporation on teflon discs. Elasticity was determined by gravimetric stress/strain analysis. Thermal analysis was determined using differential scanning calorimetry (DSC). Changes in film composition and degradation in aqueous media were determined using gel permeation chromatography (GPC). Paclitaxel release from films was measured by incubation of the films in phosphate buffered saline (PBS) with drug analysis by HPLC methods. The addition of MePEG or diblock to PLGA caused a concentration dependent increase in the elasticity of films, due to plasticizing effects. DSC analysis showed that MePEG and diblock caused a concentration dependent decrease in the glass transition temperature (Tg) of PLGA indicating miscibility of the polymers. When placed in aqueous media, more than 75% of MePEG dissolved out of the PLGA films within 2 days, whereas diblock partitioned slowly and in a controlled manner out of the films. Paclitaxel release from PLGA/MePEG films was very slow with less than 5% of the encapsulated drug being released over 2 weeks. The addition of 30% diblock to paclitaxel loaded PLGA films caused a substantial increase (five- to eight-fold) in the release rate of paclitaxel. PLGA films containing 30% diblock and either 1% or 5% paclitaxel were partially or completely degraded following perivascular implantation in rats. PMID:15363506

  15. Paclitaxel delivery systems: the use of amino acid linkers in the conjugation of paclitaxel with carboxymethyldextran to create prodrugs.

    PubMed

    Sugahara, Shu-ichi; Kajiki, Masahiro; Kuriyama, Hiroshi; Kobayashi, To-ru

    2002-05-01

    Paclitaxel was bound via its hydroxyl group to carboxymethyldextran (CMDex, 150 kDa) by means of an amino acid linker; the linker was introduced into the 2'- or 7-hydroxyl group of the paclitaxel through an ester bond. These conjugates--CMDex-2'-paclitaxel and CMDex-7-paclitaxel--were designed to be water-soluble with a paclitaxel content between 6-8% (w/w) with a degree of subsititution (DS) of the CM groups at 0.6 per sugar residue. The release of the paclitaxel from the conjugates was influenced by the hydroxyl group (2'- or 7-) of paclitaxel to which the amino acid linker was introduced, and by what amino acid was used as the linker. In mouse plasma incubated at 37 degrees C for 72 h, the most paclitaxel was released using CMDex-paclitaxel conjugate with 2'gly followed by, in descending order, 2'-ala, 2'-leu, 2'-ile, and 7-gly as the amino linkers. Colon 26, a Taxol resistant cancer, was introduced into mice and the conjugates were intravenously administered by bolus injection for a tumor distribution study, and intermittently intravenously administered for a tumor growth regression study. In both studies the highest amount of paclitaxel release was found in the CMDex-2'-gly-paclitaxel followed by CMDex-2'-ala-paclitaxel, CMDex-2'-leu-paclitaxel and paclitaxel. There was a direct correlation between the amount of paclitaxel released and the observed efficacy. CMDex-2'-ile-paclitaxel and CMDex-7-gly-paclitaxel did not show any anti-tumor activity. These results clearly demonstrate that a CMDex-paclitaxel with an appropriate amino acid linker has significant anti-tumor activity against colon 26, and that these anti-tumor effects appear to correlate with the amounts of paclitaxel released in the tumor. PMID:12033505

  16. [A patient with paclitaxel hypersensitivity treated with nab-paclitaxel].

    PubMed

    Ouchi, Akira; Ouchi, Akira; Asano, Masahiko; Aono, Keiya; Watanabe, Tetsuya; Kato, Takehiro

    2014-07-01

    A 63-year-old man with multiple liver metastases from gastric cancer was treated with S-1 plus cisplatin; however, the number of multiple liver metastases increased. The patient received paclitaxel(PTX)treatment, but a hypersensitivity reaction occurred after administering the second dose; therefore, he received docetaxel treatment. A hypersensitivity reaction occurred after administering the first dose of docetaxel; therefore, he received irinotecan treatment. However, irinotecan administration was stopped because of severe diarrhea and weight reduction. Subsequently, at the patient's request, nab-PTX treatment was initiated by administering a premedication regimen of dexamethasone(8mg)and chlorpheniramine(10mg); no hypersensitivity reactions were reported thereafter. Nab-PTX is a contraindication; however, it might be possible to use nab-PTX for treating patients with PTX hypersensitivity.

  17. Paclitaxel Albumin-stabilized Nanoparticle Formulation

    Cancer.gov

    This page contains brief information about paclitaxel albumin-stabilized nanoparticle formulation and a collection of links to more information about the use of this drug, research results, and ongoing clinical trials.

  18. Paclitaxel improves outcome from traumatic brain injury

    PubMed Central

    Cross, Donna J.; Garwin, Gregory G.; Cline, Marcella M.; Richards, Todd L.; Yarnykh, Vasily; Mourad, Pierre D.; Ho, Rodney J.Y.; Minoshima, Satoshi

    2016-01-01

    Pharmacologic interventions for traumatic brain injury (TBI) hold promise to improve outcome. The purpose of this study was to determine if the microtubule stabilizing therapeutic paclitaxel used for more than 20 years in chemotherapy would improve outcome after TBI. We assessed neurological outcome in mice that received direct application of paclitaxel to brain injury from controlled cortical impact (CCI). Magnetic resonance imaging was used to assess injury-related morphological changes. Catwalk Gait analysis showed significant improvement in the paclitaxel group on a variety of parameters compared to the saline group. MRI analysis revealed that paclitaxel treatment resulted in significantly reduced edema volume at site-of-injury (11.92 ± 3.0 and 8.86 ± 2.2 mm3 for saline vs. paclitaxel respectively, as determined by T2-weighted analysis; p ≤ 0.05), and significantly increased myelin tissue preservation (9.45 ± 0.4 vs. 8.95 ± 0.3, p ≤ 0.05). Our findings indicate that paclitaxel treatment resulted in improvement of neurological outcome and MR imaging biomarkers of injury. These results could have a significant impact on therapeutic developments to treat traumatic brain injury. PMID:26086366

  19. Nab-Paclitaxel Plus Gemcitabine for Metastatic Pancreatic Cancer

    Cancer.gov

    A summary of results from a phase III trial that compared the combination of albumin-bound paclitaxel (nab-paclitaxel [Abraxane®]) and gemcitabine (Gemzar®) versus gemcitabine alone in patients with metastatic pancreatic cancer.

  20. An Italian cost-effectiveness analysis of paclitaxel albumin (nab-paclitaxel) versus conventional paclitaxel for metastatic breast cancer patients: the COSTANza study

    PubMed Central

    Lazzaro, Carlo; Bordonaro, Roberto; Cognetti, Francesco; Fabi, Alessandra; De Placido, Sabino; Arpino, Grazia; Marchetti, Paolo; Botticelli, Andrea; Pronzato, Paolo; Martelli, Elisa

    2013-01-01

    Purpose Paclitaxel albumin (nab-paclitaxel) is a nanoparticle albumin-bound paclitaxel formulation aimed at increasing therapeutic index in metastatic breast cancer. When compared to conventional paclitaxel, nab-paclitaxel has a reported longer time to progression, higher response, lower incidence of neutropenia, no need for premedication, shorter time of administration, and in pretreated metastatic breast cancer patients, extended overall survival. This study investigates the cost-effectiveness of nab-paclitaxel versus conventional paclitaxel for pretreated metastatic breast cancer patients in Italy. Materials and methods A Markov model with progression-free, progressed, and dead states was developed to estimate costs, outcomes, and quality adjusted life years over 5 years from the Italian National Health Service viewpoint. Patients were assumed to receive nab-paclitaxel 260 mg/m2 three times weekly or conventional paclitaxel 175 mg/m2 three times weekly. Data on health care resource consumption was collected from a convenience sample of five Italian centers. Resources were valued at Euro (€) 2011. Published utility weights were applied to health states to estimate the impact of response, disease progression, and adverse events on quality adjusted life years. Three sensitivity analyses tested the robustness of the base case incremental cost-effectiveness ratio (ICER). Results and conclusion Compared to conventional paclitaxel, nab-paclitaxel gains an extra 0.165 quality adjusted life years (0.265 life years saved) and incurs additional costs of €2506 per patient treated. This translates to an ICER of €15,189 (95% confidence interval: €11,891–€28,415). One-way sensitivity analysis underscores that ICER for nab-paclitaxel remains stable despite varying taxanes cost. Threshold analysis shows that ICER for nab-paclitaxel exceeds €40,000 only if cost per mg of conventional paclitaxel is set to zero. Probabilistic sensitivity analysis highlights that nab-paclitaxel

  1. Emodin sensitizes paclitaxel-resistant human ovarian cancer cells to paclitaxel-induced apoptosis in vitro.

    PubMed

    Li, Juan; Liu, Peishu; Mao, Hongluan; Wanga, Ancong; Zhang, Xiaolei

    2009-06-01

    Ovarian cancer has the highest mortality rate among gynecologic malignancies in the world, and the development of drug resistance is a major impediment toward successful treatment of the desease. Emodin has been reported to sensitize human tumor cells to chemotherapeutic agents. The present study investigated whether emodin could overcome chemoresistance of A2780/taxol cells. Cells were treated with different concentration of emodin alone or combined with paclitaxel, then the cell viability was measured by MTT and the apoptosis was determined by flow cytometric analysis. The changes of mRNA and protein were examined by QRT-PCR and Western blotting. The function of P-glycoprotein was also determined by flow cytometry. The results showed that emodin induced apoptosis alone at a high concentration and increased paclitaxel-induced apoptosis at a low concentration. It enhanced the sensitivity of A2780/taxol cells to paclitaxel with down-regulation of P-glycoprotein, XIAP and survivin. Taken together, the results demonstrated a dual role for emodin in the inhibition of drug resistant ovarian tumor growth by increasing paclitaxel cellular concentration and re-sensitizing the resistant cells to paclitaxel. Our results suggest the possibility of an innovative chemotherapeutic strategy that uses emodin in combination with paclitaxel to increase the sensitivity of tumor cells. PMID:19424643

  2. Ototoxicity of paclitaxel in rat cochlear organotypic cultures

    SciTech Connect

    Dong, Yang; Ding, Dalian; Jiang, Haiyan; Shi, Jian-rong; Salvi, Richard; Roth, Jerome A.

    2014-11-01

    Paclitaxel (taxol) is a widely used antineoplastic drug employed alone or in combination to treat many forms of cancer. Paclitaxel blocks microtubule depolymerization thereby stabilizing microtubules and suppressing cell proliferation and other cellular processes. Previous reports indicate that paclitaxel can cause mild to moderate sensorineural hearing loss and some histopathologic changes in the mouse cochlea; however, damage to the neurons and the underlying cell death mechanisms are poorly understood. To evaluate the ototoxicity of paclitaxel in more detail, cochlear organotypic cultures from postnatal day 3 rats were treated with paclitaxel for 24 or 48 h with doses ranging from 1 to 30 μM. No obvious histopathologies were observed after 24 h treatment with any of the paclitaxel doses employed, but with 48 h treatment, paclitaxel damaged cochlear hair cells in a dose-dependent manner and also damaged auditory nerve fibers and spiral ganglion neurons (SGN) near the base of the cochlea. TUNEL labeling was negative in the organ of Corti, but positive in SGN with karyorrhexis 48 h after 30 μM paclitaxel treatment. In addition, caspase-6, caspase-8 and caspase-9 labeling was present in SGN treated with 30 μM paclitaxel for 48 h. These results suggest that caspase-dependent apoptotic pathways are involved in paclitaxel-induced damage of SGN, but not hair cells in cochlea. - Highlights: • Paclitaxel was toxic to cochlear hair cells and spiral ganglion neurons. • Paclitaxel-induced spiral ganglion degeneration was apoptotic. • Paclitaxel activated caspase-6, -8 and -8 in spiral ganglion neurons.

  3. Temperature response of bundle-sheath conductance in maize leaves.

    PubMed

    Yin, Xinyou; van der Putten, Peter E L; Driever, Steven M; Struik, Paul C

    2016-04-01

    A small bundle-sheath conductance (g bs) is essential for the C4 CO2-concentrating mechanism to suppress photorespiration effectively. To predict the productivity of C4 crops accurately under global warming, it is necessary to examine whether and how g bs responds to temperature. We investigated the temperature response of g bs in maize by fitting a C4 photosynthesis model to combined gas exchange and chlorophyll fluorescence measurements of irradiance and CO2 response curves at 21% and 2% O2 within the range of 13.5-39 °C. The analysis was based on reported kinetic constants of C4 Rubisco and phosphoenolpyruvate carboxylase and temperature responses of C3 mesophyll conductance (g m). The estimates of g bs varied greatly with leaf temperature. The temperature response of g bs was well described by the peaked Arrhenius equation, with the optimum temperature being ~34 °C. The assumed temperature responses of g m had only a slight impact on the temperature response of g bs In contrast, using extreme values of some enzyme kinetic constants changed the shape of the response, from the peaked optimum response to the non-peaked Arrhenius pattern. Further studies are needed to confirm such an Arrhenius response pattern from independent measurement techniques and to assess whether it is common across C4 species. PMID:26969744

  4. Temperature response of bundle-sheath conductance in maize leaves

    PubMed Central

    Yin, Xinyou; van der Putten, Peter E.L.; Driever, Steven M.; Struik, Paul C.

    2016-01-01

    A small bundle-sheath conductance (g bs) is essential for the C4 CO2-concentrating mechanism to suppress photorespiration effectively. To predict the productivity of C4 crops accurately under global warming, it is necessary to examine whether and how g bs responds to temperature. We investigated the temperature response of g bs in maize by fitting a C4 photosynthesis model to combined gas exchange and chlorophyll fluorescence measurements of irradiance and CO2 response curves at 21% and 2% O2 within the range of 13.5–39 °C. The analysis was based on reported kinetic constants of C4 Rubisco and phosphoenolpyruvate carboxylase and temperature responses of C3 mesophyll conductance (g m). The estimates of g bs varied greatly with leaf temperature. The temperature response of g bs was well described by the peaked Arrhenius equation, with the optimum temperature being ~34 °C. The assumed temperature responses of g m had only a slight impact on the temperature response of g bs. In contrast, using extreme values of some enzyme kinetic constants changed the shape of the response, from the peaked optimum response to the non-peaked Arrhenius pattern. Further studies are needed to confirm such an Arrhenius response pattern from independent measurement techniques and to assess whether it is common across C4 species. PMID:26969744

  5. Enhanced antitumor effect of novel dual-targeted paclitaxel liposomes

    NASA Astrophysics Data System (ADS)

    Meng, Shuyan; Su, Bo; Li, Wei; Ding, Yongmei; Tang, Liang; Zhou, Wei; Song, Yin; Li, Heyan; Zhou, Caicun

    2010-10-01

    A novel dual-targeted peptide containing an alpha V integrins specific ligand and a neuropilin-1 specific motif was developed which showed an increased specific targeting affinity to tumors. Active dual-targeted liposomes were then produced with this peptide and exhibited greater binding activity than single-targeted liposomes in vitro. Paclitaxel entrapped in this formulation greatly increased the uptake of paclitaxel in the targeting cells and significantly suppressed the growth of HUVEC and A549 cells compared with general paclitaxel injections (Taxol) and single-targeted paclitaxel liposomes. The treatment of tumor xenograft models with dual-targeted paclitaxel liposomes also resulted in better tumor growth inhibition than any other treatment groups. Therefore, the dual-targeted paclitaxel liposomes prepared in the present study might be a more promising drug for cancer treatment. Furthermore, the dual-targeting approach may produce synergistic effects that can be applied in the development of new targeted drug delivery systems.

  6. Monoclonal Antibodies Attached to Carbon Nanotube Transistors for Paclitaxel Detection

    NASA Astrophysics Data System (ADS)

    Lee, Wonbae; Lau, Calvin; Richardson, Mark; Rajapakse, Arith; Weiss, Gregory; Collins, Philip; UCI, Molecular Biology; Biochemistry Collaboration; UCI, Departments of Physics; Astronomy Collaboration

    Paclitaxel is a naturally-occurring pharmaceutical used in numerous cancer treatments, despite its toxic side effects. Partial inhibition of this toxicity has been demonstrated using weakly interacting monoclonal antibodies (3C6 and 8A10), but accurate monitoring of antibody and paclitaxel concentrations remains challenging. Here, single-molecule studies of the kinetics of antibody-paclitaxel interactions have been performed using single-walled carbon nanotube field-effect transistors. The devices were sensitized with single antibody attachments to record the single-molecule binding dynamics of paclitaxel. This label-free technique recorded a range of dynamic interactions between the antibody and paclitaxel, and it provided sensitive paclitaxel detection for pM to nM concentrations. Measurements with two different antibodies suggest ways of extending this working range and uncovering the mechanistic differences among different antibodies.

  7. Hyaluronic acid-based hydrogel for regional delivery of paclitaxel to intraperitoneal tumors

    PubMed Central

    Bajaj, Gaurav; Kim, Mi Ran; Mohammed, Sulma I.; Yeo, Yoon

    2012-01-01

    Intraperitoneal (IP) chemotherapy is an effective way of treating local and regional malignancies confined in the peritoneal cavity such as ovarian cancer. However, a persistent major challenge in IP chemotherapy is the need to provide effective drug concentrations in the peritoneal cavity for an extended period of time. We hypothesized that hyaluronic acid (HA)-based in-situ crosslinkable hydrogel would serve as a carrier of paclitaxel (PTX) particles to improve their IP retention and therapeutic effects. In-vitro gel degradation and release kinetics studies demonstrated that HA gels could entrap microparticulate PTX (>100 μm) and release the drug over 10 days, gradually degraded by hyaluronidase, but had limited effect on retention of Taxol, a 14-nm micelle form of PTX. When administered IP to tumor-bearing nude mice, PTX was best retained in the peritoneal cavity as PTX-gel (microparticulate PTX entrapped in the HA gel), whereas Taxol-gel and other Taxol-based formulations left negligible amount of PTX in the cavity after 14 days. Despite the increase in IP retention of PTX, PTX-gel did not further decrease the tumor burdens than Taxol-based formulations, presumably due to the limited dissolution of PTX. This result indicates that spatial availability of a drug does not necessarily translate to the enhanced anti-tumor effect unless it is accompanied by the temporal availability. PMID:22178261

  8. Radiosensitization of paclitaxel, etanidazole and paclitaxel+etanidazole nanoparticles on hypoxic human tumor cells in vitro.

    PubMed

    Jin, Cheng; Bai, Ling; Wu, Hong; Tian, Furong; Guo, Guozhen

    2007-09-01

    Paclitaxel and etanidazole are hypoxic radiosensitizers that exhibit cytotoxic action at different mechanisms. The poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles containing paclitaxel, etanidazole and paclitaxel+etanidazole were prepared by o/w and w/o/w emulsification-solvent evaporation method. The morphology of the nanoparticles was investigated by scanning electron microscope (SEM). The drug encapsulation efficiency (EE) and release profile in vitro were measured by high-performance liquid chromatography (HPLC). The cellular uptake of nanoparticles for the human breast carcinoma cells (MCF-7) and the human carcinoma cervicis cells (HeLa) was evaluated by transmission electronic microscopy and fluorescence microscopy. Cell viability was determined by the ability of single cell to form colonies in vitro. The prepared nanoparticles were spherical shape with size between 80 and 150 nm. The EE was higher for paclitaxel and lower for etanidazole. The drug release was controlled over time. The cellular uptake of nanoparticles was observed. Co-culture of the two tumor cell lines with drug-loaded nanoparticles demonstrated that released drug effectively sensitized hypoxic tumor cells to radiation. The radiosensitization of paclitaxel+etanidazole nanoparticles was more significant than that of single drug-loaded nanoparticles. PMID:17509678

  9. Solvent- and concentration-dependent molecular interactions of taxol (Paclitaxel).

    PubMed

    Balasubramanian, S V; Alderfer, J L; Straubinger, R M

    1994-10-01

    Taxol (paclitaxel) is a promising anticancer agent that has been approved for the treatment of ovarian cancer and is under investigation for the therapy of other tumors. Paclitaxel is poorly soluble in water, and information on its physical behavior in hydrophilic and hydrophobic environments is limited. Circular dichroism (CD) and nuclear magnetic resonance spectroscopy were used to investigate the effect of solvent and drug concentration on the solution conformation of paclitaxel. CD is sensitive to paclitaxel's environment, owing to the presence of effective chromophores in the vicinity of several chiral centers. It was found that (i) the conformation of the paclitaxel side chain depends on the polarity of the solvent and (ii) paclitaxel has a tendency to undergo concentration-dependent aggregation in solvents such as chloroform. To account for the observations, a model is proposed in which paclitaxel molecules are held together in stacks by intermolecular hydrogen bonds involving all four exchangeable protons. Intermolecular interactions and self-association of paclitaxel may have impact not only on the physical stability of the drug in existing formulations or investigational vehicles but also on the effect of paclitaxel in the stabilization of cellular microtubules.

  10. Balanced excitation and inhibition in temperature responses to meth

    PubMed Central

    Molkov, Yaroslav I; Zaretsky, Dmitry V

    2014-01-01

    Fatal hyperthermia after administration of various amphetamines is well-known clinical phenomenon, however, there is no consistent theory explaining its etiology and/or pathogenesis. Dose-dependence of temperature responses to methamphetamine is intricate. Recently, using mathematical modeling it was suggested that delicate interplay of excitatory and inhibitory mechanisms underlies this complexity. PMID:27624568

  11. Balanced excitation and inhibition in temperature responses to meth

    PubMed Central

    Molkov, Yaroslav I; Zaretsky, Dmitry V

    2014-01-01

    Fatal hyperthermia after administration of various amphetamines is well-known clinical phenomenon, however, there is no consistent theory explaining its etiology and/or pathogenesis. Dose-dependence of temperature responses to methamphetamine is intricate. Recently, using mathematical modeling it was suggested that delicate interplay of excitatory and inhibitory mechanisms underlies this complexity.

  12. Temperature responses of exercizing dogs to infusion of electrolytes

    NASA Technical Reports Server (NTRS)

    Greenleaf, J. E.; Kozlowski, S.; Nazar, K.; Kaciuba-Uscilko, H.; Brzezinska, Z.

    1974-01-01

    The effect of infusions with solutions of various ionic and osmotic composition on exercise temperature responses was studied in dogs who do not regulate their temperature by sweating. The results suggest an association between plasma Na+ and Ca++ level within the normal physiological range and the control of body temperature during exercise.

  13. Prolonged remission of recurrent cervical carcinoma following paclitaxel and carboplatin chemotherapy with paclitaxel maintenance chemotherapy.

    PubMed

    Micha, John P; Sassoon, Aaron F; Wong, Humberto; Goldstein, Bram H

    2015-08-01

    Cervical cancer recurs in ~30% of cases, for which a favorable prognosis is often unattainable. We describe a cervical cancer patient who developed metastatic disease ~5 years after her initial diagnosis. She was subsequently treated with six cycles of paclitaxel (175 mg/m) and carboplatin area under the curve (AUC) 5 chemotherapy every 21 days, and paclitaxel (135 mg/m) maintenance therapy every 21 days; the patient has remained in clinical remission after more than 5 years of follow-up. Chemotherapy has not historically been effective in managing recurrent, persistent, or metastatic cervical cancer. However, our case study involving paclitaxel and carboplatin chemotherapy with maintenance chemotherapy represents one of the longest documented remission rates in association with the management of recurrent cervical cancer.

  14. Stathmin Potentiates Vinflunine and Inhibits Paclitaxel Activity

    PubMed Central

    Malesinski, Soazig; Tsvetkov, Philipp O.; Kruczynski, Anna; Peyrot, Vincent; Devred, François

    2015-01-01

    Cell biology and crystallographic studies have suggested a functional link between stathmin and microtubule targeting agents (MTAs). In a previous study we showed that stathmin increases vinblastine (VLB) binding to tubulin, and that conversely VLB increases stathmin binding to tubulin. This constituted the first biochemical evidence of the direct relationship between stathmin and an antimitotic drug, and revealed a new mechanism of action for VLB. The question remained if the observed interaction was specific for this drug or represented a general phenomenon for all MTAs. In the present study we investigated the binding of recombinant stathmin to purified tubulin in the presence of paclitaxel or another Vinca alkaloid, vinflunine, using Isothermal Titration Calorimetry (ITC). These experiments revealed that stathmin binding to tubulin is increased in the presence of vinflunine, whereas no signal is observed in the presence of paclitaxel. Further investigation using turbidity and co-sedimentation showed that stathmin inhibited paclitaxel microtubule-stabilizing activity. Taken together with the previous study using vinblastine, our results suggest that stathmin can be seen as a modulator of MTA activity and binding to tubulin, providing molecular explanation for multiple previous cellular and in vivo studies showing that stathmin expression level affects MTAs efficiency. PMID:26030092

  15. Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment.

    PubMed

    Mo, Michelle; Erdelyi, Ildiko; Szigeti-Buck, Klara; Benbow, Jennifer H; Ehrlich, Barbara E

    2012-11-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect that occurs in many patients undergoing chemotherapy. It is often irreversible and frequently leads to early termination of treatment. In this study, we have identified two compounds, lithium and ibudilast, that when administered as a single prophylactic injection prior to paclitaxel treatment, prevent the development of CIPN in mice at the sensory-motor and cellular level. The prevention of neuropathy was not observed in paclitaxel-treated mice that were only prophylactically treated with a vehicle injection. The coadministration of lithium with paclitaxel also allows for administration of higher doses of paclitaxel (survival increases by 60%), protects against paclitaxel-induced cardiac abnormalities, and, notably, does not interfere with the antitumor effects of paclitaxel. Moreover, we have determined a mechanism by which CIPN develops and have discovered that lithium and ibudilast inhibit development of peripheral neuropathy by disrupting the interaction between paclitaxel, neuronal calcium sensor 1 (NCS-1), and the inositol 1,4,5-trisphosphate receptor (InsP3R) to prevent treatment-induced decreases in intracellular calcium signaling. This study shows that lithium and ibudilast are candidate therapeutics for the prevention of paclitaxel-induced neuropathy and could enable patients to tolerate more aggressive treatment regimens.

  16. Self-Activated Healable Hydrogels with Reversible Temperature Responsiveness.

    PubMed

    Chang, Ruixue; Wang, Xuemeng; Li, Xu; An, Heng; Qin, Jianglei

    2016-09-28

    The self-healable polymer hydrogel along with reversible temperature responsiveness was prepared through self-catalyzed dynamic acylhydrazone formation and exchange without any additional stimulus or catalyst. The hydrogel was prepared from a copolymer of N-isopropylacrylamide and acylhydrazine P(NIPAM-co-AH) cross-linked by PEO dialdehyde. Besides self-healed under catalysis of acid and aniline, the hydrogel can also self-heal activated by excess of acylhydrazine groups. Without interference of catalyst during the hydrogel formation and self-healing, this kind of hydrogel prepared from biocompatible polymers can be used in more areas including biotechnology and be more persistent. The hydrogel with a large part of the PNIPAM segment also showed temperature responsiveness around body temperature influenced by the variation in group ratio. This self-healable hydrogel has great potential application in areas related to bioscience and biotechnology. PMID:27589014

  17. A supramolecular microgel glutathione peroxidase mimic with temperature responsive activity.

    PubMed

    Yin, Yanzhen; Jiao, Shufei; Lang, Chao; Liu, Junqiu

    2014-05-21

    Glutathione peroxidase (GPx) protects cells from oxidative damage by scavenging surplus reactive oxygen species (ROS). Commonly, an appropriate amount of ROS acts as a signal molecule in the metabolism. A smart artificial GPx exhibits adjustable catalytic activity, which can potentially reduce the amount of ROS to an appropriate degree and maintain its important physiological functions in metabolism. To construct an optimum and excellent smart artificial GPx, a novel supramolecular microgel artificial GPx (SM-Te) was prepared based on the supramolecular host-guest interaction employing the tellurium-containing guest molecule (ADA-Te-ADA) and the cyclodextrin-containing host block copolymer (poly(N-isopropylacrylamide)-b-[polyacrylamides-co-poly(6-o-(triethylene glycol monoacrylate ether)-β-cyclodextrin)], PPAM-CD) as building blocks. Subsequently, based on these building blocks, SM-Te was constructed and the formation of its self-assembled structure was confirmed by dynamic light scattering, NMR, SEM, TEM, etc. Typically, benefitting from the temperature responsive properties of the PNIPAM scaffold, SM-Te also exhibited similar temperature responsive behaviour. Importantly, the GPx catalytic rates of SM-Te displayed a noticeable temperature responsive characteristic. Moreover, SM-Te exhibited the typical saturation kinetics behaviour of a real enzyme catalyst. It was proved that the changes of the hydrophobic microenvironment and the pore size in the supramolecular microgel network of SM-Te played significant roles in altering the temperature responsive catalytic behaviour. The successful construction of SM-Te not only overcomes the insurmountable disadvantages existing in previous covalent bond crosslinked microgel artificial GPx but also bodes well for the development of novel intelligent antioxidant drugs. PMID:24652520

  18. Paclitaxel Impairs Adipose Stem Cell Proliferation and Differentiation

    PubMed Central

    Choron, Rachel L.; Chang, Shaohua; Khan, Sophia; Villalobos, Miguel A.; Zhang, Ping; Carpenter, Jeffrey P.; Tulenko, Thomas N.; Liu, Yuan

    2015-01-01

    BACKGROUND Cancer patients with chemotherapy-induced immunosuppression have poor surgical site wound healing. Prior literature supports the use of human adipose-derived stem cell (hASC) lipoinjection to improve wound healing. It has been established multipotent hASCs facilitate neovascularization, accelerated epithelialization, and wound closure in animal models. While hASC wound therapy may benefit surgical cancer patients, the chemotherapeutic effects on hASCs are unknown. We hypothesized Paclitaxel, a chemotherapeutic agent, impairs hASC growth, multipotency, and induces apoptosis. METHODS hASCs were isolated and harvested from consented, chemotherapy and radiation naïve patients. Growth curves, MTT, and EdU assays measured cytotoxicity and proliferation. Oil-Red-O stain, Alazarin-Red stain, Matrigel tube-formation assay, and qPCR analyzed hASC differentiation. Annexin V assay measured apoptosis. Immunostaining and Western blot determined TNF-α expression. RESULTS hASCs were selectively more sensitive to Paclitaxel (0.01μM–30μM) than fibroblasts (p<0.05). After 12 days, Paclitaxel caused hASC growth arrest whereas control hASCs proliferated (p=0.006). Paclitaxel caused an 80.6% reduction in new DNA synthesis (p<0.001). Paclitaxel severely inhibited endothelial differentiation and capillary-like tube formation. Differentiation markers LPL (adipogenic), alkaline phosphatase (osteogenic), CD31 and vWF (endothelial) were significantly decreased (all: p<0.05) confirming Paclitaxel impaired differentiation. Paclitaxel was also found to induce apoptosis and TNF-α was up-regulated in Paclitaxel-treated hASCs (p<0.001). CONCLUSION Paclitaxel is more cytotoxic to hASCs than fibroblasts. Paclitaxel inhibits hASC proliferation, differentiation, and induces apoptosis, possibly through the TNF-α pathway. Paclitaxel’s severe inhibition of endothelial differentiation indicates neovascularization disruption, possibly causing poor wound healing in cancer patients

  19. Temperature responsive hydrogels enable transient three-dimensional tumor cultures via rapid cell recovery.

    PubMed

    Heffernan, John M; Overstreet, Derek J; Srinivasan, Sanjay; Le, Long D; Vernon, Brent L; Sirianni, Rachael W

    2016-01-01

    Recovery of live cells from three-dimensional (3D) culture would improve analysis of cell behaviors in tissue engineered microenvironments. In this work, we developed a temperature responsive hydrogel to enable transient 3D culture of human glioblastoma (GBM) cells. N-isopropylacrylamide was copolymerized with hydrophilic grafts and functionalized with the cell adhesion peptide RGD to yield the novel copolymer poly(N-isopropylacrylamide-co-Jeffamine(®) M-1000 acrylamide-co-hydroxyethylmethacrylate-RGD), or PNJ-RGD. This copolymer reversibly gels in aqueous solutions when heated under normal cell culture conditions (37°C). Moreover, these gels redissolve within 70 s when cooled to room temperature without the addition of any agents to degrade the synthetic scaffold, thereby enabling rapid recollection of viable cells after 3D culture. We tested the efficiency of cell recovery following extended 3D culture and were able to recover more than 50% of viable GBM cells after up to 7 days in culture. These data demonstrate the utility of physically crosslinked PNJ-RGD hydrogels as a platform for culture and recollection of cells in 3D.

  20. Paclitaxel Nano-Delivery Systems: A Comprehensive Review.

    PubMed

    Ma, Ping; Mumper, Russell J

    2013-02-18

    Paclitaxel is one of the most effective chemotherapeutic drugs ever developed and is active against a broad range of cancers, such as lung, ovarian, and breast cancers. Due to its low water solubility, paclitaxel is formulated in a mixture of Cremophor EL and dehydrated ethanol (50:50, v/v) a combination known as Taxol. However, Taxol has some severe side effects related to Cremophor EL and ethanol. Therefore, there is an urgent need for the development of alternative Taxol formulations. The encapsulation of paclitaxel in biodegradable and non-toxic nano-delivery systems can protect the drug from degradation during circulation and in-turn protect the body from toxic side effects of the drug thereby lowering its toxicity, increasing its circulation half-life, exhibiting improved pharmacokinetic profiles, and demonstrating better patient compliance. Also, nanoparticle-based delivery systems can take advantage of the enhanced permeability and retention (EPR) effect for passive tumor targeting, therefore, they are promising carriers to improve the therapeutic index and decrease the side effects of paclitaxel. To date, paclitaxel albumin-bound nanoparticles (Abraxane®) have been approved by the FDA for the treatment of metastatic breast cancer and non-small cell lung cancer (NSCLC). In addition, there are a number of novel paclitaxel nanoparticle formulations in clinical trials. In this comprehensive review, several types of developed paclitaxel nano-delivery systems will be covered and discussed, such as polymeric nanoparticles, lipid-based formulations, polymer conjugates, inorganic nanoparticles, carbon nanotubes, nanocrystals, and cyclodextrin nanoparticles.

  1. Assessment of Tank 241-C-106 temperature response indications

    SciTech Connect

    Eyler, L.L.

    1995-03-01

    This report presents an assessment of waste tank 241-C-106 temperature response indications. The results are obtained through evaluation of historical data for FIC surface level data and temperature indication data from thermocouples in risers 8 and 14, contained in the SACS and TMACS databases. Computer analysis is used to augment observations and conclusions about hypothesized mechanisms present in the tank that could explain the data observations. From the historical temperature indications of risers 8 and 14 (neglecting the ventilation outages), several general observational conclusions are drawn that support hypotheses explaining more recently observed behavior.

  2. Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer

    PubMed Central

    Sparano, Joseph A.; Wang, Molin; Martino, Silvana; Jones, Vicky; Perez, Edith A.; Saphner, Tom; Wolff, Antonio C.; Sledge, George W.; Wood, William C.; Davidson, Nancy E.

    2009-01-01

    BACKGROUND We compared the efficacy of two different taxanes, docetaxel and paclitaxel, given either weekly or every 3 weeks, in the adjuvant treatment of breast cancer. METHODS We enrolled 4950 women with axillary lymph node–positive or high-risk, lymph node–negative breast cancer. After randomization, all patients first received 4 cycles of intravenous doxorubicin and cyclophosphamide at 3-week intervals and were then assigned to intravenous paclitaxel or docetaxel given at 3-week intervals for 4 cycles or at 1-week intervals for 12 cycles. The primary end point was disease-free survival. RESULTS As compared with patients receiving standard therapy (paclitaxel every 3 weeks), the hazard ratio for disease-free survival was 1.27 among those receiving weekly paclitaxel (P = 0.006), 1.23 among those receiving docetaxel every 3 weeks (P = 0.02), and 1.09 among those receiving weekly docetaxel (P = 0.29) (with a hazard ratio >1 favoring the groups receiving experimental therapy). As compared with standard therapy, weekly paclitaxel was also associated with improved survival (hazard ratio, 1.32; P = 0.01). An exploratory analysis of a subgroup of patients whose tumors expressed no human epidermal growth factor receptor type 2 protein found similar improvements in disease-free and overall survival with weekly paclitaxel treatment, regardless of hormone-receptor expression. Grade 2, 3, or 4 neuropathy was more frequent with weekly paclitaxel than with paclitaxel every 3 weeks (27% vs. 20%). CONCLUSIONS Weekly paclitaxel after standard adjuvant chemotherapy with doxorubicin and cyclophosphamide improves disease-free and overall survival in women with breast cancer. (ClinicalTrials.gov number, NCT00004125.) PMID:18420499

  3. [Study of bioavailability of paclitaxel after sublingual administration].

    PubMed

    Samsonia, M; Lesiovskaia, E; Ghibradze, O; Kandelaki, M

    2015-05-01

    The bioavailability of sublingual form of paclitaxel, developed in the pharmacology laboratory of pharmaceutical company - Legion "Provisus" is studied. Sublingual form of paclitaxel is an alcoholic solution of paclitaxel (1 mg/ml) with penetrator - dimethyl sulfoxide (DMSO) addition. Experiments were performed on 180 white mongrel male mice each of 25-30 g. The animals were divided into three groups. The first group served for control. 10 mg/kg of taxol was injected (once) in the lateral tail vein of the first group animals. A solution was prepared by diluting taxol with physiological sodium chloride solution until to a final concentration of paclitaxel to 1 mg/ml. The dose of 10 mg/kg (single dose) was applied under the tongue of the second group animals. Paclitaxel (substance) was extracted with dichloromethane - Taxol (by liquid-liquid extraction) for the manufacturing of a sublingual form. Unlike the second group, the third group animals took the same dose of sublingual form of paclitaxel orally (by gavage). The concentration of paclitaxel in plasma was studied by reversed-phase HPLC with spectrophotometric detection at λ = 227 nm by Woo JS et al. (2003) method. Bioavailability was determined by comparing the concentration of paclitaxel in blood after sublingual and intravenous use of Taxol (as an area under the curve of concentration versus time). It is established that the bioavailability of sublingual forms of paclitaxel was 42.4%, Cmax = 615 ± 73 ng × ml(-1) and tmax = 30-35 min. The value of the initial volume of distribution of paclitaxel (Vd = 3,14 ± 0,85 l × kg(-1)) also shows its intensive penetration to the organs and tissues. The half-life of the drug on the terminal segment of concentration-time curve was averaged 1,06 ± 0,21 h. The results create the preconditions for further preclinical study of sublingual form of paclitaxel, as the bioavailability of paclitaxel after sublingual application allows to have a systemic effect on the tumor

  4. Paclitaxel-carboplatin induced radiation recall colitis.

    PubMed

    Kundak, Isil; Oztop, Ilhan; Soyturk, Mujde; Ozcan, Mehmet Ali; Yilmaz, Ugur; Meydan, Nezih; Gorken, Ilknur Bilkay; Kupelioglu, Ali; Alakavuklar, Mehmet

    2004-01-01

    Some chemotherapeutic agents can "recall" the irradiated volumes by skin or pulmonary reactions in cancer patients who previously received radiation therapy. We report a recall colitis following the administration of paclitaxel-containing regimen in a patient who had been irradiated for a carcinoma of the uterine cervix. A 63-year-old woman underwent a Wertheim operation because of uterine cervix carcinoma. After 8 years of follow-up, a local recurrence was observed and she received curative external radiotherapy (45 Gy) to the pelvis. No significant adverse events were observed during the radiotherapy. Approximately one year later, she was hospitalized because of metastatic disease with multiple pulmonary nodules, and a chemotherapy regimen consisting of paclitaxel and carboplatin was administered. The day after the administration of chemotherapy the patient had diarrhea and rectal bleeding. Histological examination of the biopsy taken from rectal hyperemic lesions showed a radiation colitis. The symptoms reappeared after the administration of each course of chemotherapy and continued until the death of the patient despite the interruption of the chemotherapy. In conclusion, the probability of recall phenomena should be kept in mind in patients who received previously with pelvic radiotherapy and treated later with cytotoxic chemotherapy.

  5. Controlled Delivery of Human Cells by Temperature Responsive Microcapsules

    PubMed Central

    Mak, W.C.; Olesen, K.; Sivlér, P.; Lee, C.J.; Moreno-Jimenez, I.; Edin, J.; Courtman, D.; Skog, M.; Griffith, M.

    2015-01-01

    Cell therapy is one of the most promising areas within regenerative medicine. However, its full potential is limited by the rapid loss of introduced therapeutic cells before their full effects can be exploited, due in part to anoikis, and in part to the adverse environments often found within the pathologic tissues that the cells have been grafted into. Encapsulation of individual cells has been proposed as a means of increasing cell viability. In this study, we developed a facile, high throughput method for creating temperature responsive microcapsules comprising agarose, gelatin and fibrinogen for delivery and subsequent controlled release of cells. We verified the hypothesis that composite capsules combining agarose and gelatin, which possess different phase transition temperatures from solid to liquid, facilitated the destabilization of the capsules for cell release. Cell encapsulation and controlled release was demonstrated using human fibroblasts as model cells, as well as a therapeutically relevant cell line—human umbilical vein endothelial cells (HUVECs). While such temperature responsive cell microcapsules promise effective, controlled release of potential therapeutic cells at physiological temperatures, further work will be needed to augment the composition of the microcapsules and optimize the numbers of cells per capsule prior to clinical evaluation. PMID:26096147

  6. Poly(ortho ester amides): Acid-labile Temperature-responsive Copolymers for Potential Biomedical Applications

    PubMed Central

    Tang, Rupei; Palumbo, R. Noelle; Ji, Weihang; Wang, Chun

    2009-01-01

    A new, convenient pathway is developed to synthesize highly hydrolytically labile poly(ortho ester amide) (POEA) copolymers that overcomes some of the major weaknesses of the traditional methods of synthesizing poly(ortho esters) and their derivatives. A diamine monomer containing a built-in, stabilized ortho ester group was synthesized and was used for polycondensation with diacid esters, giving rise to a series of POEA copolymers with unique stimuli-responsive properties. The POEA undergoes temperature-responsive, reversible sol-gel phase transition in water. Phase diagrams of the POEA/H2O mixture reveal the concentration-dependent existence of different phases, including hydrogel and opaque or clear solution. Such behavior may be attributed to the temperature-dependent hydrogen-bonding involving the amide groups in the POEA backbone and hydrophobic interactions between POEA chains, and it is tunable by selecting diacid monomers with different chemical structures. The kinetics of POEA mass loss in physiological aqueous buffers and release of a model macromolecular drug, fluorescently labeled dextran, are nearly zero-order, suggesting predominantly surface-restricted polymer erosion. The rates of polymer erosion and drug release are much faster at pH 5.0 than pH 7.4. No cytotoxicity was found for the polymer extracts and the polymer degradation products at concentrations as high as 1 mg/ml. The normal morphology of fibroblasts cultured directly in contact with POEA films was not altered. These novel acid-labile temperature-responsive POEA copolymers may be potentially useful for a wide range of biomedical applications such as minimal invasive delivery of controlled-release drug formulations that respond to biological temperature and acidic-pH environments in cells and tissues. PMID:19281150

  7. Paclitaxel induces acute pain via directly activating toll like receptor 4.

    PubMed

    Yan, Xisheng; Maixner, Dylan W; Yadav, Ruchi; Gao, Mei; Li, Pei; Bartlett, Michael G; Weng, Han-Rong

    2015-12-01

    Paclitaxel, a powerful anti-neoplastic drug, often causes pathological pain, which significantly reduces the quality of life in patients. Paclitaxel-induced pain includes pain that occurs immediately after paclitaxel treatment (paclitaxel-associated acute pain syndrome, P-APS) and pain that persists for weeks to years after cessation of paclitaxel treatment (paclitaxel induced chronic neuropathic pain). Mechanisms underlying P-APS remain unknown. In this study, we found that paclitaxel causes acute pain in rodents in a dose-dependent manner. The paclitaxel-induced acute pain occurs within 2 hrs after a single intravenous injection of paclitaxel. This is accompanied by low levels of paclitaxel penetrating into the cerebral spinal fluid and spinal dorsal horn. We demonstrated that an intrathecal injection of paclitaxel induces mechanical allodynia in a dose-dependent manner. Paclitaxel causes activation of toll like receptor 4 (TLR4) in the spinal dorsal horn and dorsal root ganglions. Through activating TLR4, paclitaxel increases glutamatergic synaptic activities and reduces glial glutamate transporter activities in the dorsal horn. Activations of TLR4 are necessary in the genesis of paclitaxel-induced acute pain. The cellular and molecular signaling pathways revealed in this study could provide rationales for the development of analgesics and management strategies for P-APS in patients. PMID:25775962

  8. Temperature responses to infusion of electrolytes during exercise

    NASA Technical Reports Server (NTRS)

    Greenleaf, J. E.; Kozlowski, S.; Kaciuba-Uscilko, H.; Nazar, K.; Brzezinska, Z.

    1975-01-01

    To gain more insight into the ion-osmotic influence on temperature regulation, the rectal temperature responses of mongrel dogs were measured during one hour of treadmill-running at 1.2 m/sec up a 12 deg slope. Results indicate that as in man, the rise in body temperature during exercise appears to be a regulated process. There is a direct relationship between the rise and equilibrium levels of rectal temperature and the plasma sodium and osmotic concentrations. It remains to be determined if the hypernatremic-osmolality inhibits peripheral blood flow, the panting, salivation response, or both. Some background on previous experiments on resting and exercising dogs and men is recounted.

  9. Aerosol gels

    NASA Technical Reports Server (NTRS)

    Sorensen, Christopher M. (Inventor); Chakrabarti, Amitabha (Inventor); Dhaubhadel, Rajan (Inventor); Gerving, Corey (Inventor)

    2010-01-01

    An improved process for the production of ultralow density, high specific surface area gel products is provided which comprises providing, in an enclosed chamber, a mixture made up of small particles of material suspended in gas; the particles are then caused to aggregate in the chamber to form ramified fractal aggregate gels. The particles should have a radius (a) of up to about 50 nm and the aerosol should have a volume fraction (f.sub.v) of at least 10.sup.-4. In preferred practice, the mixture is created by a spark-induced explosion of a precursor material (e.g., a hydrocarbon) and oxygen within the chamber. New compositions of matter are disclosed having densities below 3.0 mg/cc.

  10. Humidity and temperature response of photopolymer-based holographic gratings

    NASA Astrophysics Data System (ADS)

    Mikulchyk, Tatsiana; Walshe, James; Cody, Dervil; Martin, Suzanne; Naydenova, Izabela

    2015-05-01

    Holographic sensors have significant potential in various applications ranging from in vitro diagnostics to optical security. They are capable of providing fast, real-time, reversible or irreversible, visual colorimetric or optical readouts. The main challenge in the development of holographic sensors is to improve their selectivity by functionalizing the holographic recording material and achieve a response to a specific analyte. This material should be permeable to the analyte and its properties should change under exposure to the analyte. This work explores the humidity and temperature response of volume phase gratings recorded in photopolymers containing acrylamide and diacetone acrylamide as monomers, and triethanolamine and N-phenylglycine as photoinitiators. Characterization of the humidity response of photopolymer-based gratings in the relative humidity (RH) range of 20-90 % was carried out by measuring the diffraction efficiency of slanted transmission gratings and the position of the maximum intensity in the spectral response of reflection gratings. A strong humidity dependence of the diffraction efficiency of diacetone acrylamide-based transmission gratings was observed at RH=20-90%. The humidity dependence of the spectral response of the reflection gratings showed that photopolymers containing triethanolamine are more hydrophilic than photopolymers containing N-phenylglycine. The temperature response of slanted transmission gratings was investigated in the temperature (T) range of 20-60 °C. Exposure of the photopolymer layers containing triethanolamine to elevated temperature showed that the observed Bragg angle shift was caused by layer shrinkage due to water evaporation. The application of a sealing technique allowed for the observation of the photopolymer layer swelling due to the layer's thermal expansion. The results demonstrate an effective approach to obtaining photopolymer-based gratings with tuneable temperature and humidity sensitivity.

  11. Temperature-responsive compounds as in situ gelling biomedical materials.

    PubMed

    Moon, Hyo Jung; Ko, Du Young; Park, Min Hee; Joo, Min Kyung; Jeong, Byeongmoon

    2012-07-21

    Aqueous solutions that undergo sol-to-gel transition as the temperature increases have been extensively studied during the last decade. The material can be designed by controlling the hydrophilic and hydrophobic balance of the material. Basically, the molecular weight of the hydrophilic block and hydrophobic block of a compound should be fine-tuned from the synthetic point of view. In addition, stereochemistry, microsequence, topology, and nanostructures of the compound also affect the transition temperature, gel window, phase diagram, and modulus of the gel. From a practical point of view, biodegradability, biocompatibility, and interactions between the material and drug or cell should be considered in designing a thermogelling material. The interactions are particularly important in that they control drug release profile and initial burst release of the drug in the drug delivery system, and affect cell proliferation, differentiation, and biomarker expression in three-dimensional cell culture and tissue engineering application. This review provides an in-depth summary of the recent progress of thermogelling systems including polymers, low molecular compounds, and nanoemulsions. Their biomedical applications were also comparatively discussed. In addition, perspectives on future material design of a new thermogelling material and its application are suggested. PMID:22688789

  12. Paclitaxel Nano-Delivery Systems: A Comprehensive Review

    PubMed Central

    Ma, Ping; Mumper, Russell J.

    2013-01-01

    Paclitaxel is one of the most effective chemotherapeutic drugs ever developed and is active against a broad range of cancers, such as lung, ovarian, and breast cancers. Due to its low water solubility, paclitaxel is formulated in a mixture of Cremophor EL and dehydrated ethanol (50:50, v/v) a combination known as Taxol. However, Taxol has some severe side effects related to Cremophor EL and ethanol. Therefore, there is an urgent need for the development of alternative Taxol formulations. The encapsulation of paclitaxel in biodegradable and non-toxic nano-delivery systems can protect the drug from degradation during circulation and in-turn protect the body from toxic side effects of the drug thereby lowering its toxicity, increasing its circulation half-life, exhibiting improved pharmacokinetic profiles, and demonstrating better patient compliance. Also, nanoparticle-based delivery systems can take advantage of the enhanced permeability and retention (EPR) effect for passive tumor targeting, therefore, they are promising carriers to improve the therapeutic index and decrease the side effects of paclitaxel. To date, paclitaxel albumin-bound nanoparticles (Abraxane®) have been approved by the FDA for the treatment of metastatic breast cancer and non-small cell lung cancer (NSCLC). In addition, there are a number of novel paclitaxel nanoparticle formulations in clinical trials. In this comprehensive review, several types of developed paclitaxel nano-delivery systems will be covered and discussed, such as polymeric nanoparticles, lipid-based formulations, polymer conjugates, inorganic nanoparticles, carbon nanotubes, nanocrystals, and cyclodextrin nanoparticles. PMID:24163786

  13. Paclitaxel-Loaded Polymersomes for Enhanced Intraperitoneal Chemotherapy.

    PubMed

    Simón-Gracia, Lorena; Hunt, Hedi; Scodeller, Pablo D; Gaitzsch, Jens; Braun, Gary B; Willmore, Anne-Mari A; Ruoslahti, Erkki; Battaglia, Giuseppe; Teesalu, Tambet

    2016-04-01

    Peritoneal carcinomatosis is present in more than 60% of gastric cancer, 40% of ovarian cancer, and 35% of colon cancer patients. It is the second most common cause of cancer-related mortality, with a median survival of 1 to 3 months. Cytoreductive surgery combined with intraperitoneal chemotherapy is the current clinical treatment, but achieving curative drug accumulation and penetration in peritoneal carcinomatosis lesions remains an unresolved challenge. Here, we used flexible and pH-sensitive polymersomes for payload delivery to peritoneal gastric (MKN-45P) and colon (CT26) carcinoma in mice. Polymersomes were loaded with paclitaxel and in vitro drug release was studied as a function of pH and time. Paclitaxel-loaded polymersomes remained stable in aqueous solution at neutral pH for up to 4 months. In cell viability assay on cultured cancer cell lines (MKN-45P, SKOV3, CT26), paclitaxel-loaded polymersomes were more toxic than free drug or albumin-bound paclitaxel (Abraxane). Intraperitoneally administered fluorescent polymersomes accumulated in malignant lesions, and immunofluorescence revealed an intense signal inside tumors with no detectable signal in control organs. A dual targeting of tumors was observed: direct (circulation-independent) penetration, and systemic, blood vessel-associated accumulation. Finally, we evaluated preclinical antitumor efficacy of paclitaxel-polymersomes in the treatment of MKN-45P disseminated gastric carcinoma using a total dose of 7 mg/kg. Experimental therapy with paclitaxel-polymersomes improved the therapeutic index of drug over free paclitaxel and Abraxane, as evaluated by intraperitoneal tumor burden and number of metastatic nodules. Our findings underline the potential utility of the polymersome platform for delivery of drugs and imaging agents to peritoneal carcinomatosis lesions. Mol Cancer Ther; 15(4); 670-9. ©2016 AACR.

  14. Paclitaxel-loaded Polymersomes for Enhanced Intraperitoneal Chemotherapy

    PubMed Central

    Simón-Gracia, Lorena; Hunt, Hedi; Scodeller, Pablo D; Gaitzsch, Jens; Braun, Gary B; Willmore, Anne-Mari A; Ruoslahti, Erkki; Battaglia, Giuseppe; Teesalu, Tambet

    2016-01-01

    Peritoneal carcinomatosis is present in more than 60% of gastric cancer, 40% of ovarian cancer, and 35% of colon cancer patients. It is the second most common cause of cancer mortality, with a median survival of 1–3 months. Cytoreductive surgery combined with intraperitoneal chemotherapy is the current clinical treatment, but achieving curative drug accumulation and penetration in peritoneal carcinomatosis lesions remains an unresolved challenge. Here we employed flexible and pH-sensitive polymersomes for payload delivery to peritoneal gastric (MKN-45P) and colon (CT26) carcinoma in mice. Polymersomes were loaded with Paclitaxel® and in vitro drug release was studied as a function of pH and time. Paclitaxel-loaded polymersomes remained stable in aqueous solution at neutral pH for up to four months. In cell viability assay on cultured cancer cell lines (MKN-45P, SKOV3, CT26), Paclitaxel-loaded polymersomes were more toxic than free drug or albumin-bound Paclitaxel (Abraxane®). Intraperitoneally administered fluorescent polymersomes accumulated in malignant lesions, and immunofluorescence revealed intense signal inside tumors with no detectable signal in control organs. A dual targeting of tumors was observed: direct (circulation independent) penetration, and systemic, blood vessel-associated accumulation. Finally, we evaluated preclinical antitumor efficacy of polymersomes-paclitaxel in treatment of MKN-45P disseminated gastric carcinoma using a total dose of 7 mg/kg. Experimental therapy with polymersome-Paclitaxel improved the therapeutic index of drug over Paclitaxel-Cremophor and Abraxane®, as evaluated by intraperitoneal tumor burden and number of metastatic nodules. Our findings underline the potential utility of the polymersome platform for delivery of drugs and imaging agents to peritoneal carcinomatosis lesions. PMID:26880267

  15. Pharmaceutical and physical properties of paclitaxel (Taxol) complexes with cyclodextrins.

    PubMed

    Sharma, U S; Balasubramanian, S V; Straubinger, R M

    1995-10-01

    Paclitaxel (as Taxol) is under clinical investigation for treatment of a variety of cancers. Because of its low aqueous solubility, paclitaxel is administered in polyethoxylated castor oil (Cremophor EL) and ethanol, a vehicle associated with severe hypersensitivity reactions. Cyclodextrins (CyDs) are molecular complexing agents that can increase the solubility and stability of some poorly soluble drugs and were investigated here as a means to obviate the requirement for Cremophor. A variety of beta- and gamma-cyclodextrins were tested; (hydroxypropyl)-(HP beta CyD), (hydroxyethyl)-(HE beta CyD), and dimethyl-(DM beta CyD) beta CyD increased paclitaxel solubility 2 x 10(3)-fold or more and did not alter the cytostatic properties of paclitaxel in vitro. The quantity of drug solubilized increased with the CyD concentration, but precipitation upon dilution occurred with some CyDs or stoichiometries. Thermal and spectroscopic (fluorescence, IR, NMR, and circular dichroism) analyses provided evidence of complex formation that was stable in the solid state but weak in solution, suggesting an explanation for the observed precipitation upon dilution. DM beta CyD solutions of < or = 3.7 mol % (mole of drug:mole of CyD) showed no precipitation upon dilution, nor did HP beta CyD solutions of < or = 0.14 mol %. Maximum tolerated dose (MTD) experiments showed uncomplexed DM beta CyD to be toxic in mice at doses of 2 g CyD/kg body weight, the quantity required to administer paclitaxel at 10 mg/kg. HP beta CyD allowed paclitaxel administration at higher doses and had an MTD of 25 mg drug/kg. The CyDs tested are marginal in feasibility for paclitaxel administration, and their use in taxane formulation will require a reduction of the dose-limiting toxicity of the CyD itself.

  16. Rubisco Catalytic Properties and Temperature Response in Crops.

    PubMed

    Hermida-Carrera, Carmen; Kapralov, Maxim V; Galmés, Jeroni

    2016-08-01

    Rubisco catalytic traits and their thermal dependence are two major factors limiting the CO2 assimilation potential of plants. In this study, we present the profile of Rubisco kinetics for 20 crop species at three different temperatures. The results largely confirmed the existence of significant variation in the Rubisco kinetics among species. Although some of the species tended to present Rubisco with higher thermal sensitivity (e.g. Oryza sativa) than others (e.g. Lactuca sativa), interspecific differences depended on the kinetic parameter. Comparing the temperature response of the different kinetic parameters, the Rubisco Km for CO2 presented higher energy of activation than the maximum carboxylation rate and the CO2 compensation point in the absence of mitochondrial respiration. The analysis of the Rubisco large subunit sequence revealed the existence of some sites under adaptive evolution in branches with specific kinetic traits. Because Rubisco kinetics and their temperature dependency were species specific, they largely affected the assimilation potential of Rubisco from the different crops, especially under those conditions (i.e. low CO2 availability at the site of carboxylation and high temperature) inducing Rubisco-limited photosynthesis. As an example, at 25°C, Rubisco from Hordeum vulgare and Glycine max presented, respectively, the highest and lowest potential for CO2 assimilation at both high and low chloroplastic CO2 concentrations. In our opinion, this information is relevant to improve photosynthesis models and should be considered in future attempts to design more efficient Rubiscos. PMID:27329223

  17. Global temperature responses to current emissions from the transport sectors

    PubMed Central

    Berntsen, Terje; Fuglestvedt, Jan

    2008-01-01

    Transport affects climate directly and indirectly through mechanisms that cause both warming and cooling of climate, and the effects operate on very different timescales. We calculate climate responses in terms of global mean temperature and find large differences between the transport sectors with respect to the size and mix of short- and long-lived effects, and even the sign of the temperature response. For year 2000 emissions, road transport has the largest effect on global mean temperature. After 20 and 100 years the response in net temperature is 7 and 6 times higher, respectively, than for aviation. Aviation and shipping have strong but quite uncertain short-lived warming and cooling effects, respectively, that dominate during the first decades after the emissions. For shipping the net cooling during the first 4 decades is due to emissions of SO2 and NOx. On a longer timescale, the current emissions from shipping cause net warming due to the persistence of the CO2 perturbation. If emissions stay constant at 2000 levels, the warming effect from road transport will continue to increase and will be almost 4 times larger than that of aviation by the end of the century. PMID:19047640

  18. Targeted delivery of albumin bound paclitaxel in the treatment of advanced breast cancer

    PubMed Central

    Di Costanzo, Francesco; Gasperoni, Silvia; Rotella, Virginia; Di Costanzo, Federica

    2009-01-01

    Taxanes are chemotherapeutic agents with a large spectrum of antitumor activity when used as monotherapy or in combination regimens. Paclitaxel and docetaxel have poor solubility and require a complex solvent system for their commercial formulation, Cremophor EL® (CrEL) and Tween 80® respectively. Both these biological surfactants have recently been implicated as contributing not only to the hypersensitivity reactions, but also to the degree of peripheral neurotoxicity and myelosuppression, and may antagonize the cytotoxicity. Nab-paclitaxel, or nanoparticle albumin-bound paclitaxel (ABI-007; Abraxane®), is a novel formulation of paclitaxel that does not employ the CrEL solvent system. Nab-paclitaxel demonstrates greater efficacy and a favorable safety profile compared with standard paclitaxel in patients with advanced disease (breast cancer, non-small cell lung cancer, melanoma, ovarian cancer). Clinical studies in breast cancer have shown that nab-paclitaxel is significantly more effective than standard paclitaxel in terms of overall objective response rate (ORR) and time to progression. Nab-paclitaxel in combination with gemcitabine, capecitabine or bevacizumab has been shown to be very active in patients with advanced breast cancer. An economic analysis showed that nab-paclitaxel would be an economically reasonable alternative to docetaxel or standard paclitaxel in metastatic breast cancer. Favorable tumor ORR and manageable toxicities have been reported for nab-paclitaxel as monotherapy or in combination treatment in advanced breast cancer. PMID:20616905

  19. Albumin-bound paclitaxel in solid tumors: clinical development and future directions.

    PubMed

    Kundranda, Madappa N; Niu, Jiaxin

    2015-01-01

    Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free formulation of paclitaxel that was initially developed more than a decade ago to overcome toxicities associated with the solvents used in the formulation of standard paclitaxel and to potentially improve efficacy. Nab-paclitaxel has demonstrated an advantage over solvent-based paclitaxel by being able to deliver a higher dose of paclitaxel to tumors and decrease the incidence of serious toxicities, including severe allergic reactions. To date, nab-paclitaxel has been indicated for the treatment of three solid tumors in the USA. It was first approved for the treatment of metastatic breast cancer in 2005, followed by locally advanced or metastatic non-small-cell lung cancer in 2012, and most recently for metastatic pancreatic cancer in 2013. Nab-paclitaxel is also under investigation for the treatment of a number of other solid tumors. This review highlights key clinical efficacy and safety outcomes of nab-paclitaxel in the solid tumors for which it is currently indicated, discusses ongoing trials that may provide new data for the expansion of nab-paclitaxel's indications into other solid tumors, and provides a clinical perspective on the use of nab-paclitaxel in practice.

  20. Swelling and diffusion of PNIPA-based gels for localized chemotherapy and hyperthermia.

    PubMed

    Oni, Y; Soboyejo, W O

    2012-01-01

    This paper presents the results of an experimental study of the swelling and diffusion of poly(N-iso-propyl-acrylamide) PNIPA-based gels with the potential for applications in bio-micro-electro-mechanical systems (BioMEMS) for localized cancer treatment that involves both chemotherapy and hyperthermia. The swelling due to the uptake of water, rhodamine dye and the cancer drug, paclitaxel, are studied using weight gain experiments that are conducted over a range of temperatures in which hyperthermia can occur during drug delivery. The release of rhodamine dye and paclitaxel is also elucidated by considering their diffusion through the gels. The underlying mechanisms of diffusion and swelling are discussed over a temperature range in which synergistic cancer treatment can be effected by the combined use of hyperthermia and chemotherapy. PMID:23177767

  1. Paclitaxel Enhances Carboplatin-DNA Adduct Formation and Cytotoxicity

    DOE PAGES

    Jiang, Shuai; Pan, Amy W.; Lin, Tzu-yin; Zhang, Hongyong; Malfatti, Michael; Turteltaub, Kenneth; Henderson, Paul T.; Pan, Chong-xian

    2015-11-06

    This rapid report focuses on the pharmacodynamic mechanism of the carboplatin/paclitaxel combination and correlates it with its cytotoxicity. Consistent with the synergistic to additive antitumor activity (the combination index ranging from 0.53 to 0.94), cells exposed to this combination had significantly increased carboplatin-DNA adduct formation when compared to that of carboplatin alone (450 ± 30 versus 320 ± 120 adducts per 108 nucleotides at 2 h, p = 0.004). Removal of paclitaxel increased the repair of carboplatin-DNA adducts: 39.4 versus 33.1 adducts per 108 nucleotides per hour in carboplatin alone (p = 0.021). In conclusion, this rapid report provides themore » first pharmacodynamics data to support the use of carboplatin/paclitaxel combination in the clinic.« less

  2. Paclitaxel Enhances Carboplatin-DNA Adduct Formation and Cytotoxicity

    SciTech Connect

    Jiang, Shuai; Pan, Amy W.; Lin, Tzu-yin; Zhang, Hongyong; Malfatti, Michael; Turteltaub, Kenneth; Henderson, Paul T.; Pan, Chong-xian

    2015-11-06

    This rapid report focuses on the pharmacodynamic mechanism of the carboplatin/paclitaxel combination and correlates it with its cytotoxicity. Consistent with the synergistic to additive antitumor activity (the combination index ranging from 0.53 to 0.94), cells exposed to this combination had significantly increased carboplatin-DNA adduct formation when compared to that of carboplatin alone (450 ± 30 versus 320 ± 120 adducts per 108 nucleotides at 2 h, p = 0.004). Removal of paclitaxel increased the repair of carboplatin-DNA adducts: 39.4 versus 33.1 adducts per 108 nucleotides per hour in carboplatin alone (p = 0.021). In conclusion, this rapid report provides the first pharmacodynamics data to support the use of carboplatin/paclitaxel combination in the clinic.

  3. Paclitaxel targets VEGF-mediated angiogenesis in ovarian cancer treatment.

    PubMed

    Ai, Bin; Bie, Zhixin; Zhang, Shuai; Li, Ailing

    2016-01-01

    Ovarian cancer is one of the gynecologic cancers with the highest mortality, wherein vascular endothelial growth factor (VEGF) is involved in regulating tumor vascularization, growth, migration, and invasion. VEGF-mediated angiogenesis in tumors has been targeted in various cancer treatments, and anti-VEGF therapy has been used clinically for treatment of several types of cancer. Paclitaxel is a natural antitumor agent in the standard front-line treatment that has significant efficiency to treat advanced cancers, including ovarian cancer. Although platinum/paclitaxel-based chemotherapy has good response rates, most patients eventually relapse because the disease develops drug resistance. We aim to review the recent advances in paclitaxel treatment of ovarian cancer via antiangiogenesis. Single-agent therapy may be used in selected cases of ovarian cancer. However, to prevent drug resistance, drug combinations should be identified for optimal effectiveness and existing therapies should be improved. PMID:27648354

  4. Paclitaxel targets VEGF-mediated angiogenesis in ovarian cancer treatment

    PubMed Central

    Ai, Bin; Bie, Zhixin; Zhang, Shuai; Li, Ailing

    2016-01-01

    Ovarian cancer is one of the gynecologic cancers with the highest mortality, wherein vascular endothelial growth factor (VEGF) is involved in regulating tumor vascularization, growth, migration, and invasion. VEGF-mediated angiogenesis in tumors has been targeted in various cancer treatments, and anti-VEGF therapy has been used clinically for treatment of several types of cancer. Paclitaxel is a natural antitumor agent in the standard front-line treatment that has significant efficiency to treat advanced cancers, including ovarian cancer. Although platinum/paclitaxel-based chemotherapy has good response rates, most patients eventually relapse because the disease develops drug resistance. We aim to review the recent advances in paclitaxel treatment of ovarian cancer via antiangiogenesis. Single-agent therapy may be used in selected cases of ovarian cancer. However, to prevent drug resistance, drug combinations should be identified for optimal effectiveness and existing therapies should be improved. PMID:27648354

  5. Paclitaxel targets VEGF-mediated angiogenesis in ovarian cancer treatment

    PubMed Central

    Ai, Bin; Bie, Zhixin; Zhang, Shuai; Li, Ailing

    2016-01-01

    Ovarian cancer is one of the gynecologic cancers with the highest mortality, wherein vascular endothelial growth factor (VEGF) is involved in regulating tumor vascularization, growth, migration, and invasion. VEGF-mediated angiogenesis in tumors has been targeted in various cancer treatments, and anti-VEGF therapy has been used clinically for treatment of several types of cancer. Paclitaxel is a natural antitumor agent in the standard front-line treatment that has significant efficiency to treat advanced cancers, including ovarian cancer. Although platinum/paclitaxel-based chemotherapy has good response rates, most patients eventually relapse because the disease develops drug resistance. We aim to review the recent advances in paclitaxel treatment of ovarian cancer via antiangiogenesis. Single-agent therapy may be used in selected cases of ovarian cancer. However, to prevent drug resistance, drug combinations should be identified for optimal effectiveness and existing therapies should be improved.

  6. Paclitaxel Enhances Carboplatin-DNA Adduct Formation and Cytotoxicity.

    PubMed

    Jiang, Shuai; Pan, Amy W; Lin, Tzu-yin; Zhang, Hongyong; Malfatti, Michael; Turteltaub, Kenneth; Henderson, Paul T; Pan, Chong-xian

    2015-12-21

    This rapid report focuses on the pharmacodynamic mechanism of the carboplatin/paclitaxel combination and correlates it with its cytotoxicity. Consistent with the synergistic to additive antitumor activity (the combination index ranging from 0.53 to 0.94), cells exposed to this combination had significantly increased carboplatin-DNA adduct formation when compared to that of carboplatin alone (450 ± 30 versus 320 ± 120 adducts per 10(8) nucleotides at 2 h, p = 0.004). Removal of paclitaxel increased the repair of carboplatin-DNA adducts: 39.4 versus 33.1 adducts per 10(8) nucleotides per hour in carboplatin alone (p = 0.021). This rapid report provides the first pharmacodynamics data to support the use of carboplatin/paclitaxel combination in the clinic.

  7. Covalent linkage of nanodiamond-paclitaxel for drug delivery and cancer therapy

    NASA Astrophysics Data System (ADS)

    Liu, Kuang-Kai; Zheng, Wen-Wei; Wang, Chi-Ching; Chiu, Yu-Chung; Cheng, Chia-Liang; Lo, Yu-Shiu; Chen, Chinpiao; Chao, Jui-I.

    2010-08-01

    A nanoparticle-conjugated cancer drug provides a novel strategy for cancer therapy. In this study, we manipulated nanodiamond (ND), a carbon nanomaterial, to covalently link paclitaxel for cancer drug delivery and therapy. Paclitaxel was bound to the surface of 3-5 nm sized ND through a succession of chemical modifications. The ND-paclitaxel conjugation was measured by atomic force microscope and nuclear magnetic resonance spectroscopy, and confirmed with infrared spectroscopy by the detection of deuterated paclitaxel. Treatment with 0.1-50 µg ml - 1 ND-paclitaxel for 48 h significantly reduced the cell viability in the A549 human lung carcinoma cells. ND-paclitaxel induced both mitotic arrest and apoptosis in A549 cells. However, ND alone or denatured ND-paclitaxel (after treatment with strong alkaline solution, 1 M NaOH) did not induce the damage effects on A549 cells. ND-paclitaxel was taken into lung cancer cells in a concentration-dependent manner using flow cytometer analysis. The ND-paclitaxel particles were located in the microtubules and cytoplasm of A549 cells observed by confocal microscopy. Furthermore, ND-paclitaxel markedly blocked the tumor growth and formation of lung cancer cells in xenograft SCID mice. Together, we provide a functional covalent conjugation of ND-paclitaxel, which can be delivered into lung carcinoma cells and preserves the anticancer activities on the induction of mitotic blockage, apoptosis and anti-tumorigenesis.

  8. Albumin-bound paclitaxel in solid tumors: clinical development and future directions

    PubMed Central

    Kundranda, Madappa N; Niu, Jiaxin

    2015-01-01

    Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free formulation of paclitaxel that was initially developed more than a decade ago to overcome toxicities associated with the solvents used in the formulation of standard paclitaxel and to potentially improve efficacy. Nab-paclitaxel has demonstrated an advantage over solvent-based paclitaxel by being able to deliver a higher dose of paclitaxel to tumors and decrease the incidence of serious toxicities, including severe allergic reactions. To date, nab-paclitaxel has been indicated for the treatment of three solid tumors in the USA. It was first approved for the treatment of metastatic breast cancer in 2005, followed by locally advanced or metastatic non-small-cell lung cancer in 2012, and most recently for metastatic pancreatic cancer in 2013. Nab-paclitaxel is also under investigation for the treatment of a number of other solid tumors. This review highlights key clinical efficacy and safety outcomes of nab-paclitaxel in the solid tumors for which it is currently indicated, discusses ongoing trials that may provide new data for the expansion of nab-paclitaxel’s indications into other solid tumors, and provides a clinical perspective on the use of nab-paclitaxel in practice. PMID:26244011

  9. Tree canopy temperature response under experimental warming and drought

    NASA Astrophysics Data System (ADS)

    Blair, S. N.; Garrity, S. R.; Cai, M.; McDowell, N. G.

    2012-12-01

    Tree mortality associated with rising temperatures and drought has been observed in numerous locations across the globe. Simulated global climate change experiments, such as increased air temperature and reduced precipitation, can help us understand tree response to altered climate regimes and identify key physiological mechanisms involved in tree stress response. We collected canopy-level leaf temperature measurements from several piñon (Pinus edulis) and one-seed juniper (juniperus monosperma) subjected to experimental warming, drought, combined warming and drought treatments, and control conditions in a field-based experiment in northern New Mexico beginning June 2012. We examined leaf temperature responses to the treatments by using continuous measurements from infrared thermocouples located above the tree canopy. We found that leaf temperatures were approximately 5 degrees warmer in heated chambers compared to leaf temperatures of trees outside chambers. Comparisons within each treatment demonstrated that, on average, piñon had higher absolute differences between leaf temperature and air temperature values compared to juniper trees. Stomatal conductance, measured with a leaf porometer showed that within each treatment, juniper had higher stomatal conductance relative to piñon, and that heated trees had lower stomatal conductance relative to non-heated trees. These differences may be attributable to the fact that piñon trees are isohydric, meaning that they have a lower tolerance to water stress. To date, we have not observed a significant drought effect on leaf temperature, however, this is likely due to the short duration of the drought treatment to date. We expect that as the experiment progresses, a drought effect will emerge. One of the key questions that we hope to answer as data continues to be collected is how tree physiology responds to drought, heat, and the interaction between both variables. Although this case study is being conducted in

  10. Spatial Patterns of Radiative Forcing and Surface Temperature Response

    NASA Astrophysics Data System (ADS)

    Shindell, D. T.

    2014-12-01

    Examination of radiative forcing (RF), a key measure of changes in the energy balance of the Earth, facilitates understanding of the role of various drivers of climate change. For short-lived compounds, the RF can be highly inhomogeneous geographically. The relationship between the spatial patterns of RF and climate response is poorly characterized, however. Here we examine the relationship between RF and surface temperature response in the latest generation of climate models. We find that the geographic distribution of historical changes in aerosol and ozone RF strongly influences the response, leading to substantial regional differences with respect to the response to quasi-uniform well-mixed greenhouse gases (WMGHG). In particular, the response in the Northern Hemisphere (NH) extratropics and tropics follows the forcing in those regions fairly closely. There is a stronger global sensitivity to historical aerosol plus ozone RF than to WMGHG RF with equivalent global mean value, as noted previously [D T Shindell, 2014] and a stronger response in much of the NH extratropics, especially in and downwind of industrialized areas. The enhanced response is shown to be particularly large over land plus polar ocean areas, where transient response occurs more rapidly and strong snow and ice albedo feedbacks operate. This response is not attributable to greater forcing over those regions, but rather appears to reflect a broad sensitivity of NH extratropical land areas to NH extratropical forcing. The models show substantial diversity in the enhancement of land+polar ocean response to aerosols plus ozone relative to WMGHG, and for ocean response some models show reduced sensitivity to aerosols plus ozone (though the multi-model mean shows an enhancement), suggesting that different representations of land and ocean adjustment timescales and regional heat transport contribute greatly to the differences in response to inhomogeneous forcing. In addition, areas with greatest

  11. [Glucuronyl paclitaxel (Taxol) derivatives as tumor activated prodrugs].

    PubMed

    Bouvier, E; Schmidt, Fr; Monneret, Cl

    2005-01-01

    Three glucuronyl prodrugs of paclitaxel have been synthesized in order to be activated by the B-glucuronidase present within the necrotic areas of tumors. As three compartments containing prodrugs, they include a specifier, a self immolative spacer and the drug. In vitro testing clearly indicates that the two former prodrugs are stable and are more or less detoxified. As expected, in the presence of E. coli B-glucuronidase, the glycosidic linkage is hydrolyzed with a rate depending on the nature of the spacer but, once this hydrolysis has occurred, the self immolative spacer is soon eliminated leading to the liberation of the paclitaxel. PMID:15803101

  12. Free paclitaxel loaded PEGylated-paclitaxel nanoparticles: preparation and comparison with other paclitaxel systems in vitro and in vivo.

    PubMed

    Lu, Jingkai; Chuan, Xingxing; Zhang, Hua; Dai, Wenbing; Wang, Xinglin; Wang, Xueqing; Zhang, Qiang

    2014-08-25

    Previously, PEGylated paclitaxel (PEG-PTX) was found not favorable as a polymer prodrug because of its poor antitumor efficiency. But surprisingly, it was found in our study that PEG-PTX could form a novel nanoparticle system with free PTX. To address how this system works, we compared PTX loaded PEG-PTX nanoparticles (PEG-PTX/PTX) with PTX loaded PEG-PLA micelles (PEG-PLA/PTX) or PTX injection available (Taxol(®)) in vitro and in vivo. Firstly, it was found that PEG-PTX/PTX was more stable in aqueous solution than PEG-PLA/PTX in terms of PTX crystal formation and drug release. Then it was demonstrated that coumarin loaded PEG-PTX nanoparticles had a much higher uptake in MCF-7 cells compared to coumarin loaded PEG-PLA micelles. The in vivo imaging study revealed that DIR or DID (near infrared fluorescent substances) loaded PEG-PTX nanoparticles distributed more in tumors in MCF-7 tumor bearing mice than DIR or DID loaded PEG-PLA micelles and solvent system of Taxol(®). In the efficacy study with MCF-7 tumor bearing mice, PEG-PTX/PTX showed significantly higher antitumor activity than PEG-PLA/PTX at the same PTX dosage. At the dose of 10mg free PTX per kg, PEG-PTX/PTX displayed similar efficacy as Taxol(®) but less toxicity evaluated by the loss of body weight. With the increase of free PTX to 15 mg/kg, PEG-PTX/PTX showed significantly better efficacy than Taxol(®). In conclusion, with favorable characteristics in stability, cellular uptake, cytotoxicity, biodistribution, safety and efficacy, PEG-PTX/PTX seems highly potential as a nanocarrier for PTX delivery.

  13. Establishment of a paclitaxel resistant human breast cancer cell strain (MCF-7/Taxol) and intracellular paclitaxel binding protein analysis.

    PubMed

    Zuo, K-Q; Zhang, X-P; Zou, J; Li, D; Lv, Z-W

    2010-01-01

    Multidrug resistance of tumours is one of the most important factors that leads to chemotherapy failure. A multidrug-resistant breast cancer cell line, MCF-7/Taxol, was established from the drug-sensitive parent cell line MCF-7. The biological properties of MCF-7/Taxol, including its drug resistance profile and profile of paclitaxel binding proteins, were analysed and compared with the parent cell line. A number of paclitaxel binding proteins were present in MCF-7 cells but absent from MCF-7/Taxol cells, namely heat shock protein 90, actinin and dermcidin precursor. The identification of differential paclitaxel binding proteins between the multidrug-resistant MCF-7/Taxol cell line and the parent drug-sensitive cell line MCF-7 provides insight into possible mechanisms involved in resistance to these chemotherapy drugs.

  14. A comparative study of thermo-sensitive hydrogels with water-insoluble paclitaxel in molecule, nanocrystal and microcrystal dispersions

    NASA Astrophysics Data System (ADS)

    Lin, Zhiqiang; Mei, Dong; Chen, Meiwan; Wang, Yitao; Chen, Xianhui; Wang, Zhaoyang; He, Bing; Zhang, Hua; Wang, Xueqing; Dai, Wenbing; Yin, Yuxin; Zhang, Qiang

    2015-09-01

    In situ thermo-sensitive hydrogels have attracted increasing attention for alternative cancer therapies due to their long-term and effective drug levels at local sites. Besides synthesizing new thermo-sensitive polymers, we can also fabricate this delivery system by combining a hydrogel with a thermo-response and drug in a different dispersion state, such as drug nanocrystals. However, the impact of the drug dispersion state or dimension on the quality of such a local injectable system is still unknown. So, here we developed and compared three types of F127 hydrogel systems with either paclitaxel or the near infra-red probe DiR in molecules (MOs), nanocrystals (NCs) and microcrystals (MCs), respectively. With 120 nm rod-shape nanocrystals, the NCs-Gel achieved a high drug loading, moderate drug release rate and gel erosion in vitro and in vivo, medium intratumoral drug residue but the best anti-tumor efficacy in 4T1 tumor bearing BALB/c mice. With the free drug solubilized in 20 nm micelles of the gel, the MOs-Gel system demonstrated the least drug loading and the fastest drug release and gel erosion, leading to the least intratumoral residue as well as the lowest anti-tumor effect. Finally, when dispersed in micron-grade rod-shape drug crystals, the MCs-Gel exhibited a high drug loading but poor stability, precipitating in vitro and in vivo, the highest intratumoral residue but the least drug release, resulting in moderate tumor inhibition. In conclusion, this study clarifies the effect of the drug dispersion state and scale on the behavior of a thermo-sensitive hydrogel, indicating the advantage of the NCs-Gel system, and it provides a basis for the future design of the local delivery of hydrophobic anti-cancer agents.

  15. Greenland temperature response to climate forcing during the last deglaciation

    NASA Astrophysics Data System (ADS)

    Buizert, C.; Gkinis, V.; Severinghaus, J. P.; He, F.; Lecavalier, B.; Kindler, P.; Leuenberger, M.; Carlson, A. E.; Vinther, B.; White, J. W.; Liu, Z.; Otto-Bliesner, B. L.; Brook, E.

    2013-12-01

    Much of the regional and global climate variability during the last glacial termination (19-11 ka BP) can be explained as the superposition of two distinct modes (1, 2); a spatially uniform increase in global temperature correlated with greenhouse gas forcing, and a redistribution of heat associated with variability in the Atlantic meridional overturning circulation (AMOC) strength. The latter mode is expressed most clearly in the abrupt climate shifts recorded in the precipitation isotopic composition (δ18O) of Greenland ice cores, which are now widely used as a template for abrupt change in the northern hemisphere. Greenland δ18O is influenced by many factors, including source temperature, moisture transport and origin, and precipitation seasonality, complicating reconstruction of past temperatures. Here we use three non-δ18O temperature reconstructions from three ice cores and a general circulation model (GCM) to elucidate the (often abrupt) Greenland surface temperature response to external (insolation) and internal (CO2, AMOC, ice topography) climate forcings during the last termination. Our reconstructions are based on δ15N (NEEM, GISP2) and water isotope diffusion (NGRIP), both of which depend on physical processes in the firn column. The GCM and our reconstructions show excellent agreement on several key features. First, we find that the Younger Dryas (YD) period was 4-6oC warmer than the Oldest Dryas (OD) period in response to increased summer insolation and CO2 forcing. By contrast, δ18O-based reconstrucions from Greenland summit suggest the YD to be the colder of the two periods. Our finding is consistent with non-ice core NH proxy reconstructions, as well as with East Greenland deglacial moraine sequences that suggest only a modest glacial re-advance during the YD. Second, the YD-OD temperature difference shows a polar amplification signal, with warming being greatest at the northernmost NEEM site. By isolating different forcings in the GCM, we

  16. [Nab-Paclitaxel plus Gemcitabine for Metastatic Pancreatic Cancer].

    PubMed

    Katsura, Yoshiteru; Takeda, Yutaka; Ohmura, Yoshiaki; Motoyama, Yurina; Ishida, Tomo; Morimoto, Yoshihiro; Matsushita, Katsunori; Naito, Atsushi; Murakami, Kohei; Kagawa, Yoshinori; Okishiro, Masatsugu; Takeno, Atsushi; Egawa, Chiyomi; Kato, Takeshi; Tamura, Shigeyuki

    2015-11-01

    Pancreatic ductal carcinoma is a highly aggressive cancer, with one of the highest mortality rates among gastrointestinal cancers. Nab-paclitaxel plus gemcitabine (GEM) significantly improved overall survival, progression-free survival, and response rate in a phase Ⅲ trial in 151 community and academic centers in 11 countries. As a result, nab-paclitaxel plus GEM was approved for use in December 2014 in Japan. We report a case of a patient with pancreatic cancer who underwent this chemotherapy. A 47-year-old man was admitted to our hospital for evaluation of pancreatic lesions. Computed tomography revealed a hypoattenuating tumor in the body of the pancreas. After the patient underwent preoperative chemoradiotherapy under the diagnosis of cStage Ⅳa cancer, we planned to perform distal pancreatectomy. However, this case was inoperable because we found 3 liver metastases during surgery. On postoperative day 14, we treated the patient with nab-paclitaxel plus GEM. Grade 2 toxicities included neutropenia, diarrhea, and peripheral neuropathy, but serious adverse events did not occur. The progression-free survival was 5 months. He remained alive for 7 months after the chemotherapy. In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus GEM can be considered as the standard treatment. PMID:26805366

  17. Alpha fetoprotein antagonizes apoptosis induced by paclitaxel in hepatoma cells in vitro.

    PubMed

    Zhu, Mingyue; Li, Wei; Lu, Yan; Dong, Xu; Chen, Yi; Lin, Bo; Xie, Xieju; Guo, Junli; Li, Mengsen

    2016-01-01

    Hepatocellular carcinoma (HCC) cell resistance to the effects of paclitaxel has not been adequately addressed. In this study, we found that paclitaxel significantly inhibited the viability of HLE, Bel 7402 and L-02 cells in a dose- and time-dependent manner. HLE cells and L-02 cells resisted the cytotoxicity of paclitaxel when transfected with pcDNA3.1-afp vectors. However, Bel 7402 cell sensitivity to paclitaxel was increased when transfected with alpha fetoprotein (AFP)-siRNA. Bel 7402 cell resistance to paclitaxel was associated with the expression of the "stemness" markers CD44 and CD133. Paclitaxel significantly inhibited growth and promoted apoptosis in HLE cells and L-02 cells by inducing fragmentation of caspase-3 and inhibiting the expression of Ras and Survivin, but pcDNA3.1-afp vectors prevented these effects. However, paclitaxel could not significantly promote the cleavage of caspase-3 or suppress the expression of Ras and Survivin in Bel 7402 cells. Silenced expression of AFP may be synergistic with paclitaxel to restrain proliferation and induce apoptosis, enhance cleavage of caspase-3, and suppress the expression of Ras and Survivin. Taken together, AFP may be an important molecule acting against paclitaxel-inhibited proliferation and induced apoptosis in HCC cells via repressing the activity of caspase-3 and stimulating the expression of Ras and Survivin. Targeted inhibition of AFP expression after treatment with paclitaxel is an available strategy for the therapy of patients with HCC. PMID:27255186

  18. Alpha fetoprotein antagonizes apoptosis induced by paclitaxel in hepatoma cells in vitro

    PubMed Central

    Zhu, Mingyue; Li, Wei; Lu, Yan; Dong, Xu; Chen, Yi; Lin, Bo; Xie, Xieju; Guo, Junli; Li, Mengsen

    2016-01-01

    Hepatocellular carcinoma (HCC) cell resistance to the effects of paclitaxel has not been adequately addressed. In this study, we found that paclitaxel significantly inhibited the viability of HLE, Bel 7402 and L-02 cells in a dose- and time-dependent manner. HLE cells and L-02 cells resisted the cytotoxicity of paclitaxel when transfected with pcDNA3.1-afp vectors. However, Bel 7402 cell sensitivity to paclitaxel was increased when transfected with alpha fetoprotein (AFP)-siRNA. Bel 7402 cell resistance to paclitaxel was associated with the expression of the “stemness” markers CD44 and CD133. Paclitaxel significantly inhibited growth and promoted apoptosis in HLE cells and L-02 cells by inducing fragmentation of caspase-3 and inhibiting the expression of Ras and Survivin, but pcDNA3.1-afp vectors prevented these effects. However, paclitaxel could not significantly promote the cleavage of caspase-3 or suppress the expression of Ras and Survivin in Bel 7402 cells. Silenced expression of AFP may be synergistic with paclitaxel to restrain proliferation and induce apoptosis, enhance cleavage of caspase-3, and suppress the expression of Ras and Survivin. Taken together, AFP may be an important molecule acting against paclitaxel-inhibited proliferation and induced apoptosis in HCC cells via repressing the activity of caspase-3 and stimulating the expression of Ras and Survivin. Targeted inhibition of AFP expression after treatment with paclitaxel is an available strategy for the therapy of patients with HCC. PMID:27255186

  19. Targeted chemotherapy with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in metastatic breast cancer: which benefit for which patients?

    PubMed Central

    Palumbo, Raffaella; Sottotetti, Federico; Bernardo, Antonio

    2016-01-01

    The therapeutic goals in metastatic breast cancer (MBC) remain palliative in nature, aimed at controlling symptoms, improving or maintaining quality of life and prolonging survival. The advent of new drugs and new formulations of standard agents has led to better outcomes in patients with advanced or metastatic disease. These developments have also allowed a tailored therapeutic approach, in which the molecular biology of the tumour, the treatment history, and patient attitudes are taken into account in the decision-making process. Targeting drug delivery to the tumour is a promising mean of increasing the therapeutic index of highly active agents such as the taxanes, and nanoparticle albumin-bound paclitaxel (nab-paclitaxel), the first nanotechnology-based drug developed in cancer treatment, is one such advance. Data from randomized trials support the efficacy of single-agent nab-paclitaxel as first-line and further treatment lines in MBC at the registered 3-weekly schedule of 260 mg/m2, but emerging evidence suggests its activity as a weekly regimen or combined with other agents in various clinical scenarios. Thus, nab-paclitaxel seems to offer flexibility in terms of dosing schedules, allowing physicians to tailor the dose according to different clinical situations. This paper reviews the clinical trial background for nab-paclitaxel in MBC, focusing on specific ‘difficult-to-treat’ patient populations, such as taxane-pretreated or elderly women, as well as those with triple-negative, HER2-positive and poor-prognostic-factors disease. Moving beyond evidence-based information, ‘real life’ available experiences are also discussed with the aim of providing an update for daily clinical practice. PMID:27239239

  20. Subcutaneous administration of paclitaxel in dogs with cancer: A preliminary study.

    PubMed

    Silva, Daniella M; Franciosi, Aline I; Pezzini, Paula C F; Guérios, Simone D

    2015-08-01

    Intravenous paclitaxel has been underused in dogs due to severe and acute hypersensitivity reactions. Subcutaneous (SC) administration of paclitaxel and its safety are unknown. In this preliminary study, SC administration of paclitaxel was evaluated for hypersensitivity reactions and toxicity in 21 dogs with advanced cancer. Dogs received 1 to 5 paclitaxel doses, ranging from 85 to 170 mg/m(2), SC every 14 or 21 days. A total of 40 paclitaxel doses were administered and none of the 21 dogs developed systemic or acute local hypersensitivity reactions. Severe skin lesions at the injection site developed in 2 dogs after the 4th injection at the same location. Grade 4 neutropenia was observed in 50% of the dogs 5 days after the first treatment at 115 mg/m(2) (n = 14). Two animals developed Grade 5 diarrhea and died likely due to hemodynamic failure or sepsis. Paclitaxel can be administered SC in dogs with no hypersensitivity reaction.

  1. Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery

    PubMed Central

    Wang, Yonglu; Li, Xueming; Wang, Liyao; Xu, Yuanlong; Cheng, Xiaodan; Wei, Ping

    2011-01-01

    Paclitaxel is a diterpenoid isolated from Taxus brevifolia. It is effective for various cancers, especially ovarian and breast cancer. Due to its aqueous insolubility, it is administered dissolved in ethanol and Cremophor® EL (BASF, Ludwigshafen, Germany), which can cause serious allergic reactions. In order to eliminate Cremophor EL, paclitaxel was formulated as a nanosuspension by high-pressure homogenization. The nanosuspension was lyophilized to obtain the dry paclitaxel nanoparticles (average size, 214.4 ± 15.03 nm), which enhanced both the physical and chemical stability of paclitaxel nanoparticles. Paclitaxel dissolution was also enhanced by the nanosuspension. Differential scanning calorimetry showed that the crystallinity of paclitaxel was preserved during the high-pressure homogenization process. The pharmacokinetics and tissue distribution of paclitaxel were compared after intravenous administration of paclitaxel nanosuspension and paclitaxel injection. In rat plasma, paclitaxel nanosuspension exhibited a significantly (P < 0.01) reduced area under the concentration curve (AUC)0–∞ (20.343 ± 9.119 μg · h · mL−1 vs 5.196 ± 1.426 μg · h · mL−1), greater clearance (2.050 ± 0.616 L · kg−1 · h−1 vs 0.556 ± 0.190 L · kg−1 · h−1), and shorter elimination half-life (5.646 ± 2.941 vs 3.774 ± 1.352 hours) compared with the paclitaxel solution. In contrast, the paclitaxel nanosuspension resulted in a significantly greater AUC0–∞ in liver, lung, and spleen (all P < 0.01), but not in heart or kidney. PMID:21796250

  2. Treatment of recurrent Kaposi's sarcoma of an AIDS patient with weekly paclitaxel.

    PubMed

    Hsu, C H; Chen, M Y; Cheng, A L

    2000-01-01

    Paclitaxel was recently recognized as an active chemotherapeutic agent for acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). However, the best way to administer paclitaxel in AIDS-KS patients remains unknown. Herein, we reported an AIDS-associated KS patient whose disease progressed on the first-line chemotherapy with doxorubicin and bleomycin, but later responded well to weekly 1-hour infusion of 70 mg/m2 paclitaxel. It is particular noteworthy that this weekly dosing schedule resulted in almost negligible toxicities. The authors suggested a prospective study of weekly paclitaxel for AIDS-KS should be started as soon as possible.

  3. Label-free detection of anticancer drug paclitaxel in living cells by confocal Raman microscopy

    NASA Astrophysics Data System (ADS)

    Salehi, H.; Derely, L.; Vegh, A.-G.; Durand, J.-C.; Gergely, C.; Larroque, C.; Fauroux, M.-A.; Cuisinier, F. J. G.

    2013-03-01

    Confocal Raman microscopy, a non-invasive, label-free, and high spatial resolution imaging technique is employed to trace the anticancer drug paclitaxel in living Michigan Cancer Foundation-7 (MCF-7) cells. The Raman images were treated by K-mean cluster analysis to detect the drug in cells. Distribution of paclitaxel in cells is verified by calculating the correlation coefficient between the reference spectrum of the drug and the whole Raman image spectra. A time dependent gradual diffusion of paclitaxel all over the cell is observed suggesting a complementary picture of the pharmaceutical action of this drug based on rapid binding of free tubulin to crystallized paclitaxel.

  4. Paclitaxel stimulates chromosomal fusion and instability in cells with dysfunctional telomeres: Implication in multinucleation and chemosensitization

    SciTech Connect

    Park, Jeong-Eun; Woo, Seon Rang; Kang, Chang-Mo; Juhn, Kyoung-Mi; Ju, Yeun-Jin; Shin, Hyun-Jin; Joo, Hyun-Yoo; Park, Eun Ran; Park, In-chul; Hong, Sung Hee; Hwang, Sang-Gu; Lee, Jung-Kee; Kim, Hae Kwon; Cho, Myung-Haing; Park, Gil Hong; Lee, Kee-Ho

    2011-01-14

    Research highlights: {yields} Paclitaxel serves as a stimulator of chromosomal fusion in cells in which telomeres are dysfunctional. {yields} Typical fusions involve p-arms, but paclitaxel-induced fusions occur between both q- and p-arms. {yields} Paclitaxel-stimulated fusions in cells in which telomeres are dysfunctional evoke prolonged G2/M cell cycle arrest and delay multinucleation. {yields} Upon telomere erosion, paclitaxel promotes chromosomal instability and subsequent apoptosis. {yields} Chromosomal fusion enhances paclitaxel chemosensitivity under telomere dysfunction. -- Abstract: The anticancer effect of paclitaxel is attributable principally to irreversible promotion of microtubule stabilization and is hampered upon development of chemoresistance by tumor cells. Telomere shortening, and eventual telomere erosion, evoke chromosomal instability, resulting in particular cellular responses. Using telomerase-deficient cells derived from mTREC-/-p53-/- mice, here we show that, upon telomere erosion, paclitaxel propagates chromosomal instability by stimulating chromosomal end-to-end fusions and delaying the development of multinucleation. The end-to-end fusions involve both the p- and q-arms in cells in which telomeres are dysfunctional. Paclitaxel-induced chromosomal fusions were accompanied by prolonged G2/M cell cycle arrest, delayed multinucleation, and apoptosis. Telomere dysfunctional cells with mutlinucleation eventually underwent apoptosis. Thus, as telomere erosion proceeds, paclitaxel stimulates chromosomal fusion and instability, and both apoptosis and chemosensitization eventually develop.

  5. Severe hyponatremia caused by nab-paclitaxel-induced syndrome of inappropriate antidiuretic hormone secretion

    PubMed Central

    Neuzillet, Cindy; Babai, Samy; Kempf, Emmanuelle; Pujol, Géraldine; Rousseau, Benoît; Le-Louët, Hervé; Christophe Tournigand

    2016-01-01

    Abstract Incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing. Most patients have advanced disease at diagnosis and therapeutic options in this setting are limited. Gemcitabine plus nab-paclitaxel regimen was demonstrated to increase survival compared with gemcitabine monotherapy and is therefore indicated as first-line therapy in patients with metastatic PDAC and performance status Eastern Cooperative Oncology Group (ECOG) 0-2. The safety profile of gemcitabine and nab-paclitaxel combination includes neutropenia, fatigue, and neuropathy as most common adverse events of grade 3 or higher. No case of severe hyponatremia associated with the use of nab-paclitaxel for the treatment of PDAC has been reported to date. We report the case of a 72-year-old Caucasian man with a metastatic PDAC treated with gemcitabine and nab-paclitaxel regimen, who presented with a severe hyponatremia (grade 4) caused by a documented syndrome of inappropriate antidiuretic hormone secretion (SIADH). This SIADH was attributed to nab-paclitaxel after a rigorous imputability analysis, including a rechallenge procedure with dose reduction. After dose and schedule adjustment, nab-paclitaxel was pursued without recurrence of severe hyponatremia and with maintained efficacy. Hyponatremia is a rare but potentially severe complication of nab-paclitaxel therapy that medical oncologists and gastroenterologists should be aware of. Nab-paclitaxel-induced hyponatremia is manageable upon dose and schedule adaptation, and should not contraindicate careful nab-paclitaxel reintroduction. This is of particular interest for a disease in which the therapeutic options are limited. PMID:27368013

  6. ISOLATION AND IDENTIFICATION OF AN ENDOPHYTIC FUNGUS PRODUCING PACLITAXEL FROM TAXUS WALLICHIANA VAR MAIREI.

    PubMed

    Zaiyou, Jian; Hongsheng, Wang; Ning, Wang; Li, Meng; Guifang, Xu

    2015-12-01

    The objective of this study was to isolate endophytic fungi producing paclitaxel from yew for the purpose of paclitaxel manufacture. Surface sterilized bark of Taxus wallichiana var. mairei was used as source material and potato dextrose agar culture medium was used in isolation of endophytic fungi. Fungal cultures were extracted with a mixture of chloroform / methanol (1:1, v/v) and the paclitaxel in the extracts was determined and authenticated with LC-MS. An endophytic fungus that produced paclitaxel was identified by ITS rDNA and 26S D1/D2 rDNA sequencing. The results showed that a total of 435 endophytic fungal strains were isolated from T. wallichiana var. mairei and purified. Only one of these strains produced paclitaxel and it belongs to Fusarium. The paclitaxel productivity in whole PDB culture and that in spent culture medium from this strain is 0.0153 mg/L and 0.0119 mg/L respectively. The paclitaxel content in dry mycelium is 0.27 mg/kg. This isolated endophytic fungus produced paclitaxel at a considerable level and shows potentiality as a producing strain for paclitaxel manufacture after strain improvement.

  7. Paclitaxel injection concentrate for nanodispersion versus nab-paclitaxel in women with metastatic breast cancer: a multicenter, randomized, comparative phase II/III study.

    PubMed

    Jain, Minish M; Gupte, Smita U; Patil, Shekhar G; Pathak, Anand B; Deshmukh, Chetan D; Bhatt, Niraj; Haritha, Chiramana; Govind Babu, K; Bondarde, Shailesh A; Digumarti, Raghunadharao; Bajpai, Jyoti; Kumar, Ravi; Bakshi, Ashish V; Bhattacharya, Gouri Sankar; Patil, Poonam; Subramanian, Sundaram; Vaid, Ashok K; Desai, Chirag J; Khopade, Ajay; Chimote, Geetanjali; Bapsy, Poonamalle P; Bhowmik, Shravanti

    2016-02-01

    Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab-paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m(2) [n = 64] and 295 mg/m(2) [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m(2) every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m(2

  8. Late acute thrombosis after paclitaxel eluting stent implantation

    PubMed Central

    Liistro, F; Colombo, A

    2001-01-01

    Late (more than six months) total occlusion after coronary stenting is a progressive phenomenon occurring in approximately 4% of patients, leading to acute myocardial infarction in less than 0.5%. The process must be related to severe and progressive intimal hyperplasia. In patients receiving coronary stenting with simultaneous brachytherapy, late total occlusion has been reported at a higher rate and to be related to stent thrombosis rather than intimal hyperplasia. Late total occlusion presenting with an acute clinical event seven months after the implantation of a paclitaxel drug eluting stent is reported. The occlusion developed soon after the interruption of ticlopidine treatment, suggesting that the event had a thrombotic genesis and that the risk is not confined to the first six month period.


Keywords: paclitaxel eluting stent; late thrombosis PMID:11514475

  9. Delineating intracellular pharmacokinetics of paclitaxel delivered by PLGA nanoparticles.

    PubMed

    Li, Mingguang; Czyszczon, Emilia Anna; Reineke, Joshua James

    2013-12-01

    Although many studies have shown that drug delivery and efficacy can be improved by nano-sized drug carriers, we understand little regarding their pharmacokinetics (PK). PK calculations for drugs delivered by carriers are more complex than those for drug-only solutions. The overall PK depends on many factors, including drug-release rate and the PK of both the drug itself and the carrier. We built a mathematical model to describe the intracellular PK of paclitaxel delivered by nanoparticles. Paclitaxel was incorporated into poly (lactic-co-glycolic acid) nanoparticles, which were chemically labeled with a fluorescence probe for quantification. PK profiles of drug alone, nanoparticles alone, and drug delivered by nanoparticles were studied in human breast cancer MCF7 cells. Simulated results from the model were similar to observed data, indicating that the model was properly developed. The model clearly and quantitatively represented the effects of relative factors, such as drug dose, drug-release kinetics, and nanoparticle PK, on the PK of paclitaxel delivered by nanoparticles. We also used this model to estimate the intracellular drug-release rate, which was found to be slightly slower than the in vitro release rate in this study. This mathematical model could be used to provide guidelines to design, evaluate, and optimize nano-sized drug carriers. PMID:25786375

  10. Quantitative Proteomic Analysis of Ovarian Cancer Cells Identified Mitochondrial Proteins Associated with Paclitaxel Resistance

    PubMed Central

    Tian, Yuan; Tan, Aik-Choon; Sun, Xiaer; Olson, Matthew T; Xie, Zhi; Jinawath, Natini; Chan, Daniel W.; Shih, Ie-Ming; Zhang, Zhen; Zhang, Hui

    2010-01-01

    Paclitaxel has been widely used as an anti-mitotic agent in chemotherapy for a variety of cancers and adds substantial efficacy as the first-line chemotherapeutic regimen for ovarian cancers. However, the frequent occurrence of paclitaxel resistance limits its function in long-term management. Despite abundant clinical and cellular demonstration of paclitaxel resistant tumors, the molecular mechanisms leading to paclitaxel resistance are poorly understood. Using genomic approaches, we have previously identified an association between a BTB/POZ gene, Nac1, and paclitaxel resistance in ovarian cancer. The experiments presented here have applied multiple quantitative proteomic methods to identify protein changes associated with paclitaxel resistance and Nac1 function. The SKOV-3 ovarian serous carcinoma cell line, which has inducible expression of dominant negative Nac1, was used to determine the paclitaxel treatment associated changes in the presence and absence of functional Nac1. Quantitative proteomic analyses were performed using iTRAQ labeling and mass spectrometry. Two label-free quantitative proteomic methods: LC-MS and spectral count were used to increase confidence of proteomic quantification. A total of 1371 proteins were quantified by at least one of the quantitative proteomic methods. Candidate proteins related to paclitaxel and NAC1 function were identified in this study. Go analysis of the protein changes identified upon paclitaxel resistance revealed that cell component enrichment related to mitochondria. Moreover, tubulin and mitochondrial proteins were the major cellular components with changes associated with paclitaxel treatment. This suggests that mitochondria may play a role in paclitaxel resistance. PMID:21113235

  11. Effects of Jia-Wei-Xiao-Yao-San on the Peripheral and Lymphatic Pharmacokinetics of Paclitaxel in Rats

    PubMed Central

    Hou, Mei-Ling; Lu, Chia-Ming

    2016-01-01

    Paclitaxel is effective against breast cancer. The herbal medicine, Jia-Wei-Xiao-Yao-San (JWXYS), is the most frequent prescription used to relieve the symptoms of breast cancer treatments. The aim of the study was to investigate the herb-drug interaction effects of a herbal medicine on the distribution of paclitaxel to lymph. A validated ultraperformance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method was used to determine the paclitaxel levels in rat plasma and lymph after intravenous infusion of paclitaxel alone with or without 7 days of JWXYS pretreatment. The pharmacokinetic results indicate that paclitaxel concentrations in plasma exceeded those in lymph by approximately 3.6-fold. The biodistribution of paclitaxel from plasma to lymph was 39 ± 5%; however, this increased to 45 ± 4% with JWXYS pretreatment. With JWXYS pretreatment, the AUC and Cmax of paclitaxel in plasma were significantly reduced by approximately 1.5-fold, compared to paclitaxel alone. Additionally, JWXYS decreased the AUC and Cmax of paclitaxel in lymph. However, the lymph absorption rate of paclitaxel with or without JWXYS pretreatment was not significantly changed (27 ± 3 and 30 ± 2%, resp.). Our findings demonstrate that when paclitaxel is prescribed concurrently with herbal medicine, monitoring of the blood pharmacokinetics of paclitaxel is recommended. PMID:27057200

  12. Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish.

    PubMed

    Lisse, Thomas S; Middleton, Leah J; Pellegrini, Adriana D; Martin, Paige B; Spaulding, Emily L; Lopes, Olivia; Brochu, Elizabeth A; Carter, Erin V; Waldron, Ashley; Rieger, Sandra

    2016-04-12

    Paclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in cancer treatment and in a number of curative and palliative regimens. Despite its beneficial effects on cancer, paclitaxel also damages healthy tissues, most prominently the peripheral sensory nervous system. The mechanisms leading to paclitaxel-induced peripheral neuropathy remain elusive, and therapies that prevent or alleviate this condition are not available. We established a zebrafish in vivo model to study the underlying mechanisms and to identify pharmacological agents that may be developed into therapeutics. Both adult and larval zebrafish displayed signs of paclitaxel neurotoxicity, including sensory axon degeneration and the loss of touch response in the distal caudal fin. Intriguingly, studies in zebrafish larvae showed that paclitaxel rapidly promotes epithelial damage and decreased mechanical stress resistance of the skin before induction of axon degeneration. Moreover, injured paclitaxel-treated zebrafish skin and scratch-wounded human keratinocytes (HEK001) display reduced healing capacity. Epithelial damage correlated with rapid accumulation of fluorescein-conjugated paclitaxel in epidermal basal keratinocytes, but not axons, and up-regulation of matrix-metalloproteinase 13 (MMP-13, collagenase 3) in the skin. Pharmacological inhibition of MMP-13, in contrast, largely rescued paclitaxel-induced epithelial damage and neurotoxicity, whereas MMP-13 overexpression in zebrafish embryos rendered the skin vulnerable to injury under mechanical stress conditions. Thus, our studies provide evidence that the epidermis plays a critical role in this condition, and we provide a previously unidentified candidate for therapeutic interventions. PMID:27035978

  13. MiR-1204 sensitizes nasopharyngeal carcinoma cells to paclitaxel both in vitro and in vivo.

    PubMed

    Peng, Xiaowei; Cao, Peiguo; Li, Jingjing; He, Dong; Han, Shuang; Zhou, Jianda; Tan, Guolin; Li, Wei; Yu, Fenghui; Yu, Jianjun; Li, Zan; Cao, Ke

    2015-01-01

    Nasopharyngeal carcinoma (NPC) is an endemic tumor with a relatively high incidence in Southern China and Southeast Asia. Paclitaxel combination chemotherapy has been used for treatment of advanced NPC. However, treatment failure often occurs due to development of acquired paclitaxel resistance. In this study, we first established a paclitaxel-resistant CNE-1/Taxol, HNE-2/Taxol and 5-8F/Taxol cell sublines by treating the parental CNE-1, HNE-2 and 5-8F cells with increasing doses of paclitaxel for about 5 months, respectively. Then, microRNA arrays were used to screen differentially expressed miRNAs between the CNE-1/Taxol cells and the parental CNE-1 cells. We found 13 differentially expressed miRNAs, of which miR-1204 was significantly downregulated in the paclitaxel-resistant CNE-1/Taxol cells. We restored miR-1204 expression in the CNE-1/Taxol, HNE-2/Taxol and 5-8F/Taxol cells and found that restoration of miR-1204 re-sensitized the paclitaxel-resistant CNE-1/Taxol, HNE-2/Taxol and 5-8F/Taxol cells to paclitaxel both in vitro. Finally, we demonstrated that restoration of miR-1204 in significantly inhibits tumor growth in vivo. Thus, our study provides important information for the development of targeted gene therapy for reversing paclitaxel resistance in NPC.

  14. TXNDC17 promotes paclitaxel resistance via inducing autophagy in ovarian cancer.

    PubMed

    Zhang, Song-Fa; Wang, Xin-Yu; Fu, Zhi-Qin; Peng, Qiao-Hua; Zhang, Jian-Yang; Ye, Feng; Fu, Yun-Feng; Zhou, Cai-Yun; Lu, Wei-Guo; Cheng, Xiao-Dong; Xie, Xing

    2015-01-01

    Paclitaxel is recommended as a first-line chemotherapeutic agent against ovarian cancer, but drug resistance becomes a major limitation of its success clinically. The key molecule or mechanism associated with paclitaxel resistance in ovarian cancer still remains unclear. Here, we showed that TXNDC17 screened from 356 differentially expressed proteins by LC-MS/MS label-free quantitative proteomics was more highly expressed in paclitaxel-resistant ovarian cancer cells and tissues, and the high expression of TXNDC17 was associated with poorer prognostic factors and exhibited shortened survival in 157 ovarian cancer patients. Moreover, paclitaxel exposure induced upregulation of TXNDC17 and BECN1 expression, increase of autophagosome formation, and autophagic flux that conferred cytoprotection for ovarian cancer cells from paclitaxel. TXNDC17 inhibition by siRNA or enforced overexpression by a pcDNA3.1(+)-TXNDC17 plasmid correspondingly decreased or increased the autophagy response and paclitaxel resistance. Additionally, the downregulation of BECN1 by siRNA attenuated the activation of autophagy and cytoprotection from paclitaxel induced by TXNDC17 overexpression in ovarian cancer cells. Thus, our findings suggest that TXNDC17, through participation of BECN1, induces autophagy and consequently results in paclitaxel resistance in ovarian cancer. TXNDC17 may be a potential predictor or target in ovarian cancer therapeutics.

  15. Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

    PubMed Central

    Lisse, Thomas S.; Middleton, Leah J.; Pellegrini, Adriana D.; Martin, Paige B.; Spaulding, Emily L.; Lopes, Olivia; Brochu, Elizabeth A.; Carter, Erin V.; Waldron, Ashley; Rieger, Sandra

    2016-01-01

    Paclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in cancer treatment and in a number of curative and palliative regimens. Despite its beneficial effects on cancer, paclitaxel also damages healthy tissues, most prominently the peripheral sensory nervous system. The mechanisms leading to paclitaxel-induced peripheral neuropathy remain elusive, and therapies that prevent or alleviate this condition are not available. We established a zebrafish in vivo model to study the underlying mechanisms and to identify pharmacological agents that may be developed into therapeutics. Both adult and larval zebrafish displayed signs of paclitaxel neurotoxicity, including sensory axon degeneration and the loss of touch response in the distal caudal fin. Intriguingly, studies in zebrafish larvae showed that paclitaxel rapidly promotes epithelial damage and decreased mechanical stress resistance of the skin before induction of axon degeneration. Moreover, injured paclitaxel-treated zebrafish skin and scratch-wounded human keratinocytes (HEK001) display reduced healing capacity. Epithelial damage correlated with rapid accumulation of fluorescein-conjugated paclitaxel in epidermal basal keratinocytes, but not axons, and up-regulation of matrix-metalloproteinase 13 (MMP-13, collagenase 3) in the skin. Pharmacological inhibition of MMP-13, in contrast, largely rescued paclitaxel-induced epithelial damage and neurotoxicity, whereas MMP-13 overexpression in zebrafish embryos rendered the skin vulnerable to injury under mechanical stress conditions. Thus, our studies provide evidence that the epidermis plays a critical role in this condition, and we provide a previously unidentified candidate for therapeutic interventions. PMID:27035978

  16. A Liposomal Formulation Able to Incorporate a High Content of Paclitaxel and Exert Promising Anticancer Effect

    PubMed Central

    Kan, Pei; Tsao, Chih-Wan; Wang, Ae-June; Su, Wu-Chou; Liang, Hsiang-Fa

    2011-01-01

    A liposome formulation for paclitaxel was developed in this study. The liposomes, composed of naturally unsaturated and hydrogenated phosphatidylcholines, with significant phase transition temperature difference, were prepared and characterized. The liposomes exhibited a high content of paclitaxel, which was incorporated within the segregated microdomains coexisting on phospholipid bilayer of liposomes. As much as 15% paclitaxel to phospholipid molar ratio were attained without precipitates observed during preparation. In addition, the liposomes remained stable in liquid form at 4°C for at least 6 months. The special composition of liposomal membrane which could reduce paclitaxel aggregation could account for such a capacity and stability. The cytotoxicity of prepared paclitaxel liposomes on the colon cancer C-26 cell culture was comparable to Taxol. Acute toxicity test revealed that LD50 for intravenous bolus injection in mice exceeded by 40 mg/kg. In antitumor efficacy study, the prepared liposomal paclitaxel demonstrated the increase in the efficacy against human cancer in animal model. Taken together, the novel formulated liposomes can incorporate high content of paclitaxel, remaining stable for long-term storage. These animal data also demonstrate that the liposomal paclitaxel is promising for further clinical use. PMID:21490755

  17. Proliferation, migration and invasion of human glioma cells exposed to paclitaxel (Taxol) in vitro.

    PubMed Central

    Terzis, A. J.; Thorsen, F.; Heese, O.; Visted, T.; Bjerkvig, R.; Dahl, O.; Arnold, H.; Gundersen, G.

    1997-01-01

    Paclitaxel (Taxol), an anti-cancer drug derived from Taxus species, was tested for its anti-migrational, anti-invasive and anti-proliferative effect on two human glioma cell lines (GaMg and D-54Mg) grown as multicellular tumour spheroids. In addition, the direct effect of paclitaxel on glioma cells was studied using flow cytometry and scanning confocal microscopy. Both cell lines showed a dose-dependent growth and migratory response to paclitaxel. The GaMg cells were found to be 5-10 times more sensitive to paclitaxel than D-54Mg cells. Paclitaxel also proved to be remarkably effective in preventing invasion in a co-culture system in which tumour spheroids were confronted with fetal rat brain cell aggregates. Control experiments with Cremophor EL (the solvent of paclitaxel for clinical use) in this study showed no effect on tumour cell migration, cell proliferation or cell invasion. Scanning confocal microscopy of both cell lines showed an extensive random organization of the microtubules in the cytoplasm. After paclitaxel exposure, the GaMg and the D-54Mg cells exhibited a fragmentation of the nuclear material, indicating a possible induction of apoptosis. In line with this, flow cytometric DNA histograms showed an accumulation of cells in the G2/M phase of the cell cycle after 24 h of paclitaxel exposure. After 48 h, a deterioration of the DNA histograms was observed indicating nuclear fragmentation. Images Figure 3 Figure 6 PMID:9192976

  18. Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug

    PubMed Central

    Brunetti, Jlenia; Pillozzi, Serena; Falciani, Chiara; Depau, Lorenzo; Tenori, Eleonora; Scali, Silvia; Lozzi, Luisa; Pini, Alessandro; Arcangeli, Annarosa; Menichetti, Stefano; Bracci, Luisa

    2015-01-01

    Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility in water complicates its formulation. In this paper we report the in vitro and in vivo activity of a new form of paclitaxel, modified for conjugation with a tumor-selective tetrabranched peptide carrier (NT4). NT4 selectively targets tumor cells by binding to membrane sulfated glycosaminoglycans (GAG) and to endocytic receptors, like LRP1 and LRP6, which are established tumor markers. Biological activity of NT4-paclitaxel was tested in vitro on MDA-MB 231 and SKOV-3 cell lines, representing breast and ovarian cancer, respectively, and in vivo in an orthotopic mouse model of human breast cancer. Using in vivo bioluminescence imaging, we found that conjugation of paclitaxel with the NT4 peptide led to increased therapeutic activity of the drug in vivo. NT4-paclitaxel induced tumor regression, whereas treatment with unconjugated paclitaxel only produced a reduction in tumor growth. Moreover, unlike paclitaxel, NT4-paclitaxel is very hydrophilic, which may improve its pharmacokinetic profile and allow the use of less toxic dilution buffers, further decreasing its general chemotherapic toxicity. PMID:26626158

  19. Bridging converts a noncytotoxic nor-paclitaxel derivative to a cytotoxic analogue by constraining it to the T-Taxol conformation.

    PubMed

    Tang, Shoubin; Yang, Chao; Brodie, Peggy; Bane, Susan; Ravindra, Rudravajhala; Sharma, Shubhada; Jiang, Yi; Snyder, James P; Kingston, David G I

    2006-08-31

    The synthesis of the bridged A-nor-paclitaxel 4 has been achieved from paclitaxel in a key test of the T-Taxol conformational hypothesis. Although the unbridged A-nor-paclitaxel 3 is essentially noncytotoxic, the bridged analogue 4 is strongly cytotoxic. This result provides strong evidence for the T-Taxol conformation as the bioactive tubulin-binding conformation of paclitaxel.

  20. Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel.

    PubMed

    Moes, Johannes; Koolen, Stijn; Huitema, Alwin; Schellens, Jan; Beijnen, Jos; Nuijen, Bastiaan

    2013-01-01

    For the clinical development of low-dose metronomic (LDM) chemotherapy of paclitaxel, oral administration is vital. However, the development of an oral formulation is difficult due to paclitaxel's low oral bioavailability, caused by its low permeability and low solubility. We increased the oral bioavailability of paclitaxel by combining a pharmacokinetic booster, ritonavir, with a new oral solid dispersion formulation of paclitaxel. The combined use of Hansen solubility parameters and dissolution experiments resulted in the development of a solid dispersion formulation containing 1/11 w/w paclitaxel, 9/11 w/w polyvinylpyrrolidone (PVP) K30, and 1/11 w/w sodium lauryl sulfate (SLS). Analysis of the solid dispersion formulation by X-ray diffraction, Fourier transform infrared (FT-IR) spectroscopy, and modulated differential scanning calorimetry (mDSC) confirmed the amorphous nature of paclitaxel and the fine dispersion of paclitaxel in the matrix of PVP-K30 and SLS. Furthermore, in vitro tests showed a major increase in the apparent solubility and dissolution rate of paclitaxel. To test the clinical significance of these findings, the solid dispersion formulation of paclitaxel (ModraPac001 10mg capsule) was compared to the paclitaxel premix solution in four patients with advanced cancer. Although the mean systemic exposure to paclitaxel after oral administration of the solid dispersion formulation was slightly lower compared to the paclitaxel premix solution (190±63.1ng/mLh for vs. 247±100ng/mLh), the systemic exposure to paclitaxel is clinically relevant [1,2]. In addition to this, the favorable pharmaceutical characteristics, for example, neutral taste, dosing accuracy, and the 2-year ambient shelf life, make the ModraPac001 10mg capsule an attractive candidate for oral paclitaxel chemotherapy. Currently, the ModraPac001 formulation is applied in the first clinical trial with oral LDM chemotherapy of paclitaxel.

  1. First line treatment of advanced non-small-cell lung cancer - specific focus on albumin bound paclitaxel.

    PubMed

    Gupta, Neha; Hatoum, Hassan; Dy, Grace K

    2014-01-01

    Lung cancer is the leading cause of cancer mortality worldwide in both men and women. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for more than 80% of cases. Paclitaxel has a broad spectrum of activity against various malignancies, including NSCLC. Paclitaxel is poorly soluble in water and thus, until recently, its commercially available preparations contained a non-ionic solvent Cremophor EL®. Cremophor EL® improves the solubility of paclitaxel and allows its intravenous administration. However, certain side-effects associated with paclitaxel, such as hypersensitivity reactions, myelosuppression, and peripheral neuropathy, are known to be worsened by Cremophor®. Nanoparticle albumin-bound paclitaxel ([nab-paclitaxel] ABRAXANE® ABI-007) is a new generation formulation of paclitaxel that obviates the need for Cremophor®, resulting in a safer and faster infusion without requiring the use of premedications to avoid hypersensitivity. Albumin-binding receptor-mediated delivery and lack of sequestering Cremophor® micelles allow higher intratumoral concentration of pharmacologically active paclitaxel. Multiple clinical trials have demonstrated a superior tolerability profile of nab-paclitaxel in comparison to solvent-bound paclitaxel (sb-paclitaxel). A recent Phase III trial compared the effects of weekly nab-paclitaxel in combination with carboplatin versus sb-paclitaxel in combination with carboplatin given every 3 weeks for first line treatment of NSCLC. This trial highlights the weekly nab-paclitaxel combination as an alternate treatment option for NSCLC, with higher response rate in squamous cell NSCLC and longer survival in elderly patients. This review will focus on the properties of nab-paclitaxel and its use in the first line treatment of NSCLC.

  2. In vitro and in vivo targeting effect of folate decorated paclitaxel loaded PLA-TPGS nanoparticles.

    PubMed

    Thu, Ha Phuong; Nam, Nguyen Hoai; Quang, Bui Thuc; Son, Ho Anh; Toan, Nguyen Linh; Quang, Duong Tuan

    2015-11-01

    Paclitaxel is one of the most effective chemotherapeutic agents for treating various types of cancer. However, the clinical application of paclitaxel in cancer treatment is considerably limited due to its poor water solubility and low therapeutic index. Thus, it requires an urgent solution to improve therapeutic efficacy of paclitaxel. In this study, folate decorated paclitaxel loaded PLA-TPGS nanoparticles were prepared by a modified emulsification/solvent evaporation method. The obtained nanoparticles were characterized by Field Emission Scanning Electron Microscopy (FESEM), Fourier Transform Infrared (FTIR) and Dynamic Light Scattering (DLS) method. The spherical nanoparticles were around 50 nm in size with a narrow size distribution. Targeting effect of nanoparticles was investigated in vitro on cancer cell line and in vivo on tumor bearing nude mouse. The results indicated the effective targeting of folate decorated paclitaxel loaded copolymer nanoparticles on cancer cells both in vitro and in vivo. PMID:26702264

  3. Water-soluble prodrugs of paclitaxel containing self-immolative disulfide linkers.

    PubMed

    Gund, Machhindra; Khanna, Amit; Dubash, Nauzer; Damre, Anagha; Singh, Kishore S; Satyam, Apparao

    2015-01-01

    A new series of disulfide-containing prodrugs of paclitaxel were designed, synthesized and evaluated against 6 cancer cell lines. Some of these prodrugs exhibited nearly equal or slightly better anticancer activity when compared to that of paclitaxel. These prodrugs contain water-soluble groups such as amino, carboxyl, hydroxyl, amino acids, etc., and exhibited 6-140 fold increase in aqueous solubility when compared to paclitaxel. One of these prodrugs exhibited improved water solubility, better in vitro anticancer activity and significantly superior oral bioavailability in mice when compared to those of paclitaxel. Thus, we have identified a very promising lead compound for further optimization and evaluation as a potentially bioavailable water-soluble prodrug of paclitaxel.

  4. Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers.

    PubMed

    Moisan, Francois; Francisco, Edgar B; Brozovic, Anamaria; Duran, George E; Wang, Yan C; Chaturvedi, Shalini; Seetharam, Shobha; Snyder, Linda A; Doshi, Parul; Sikic, Branimir I

    2014-10-01

    Ovarian cancer is associated with a leukocyte infiltrate and high levels of chemokines such as CCL2. We tested the hypothesis that CCL2 inhibition can enhance chemotherapy with carboplatin and paclitaxel. Elevated CCL2 expression was found in three non-MDR paclitaxel resistant ovarian cancer lines ES-2/TP, MES-OV/TP and OVCAR-3/TP, compared to parental cells. Mice xenografted with these cells were treated with the anti-human CCL2 antibody CNTO 888 and the anti-mouse MCP-1 antibody C1142, with and without paclitaxel or carboplatin. Our results show an additive effect of CCL2 blockade on the efficacy of paclitaxel and carboplatin. This therapeutic effect was largely due to inhibition of mouse stromal CCL2. We show that inhibition of CCL2 can enhance paclitaxel and carboplatin therapy of ovarian cancer.

  5. Antagonism of miRNA-21 Sensitizes Human Gastric Cancer Cells to Paclitaxel.

    PubMed

    Jin, Bo; Liu, Yanping; Wang, Haijiang

    2015-05-01

    The development of drug resistance has largely limited the clinical outcome of anti-cancer treatment. Recent work has highlighted the involvement of non-coding RNAs, microRNAs (miRNAs), in cancer development. The present study aimed to investigate the role of miR-21 in the development of drug resistance to paclitaxel in gastric cancer cells. Our study found that the expression of miR-21 upregulated in the paclitaxel resistant cell line SGC7901/paclitaxel compared to its parental line SGC7901. Moreover, over-expression of miR-21 significantly decreased antiproliferative effects and apoptosis induced by paclitaxel, while knockdown of miR-21 dramatically increased antiproliferative effects and apoptosis induction by paclitaxel. Moreover, our results demonstrated that miR-21 may modulate the sensitivity to PTX, at least in part, by regulating the expression of P-glycoprotein. PMID:27040946

  6. Nab-paclitaxel as alternative treatment regimen in advanced cholangiocellular carcinoma

    PubMed Central

    Unseld, Matthias; Scheithauer, Werner; Weigl, Roman; Kornek, Gabriela; Stranzl, Nadja; Bianconi, Daniela; Brunauer, Georg; Steger, Guenther; Zielinski, Christoph C.

    2016-01-01

    Background Advanced cholangiocellular carcinoma has a poor prognosis with limited therapeutic options. Nab-paclitaxel has recently been described to be beneficial in metastatic pancreatic cancer improving overall and progression free survival (PFS). The potential antitumor activity of nab-paclitaxel in cholangiocellular carcinoma is hitherto unknown. Methods We retrospectively analyzed an institutional cholangiocellular carcinoma registry to determine the potential biological activity of nab-paclitaxel in advanced intrahepatic cholangiocellular carcinoma. Disease control rate (DCR), PFS and overall survival (OS) upon nab-paclitaxel based treatment, after failure of platinum-containing first-line combination chemotherapy, was assessed. Results Twelve patients were identified. Five of 12 patients (42%) received nab-paclitaxel as second line, and 7 patients (56%) as third-line treatment. The objective DCR with nab-paclitaxel was 83% (10/12 patients). One patient had a complete remission (CR), two patients had a partial remission (PR) and 7 patients had stable disease (SD). Disease was rated progressive in two patients. In all 12 patients receiving nab-paclitaxel the median time to progression was 6 months (range, 2.1–19.5 months). Median OS after initiation of nab-paclitaxel treatment was 9 months (2.1–28.4 months). The median time of survival after diagnosis of advanced disease was 21.5 months, whereby 3 patients were alive at the date of censoring (04/01/2015). Conclusions This is the first report suggesting substantial antitumor activity of nab-paclitaxel in advanced cholangiocellular carcinoma. In this small series, nab-paclitaxel based salvage chemotherapy appears to have a biological activity by controlling the disease and positively affecting survival. Randomized trials in this disease entity and subgroup of patients are urged. PMID:27563449

  7. Microbial degradation of Paclitaxel using Citrobacter amalonaticus Rashtia isolated from pharmaceutical wastewater: kinetic and thermodynamic study.

    PubMed

    Zamani, Hojjatolah; Grakoee, Seyed Reza; Rakhshaee, Roohan

    2016-08-01

    Paclitaxel is a highly toxic anticancer agent which is used in a wide range against ovarian, breast, lung, and prostate cancers. Paclitaxel is manufactured recently in the north of Iran which may lead to the introduction of the drug into the environment via pharmaceutical wastewater. To our knowledge, Paclitaxel degradation is currently performed using physicochemical methods and biological degradation of Paclitaxel has not been reported. In this study, a Paclitaxel degrading bacterium was isolated from pharmaceutical wastewater for the first time. The bacterium was identified using biochemical and molecular assays and its Paclitaxel degradation potential was evaluated using High Performance Liquid Chromatography (HPLC). In addition, kinetic and thermodynamic study of Paclitaxel degradation at different experimental conditions was performed. A Citrobacter species named as C. amalonaticus Rashtia able to degrade and utilize Paclitaxel as the sole carbon source was isolated. The isolated strain tolerated high level concentration of Paclitaxel (0.4 mg/mL) in liquid culture media and was able to degrade spillage-level concentrations of the drug (0.01-0.1 mg/mL) with 87-93 % efficacy under aerobic condition. Kinetic and thermodynamic study at different pHs (4.0, 7.0 and 10.0) and temperatures (285, 295 and 310 K) revealed that Paclitaxel degradation is a non-spontaneous process and the highest rate constant was observed in the basic condition and at the highest temperature. The ΔG values at 285, 295 and 310 K were determined 103.3, 105.9 and 109.9 kJ/mol, respectively. In addition, The ΔH and activation energy (Ea) of the process were determined +28.7 kJ/mol and +30.87 kJ/mol, respectively. PMID:27339310

  8. Microbial degradation of Paclitaxel using Citrobacter amalonaticus Rashtia isolated from pharmaceutical wastewater: kinetic and thermodynamic study.

    PubMed

    Zamani, Hojjatolah; Grakoee, Seyed Reza; Rakhshaee, Roohan

    2016-08-01

    Paclitaxel is a highly toxic anticancer agent which is used in a wide range against ovarian, breast, lung, and prostate cancers. Paclitaxel is manufactured recently in the north of Iran which may lead to the introduction of the drug into the environment via pharmaceutical wastewater. To our knowledge, Paclitaxel degradation is currently performed using physicochemical methods and biological degradation of Paclitaxel has not been reported. In this study, a Paclitaxel degrading bacterium was isolated from pharmaceutical wastewater for the first time. The bacterium was identified using biochemical and molecular assays and its Paclitaxel degradation potential was evaluated using High Performance Liquid Chromatography (HPLC). In addition, kinetic and thermodynamic study of Paclitaxel degradation at different experimental conditions was performed. A Citrobacter species named as C. amalonaticus Rashtia able to degrade and utilize Paclitaxel as the sole carbon source was isolated. The isolated strain tolerated high level concentration of Paclitaxel (0.4 mg/mL) in liquid culture media and was able to degrade spillage-level concentrations of the drug (0.01-0.1 mg/mL) with 87-93 % efficacy under aerobic condition. Kinetic and thermodynamic study at different pHs (4.0, 7.0 and 10.0) and temperatures (285, 295 and 310 K) revealed that Paclitaxel degradation is a non-spontaneous process and the highest rate constant was observed in the basic condition and at the highest temperature. The ΔG values at 285, 295 and 310 K were determined 103.3, 105.9 and 109.9 kJ/mol, respectively. In addition, The ΔH and activation energy (Ea) of the process were determined +28.7 kJ/mol and +30.87 kJ/mol, respectively.

  9. Sol-Gel Glasses

    NASA Technical Reports Server (NTRS)

    Mukherjee, S. P.

    1985-01-01

    Multicomponent homogeneous, ultrapure noncrystalline gels/gel derived glasses are promising batch materials for the containerless glass melting experiments in microgravity. Hence, ultrapure, homogeneous gel precursors could be used to: (1) investigate the effect of the container induced nucleation on the glass forming ability of marginally glass forming compositions; and (2) investigate the influence of gravity on the phase separation and coarsening behavior of gel derived glasses in the liquid-liquid immiscibility zone of the nonsilicate systems having a high density phase. The structure and crystallization behavior of gels in the SiO2-GeO2 as a function of gel chemistry and thermal treatment were investigated. As are the chemical principles involved in the distribution of a second network former in silica gel matrix being investigated. The procedures for synthesizing noncrystalline gels/gel-monoliths in the SiO2-GeO2, GeO2-PbO systems were developed. Preliminary investigations on the levitation and thermal treatment of germania silicate gel-monoliths in the Pressure Facility Acoustic Levitator were done.

  10. Treatment of recurrent and platinum-refractory stage IV non-small cell lung cancer with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as a single agent.

    PubMed

    Saxena, Ashish; Schneider, Bryan J; Christos, Paul J; Audibert, Lauren F; Cagney, Jennifer M; Scheff, Ronald J

    2016-02-01

    The role of single-agent nab-paclitaxel in relapsed or platinum-refractory advanced non-small cell lung cancer (NSCLC) has not been well reported in Western populations. We reviewed our own institution's experience using nab-paclitaxel in these settings. We analyzed the records of stage IV NSCLC patients with relapsed or platinum-refractory disease treated with single-agent nab-paclitaxel at Weill Cornell Medical College between October 2008 and December 2013. The primary endpoint of the study was treatment failure-free survival (TFFS), defined as the time from the start of nab-paclitaxel therapy to discontinuation of the drug for any reason. The best overall response was recorded for each patient, and overall response and disease control rates were calculated. Thirty-one stage IV NSCLC patients received a median of 4 cycles (range 1-40) of nab-paclitaxel. Dose reduction or drug discontinuation due to toxicity occurred in 10 patients, mainly because of grade 2/3 fatigue or peripheral neuropathy. The overall response rate was 16.1 %, and the disease control rate was 64.5 %. Median TFFS was 3.5 months (95 % CI 1.3-5.3 months). No statistically significant difference in TFFS based on line of therapy or prior taxane exposure was identified. There was a statistically significant decrease in TFFS for patients with non-adenocarcinoma histology, although there were only five patients in this group. There was a trend toward reduction in the risk of treatment failure with increasing age. One patient remained on nab-paclitaxel therapy for over 3 years. Single-agent nab-paclitaxel was well tolerated and demonstrated efficacy in advanced NSCLC patients with relapsed or platinum-refractory disease. Further prospective clinical trials with nab-paclitaxel in these settings are warranted.

  11. Gemcitabine plus paclitaxel versus carboplatin plus either gemcitabine or paclitaxel in advanced non-small-cell lung cancer: a literature-based meta-analysis.

    PubMed

    Li, Chenguang; Sun, Yihua; Pan, Yunjian; Wang, Qifeng; Yang, Shu; Chen, Haiquan

    2010-10-01

    The combination of gemcitabine plus paclitaxel has been proposed as an alternative to the platinum-based combinations for treatment of advanced non-small-cell lung cancer (NSCLC). However, conflicting results have been reported. This meta-analysis was performed to compare the activity, efficacy, and toxicity of gemcitabine plus paclitaxel versus carboplatin plus either gemcitabine or paclitaxel in patients with untreated advanced NSCLC. Randomized phase II and phase III clinical trials comparing gemcitabine plus paclitaxel with carboplatin plus gemcitabine or paclitaxel were collected from electronic databases (Medline, EMBASE, and the Cochrane Central Register of Controlled Trials), relevant reference lists, and abstract books. The published languages and years were not limited. Pooled odds ratios (ORs) were calculated for the 1-year survival rate (1-year SR), the overall response rate (ORR), and grade 3 and grade 4 toxicities. Four randomized controlled trials (2186 patients) were identified from 2051 reports. They were all published as full-text articles. No significant heterogeneity was detected in these studies. A significant difference in ORR favoring gemcitabine plus paclitaxel over carboplatin-based doublets was observed [OR = 1.20; 95% confidence interval (95% CI) = 1.02-1.42; P = 0.03], whereas the trend toward an improved 1-year SR was not significant (OR = 1.07; 95% CI = 0.91-1.26; P = 0.41). An increased risk of grade 3-4 toxicities for patients receiving carboplatin-based chemotherapy was statistically demonstrated. The gemcitabine plus paclitaxel combination showed an improved ORR and a better toxicity profile but a similar 1-year SR compared to carboplatin-based doublets. For nonplatinum-based chemotherapy, gemcitabine plus paclitaxel is a useful alternative. PMID:20703493

  12. Injectable pH- and temperature-responsive poly(N-isopropylacrylamide-co-propylacrylic acid) copolymers for delivery of angiogenic growth factors

    PubMed Central

    Garbern, Jessica C.; Hoffman, Allan S.; Stayton, Patrick S.

    2010-01-01

    A new sharply pH- and temperature-responsive hydrogel system was designed for delivering drugs to regions of local acidosis, as found in wound healing, tumor sites, or sites of ischemia. The reversible addition fragmentation chain transfer (RAFT) polymerization technique was used to synthesize copolymers of N-isopropylacrylamide (NIPAAM) and propylacrylic acid (PAA) with feed ratios of PAA between 0 and 20 mol %. The pH-responsive viscoelastic properties of these materials as a function of pH and temperature were quantified by rheometry. At physiologic pH (7.4) and 5 wt %, the polymer did not form gels, but rather remained soluble at temperatures as high as 50 °C. At lower pH values (pH ca. 5.5 and below) the polymer was liquid at 20 °C but exhibited a sol-gel phase transformation with increasing temperature and existed as a physical gel at 37 °C. Incorporation of the hydrophobic monomer, butyl acrylate, into the random copolymer raised the pH of gel formation to greater than 6.0 at 37 °C. Drug loading studies demonstrated that p(NIPAAm-co-PAA) hydrogels are able to maintain the bioactivity of basic fibroblast growth factor following storage in hydrogel for 40 h and can provide sustained pH-dependent release of vascular endothelial growth factor over a period of at least three weeks. This hydrogel system will thus gel at controllable acidic pH values upon injection, and is designed to undergo gradual dissolution as it performs its drug delivery function and the ischemic site returns to physiological pH. PMID:20509687

  13. Orexinergic Neurotransmission in Temperature Responses to Methamphetamine and Stress: Mathematical Modeling as a Data Assimilation Approach

    PubMed Central

    Behrouzvaziri, Abolhassan; Fu, Daniel; Tan, Patrick; Yoo, Yeonjoo; Zaretskaia, Maria V.; Rusyniak, Daniel E.; Molkov, Yaroslav I.; Zaretsky, Dmitry V.

    2015-01-01

    Experimental Data Orexinergic neurotransmission is involved in mediating temperature responses to methamphetamine (Meth). In experiments in rats, SB-334867 (SB), an antagonist of orexin receptors (OX1R), at a dose of 10 mg/kg decreases late temperature responses (t>60 min) to an intermediate dose of Meth (5 mg/kg). A higher dose of SB (30 mg/kg) attenuates temperature responses to low dose (1 mg/kg) of Meth and to stress. In contrast, it significantly exaggerates early responses (t<60 min) to intermediate and high doses (5 and 10 mg/kg) of Meth. As pretreatment with SB also inhibits temperature response to the stress of injection, traditional statistical analysis of temperature responses is difficult. Mathematical Modeling We have developed a mathematical model that explains the complexity of temperature responses to Meth as the interplay between excitatory and inhibitory nodes. We have extended the developed model to include the stress of manipulations and the effects of SB. Stress is synergistic with Meth on the action on excitatory node. Orexin receptors mediate an activation of on both excitatory and inhibitory nodes by low doses of Meth, but not on the node activated by high doses (HD). Exaggeration of early responses to high doses of Meth involves disinhibition: low dose of SB decreases tonic inhibition of HD and lowers the activation threshold, while the higher dose suppresses the inhibitory component. Using a modeling approach to data assimilation appears efficient in separating individual components of complex response with statistical analysis unachievable by traditional data processing methods. PMID:25993564

  14. Evolving Evidence of the Efficacy and Safety of nab-Paclitaxel in the Treatment of Cancers with Squamous Histologies

    PubMed Central

    Loong, Herbert H.; Chan, Alvita C.Y.; Wong, Ashley C.Y.

    2016-01-01

    Taxanes, such as paclitaxel and docetaxel, are well-established cytotoxic chemotherapeutics used in the treatment of a variety of cancers, including those of squamous histology. In their formulation, both agents require solvents, which have been associated with hypersensitivity reactions, peripheral neuropathy, hepatic toxicities, and impaired drug delivery. nab-Paclitaxel is a novel, albumin-bound form of paclitaxel with improved tolerability, bioavailability, and efficacy compared with solvent-based paclitaxel. Currently, nab-paclitaxel is approved for the treatment of metastatic breast cancer, locally advanced/metastatic non-small cell lung cancer (NSCLC), and metastatic pancreatic cancer. Clinical studies suggest that nab-paclitaxel may be particularly effective in cancers with squamous histology, including NSCLC. This article reviews the emerging evidence supporting nab-paclitaxel as an effective agent in the treatment of malignancies of squamous histology. PMID:26918039

  15. Synthesis, characterization, and evaluation of paclitaxel loaded in six-arm star-shaped poly(lactic-co-glycolic acid)

    PubMed Central

    Chen, Yongxia; Yang, Ziying; Liu, Chao; Wang, Cuiwei; Zhao, Shunxin; Yang, Jing; Sun, Hongfan; Zhang, Zhengpu; Kong, Deling; Song, Cunxian

    2013-01-01

    Background Star-shaped polymers provide more terminal groups, and are promising for application in drug-delivery systems. Methods A new series of six-arm star-shaped poly(lactic-co-glycolic acid) (6-s-PLGA) was synthesized by ring-opening polymerization. The structure and properties of the 6-s-PLGA were characterized by carbon-13 nuclear magnetic resonance spectroscopy, infrared spectroscopy, gel permeation chromatography, and differential scanning calorimetry. Then, paclitaxel-loaded six-arm star-shaped poly(lactic-co-glycolic acid) nanoparticles (6-s-PLGA-PTX-NPs) were prepared under the conditions optimized by the orthogonal testing. High-performance liquid chromatography was used to analyze the nanoparticles’ encapsulation efficiency and drug-loading capacity, dynamic light scattering was used to determine their size and size distribution, and transmission electron microscopy was used to evaluate their morphology. The release performance of the 6-s-PLGA-PTX-NPs in vitro and the cytostatic effect of 6-s-PLGA-PTX-NPs were investigated in comparison with paclitaxel-loaded linear poly(lactic-co-glycolic acid) nanoparticles (L-PLGA-PTX-NPs). Results The results of carbon-13 nuclear magnetic resonance spectroscopy and infrared spectroscopy suggest that the polymerization was successfully initiated by inositol and confirm the structure of 6-s-PLGA. The molecular weights of a series of 6-s-PLGAs had a ratio corresponding to the molar ratio of raw materials to initiator. Differential scanning calorimetry revealed that the 6-s-PLGA had a low glass transition temperature of 40°C–50°C. The 6-s-PLGA-PTX-NPs were monodispersed with an average diameter of 240.4±6.9 nm in water, which was further confirmed by transmission electron microscopy. The encapsulation efficiency of the 6-s-PLGA-PTX-NPs was higher than that of the L-PLGA-PTX-NPs. In terms of the in vitro release of nanoparticles, paclitaxel (PTX) was released more slowly and more steadily from 6-s-PLGA than from

  16. CONFORMANCE IMPROVEMENT USING GELS

    SciTech Connect

    Randall S. Seright

    2003-09-01

    This report describes work performed during the second year of the project, ''Conformance Improvement Using Gels.'' The project has two objectives. The first objective is to identify gel compositions and conditions that substantially reduce flow through fractures that allow direct channeling between wells, while leaving secondary fractures open so that high fluid injection and production rates can be maintained. The second objective is to optimize treatments in fractured production wells, where the gel must reduce permeability to water much more than that to oil. Pore-level images from X-ray computed microtomography were re-examined for Berea sandstone and porous polyethylene. This analysis suggests that oil penetration through gel-filled pores occurs by a gel-dehydration mechanism, rather than a gel-ripping mechanism. This finding helps to explain why aqueous gels can reduce permeability to water more than to oil. We analyzed a Cr(III)-acetate-HPAM gel treatment in a production well in the Arbuckle formation. The availability of accurate pressure data before, during, and after the treatment was critical for the analysis. After the gel treatment, water productivity was fairly constant at about 20% of the pre-treatment value. However, oil productivity was stimulated by a factor of 18 immediately after the treatment. During the six months after the treatment, oil productivity gradually decreased to approach the pre-treatment value. To explain this behavior, we proposed that the fracture area open to oil flow was increased substantially by the gel treatment, followed by a gradual closing of the fractures during subsequent production. For a conventional Cr(III)-acetate-HPAM gel, the delay between gelant preparation and injection into a fracture impacts the placement, leakoff, and permeability reduction behavior. Formulations placed as partially formed gels showed relatively low pressure gradients during placement, and yet substantially reduced the flow capacity of

  17. CONFORMANCE IMPROVEMENT USING GELS

    SciTech Connect

    Randall S. Seright

    2004-09-30

    This report describes work performed during the third and final year of the project, ''Conformance Improvement Using Gels.'' Corefloods revealed throughput dependencies of permeability reduction by polymers and gels that were much more prolonged during oil flow than water flow. This behavior was explained using simple mobility ratio arguments. A model was developed that quantitatively fits the results and predicts ''clean up'' times for oil productivity when production wells are returned to service after application of a polymer or gel treatment. X-ray computed microtomography studies of gels in strongly water-wet Berea sandstone and strongly oil-wet porous polyethylene suggested that oil penetration through gel-filled pores occurs by a gel-dehydration mechanism, rather than gel-ripping or gel-displacement mechanisms. In contrast, analysis of data from the University of Kansas suggests that the gel-ripping or displacement mechanisms are more important in more permeable, strongly water-wet sandpacks. These findings help to explain why aqueous gels can reduce permeability to water more than to oil under different conditions. Since cement is the most commonly used material for water shutoff, we considered when gels are preferred over cements. Our analysis and experimental results indicated that cement cannot be expected to completely fill (top to bottom) a vertical fracture of any width, except near the wellbore. For vertical fractures with apertures less than 4 mm, the cement slurry will simply not penetrate very far into the fracture. For vertical fractures with apertures greater than 4 mm, the slurry may penetrate a substantial distance into the bottom part of the fracture. However, except near the wellbore, the upper part of the fracture will remain open due to gravity segregation. We compared various approaches to plugging fractures using gels, including (1) varying polymer content, (2) varying placement (extrusion) rate, (3) using partially formed gels, (4

  18. Non-invasive endotracheal delivery of paclitaxel-loaded alginate microparticles.

    PubMed

    Alipour, Shohreh; Montaseri, Hashem; Khalili, Azadeh; Tafaghodi, Mohsen

    2016-10-01

    Aerosolized chemotherapeutics leads to higher, localized and continuous concentrations of active agents in lung tissue with lower side effects for other organs. The present study was performed on jugular vein cannulated rats which endothracheally received 4 mg/kg of free paclitaxel powder (Free-PTX), paclitaxel-loaded alginate microparticles (PTX-ALG-MPs) and i.v. paclitaxel (Anzatax(®)). Pharmacokinetic parameters for Free-PTX and PTX-ALG-MPs contain higher AUC, mean residence time (MRT),half-life and bioavailability, with lower elimination constant (ke). Statistical analysis showed that the amount of paclitaxel per gram of lung tissue after 0.5, 6 and 24 h after administration of Free-PTX was lower than PTX-ALG-MPs. Lung tissue AUC for Free-PTX was lower than PTX-ALG-MPs. According to the obvious advantages obtained, such as dose lowering and increasing paclitaxel residence time and half-life. It should be noted that cell cytotoxicity test on normal airway cell lines was not examined in this study but due to previous reports on safety of inhaled paclitaxel, it can be suggested that pulmonary delivery of paclitaxel can be a useful non-invasive route of administration compared with i.v administration. PMID:27447444

  19. Intraplantar injection of linalool reduces paclitaxel-induced acute pain in mice.

    PubMed

    Katsuyama, Soh; Kuwahata, Hikari; Yagi, Tomomi; Kishikawa, Yukinaga; Komatsu, Takaaki; Sakurada, Tsukasa; Nakamura, Hitoshi

    2012-06-01

    Linalool is the principal component of many essential oils known to possess biological activities. We previously reported that intraplantar injection of linalool reduces the nociceptive response as assayed by the capsaicin test. In this study, we sought to determine whether intraplantar injection of linalool could influence the induction of acute pain (allodynia and hyperalgesia) by paclitaxel in mice. Paclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors, but it sometimes induces moderate to severe acute pain. Paclitaxel administered intraperitoneally as a single dose of 5, 10 or 20 mg/kg produced mechanical allodynia and hyperalgesia in mice. Paclitaxel-induced mechanical allodynia and hyperalgesia began 1 day after administration of paclitaxel and resolved within 7 days. Linalool injected into the hindpaw caused a significant reduction in paclitaxel-induced mechanical allodynia and hyperalgesia. Pretreatment with naloxone hydrochloride, an opioid receptor antagonist, or naloxone methiodide, a peripherally acting µ-opioid receptor-preferring antagonist, significantly reversed linalool-induced antiallodynia and antihyperalgesia. Our results provide evidence for the involvement of peripheral opioids in antiallodynia and antihyperalgesia induced by linalool. These results suggest that activation of peripheral opioid receptors may play an important role in reducing paclitaxel-induced mechanical allodynia and hyperalgesia.

  20. BetaIII-tubulin induces paclitaxel resistance in association with reduced effects on microtubule dynamic instability.

    PubMed

    Kamath, Kathy; Wilson, Leslie; Cabral, Fernando; Jordan, Mary Ann

    2005-04-01

    The development of resistance to paclitaxel in tumors is one of the most significant obstacles to successful therapy. Overexpression of the betaIII-tubulin isotype has been associated with paclitaxel resistance in a number of cancer cell lines and in tumors, but the mechanism of resistance has remained unclear. Paclitaxel inhibits cancer cell proliferation by binding to the beta-subunit of tubulin in microtubules and suppressing microtubule dynamic instability, leading to mitotic arrest and cell death. We hypothesized that betaIII-tubulin overexpression induces resistance to paclitaxel either by constitutively enhancing microtubule dynamic instability in resistant cells or by rendering the microtubules less sensitive to the suppression of dynamics by paclitaxel. Using Chinese hamster ovary cells that inducibly overexpress either betaI- or betaIII-tubulin, we analyzed microtubule dynamic instability during interphase by microinjection of rhodamine-labeled tubulin and time-lapse fluorescence microscopy. In the absence of paclitaxel, there were no differences in any aspect of dynamic instability between the two beta-tubulin-overexpressing cell types. However, in the presence of 150 nm paclitaxel, dynamic instability was suppressed to a significantly lesser extent (suppressed only 12%) in cells overexpressing betaIII-tubulin than in cells overexpressing similar levels of betaI-tubulin (suppressed 47%). The results suggest that overexpression of betaIII-tubulin induces paclitaxel resistance by reducing the ability of paclitaxel to suppress microtubule dynamics. The results also suggest that endogenous regulators of microtubule dynamics may differentially interact with individual tubulin isotypes, supporting the idea that differential expression of tubulin isotypes has functional consequences in cells.

  1. A Review of Paclitaxel and Novel Formulations Including Those Suitable for Use in Dogs.

    PubMed

    Khanna, C; Rosenberg, M; Vail, D M

    2015-01-01

    Paclitaxel is a commonly used chemotherapeutic agent with a broad spectrum of activity against cancers in humans. In 1992, paclitaxel was approved by the U.S. Food and Drug Administration (FDA) as Taxol(®) for use in advanced ovarian cancer. Two years later, it was approved for the treatment of metastatic breast cancer. Paclitaxel was originally isolated from the bark of the Pacific yew tree, Taxus brevifolia in 1971. Taxanes are a family of microtubule inhibitors. As a member of this family, paclitaxel suppresses spindle microtubule dynamics. This activity results in the blockage of the metaphase-anaphase transitions, and ultimately in the inhibition of mitosis, and induction of apoptosis in a wide spectrum of cancer cells. Additional anticancer activities of paclitaxel have been defined that are independent of these effects on the microtubules and may include the suppression of cell proliferation as well as antiangiogenic effects. Based on its targeting of a fundamental feature of the cancer phenotype, the mitotic complex, it is not surprising that paclitaxel has been found to be active in a wide variety of cancers in humans. This review summarizes the evidence in support of paclitaxel's broad anticancer activity and introduces the rationale for, and the progress in development of novel formulations of paclitaxel that may preferentially target cancers and that are not associated with the risks for hypersensitivity in dogs. Of note, a novel nanoparticle formulation of paclitaxel that substantially limits hypersensitivity was recently given conditional approval by the FDA Center for Veterinary Medicine for use in dogs with resectable and nonresectable squamous cell carcinoma and nonresectable stage III, IV and V mammary carcinoma.

  2. Characterization of paclitaxel (Taxol) sensitivity in human glioma- and medulloblastoma-derived cell lines.

    PubMed Central

    Tseng, S. H.; Bobola, M. S.; Berger, M. S.; Silber, J. R.

    1999-01-01

    Paclitaxel (Taxol), a cytotoxic natural product that disrupts microtubule integrity, is being clinically evaluated for use against gliomas. We examined paclitaxel-induced killing in seven cell lines derived from human malignant astrocytic gliomas and medulloblastomas with the goal of characterizing range of sensitivity, contribution of P-glycoprotein 170-mediated drug efflux to resistance, and cross-resistance with alkylating agents. Exposure to paclitaxel for 8 h or less produced biphasic survival curves for all lines, with 40-75% of cells comprising a subpopulation that was 9-26 times more resistant to paclitaxel than the more sensitive fraction. Increasing exposure to 24 h eliminated the resistant subpopulation, increasing sensitivity 50- to 400-fold. The dose producing one log of kill (LD10) after a 24-h exposure ranged from 4 to 18 nM, comparable to concentrations in the cerebrospinal fluid of brain tumor patients given a 3-h infusion of paclitaxel. Concurrent exposure to paclitaxel and either nimodipine or verapamil, inhibitors of P-glycoprotein activity, did not increase sensitivity, demonstrating that the fivefold range in sensitivity was not due to P-glycoprotein-mediated drug efflux. Importantly, there was no correlation between LD10 for paclitaxel and LD10 for 1,3-bis(2-chloroethyl)-1-nitrosourea, streptozotocin, and temozolomide, indicating no expression of cross-resistance to these different classes of tumoricidal agents. Our results suggest that greater clinical efficacy of paclitaxel against malignant brain tumors may be obtained by infusion for 24 h or longer and support the use of paclitaxel in combination with alkylating agents. PMID:11550305

  3. Prostate cancer cell response to paclitaxel is affected by abnormally expressed securin PTTG1.

    PubMed

    Castilla, Carolina; Flores, M Luz; Medina, Rafael; Pérez-Valderrama, Begoña; Romero, Francisco; Tortolero, María; Japón, Miguel A; Sáez, Carmen

    2014-10-01

    PTTG1 protein, the human securin, has a central role in sister chromatid separation during mitosis, and its altered expression has been reported in many tumor types. Paclitaxel is a widely used chemotherapeutic drug, whose mechanism of action is related to its ability to arrest cells in mitosis and the subsequent induction of the intrinsic apoptotic pathway. By using two prostate cancer cell lines with different responses to paclitaxel treatment, we have identified two situations in which PTTG1 influences cell fate differentially. In slippage-prone PC3 cells, both PTTG1 downregulation and overexpression induce an increase in mitotic cells that is associated with diminished apoptosis after paclitaxel treatment. In LNCaP cells, however, PTTG1 downregulation prevents mitotic entry and, subsequently, inhibits mitosis-associated, paclitaxel-induced apoptosis. In contrast, PTTG1 overexpression induces an increase in mitotic cells and apoptosis after paclitaxel treatment. We have also identified a role for Mcl-1 protein in preventing apoptosis during mitosis in PC3 cells, as simultaneous PTTG1 and Mcl-1 silencing enhances mitosis-associated apoptosis after paclitaxel treatment. The finding that a more efficient mitotic arrest alone in PC3 cells is not enough to increase apoptosis was also confirmed with the observation that a selected paclitaxel-resistant PC3 cell line showed an apoptosis-resistant phenotype associated with increased mitosis upon paclitaxel treatment. These findings could contribute to identify putative responsive and nonresponsive cells and help us to approach incomplete responses to paclitaxel in the clinical setting. PMID:25122070

  4. CONFORMANCE IMPROVEMENT USING GELS

    SciTech Connect

    Randall S. Seright

    2004-03-01

    This technical progress report describes work performed from September 1, 2003, through February 29, 2004, for the project, ''Conformance Improvement Using Gels.'' We examined the properties of several ''partially formed'' gels that were formulated with a combination of high and low molecular weight HPAM polymers. After placement in 4-mm-wide fractures, these gels required about 25 psi/ft for brine to breach the gel (the best performance to date in fractures this wide). After this breach, stabilized residual resistance factors decreased significantly with increased flow rate. Also, residual resistance factors were up to 9 times greater for water than for oil. Nevertheless, permeability reduction factors were substantial for both water and oil flow. Gel with 2.5% chopped fiberglass effectively plugged 4-mm-wide fractures if a 0.5-mm-wide constriction was present. The ability to screen-out at a constriction appears crucial for particulate incorporation to be useful in plugging fractures. In addition to fiberglass, we examined incorporation of polypropylene fibers into gels. Once dispersed in brine or gelant, the polypropylene fibers exhibited the least gravity segregation of any particulate that we have tested to date. In fractures with widths of at least 2 mm, 24-hr-old gels (0.5% high molecular weight HPAM) with 0.5% fiber did not exhibit progressive plugging during placement and showed extrusion pressure gradients similar to those of gels without the fiber. The presence of the fiber roughly doubled the gel's resistance to first breach by brine flow. The breaching pressure gradients were not as large as for gels made with high and low molecular weight polymers (mentioned above). However, their material requirements and costs (i.e., polymer and/or particulate concentrations) were substantially lower than for those gels. A partially formed gel made with 0.5% HPAM did not enter a 0.052-mm-wide fracture when applying a pressure gradient of 65 psi/ft. This result

  5. Design and Synthesis of (+)-Discodermolide-Paclitaxel Hybrids Leading to Enhanced Biological Activity1

    PubMed Central

    Smith, Amos B.; Sugasawa, Keizo; Atasoylu, Onur; Yang, Chia-Ping Huang; Horwitz, Susan Band

    2011-01-01

    Potential binding modes of (+)-discodermolide at the paclitaxel binding site of tubulin have been identified by computational studies based on earlier structural and SAR data. Examination of the prospective binding modes reveal that the aromatic pocket occupied by the paclitaxel side-chain is unoccupied by (+)-discodermolide. Based on these findings, a small library of (+)-discodermolide-paclitaxel hybrids have been designed and synthesized. Biological evaluation reveals a two- to eight- fold increase in antiproliferative activity compared to the parent molecule using the A549 and MCF-7 cancer cell lines. PMID:21870795

  6. Design and synthesis of (+)-discodermolide-paclitaxel hybrids leading to enhanced biological activity.

    PubMed

    Smith, Amos B; Sugasawa, Keizo; Atasoylu, Onur; Yang, Chia-Ping Huang; Horwitz, Susan Band

    2011-09-22

    Potential binding modes of (+)-discodermolide at the paclitaxel binding site of tubulin have been identified by computational studies based on earlier structural and SAR data. Examination of the prospective binding modes reveal that the aromatic pocket occupied by the paclitaxel side chain is unoccupied by (+)-discodermolide. Based on these findings, a small library of (+)-discodermolide-paclitaxel hybrids have been designed and synthesized. Biological evaluation reveals a two- to eight-fold increase in antiproliferative activity compared to the parent molecule using the A549 and MCF-7 cancer cell lines.

  7. Pharmacological stimulation of the regenerative capacity of rat testes damaged by paclitaxel.

    PubMed

    Borovskaya, T G; Dygai, A M; Shchemerova, Y A; Vychuzhanina, A V; Poluektova, M E; Goldberg, V E; Kinsht, D N; Ershov, K I; Madonov, P G

    2014-04-01

    Productivity of spermatogenesis and the population of spermatogonial cells were substantially reduced in male Wistar rats 3 months after administration of cytostatic drug paclitaxel, damaging stem spermatogonia. However, signs of reparative regeneration appeared in the testicular tissue. In animals receiving paclitaxel in combination with granulocyte CSF, the same period of observation, the number of spermatogonia and the efficiency of spermatogenesis at the same terms of the study did not differ from those in intact animals. Intensive recovery processes started 1 month earlier than after administration of paclitaxel alone. These data attest to pronounced potentiating effect of granulocyte CSF on reparative regeneration of the testicular tissue.

  8. Nanoparticle Albumin Bound Paclitaxel in the Treatment of Human Cancer: Nanodelivery Reaches Prime-Time?

    PubMed Central

    Cucinotto, Iole; Fiorillo, Lucia; Gualtieri, Simona; Arbitrio, Mariamena; Ciliberto, Domenico; Staropoli, Nicoletta; Grimaldi, Anna; Luce, Amalia; Tassone, Pierfrancesco; Caraglia, Michele; Tagliaferri, Pierosandro

    2013-01-01

    Nanoparticle albumin bound paclitaxel (nab-paclitaxel) represents the first nanotechnology-based drug in cancer treatment. We discuss the development of this innovative compound and report the recent changing-practice results in breast and pancreatic cancer. A ground-breaking finding is the demonstration that nab-paclitaxel can not only enhance the activity and reduce the toxicity of chromophore-diluted compound, but also exert activity in diseases considered refractory to taxane-based treatment. This is the first clinical demonstration of major activity of nanotechnologically modified drugs in the treatment of human neoplasms. PMID:23738077

  9. Paclitaxel loaded PEGylated gleceryl monooleate based nanoparticulate carriers in chemotherapy.

    PubMed

    Jain, Vikas; Swarnakar, Nitin K; Mishra, Prabhat R; Verma, Ashwni; Kaul, Ankur; Mishra, Anil K; Jain, Narendra K

    2012-10-01

    A PEGylated drug delivery system of paclitaxel (PTX), based on glyceryl monooleate (GMO) was prepared by optimizing various parameters to explore its potential in anticancer therapy. The prepared system was characterized through polarized light microscopy, TEM, AFM and SAXS to reveal its liquid crystalline nature. As GMO based LCNPs exhibit high hemolytic toxicity and faster release of entrapped drug (66.2 ± 2.5% in 24 h), PEGylation strategy was utilized to increase the hemocompatibility (reduction in hemolysis from 60.3 ± 10.2 to 4.4 ± 1.3%) and control the release of PTX (43.6 ± 3.2% released in 24 h). The cytotoxic potential and cellular uptake was assessed in MCF-7 cell lines. Further, biodistribution studies were carried out in EAT (Ehrlich Ascites tumor) bearing mice using (99m)Tc-(Technetium radionuclide) labeled formulations and an enhanced circulation time and tumor accumulation (14 and 8 times, respectively) were observed with PEGylated carriers over plain ones, at 24 h. Finally, tumor growth inhibition experiment was performed and after 15 days, control group exhibited 15 times enhancement in tumor volume, while plain and PEGylated systems exhibited only 8 and 4 times enhancement, respectively, as compared to initial tumor volume. The results suggest that PEGylation enhances the hemocompatibility and efficacy of GMO based system that may serve as an efficient i.v. delivery vehicle for paclitaxel.

  10. Doxorubicin and paclitaxel loaded microbubbles for ultrasound triggered drug delivery

    PubMed Central

    Cochran, Michael C.; Eisenbrey, John; Ouma, Richard O.; Soulen, Michael; Wheatley, Margaret A.

    2011-01-01

    A polymer ultrasound contrast agent (UCA) developed in our lab has been shown to greatly reduce in size when exposed to ultrasound, resulting in nanoparticles less than 400 nm in diameter capable of escaping the leaky vasculature of a tumor to provide a sustained release of drug. Previous studies with the hydrophilic drug doxorubicin (DOX) demonstrated enhanced drug delivery to tumors when triggered with ultrasound. However the therapeutic potential has been limited due to the relatively low payload of DOX. This study compares the effects of loading the hydrophobic drug paclitaxel (PTX) on the agent’s acoustic properties, drug payload, tumoricidal activity, and the ability to deliver drugs through 400 nm pores. A maximum payload of 129.46 ± 1.80 μg PTX/mg UCA (encapsulation efficiency 71.92 ± 0.99 %) was achieved, 20 times greater than the maximum payload of DOX (6.2 μg/mg), while maintaining the acoustic properties. In vitro, the tumoricidal activity of paclitaxel loaded UCA exposed to ultrasound was significantly greater than controls not exposed to ultrasound (p<0.0016). This study has shown that PTX loaded UCA triggered with focused ultrasound have the potential to provide a targeted and sustained delivery of drug to tumors. PMID:21609756

  11. Sialoganglioside Micelles for Enhanced Paclitaxel Solubility: In Vitro Characterization.

    PubMed

    Heredia, Valeria; Alasino, Roxana V; Leonhard, Victoria; Garro, Ariel G; Maggio, Bruno; Beltramo, Dante M

    2016-01-01

    Efficiency of mono-sialogangliosides to load Paclitaxel (Ptx) has recently been found to depend on the structure of the polysaccharide chain. In this study, we demonstrated that incorporation of only one more sialic acid into the ganglioside molecule, independently of its position, causes a 4-fold increase in Ptx-loading capacity, the maximum being at a 5:1 molar ratio (di-sialoganglioside/Paclitaxel, GD/Ptx). These complexes are stable in solution for at least 3 months, and over 90% of Ptx remains loaded in the micelles after extreme stress conditions such as high-speed centrifugation, lyophilization, or freeze-thaw cycles. Ganglioside micelles protect 50% of the initially loaded Ptx from alkaline hydrolysis after 24 h at pH 10. Dynamic light scattering studies revealed that GD micelles increase their size from 9 to 12 nm when loaded with Ptx. Transmission electron microscopy shows a homogeneous population of spherical micelles either with or without Ptx. In vitro biological activity was similar to that of the free drug. These results provide further options of self-assembled nanostructures of di- and tri-sialogangliosides with a higher loading capacity. PMID:26852858

  12. Preparation, characterization, and efficacy of thermosensitive liposomes containing paclitaxel.

    PubMed

    Wang, Zhi-Yuan; Zhang, Hui; Yang, Yang; Xie, Xiang-Yang; Yang, Yan-Fang; Li, Zhiping; Li, Ying; Gong, Wei; Yu, Fang-Lin; Yang, Zhenbo; Li, Ming-Yuan; Mei, Xing-Guo

    2016-05-01

    To increase the anti-tumor activity of paclitaxel (PTX), novel temperature-sensitive liposomes loading paclitaxel (PTX-TSL) were developed. In vitro, characteristics of PTX-TSL were evaluated. The mean particle diameter was about 100 nm, and the entrapment efficiency was larger than 95%. The phase-transition temperature of PTX-TSL determined by differential scanning calorimetry was about 42 °C. The result of in vitro drug release from PTX-TSL illustrated that release rate at 37 °C was obviously lower than that at 42 °C. Stability data indicated that the liposome was physically and chemically stable for at least 3 months at -20 °C. In vivo study, after three injections with hyperthermia in the xenograft lung tumor model, PTX-TSL showed distinguished tumor growth suppression, compared with non-temperature-sensitive liposome and free drug. The results of intratumoral drug concentration indicated that PTX-TSL combined with hyperthermia delivered more paxlitaxel into the tumor location than the other two paxlitaxel formulations. In summary, PTX-TSL combined with hyperthermia significantly inhibited tumor growth, due to the increased targeting efficiency of PTX to tumor tissues. Such approach may enhance the delivery efficiency of chemotherapeutics into solid tumors. PMID:26666408

  13. Fabrication of paclitaxel nanocrystals by femtosecond laser ablation and fragmentation.

    PubMed

    Kenth, Sukhdeep; Sylvestre, Jean-Philippe; Fuhrmann, Kathrin; Meunier, Michel; Leroux, Jean-Christophe

    2011-03-01

    Nanonization, which involves formulating the drug powder as nanometer-sized particles, is a known method to improve drug absorption and allow the intravenous administration of insoluble drugs. This study investigated a novel femtosecond (fs) laser technique for the fabrication of nanocrystals in aqueous solution of the insoluble model drug paclitaxel. Two distinct methods of this technology, ablation and fragmentation, were investigated and the influence of laser power, focusing position and treatment time on the particle size, drug concentration, and degradation was studied. The colloidal suspensions were characterized with respect to size, chemical composition, morphology, and polymorphic state. Optimal laser fragmentation conditions generated uniformly sized paclitaxel nanoparticles (<500 nm) with quantifiable degradation, while ablation followed by fragmentation was associated with a larger polydispersity. Laser treatment at higher powers produced smaller particles with larger amount of degradation. The crystalline morphology of the drug was retained upon nanonization, but the anhydrous crystals were converted to a hydrated form, a phenomenon also observed during bead milling. These findings suggest that drug nanocrystals can be produced with fs laser technology using very little drug quantities, which may be an asset for preclinical evaluation of new drug candidates.

  14. Promotion of mitotic catastrophe via activation of PTEN by paclitaxel with supplement of mulberry water extract in bladder cancer cells

    PubMed Central

    Chen, Nien-Cheng; Chyau, Charng-Cherng; Lee, Yi-Ju; Tseng, Hsien-Chun; Chou, Fen-Pi

    2016-01-01

    Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. Mulberry fruit is rich in phenolic compounds and flavonoids and exhibits chemopreventive activities. In this study, mulberry water extract (MWE) was used as a supplement to synergize with the effects of paclitaxel in the treatment of the TSGH 8301 human bladder cancer cell line. Treatment with paclitaxel combined with MWE (paclitaxel/MWE) enhanced the cytotoxicity of paclitaxel and induced severe G2/M arrest, mitotic catastrophe and subsequent apoptosis, as shown by MTT assay, HE staining and flow cytometry analyses. Differences in the expression and activation of Aurora A and Plk1between cells treated with paclitaxel/MWE and paclitaxel alone suggested that the combined treatment caused a defect in the early steps of cytokinesis. Paclitaxel/MWE decreased EEA1immunofluorescence staining and increased the expression of PTEN, indicating that the regimen inhibited the formation of the recycling endosome, which is required for cytokinesis. Paclitaxel/MWE also retarded tumor growth in a TSGH 8301 xenograft model via activation of PTEN and Caspase 3. These data demonstrated a synergistic effect on the anticancer efficacy of paclitaxel through MWE supplementation by promoting mitotic catastrophe through the activation of PTEN, providing a novel and effective therapeutic option for bladder cancer treatment strategies. PMID:26838546

  15. Effects of repeated milnacipran and fluvoxamine treatment on mechanical allodynia in a mouse paclitaxel-induced neuropathic pain model.

    PubMed

    Katsuyama, Soh; Sato, Kazuma; Yagi, Tomomi; Kishikawa, Yukinaga; Nakamura, Hitoshi

    2013-04-01

    Paclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors, but it frequently causes peripheral neuropathy. Milnacipran, a serotonin/noradrenaline reuptake inhibitor and fluvoxamine, a selective serotonin reuptake inhibitor, have shown efficacy against several chronic pain syndromes. In this study, we investigated the attenuation of paclitaxel-induced mechanical allodynia in mice by milnacipran and fluvoxamine. Paclitaxel was administered once per day (2 mg/kg, intraperitoneally (i.p.)) for 5 days to mice. Mechanical allodynia was evaluated by measuring the withdrawal response to stimulation with a von Frey filament. In paclitaxel-treated mice, mechanical allodynia was observed on days 3-15 of paclitaxel administration. A single administration of milnacipran (20 mg/kg, i.p.) or fluvoxamine (40 mg/kg, i.p.) had no effect on paclitaxel- induced mechanical allodynia. However, repeated administration of milnacipran (10, 20 mg/kg, once per day, i.p.) for 5 days significantly reduced paclitaxel-induced mechanical allodynia. In contrast, repeated fluvoxamine administration (40 mg/kg, once per day, i.p.) for 5 days resulted in a weak attenuation of paclitaxel-induced mechanical allodynia. These results suggest that chronic paclitaxel administration induces mechanical allodynia, and that repeated milnacipran administration may be an effective therapeutic approach for the treatment of neuropathic pain caused by paclitaxel treatment for cancer.

  16. Intratumoral delivery of paclitaxel using a thermosensitive hydrogel in human tumor xenografts.

    PubMed

    Kim, Jung Ho; Lee, Joo-Ho; Kim, Kwang-Suck; Na, Kun; Song, Soo-Chang; Lee, Jaehwi; Kuh, Hyo-Jeong

    2013-01-01

    Poly(organophosphazene), a novel thermosensitive hydrogel, is an injectable drug delivery system (DDS) that transforms from sol to gel at body temperature. Paclitaxel (PTX) is a mitotic inhibitor used in the treatment of various solid tumors. Due to its poor solubility in water and efflux systems in the gastrointestinal tract, PTX is a good candidate for local DDS. Here, we evaluated the penetration kinetics of PTX released from the PTX-poly(organophosphazene) hydrogel mixture in multicellular layers (MCLs) of human cancer cells. We also investigated the tumor pharmacokinetics of PTX (60 mg/kg) when administered as an intratumoral injection using poly(organophosphazene) in mice with human tumor xenografts. When PTX was formulated at 0.6 % w/w into a 10 % w/w hydrogel, the in vitro and in vivo release were found to be 40 and 90 % of the dose, respectively, in a sustained manner over 4 weeks. Exposure of MCLs to PTX-hydrogel showed time-dependent drug penetration and accumulation. In mice, the hydrogel mass was well retained over 6 weeks, and the PTX concentration in the tumor tissue was maximal at 14 days, which rapidly decreased and coincided with rebound tumor growth after 14 days of suppression. These data indicate that PTX-hydrogel should be intratumorally injected every 14 days, or drug release duration should be prolonged in order to achieve a long-term antitumor effect. Overall, poly(organophosphazene) represents a novel thermosensitive DDS for intratumoral delivery of PTX, which can accommodate a large dose of the drug in addition to reducing its systemic exposure by restricting biodistribution to tumor tissue alone. PMID:23371803

  17. The microtubule-stabilizing agent discodermolide competitively inhibits the binding of paclitaxel (Taxol) to tubulin polymers, enhances tubulin nucleation reactions more potently than paclitaxel, and inhibits the growth of paclitaxel-resistant cells.

    PubMed

    Kowalski, R J; Giannakakou, P; Gunasekera, S P; Longley, R E; Day, B W; Hamel, E

    1997-10-01

    The lactone-bearing polyhydroxylated alkatetraene (+)-discodermolide, which was isolated from the sponge Discodermia dissoluta, induces the polymerization of purified tubulin with and without microtubule-associated proteins or GTP, and the polymers formed are stable to cold and calcium. These effects are similar to those of paclitaxel (Taxol), but discodermolide is more potent. We confirmed that these properties represent hypernucleation phenomena; we obtained lower tubulin critical concentrations and shorter polymers with discodermolide than paclitaxel under a variety of reaction conditions. Furthermore, we demonstrated that discodermolide is a competitive inhibitor with [3H]paclitaxel in binding to tubulin polymer, with an apparent Ki value of 0.4 microM. Multidrug-resistant human colon and ovarian carcinoma cells overexpressing P-glycoprotein, which are 900- and 2800-fold resistant to paclitaxel, respectively, relative to the parental lines, retained significant sensitivity to discodermolide (25- and 89-fold more resistant relative to the parental lines). Ovarian carcinoma cells that are 20-30-fold more resistant to paclitaxel than the parental line on the basis of expression of altered beta-tubulin polypeptides retained nearly complete sensitivity to discodermolide. The effects of discodermolide on the reorganization of the microtubules of Potorous tridactylis kidney epithelial cells were examined at different times. Intracellular microtubules were reorganized into bundles in interphase cells much more rapidly after discodermolide treatment compared with paclitaxel treatment. A variety of spindle aberrations were observed after treatment with both drugs. The proportions of the different types of aberration were different for the two drugs and changed with the length of drug treatment.

  18. Injectable, thermo-reversible and complex coacervate combination gels for protein drug delivery.

    PubMed

    Jin, Kwang-Mi; Kim, Yong-Hee

    2008-05-01

    Injectable and thermo-reversible physical combination gels were formed in aqueous solution by preparing complex coacervate with two oppositely charged biomacromolecules that composed of negatively charged chondroitin 6-sulfate and positively charged high molecular weight gelatin type A and co-formulating with a negative, thermo-sensitive polysaccharide, methylcellulose containing a salting-out salt, ammonium sulfate. The combination of complex coacervation and a thermo-reversible gel demonstrated synergistic effects on the complex coacervate formation the release rates of model proteins and in situ gel depot formation. Gels indicated sustained release patterns of the protein over 25 days with minimal initial bursts. Optimized novel in situ gel depot systems containing dual advantages of complex coacervation and temperature responsiveness demonstrated a potential for efficient protein drug delivery in terms of high protein loading, sustained protein release, ease of administration, an aqueous environment without toxic organic solvents, and a simple fabrication method.

  19. Poly-cyclodextrin and poly-paclitaxel nano-assembly for anticancer therapy

    NASA Astrophysics Data System (ADS)

    Namgung, Ran; Mi Lee, Yeong; Kim, Jihoon; Jang, Yuna; Lee, Byung-Heon; Kim, In-San; Sokkar, Pandian; Rhee, Young Min; Hoffman, Allan S.; Kim, Won Jong

    2014-05-01

    Effective anticancer therapy can be achieved by designing a targeted drug-delivery system with high stability during circulation and efficient uptake by the target tumour cancer cells. We report here a novel nano-assembled drug-delivery system, formed by multivalent host-guest interactions between a polymer-cyclodextrin conjugate and a polymer-paclitaxel conjugate. The multivalent inclusion complexes confer high stability to the nano-assembly, which efficiently delivers paclitaxel into the targeted cancer cells via both passive and active targeting mechanisms. The ester linkages between paclitaxel and the polymer backbone permit efficient release of paclitaxel within the cell by degradation. This novel targeted nano-assembly exhibits significant antitumour activity in a mouse tumour model. The strategy established in this study also provides knowledge for the development of advanced anticancer drug delivery.

  20. Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer

    PubMed Central

    Chan, J.K.; Brady, M.F.; Penson, R.T.; Huang, H.; Birrer, M.J.; Walker, J.L.; DiSilvestro, P.A.; Rubin, S.C.; Martin, L.P.; Davidson, S.A.; Huh, W.K.; O’Malley, D.M.; Boente, M.P.; Michael, H.; Monk, B.J.

    2016-01-01

    BACKGROUND A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab. METHODS We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival. RESULTS A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P = 0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P = 0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P = 0.60). A test for

  1. Cost-effectiveness of paclitaxel plus cisplatin in advanced non-small-cell lung cancer

    PubMed Central

    Earle, C C; Evans, W K

    1999-01-01

    The aim of this study was to assess the cost-effectiveness of combination chemotherapy with paclitaxel/cisplatin, compared with standard etoposide/cisplatin in patients with advanced non-small cell lung cancer (NSCLC). We obtained the primary survival and resource utilization data from a large three-arm randomized trial comparing: paclitaxel 135 mg m−2 by 24-h intravenous (i.v.) infusion + cisplatin; paclitaxel 250 mg m−2 by 24-h i.v. infusion + cisplatin + granulocyte colony-stimulating factor (G-CSF); and standard etoposide/cisplatin in patients with stage IIIb or IV NSCLC. We also modelled the regimens with paclitaxel 135 mg m−2 + cisplatin administered as an outpatient by 3-h infusion, as clinical data suggest that this is equivalent to 24-h infusion. We collected costing data from the Ottawa Regional Cancer Centre and applied it to the resources consumed in the randomized trial. We integrated these data into the Statistics Canada POpulation HEalth Model (POHEM), which generated hypothetical cohorts of patients treated with each regimen. The POHEM model assigned diagnostic work-up, treatment, disease progression and survival characteristics to each individual in these cohorts and tabulated the costs associated with each. We did sensitivity analyses around the costs of chemotherapy and its administration, and the survival differences between the two regimens. All costs are in 1997 Canadian dollars ($1.00 Canadian ˜ £0.39 sterling). The perspective is that of the Canadian health care system. In the trial, the two paclitaxel-containing arms had almost identical survival curves with a median survival of 9.7 months compared with 7.4 months for etoposide/cisplatin. As administered in the trial, paclitaxel/cisplatin cost $76 370 per life-year gained (LYG) and paclitaxel/cisplatin/G-CSF $138 578 per LYG relative to etoposide/cisplatin. However, when modelled as an outpatient 3-h infusion, paclitaxel/cisplatin was moderately cost-effective at $30 619 per LYG

  2. Temperature response of a number of plastic dosimeters for radiation processing

    NASA Astrophysics Data System (ADS)

    Sohrabpour, M.; Kazemi, A. A.; Mousavi, H.; Solati, K.

    1993-10-01

    Various plastic dosemeters are employed for dosimetry control of radiation processing within gamma and electron irradiation facilities. The temperature response of a dosimeter is important when the dose to such a dosimeter is accumulated under varying irradiation temperatures. Such measurements would be significant for proper assessment of the dose for better process control, as well as, performance evaluation of dosimetry systems. In this work we have developed a high current peltier junction temperature controller system for our Gammacell-220. This system has been designed to regulate the operating temperature of the irradiation chamber in the range of 0 to 80 C this system has been applied to measure the temperature response of the red perspex, a local clear PMMA, Gammex, Gammachrome, and Gafchromic dosimeters. The curves of relative performance or variation of the induced optical densities of the above dosemeters versus the irradiation temperature at fixed dose values are obtained.

  3. Transient temperature response of functionally gradient material subjected to partial stepwise heating

    SciTech Connect

    Makino, Atsushi; Araki, Nobuyuki; Kitajima, Hidetoshi; Ohashi, Kentaro

    1996-01-01

    Functionally gradient materials (FGMs) with distributed properties have attracted special interests as advanced heat-shielding/structural materials in future space applications. The objective of the present study is to derive an analytical solution of the temperature response in a multilayer-type FGM, the front surface of which is subjected to partial, stepwise heating. Heat losses from the front, rear, and side surfaces are also considered. The Laplace transform has been used to obtain the analytical solution. This solution is expected to elucidate the dependence of the temperature response on the various parameters, such as thermophysical properties and heat losses. It is also expected to reduce the calculation time to obtain thermal stress and/or strain in large-scale numerical calculations. Appropriateness of this solution has also been demonstrated by comparing the present results and the experimental results obtained by the National Aerospace Laboratory, Japan.

  4. Temperature-responsive Solid-phase Extraction Column for Biological Sample Pretreatment.

    PubMed

    Akimaru, Michiko; Okubo, Kohei; Hiruta, Yuki; Kanazawa, Hideko

    2015-01-01

    We have developed a novel solid-phase extraction (SPE) system utilizing a temperature-responsive polymer hydrogel-modified stationary phase. Aminopropyl silica beads (average diameter, 40 - 64 μm) were coated with poly(N-isopropylacrylamide) (PNIPAAm)-based thermo-responsive hydrogels. Butyl methacrylate (BMA) and N,N-dimethylaminopropyl acrylamide (DMAPAAm) were used as the hydrophobic and cationic monomers, respectively, and copolymerized with NIPAAm. To evaluate the use of this SPE cartridge for the analysis of drugs and proteins in biological fluids, we studied the separation of phenytoin and theophylline from human serum albumin (HSA) as a model system. The retention of the analytes in an exclusively aqueous eluent could be modulated by changing the temperature and salt content. These results indicated that this temperature-responsive SPE system can be applied to the pretreatment of biological samples for the measurement of serum drug levels.

  5. Overexpression of centrosomal protein Nlp confers breast carcinoma resistance to paclitaxel.

    PubMed

    Zhao, Weihong; Song, Yongmei; Xu, Binghe; Zhan, Qimin

    2012-02-01

    Nlp (ninein-like protein), an important molecule involved in centrosome maturation and spindle formation, plays an important role in tumorigenesis and its abnormal expression was recently observed in human breast and lung cancers. In this study, the correlation between overexpression of Nlp and paclitaxel chemosensitivity was investigated to explore the mechanisms of resistance to paclitaxel and to understand the effect of Nlp upon apoptosis induced by chemotherapeutic agents. Nlp expression vector was stably transfected into breast cancer MCF-7 cells. With Nlp overexpression, the survival rates, cell cycle distributions and apoptosis were analyzed in transfected MCF-7 cells by MTT test and FCM approach. The immunofluorescent assay was employed to detect the changes of microtubule after paclitaxel treatment. Immunoblotting analysis was used to examine expression of centrosomal proteins and apoptosis associated proteins. Subsequently, Nlp expression was retrospectively examined with 55 breast cancer samples derived from paclitaxel treated patients. Interestingly, the survival rates of MCF-7 cells with Nlp overexpressing were higher than that of control after paclitaxel treatment. Nlp overexpression promoted G2-M arrest and attenuated apoptosis induced by paclitaxel, which was coupled with elevated Bcl-2 protein. Nlp expression significantly lessened the microtubule polymerization and bundling elicited by paclitaxel attributing to alteration on the structure or dynamics of β-tubulin but not on its expression. The breast cancer patients with high expression of Nlp were likely resistant to the treatment of paclitaxel, as the response rate in Nlp negative patients was 62.5%, whereas was 58.3 and 15.8% in Nlp (+) and Nlp (++) patients respectively (p = 0.015). Nlp expression was positive correlated with those of Plk1 and PCNA. These findings provide insights into more rational chemotherapeutic regimens in clinical practice, and more effective approaches might be

  6. Effect of Paclitaxel on Antitumor Activity of Cyclophosphamide: Study on Two Transplanted Tumors in Mice.

    PubMed

    Kaledin, V I; Nikolin, V P; Popova, N A; Pyshnaya, I A; Bogdanova, L A; Morozkova, T S

    2015-11-01

    Antitumor effect of paclitaxel used as the monotherapy or in combination with cyclophosphamide was studied on CBA/LacSto mice with transplanted LS and RLS tumors characterized by high (LS) and low (RLS) sensitivity to cyclophosphamide. The therapeutic effects of cyclophosphamide and paclitaxel were summed in animals with drug-resistant RLS tumor, while combined use of these drugs in LS tumor highly sensitive to the apoptogenic effect of cyclophosphamide was no more effective than cyclophosphamide alone. PMID:26597686

  7. Cardioprotective effect of royal jelly on paclitaxel-induced cardio-toxicity in rats

    PubMed Central

    Malekinejad, Hassan; Ahsan, Sima; Delkhosh-Kasmaie, Fatemeh; Cheraghi, Hadi; Rezaei-Golmisheh, Ali; Janbaz-Acyabar, Hamed

    2016-01-01

    Objective(s): Paclitaxel is a potent chemotherapy agent with severe side effects, including allergic reactions, cardiovascular problems, complete hair loss, joint and muscle pain, which may limit its use and lower its efficiency. The cardioprotective effect of royal jelly was investigated on paclitaxel-induced damages. Materials and Methods: Adult male Wistar rats were divided into control and test groups (n=8). The test group was assigned into five subgroups; 4 groups, along with paclitaxel administration (7.5 mg/kg BW, weekly), received various doses of royal jelly (50, 100, and 150 mg/kg BW) for 28 consecutive days. The last group received only royal jelly at 100 mg/kg. In addition to oxidative and nitrosative stress biomarkers, the creatine kinase (CK-BM) level was also determined. To show the cardioprotective effect of royal jelly on paclitaxel-induced damages, histopathological examinations were conducted. Results: Royal jelly lowered the paclitaxel-elevated malondialdehyde and nitric oxide levels in the heart. Royal jelly could also remarkably reduce the paclitaxel-induced cardiac biomarker of creatine kinase (CK-BM) level and pathological injuries such as diffused edema, hemorrhage, congestion, hyaline exudates, and necrosis. Moreover, royal jelly administration in a dose-dependent manner resulted in a significant (P<0.05) increase in the paclitaxel-reduced total antioxidant capacity. Conclusion: Our data suggest that the paclitaxel-induced histopathological and biochemical alterations could be protected by the royal jelly administration. The cardioprotective effect of royal jelly may be related to the suppression of oxidative and nitrosative stress. PMID:27081469

  8. A novel self-microemulsifying formulation of paclitaxel for oral administration to patients with advanced cancer

    PubMed Central

    Veltkamp, S A; Thijssen, B; Garrigue, J S; Lambert, G; Lallemand, F; Binlich, F; Huitema, A D R; Nuijen, B; Nol, A; Beijnen, J H; Schellens, J H M

    2006-01-01

    To explore the parmacokinetics, safety and tolerability of paclitaxel after oral administration of SMEOF#3, a novel Self-Microemulsifying Oily Formulation, in combination with cyclosporin A (CsA) in patients with advanced cancer. Seven patients were enrolled and randomly assigned to receive oral paclitaxel (SMEOF#3) 160 mg+CsA 700 mg on day 1, followed by oral paclitaxel (Taxol®) 160 mg+CsA 700 mg on day 8 (group I) or vice versa (group II). Patients received paclitaxel (Taxol®) 160 mg as 3-h infusion on day 15. The median (range) area under the plasma concentration–time curve of paclitaxel was 2.06 (1.15–3.47) μg h ml−1 and 1.97 (0.58–3.22) μg h ml−1 after oral administration of SMEOF#3 and Taxol®, respectively, and 4.69 (3.90–6.09) μg h ml−1 after intravenous Taxol®. Oral SMEOF#3 resulted in a lower median Tmax of 2.0 (0.5–2.0) h than orally applied Taxol® (Tmax=4.0 (0.8–6.1) h, P=0.02). The median apparent bioavailability of paclitaxel was 40 (19–83)% and 55 (9–70)% for the oral SMEOF#3 and oral Taxol® formulation, respectively. Oral paclitaxel administered as SMEOF#3 or Taxol® was safe and well tolerated by the patients. Remarkably, the SMEOF#3 formulation resulted in a significantly lower Tmax than orally applied Taxol®, probably due to the excipients in the SMEOF#3 formulation resulting in a higher absorption rate of paclitaxel. PMID:16926835

  9. Effect of Paclitaxel on Antitumor Activity of Cyclophosphamide: Study on Two Transplanted Tumors in Mice.

    PubMed

    Kaledin, V I; Nikolin, V P; Popova, N A; Pyshnaya, I A; Bogdanova, L A; Morozkova, T S

    2015-11-01

    Antitumor effect of paclitaxel used as the monotherapy or in combination with cyclophosphamide was studied on CBA/LacSto mice with transplanted LS and RLS tumors characterized by high (LS) and low (RLS) sensitivity to cyclophosphamide. The therapeutic effects of cyclophosphamide and paclitaxel were summed in animals with drug-resistant RLS tumor, while combined use of these drugs in LS tumor highly sensitive to the apoptogenic effect of cyclophosphamide was no more effective than cyclophosphamide alone.

  10. Prevention of Paclitaxel-Induced Neuropathy Through Activation of the Central Cannabinoid Type 2 Receptor System

    PubMed Central

    Naguib, Mohamed; Xu, Jijun J.; Diaz, Philippe; Brown, David L.; Cogdell, David; Bie, Bihua; Hu, Jianhua; Craig, Suzanne; Hittelman, Walter N.

    2012-01-01

    Background Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB2) receptors are expressed in the microglia in neurodegenerative disease models. Methods To explore the potential of CB2 agonists for preventing paclitaxel-induced neuropathy, we designed and synthesized a novel CB2-selective agonist, namely MDA7. The effect of MDA7 in preventing paclitaxel-induced allodynia was assessed in rats and in CB2+/+ and CB2–/– mice. We hypothesize that the CB2 receptor functions in a negative-feedback loop and that early MDA7 administration can blunt the neuroinflammatory response to paclitaxel and prevent mechanical allodynia through interference with specific signaling pathways. Results We found that MDA7 prevents paclitaxel-induced mechanical allodynia in rats and mice in a dose- and time-dependent manner without compromising paclitaxel's antineoplastic effect. MDA7's neuroprotective effect was absent in CB2-/- mice and was blocked by CB2 antagonists, suggesting that MDA7's action directly involves CB2 receptor activation. MDA7 treatment was found to interfere with early events in the paclitaxel-induced neuroinflammatory response as evidenced by relatively reduced Toll-like receptor and CB2 expression in the lumbar spinal cord, reduced levels of extracellular signal regulated kinase 1/2 activity, reduced numbers of activated microglia and astrocytes, and reduced secretion of proinflammatory mediators in vivo and in in vitro models. Conclusions Our findings suggest an innovative therapeutic approach to prevent chemotherapy-induced neuropathy and may permit more aggressive use of active chemotherapeutic regimens with reduced long-term sequelae

  11. Paclitaxel metabolism in rat and human liver microsomes is inhibited by phenolic antioxidants.

    PubMed

    Václavíková, Radka; Horský, Stanislav; Simek, Petr; Gut, Ivan

    2003-09-01

    Paclitaxel is an important, recently introduced anti-neoplastic drug. Paclitaxel metabolites are virtually inactive in comparison with the parent drug. The study investigated whether phenolic antioxidants could inhibit metabolic inactivation sufficiently to increase paclitaxel effects. Cytochrome p450 (CYP)-catalysed metabolism of paclitaxel was investigated in rat and human liver microsomes. In rat microsomes, paclitaxel was metabolised mainly to C3'-hydroxypaclitaxel (C3'-OHP), less to C2-hydroxypaclitaxel (C2-OHP), di-hydroxypaclitaxel (di-OHP) and another monohydroxylated paclitaxel. In human liver microsomes, 6alpha-hydroxypaclitaxel (6alpha-OHP), formed by CYP2C8, was the main metabolite, while C3'-OHP, C2-OHP and another product different from di-OHP were minor metabolites, formed by CYP3A4. In individual human livers 6alpha-OHP was formed at 1.8-fold to 13-fold higher rates than C3'-OHP. Kinetic parameters (K(m) and V(max)) of production of various metabolites in rat and human liver microsomes revealed differences between species as well as human individual differences. Nine phenolic antioxidants ((+)-catechin, (-)-epicatechin, fisetin, gallic acid, morin, myricetin, naringenin, quercetin and resveratrol) were tested for inhibition of paclitaxel metabolism. In rat microsomes, resveratrol was more inhibitory than fisetin; the other phenolic antioxidants were without effect. In human microsomes, the inhibiting potency decreased in the order fisetin >quercetin >morin >resveratrol, while the other phenolic antioxidants were not inhibitory; the formation of 6alpha-OHP (CYP2C8) was generally more inhibited than that of C3'-OHP. The inhibition was mostly mixed-type. The results suggest that oral administration of some phenolic substances might increase paclitaxel blood concentrations during chemotherapy.

  12. Temperature responses of dark respiration in relation to leaf sugar concentration.

    PubMed

    Hüve, Katja; Bichele, Irina; Ivanova, Hiie; Keerberg, Olav; Pärnik, Tiit; Rasulov, Bahtijor; Tobias, Mari; Niinemets, Ulo

    2012-04-01

    Changes in leaf sugar concentrations are a possible mechanism of short-term adaptation to temperature changes, with natural fluctuations in sugar concentrations in the field expected to modify the heat sensitivity of respiration. We studied temperature-response curves of leaf dark respiration in the temperate tree Populus tremula (L.) in relation to leaf sugar concentration (1) under natural conditions or (2) leaves with artificially enhanced sugar concentration. Temperature-response curves were obtained by increasing the leaf temperature at a rate of 1°C min⁻¹. We demonstrate that respiration, similarly to chlorophyll fluorescence, has a break-point at high temperature, where respiration starts to increase with a faster rate. The average break-point temperature (T(RD) ) was 48.6 ± 0.7°C at natural sugar concentration. Pulse-chase experiments with ¹⁴CO₂ demonstrated that substrates of respiration were derived mainly from the products of starch degradation. Starch degradation exhibited a similar temperature-response curve as respiration with a break-point at high temperatures. Acceleration of starch breakdown may be one of the reasons for the observed high-temperature rise in respiration. We also demonstrate that enhanced leaf sugar concentrations or enhanced osmotic potential may protect leaf cells from heat stress, i.e. higher sugar concentrations significantly modify the temperature-response curve of respiration, abolishing the fast increase of respiration. Sugars or enhanced osmotic potential may non-specifically protect respiratory membranes or may block the high-temperature increase in starch degradation and consumption in respiratory processes, thus eliminating the break-points in temperature curves of respiration in sugar-fed leaves.

  13. A graphene-based smart catalytic system with superior catalytic performances and temperature responsive catalytic behaviors.

    PubMed

    Qi, Junjie; Lv, Weipeng; Zhang, Guanghui; Li, Yang; Zhang, Guoliang; Zhang, Fengbao; Fan, Xiaobin

    2013-07-21

    We have successfully developed a unique graphene-based smart catalytic system which consists of the graphene supported Au-Pt bimetallic nanocatalyst with a well-defined core-shell structure and a dextran-based temperature-responsive polymer. The unique catalytic system possesses excellent catalytic performances and the catalytic activities could be readily switched on or off at different temperature windows. PMID:23740038

  14. Viscoelasticity of silica gels

    SciTech Connect

    Scherer, G.W.

    1995-12-01

    The response of silica gels to mechanical loads depends on the properties of the solid phase and the permeability of the network. Understanding this behavior is essential for modeling of stresses developed during drying or heating of gels. The permeability and the mechanical properties are readily determined from a simple beam-bending experiment, by measuring the load relaxation that occurs at constant deflection. Load decay results from movement of the liquid within the network; in addition, there may be viscoelastic relaxation of the network itself. Silica gel is viscoelastic in chemically aggressive media, but in inert liquids (such as ethanol or acetone) it is elastic. Experiments show that the viscoelastic relaxation time decreases as the concentration and pH of the water in the pore liquid increase. During drying, the permeability decreases and the viscosity increases, both exhibiting a power-law dependence on density of the gel network.

  15. Convergence in the temperature response of leaf respiration across biomes and plant functional types.

    PubMed

    Heskel, Mary A; O'Sullivan, Odhran S; Reich, Peter B; Tjoelker, Mark G; Weerasinghe, Lasantha K; Penillard, Aurore; Egerton, John J G; Creek, Danielle; Bloomfield, Keith J; Xiang, Jen; Sinca, Felipe; Stangl, Zsofia R; Martinez-de la Torre, Alberto; Griffin, Kevin L; Huntingford, Chris; Hurry, Vaughan; Meir, Patrick; Turnbull, Matthew H; Atkin, Owen K

    2016-04-01

    Plant respiration constitutes a massive carbon flux to the atmosphere, and a major control on the evolution of the global carbon cycle. It therefore has the potential to modulate levels of climate change due to the human burning of fossil fuels. Neither current physiological nor terrestrial biosphere models adequately describe its short-term temperature response, and even minor differences in the shape of the response curve can significantly impact estimates of ecosystem carbon release and/or storage. Given this, it is critical to establish whether there are predictable patterns in the shape of the respiration-temperature response curve, and thus in the intrinsic temperature sensitivity of respiration across the globe. Analyzing measurements in a comprehensive database for 231 species spanning 7 biomes, we demonstrate that temperature-dependent increases in leaf respiration do not follow a commonly used exponential function. Instead, we find a decelerating function as leaves warm, reflecting a declining sensitivity to higher temperatures that is remarkably uniform across all biomes and plant functional types. Such convergence in the temperature sensitivity of leaf respiration suggests that there are universally applicable controls on the temperature response of plant energy metabolism, such that a single new function can predict the temperature dependence of leaf respiration for global vegetation. This simple function enables straightforward description of plant respiration in the land-surface components of coupled earth system models. Our cross-biome analyses shows significant implications for such fluxes in cold climates, generally projecting lower values compared with previous estimates. PMID:27001849

  16. Convergence in the temperature response of leaf respiration across biomes and plant functional types

    PubMed Central

    Heskel, Mary A.; O’Sullivan, Odhran S.; Reich, Peter B.; Tjoelker, Mark G.; Weerasinghe, Lasantha K.; Penillard, Aurore; Egerton, John J. G.; Creek, Danielle; Bloomfield, Keith J.; Xiang, Jen; Sinca, Felipe; Stangl, Zsofia R.; Martinez-de la Torre, Alberto; Griffin, Kevin L.; Huntingford, Chris; Hurry, Vaughan; Meir, Patrick; Turnbull, Matthew H.; Atkin, Owen K.

    2016-01-01

    Plant respiration constitutes a massive carbon flux to the atmosphere, and a major control on the evolution of the global carbon cycle. It therefore has the potential to modulate levels of climate change due to the human burning of fossil fuels. Neither current physiological nor terrestrial biosphere models adequately describe its short-term temperature response, and even minor differences in the shape of the response curve can significantly impact estimates of ecosystem carbon release and/or storage. Given this, it is critical to establish whether there are predictable patterns in the shape of the respiration–temperature response curve, and thus in the intrinsic temperature sensitivity of respiration across the globe. Analyzing measurements in a comprehensive database for 231 species spanning 7 biomes, we demonstrate that temperature-dependent increases in leaf respiration do not follow a commonly used exponential function. Instead, we find a decelerating function as leaves warm, reflecting a declining sensitivity to higher temperatures that is remarkably uniform across all biomes and plant functional types. Such convergence in the temperature sensitivity of leaf respiration suggests that there are universally applicable controls on the temperature response of plant energy metabolism, such that a single new function can predict the temperature dependence of leaf respiration for global vegetation. This simple function enables straightforward description of plant respiration in the land-surface components of coupled earth system models. Our cross-biome analyses shows significant implications for such fluxes in cold climates, generally projecting lower values compared with previous estimates. PMID:27001849

  17. Convergence in the temperature response of leaf respiration across biomes and plant functional types.

    PubMed

    Heskel, Mary A; O'Sullivan, Odhran S; Reich, Peter B; Tjoelker, Mark G; Weerasinghe, Lasantha K; Penillard, Aurore; Egerton, John J G; Creek, Danielle; Bloomfield, Keith J; Xiang, Jen; Sinca, Felipe; Stangl, Zsofia R; Martinez-de la Torre, Alberto; Griffin, Kevin L; Huntingford, Chris; Hurry, Vaughan; Meir, Patrick; Turnbull, Matthew H; Atkin, Owen K

    2016-04-01

    Plant respiration constitutes a massive carbon flux to the atmosphere, and a major control on the evolution of the global carbon cycle. It therefore has the potential to modulate levels of climate change due to the human burning of fossil fuels. Neither current physiological nor terrestrial biosphere models adequately describe its short-term temperature response, and even minor differences in the shape of the response curve can significantly impact estimates of ecosystem carbon release and/or storage. Given this, it is critical to establish whether there are predictable patterns in the shape of the respiration-temperature response curve, and thus in the intrinsic temperature sensitivity of respiration across the globe. Analyzing measurements in a comprehensive database for 231 species spanning 7 biomes, we demonstrate that temperature-dependent increases in leaf respiration do not follow a commonly used exponential function. Instead, we find a decelerating function as leaves warm, reflecting a declining sensitivity to higher temperatures that is remarkably uniform across all biomes and plant functional types. Such convergence in the temperature sensitivity of leaf respiration suggests that there are universally applicable controls on the temperature response of plant energy metabolism, such that a single new function can predict the temperature dependence of leaf respiration for global vegetation. This simple function enables straightforward description of plant respiration in the land-surface components of coupled earth system models. Our cross-biome analyses shows significant implications for such fluxes in cold climates, generally projecting lower values compared with previous estimates.

  18. Temperature-Responsive Smart Nanocarriers for Delivery Of Therapeutic Agents: Applications and Recent Advances.

    PubMed

    Karimi, Mahdi; Sahandi Zangabad, Parham; Ghasemi, Alireza; Amiri, Mohammad; Bahrami, Mohsen; Malekzad, Hedieh; Ghahramanzadeh Asl, Hadi; Mahdieh, Zahra; Bozorgomid, Mahnaz; Ghasemi, Amir; Rahmani Taji Boyuk, Mohammad Reza; Hamblin, Michael R

    2016-08-24

    Smart drug delivery systems (DDSs) have attracted the attention of many scientists, as carriers that can be stimulated by changes in environmental parameters such as temperature, pH, light, electromagnetic fields, mechanical forces, etc. These smart nanocarriers can release their cargo on demand when their target is reached and the stimulus is applied. Using the techniques of nanotechnology, these nanocarriers can be tailored to be target-specific, and exhibit delayed or controlled release of drugs. Temperature-responsive nanocarriers are one of most important groups of smart nanoparticles (NPs) that have been investigated during the past decades. Temperature can either act as an external stimulus when heat is applied from the outside, or can be internal when pathological lesions have a naturally elevated termperature. A low critical solution temperature (LCST) is a special feature of some polymeric materials, and most of the temperature-responsive nanocarriers have been designed based on this feature. In this review, we attempt to summarize recent efforts to prepare innovative temperature-responsive nanocarriers and discuss their novel applications. PMID:27349465

  19. A new 2α,5α,10β,14β-tetraacetoxy-4(20),11-taxadiene (SIA) derivative overcomes paclitaxel resistance by inhibiting MAPK signaling and increasing paclitaxel accumulation in breast cancer cells.

    PubMed

    Mei, Mei; Xie, Dan; Zhang, Yi; Jin, Jing; You, Feng; Li, Yan; Dai, Jungui; Chen, Xiaoguang

    2014-01-01

    Tumor resistance due to multiple mechanisms seriously hinders the efficacy of chemotherapy drugs such as paclitaxel. The most widely studied P-glycoprotein inhibitors still have limited ability to reverse resistance in the clinic. In this study, NPB304, a novel Sinenxan A (SIA) derivative, was found to significantly sensitize resistant breast cancer cells to paclitaxel in vitro and in vivo. Treatment with NPB304 increased paclitaxel-induced apoptosis in a p53-dependent manner through PARP cleavage. Importantly, NPB304 enhanced the antitumor effect of paclitaxel in resistant breast tumor xenografts in nude mice without significantly affecting weight loss. NPB304 regulated cell resistance through inhibition of MAPK pathway components, including p-ERK and p-p38. Moreover, NPB304 increased paclitaxel accumulation by affecting P-gp function. In addition to increasing Rhodamine 123 accumulation, NPB304 promoted bidirectional permeability but decreased the efflux ratio of paclitaxel in a Caco-2 monolayer model, thereby increasing the intracellular concentration of paclitaxel. Similarly, NPB304 increased the concentration of paclitaxel in the resistant tumor tissue. Hence, NPB304 is a novel compound that promotes the sensitization of resistant cells to paclitaxel through multiple mechanisms and has the potential for use in combination therapies to treat resistant breast cancer.

  20. Conformance Improvement Using Gels

    SciTech Connect

    Seright, Randall S.; Schrader; II Hagstrom, John; Wang, Ying; Al-Dahfeeri, Abdullah; Marin, Amaury

    2002-09-26

    This research project had two objectives. The first objective was to identify gel compositions and conditions that substantially reduce flow through fractures that allow direct channeling between wells, while leaving secondary fractures open so that high fluid injection and production rates can be maintained. The second objective was to optimize treatments in fractured production wells, where the gel must reduce permeability to water much more than that to oil.

  1. Crystallization from Gels

    NASA Astrophysics Data System (ADS)

    Narayana Kalkura, S.; Natarajan, Subramanian

    Among the various crystallization techniques, crystallization in gels has found wide applications in the fields of biomineralization and macromolecular crystallization in addition to crystallizing materials having nonlinear optical, ferroelectric, ferromagnetic, and other properties. Furthermore, by using this method it is possible to grow single crystals with very high perfection that are difficult to grow by other techniques. The gel method of crystallization provides an ideal technique to study crystal deposition diseases, which could lead to better understanding of their etiology. This chapter focuses on crystallization in gels of compounds that are responsible for crystal deposition diseases. The introduction is followed by a description of the various gels used, the mechanism of gelling, and the fascinating phenomenon of Liesegang ring formation, along with various gel growth techniques. The importance and scope of study on crystal deposition diseases and the need for crystal growth experiments using gel media are stressed. The various crystal deposition diseases, viz. (1) urolithiasis, (2) gout or arthritis, (3) cholelithiasis and atherosclerosis, and (4) pancreatitis and details regarding the constituents of the crystal deposits responsible for the pathological mineralization are discussed. Brief accounts of the theories of the formation of urinary stones and gallstones and the role of trace elements in urinary stone formation are also given. The crystallization in gels of (1) the urinary stone constituents, viz. calcium oxalate, calcium phosphates, uric acid, cystine, etc., (2) the constituents of the gallstones, viz. cholesterol, calcium carbonate, etc., (3) the major constituent of the pancreatic calculi, viz., calcium carbonate, and (4) cholic acid, a steroidal hormone are presented. The effect of various organic and inorganic ions, trace elements, and extracts from cereals, herbs, and fruits on the crystallization of major urinary stone and gallstone

  2. Cost-Benefit Analysis of Nanoparticle Albumin-Bound Paclitaxel versus Solvent-Based Paclitaxel for the Treatment of Metastatic Breast Cancer in the United States

    NASA Astrophysics Data System (ADS)

    Vichansavakul, Kittaya

    Breast cancer is the second leading cause of death among women in the US. Although early detection and treatment help to increase survival rates, some unfortunate patients develop metastatic breast cancer that has no cure. Palliative treatment is the main objective in this group of patients in order to prolong life and reduce toxicities from interventions. In the advancement of treatment for metastatic breast cancer, solvent-based paclitaxel has been widely used. However, solvent-based paclitaxel often causes adverse reactions. Therefore, researchers have developed a new chemotherapy based on nanotechnology. One of these drugs is the Nanoparticle albumin-bound Paclitaxel. This nanodrug aims to increase therapeutic index by reducing adverse reactions from solvents and to improve efficacy of conventional cytotoxic chemotherapy. Breast cancer is a disease with high epidemiological and economic burden. The treatment of metastatic breast cancer has not only high direct costs but also high indirect costs. Breast cancer affects mass populations, especially women younger than 50 years of age. It relates to high indirect costs due to lost productivity and premature death because the majority of these patients are in the workforce. Because of the high cost of breast cancer therapies and short survival rates, the question is raised whether the costs and benefits are worth paying or not. Due to the rising costs in healthcare and new financing policies that have been developed to address this issue, economic evaluation is an important aspect of the development and use of any new interventions. To guide policy makers on how to allocate limited healthcare resources in the most efficient and effective manner, many economic evaluation methods can be used to measure the costs, benefits, and impacts of healthcare innovations. Currently, economic evaluation and health outcomes studies have focused greatly on cost-effectiveness and cost-utility analysis. However, the previous studies

  3. Paclitaxel-based regimens as first-line treatment in advanced gastric cancer.

    PubMed

    Guo, Zengqing; Wang, Xiaojie; Lin, Rongbo; Chen, Ling; Fan, Nanfeng; Chen, Yu; Lin, Jinyuan; Yu, Jiami

    2015-02-01

    The aim of this study was to evaluate the efficacy and safety of paclitaxel-based regimens as first-line treatments in advanced gastric cancer. We reviewed 397 previously untreated patients with advanced gastric cancer, who non-randomly received one of three paclitaxel-based regimens: paclitaxel plus fluorouracil/leucovorin (PF), paclitaxel plus oxaliplatin (PO), and paclitaxel plus oxaliplatin plus fluorouracil/leucovorin (POF) between January 2003 and December 2010. The PF, PO, and POF response rates were 47.13, 52.08, and 63.78%, respectively. Overall survivals (OS) were 11.2, 11.7, and 11.7 months, respectively. Progression-free survivals (PFS) were 6.6, 7.2, and 7.1 months, respectively. Leucopenia was higher on the triplet regimen than the doublet regimens. The paclitaxel-based regimens appeared to be effective in patients with advanced gastric cancer. The triplet regimen produced a higher response rate than either doublet regimen with more side effects, while survivals were similar among all three treatments.

  4. Nanosuspension delivery of paclitaxel to xenograft mice can alter drug disposition and anti-tumor activity

    NASA Astrophysics Data System (ADS)

    Chiang, Po-Chang; Gould, Stephen; Nannini, Michelle; Qin, Ann; Deng, Yuzhong; Arrazate, Alfonso; Kam, Kimberly R.; Ran, Yingqing; Wong, Harvey

    2014-04-01

    Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery.

  5. Vaginal delivery of paclitaxel via nanoparticles with non-mucoadhesive surfaces suppresses cervical tumor growth

    PubMed Central

    Yang, Ming; Yu, Tao; Wang, Ying-Ying; Lai, Samuel K.; Zeng, Qi; Miao, Bolong; Tang, Benjamin C.; Simons, Brian W.; Ensign, Laura; Liu, Guanshu; Chan, Kannie W. Y.; Juang, Chih-Yin; Mert, Olcay; Wood, Joseph; Fu, Jie; McMahon, Michael T.; Wu, T.-C.; Hung, Chien-Fu; Hanes, Justin

    2014-01-01

    Local delivery of chemotherapeutics in the cervicovaginal tract using nanoparticles may reduce adverse side effects associated with systemic chemotherapy, while improving outcomes for early stage cervical cancer. We hypothesize drug-loaded nanoparticles must rapidly penetrate cervicovaginal mucus (CVM) lining the female reproductive tract to effectively deliver their payload to underlying diseased tissues in a uniform and sustained manner. We develop paclitaxel-loaded nanoparticles, composed entirely of polymers used in FDA-approved products, which rapidly penetrate human CVM and provide sustained drug release with minimal burst effect. We further employ a mouse model with aggressive cervical tumors established in the cervicovaginal tract to compare paclitaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (conventional particles , or CP) and similar particles coated with Pluronic® F127 (mucus-penetrating particles , or MPP). CP are mucoadhesive and, thus, aggregated in mucus, while MPP achieve more uniform distribution and close proximity to cervical tumors. Paclitaxel-MPP suppress tumor growth more effectively and prolong median survival of mice compared to free paclitaxel or paclitaxel-CP. Histopathological studies demonstrate minimal toxicity to the cervicovaginal epithelia, suggesting paclitaxel-MPP may be safe for intravaginal use. These results demonstrate for the first time the in vivo advantages of polymer-based MPP for treatment of tumors localized to a mucosal surface. PMID:24339398

  6. Temperature response of photosynthesis and internal conductance to CO2: results from two independent approaches.

    PubMed

    Warren, C R; Dreyer, E

    2006-01-01

    The internal conductance to CO(2) transfer from intercellular spaces to chloroplasts poses a major limitation to photosynthesis, but few studies have investigated its temperature response. The aim of this study was to determine the temperature response of photosynthesis and internal conductance between 10 degrees C and 35 degrees C in seedlings of a deciduous forest tree species, Quercus canariensis. Internal conductance was estimated via simultaneous measurements of gas exchange and chlorophyll fluorescence ("variable J method"). Two of the required parameters, the intercellular photocompensation point (C(i)*) and rate of mitochondrial respiration in the light (R(d)), were estimated by the Laisk method. These were used to calculate the chloroplastic photocompensation point (Gamma*) in a simultaneous equation with g(i). An independent estimate of internal conductance was obtained by a novel curve-fitting method based on the curvature of the initial Rubisco-limited portion of an A/C(i) curve. The temperature responses of the rate of Rubisco carboxylation (V(cmax)) and the RuBP limited rate of electron transport (J(max)) were determined from chloroplastic CO(2) concentrations. The rate of net photosynthesis peaked at 24 degrees C. C(i)* was similar to reports for other species with a C(i)* of 39 micromol mol(-1) at 25 degrees C and an activation energy of 34 kJ mol(-1). Gamma* was very similar to the published temperature response for Spinacia oleracea from 20 degrees C to 35 degrees C, but was slightly greater at 10 degrees C and 15 degrees C. J(max) peaked at 30 degrees C, whereas V(cmax) did not reach a maximum between 10 degrees C and 35 degrees C. Activation energies were 49 kJ mol(-1) for V(cmax) and 100 kJ mol(-1) for J(max). Both methods showed that internal conductance doubled from 10 degrees C to 20 degrees C, and then was nearly temperature-independent from 20 degrees C to 35 degrees C. Hence, the temperature response of internal conductance could not be

  7. Fluorescence properties of several chemotherapy drugs: doxorubicin, paclitaxel and bleomycin

    PubMed Central

    Motlagh, Najme Sadat Hosseini; Parvin, Parviz; Ghasemi, Fatemah; Atyabi, Fatemeh

    2016-01-01

    Several chemo-drugs act as the biocompatible fluorophores. Here, the laser induced fluorescence (LIF) properties of doxorubicin, paclitaxel and bleomycin are investigated. The absorption lines mostly lie over UV range according to the UV-VIS spectra. Therefore, a single XeCl laser provokes the desired transitions of the chemo-drugs of interest at 308 nm. It is shown that LIF spectra are strongly dependent on the fluorophore concentration giving rise to the sensible red shift. This happens when large overlapping area appears between absorption and emission spectra accordingly. The red shift is taken into account as a characteristic parameter of a certain chemo-drug. The fluorescence extinction (α) and self-quenching (k) coefficients are determined based on the best fitting of the adopted Lambert-Beer equation over experimental data. The quantum yield of each chemo-drug is also measured using the linearity of the absorption and emission rates. PMID:27375954

  8. Rethinking production of Taxol® (paclitaxel) using endophyte biotechnology.

    PubMed

    Kusari, Souvik; Singh, Satpal; Jayabaskaran, Chelliah

    2014-06-01

    Taxol® (generic name paclitaxel) represents one of the most clinically valuable natural products known to mankind in the recent past. More than two decades have elapsed since the notable discovery of the first Taxol®-producing endophytic fungus, which was followed by a plethora of reports on other endophytes possessing similar biosynthetic potential. However, industrial-scale Taxol® production using fungal endophytes, although seemingly promising, has not seen the light of the day. In this opinion article, we embark on the current state of knowledge on Taxol® biosynthesis focusing on the chemical ecology of its producers, and ask whether it is actually possible to produce Taxol® using endophyte biotechnology. The key problems that have prevented the exploitation of potent endophytic fungi by industrial bioprocesses for sustained production of Taxol® are discussed. PMID:24810040

  9. Fluorescence properties of several chemotherapy drugs: doxorubicin, paclitaxel and bleomycin.

    PubMed

    Motlagh, Najme Sadat Hosseini; Parvin, Parviz; Ghasemi, Fatemah; Atyabi, Fatemeh

    2016-06-01

    Several chemo-drugs act as the biocompatible fluorophores. Here, the laser induced fluorescence (LIF) properties of doxorubicin, paclitaxel and bleomycin are investigated. The absorption lines mostly lie over UV range according to the UV-VIS spectra. Therefore, a single XeCl laser provokes the desired transitions of the chemo-drugs of interest at 308 nm. It is shown that LIF spectra are strongly dependent on the fluorophore concentration giving rise to the sensible red shift. This happens when large overlapping area appears between absorption and emission spectra accordingly. The red shift is taken into account as a characteristic parameter of a certain chemo-drug. The fluorescence extinction (α) and self-quenching (k) coefficients are determined based on the best fitting of the adopted Lambert-Beer equation over experimental data. The quantum yield of each chemo-drug is also measured using the linearity of the absorption and emission rates. PMID:27375954

  10. Rethinking production of Taxol® (paclitaxel) using endophyte biotechnology.

    PubMed

    Kusari, Souvik; Singh, Satpal; Jayabaskaran, Chelliah

    2014-06-01

    Taxol® (generic name paclitaxel) represents one of the most clinically valuable natural products known to mankind in the recent past. More than two decades have elapsed since the notable discovery of the first Taxol®-producing endophytic fungus, which was followed by a plethora of reports on other endophytes possessing similar biosynthetic potential. However, industrial-scale Taxol® production using fungal endophytes, although seemingly promising, has not seen the light of the day. In this opinion article, we embark on the current state of knowledge on Taxol® biosynthesis focusing on the chemical ecology of its producers, and ask whether it is actually possible to produce Taxol® using endophyte biotechnology. The key problems that have prevented the exploitation of potent endophytic fungi by industrial bioprocesses for sustained production of Taxol® are discussed.

  11. Paclitaxel inhibits cell proliferation and collagen lattice contraction via TGF-β signaling pathway in human tenon's fibroblasts in vitro.

    PubMed

    Chen, Ninghong; Guo, Dadong; Guo, Yuanyuan; Sun, Yuanyuan; Bi, Hongsheng; Ma, Xiaohua

    2016-04-15

    As an anti-microtubule agent, paclitaxel has been widely applied clinically. However, the effects of paclitaxel on human tenon's fibroblast (HTF) proliferation and migration in vitro was still unclear. In the present study, we explored the influences of paclitaxel on HTF cell proliferation, cell viability, cell cycle phase distribution under various concentrations of paclitaxel (i.e., 0, 10(-8), 10(-7), 10(-6)mol/l) via real-time cell electronic system and flow cytometry, further determined the expression of TGF-β1 and connective tissue growth factor (CTGF) after treatment with different concentrations of paclitaxel. Moreover, extra cellular matrix production and collagen lattice contraction assay were also explored. The results indicate that paclitaxel could apparently inhibit the cell viability, induces the elevation of S and G2/M phases of HTFs, and downregulates the expression of both TGF-β1 and CTGF. Meanwhile, the levels of fibronectin extra domain A (EDA), collagen and collagen lattice contraction were apparently reduced after treatment with paclitaxel. Overall, paclitaxel could apparently inhibit the proliferation of HTFs and leads to cell cycle arrest at both S and G2/M phases, attenuates the generation of collagen and collagen lattice contraction, decreases the expressions of TGF-β1, CTGF and fibronectin EDA. The inhibitory mechanism of paclitaxel on HTFs is involved in TGF-β1 signaling pathway.

  12. Rationalization of paclitaxel insensitivity of yeast β-tubulin and human βIII-tubulin isotype using principal component analysis

    PubMed Central

    2012-01-01

    Background The chemotherapeutic agent paclitaxel arrests cell division by binding to the hetero-dimeric protein tubulin. Subtle differences in tubulin sequences, across eukaryotes and among β-tubulin isotypes, can have profound impact on paclitaxel-tubulin binding. To capture the experimentally observed paclitaxel-resistance of human βIII tubulin isotype and yeast β-tubulin, within a common theoretical framework, we have performed structural principal component analyses of β-tubulin sequences across eukaryotes. Results The paclitaxel-resistance of human βIII tubulin isotype and yeast β-tubulin uniquely mapped on to the lowest two principal components, defining the paclitaxel-binding site residues of β-tubulin. The molecular mechanisms behind paclitaxel-resistance, mediated through key residues, were identified from structural consequences of characteristic mutations that confer paclitaxel-resistance. Specifically, Ala277 in βIII isotype was shown to be crucial for paclitaxel-resistance. Conclusions The present analysis captures the origin of two apparently unrelated events, paclitaxel-insensitivity of yeast tubulin and human βIII tubulin isotype, through two common collective sequence vectors. PMID:22849332

  13. Preparation of a Thermosensitive Gel Composed of a mPEG-PLGA-PLL-cRGD Nanodrug Delivery System for Pancreatic Tumor Therapy.

    PubMed

    Shen, Ming; Xu, Yuan-Yuan; Sun, Ying; Han, Bao-Shan; Duan, You-Rong

    2015-09-23

    It is hypothesized that a gel (NP-Gel) composed of thermosensitive gel (Gel) and nanoparticles (NP) can prolong drug release time and overcome the drug resistance of pancreatic tumor cells. Paclitaxel (PTX)-loaded monomethoxy (polyethylene glycol)-poly(d,l-lactide-co-glycolide)-poly(l-lysine)-cyclic peptide (arginine-glycine-aspartic-glutamic-valine acid) (mPEG-PLGA-PLL-cRGD) NP and NP-Gel were designed, optimized, and characterized using dynamic light scattering, transmission electron microscopy, high efficiency liquid chromatography, and rheological analyses. Aspc-1/PTX cell was used in a cell uptake test. A 3D cell model was used to mimic PTX elimination in tissue. The in vivo sustained release and antitumor effects were studied in Aspc-1/PTX-loaded nude mice with xerographic and in situ tumors. The NP were 133.7 ± 28.3 nm with 85.03% entrapped efficiency, 1.612% loaded ratio, and suitable rheological properties. PTX was released as NP from NP-Gel, greatly prolonging the release and elimination times to afford long-term effects. NP-Gel enhanced the uptake of PTX by Aspc-1/PTX cells more than using NP or the Gel alone. Gel and NP-Gel remained solid in the tumor and stayed over 50 days versus the several days of NP in solution. NP-Gel exhibited a much higher inhibition rate in vivo than in solution, NP, or the Gel alone. In conclusion, the antitumor effects of NP-Gel might arise from synergic effects from NP and the Gel. NP primarily reversed drug resistance, while the Gel prolonged release time considerably in situ. This preparation proved effective with a very small PTX dose (250 μg/kg) and exhibited few toxic effects in normal tissue.

  14. Preparation of a Thermosensitive Gel Composed of a mPEG-PLGA-PLL-cRGD Nanodrug Delivery System for Pancreatic Tumor Therapy.

    PubMed

    Shen, Ming; Xu, Yuan-Yuan; Sun, Ying; Han, Bao-Shan; Duan, You-Rong

    2015-09-23

    It is hypothesized that a gel (NP-Gel) composed of thermosensitive gel (Gel) and nanoparticles (NP) can prolong drug release time and overcome the drug resistance of pancreatic tumor cells. Paclitaxel (PTX)-loaded monomethoxy (polyethylene glycol)-poly(d,l-lactide-co-glycolide)-poly(l-lysine)-cyclic peptide (arginine-glycine-aspartic-glutamic-valine acid) (mPEG-PLGA-PLL-cRGD) NP and NP-Gel were designed, optimized, and characterized using dynamic light scattering, transmission electron microscopy, high efficiency liquid chromatography, and rheological analyses. Aspc-1/PTX cell was used in a cell uptake test. A 3D cell model was used to mimic PTX elimination in tissue. The in vivo sustained release and antitumor effects were studied in Aspc-1/PTX-loaded nude mice with xerographic and in situ tumors. The NP were 133.7 ± 28.3 nm with 85.03% entrapped efficiency, 1.612% loaded ratio, and suitable rheological properties. PTX was released as NP from NP-Gel, greatly prolonging the release and elimination times to afford long-term effects. NP-Gel enhanced the uptake of PTX by Aspc-1/PTX cells more than using NP or the Gel alone. Gel and NP-Gel remained solid in the tumor and stayed over 50 days versus the several days of NP in solution. NP-Gel exhibited a much higher inhibition rate in vivo than in solution, NP, or the Gel alone. In conclusion, the antitumor effects of NP-Gel might arise from synergic effects from NP and the Gel. NP primarily reversed drug resistance, while the Gel prolonged release time considerably in situ. This preparation proved effective with a very small PTX dose (250 μg/kg) and exhibited few toxic effects in normal tissue. PMID:26366977

  15. CONFORMANCE IMPROVEMENT USING GELS

    SciTech Connect

    Randall S. Seright

    2002-02-28

    This technical progress report describes work performed from June 20 through December 19, 2001, for the project, ''Conformance Improvement Using Gels''. Interest has increased in some new polymeric products that purport to substantially reduce permeability to water while causing minimum permeability reduction to oil. In view of this interest, we are currently studying BJ's Aqua Con. Results from six corefloods revealed that the Aqua Con gelant consistently reduced permeability to water more than that to oil. However, the magnitude of the disproportionate permeability reduction varied significantly for the various experiments. Thus, as with most materials tested to date, the issue of reproducibility and control of the disproportionate permeability remains to be resolved. Concern exists about the ability of gels to resist washout after placement in fractures. We examined whether a width constriction in the middle of a fracture would cause different gel washout behavior upstream versus downstream of the constriction. Tests were performed using a formed Cr(III)-acetate-HPAM gel in a 48-in.-long fracture with three sections of equal length, but with widths of 0.08-, 0.02-, and 0.08-in., respectively. The pressure gradients during gel extrusion (i.e., placement) were similar in the two 0.08-in.-wide fracture sections, even though they were separated by a 0.02-in.-wide fracture section. The constriction associated with the middle fracture section may have inhibited gel washout during the first pulse of brine injection after gel placement. However, during subsequent phases of brine injection, the constriction did not inhibit washout in the upstream fracture section any more than in the downstream section.

  16. A novel biosensor for quantitative monitoring of on-target activity of paclitaxel

    NASA Astrophysics Data System (ADS)

    Townley, H. E.; Zheng, Y.; Goldsmith, J.; Zheng, Y. Y.; Stratford, M. R. L.; Dobson, P. J.; Ahmed, A. A.

    2014-12-01

    This study describes a system for quantifying paclitaxel activity using the C-terminus of α-tubulin as a biomarker. Following stabilization of microtubules with paclitaxel, a specific detyrosination reaction occurs at the C-terminus of α-tubulin which could be used to assess efficacy. A fluorescence resonance energy transfer (FRET) based biosensor was synthesized comprising a short peptide that corresponded to the C-terminus of α-tubulin, a fluorophore (Abz), and a quencher (Dnp). The fluorophore added to the end of the peptide can be released upon enzymatic detyrosination. In addition, a single fluorophore-tagged peptide was also conjugated to mesoporous silica nanoparticles to examine the feasibility of combining the drug with the peptide biomarker. As a proof of concept, we found that the degree of peptide cleavage, and therefore enzymatic activity, was directly correlated with exogenous bovine carboxypeptidase (CPA) an enzyme that mimics endogenous detyrosination. In addition, we show that cell lysates obtained from paclitaxel-treated cancer cells competed with exogenous CPA for biosensor cleavage in a paclitaxel dose-dependent manner. Our work provides strong evidence for the feasibility of combining paclitaxel with a novel biosensor in a multi-load nanoparticle.This study describes a system for quantifying paclitaxel activity using the C-terminus of α-tubulin as a biomarker. Following stabilization of microtubules with paclitaxel, a specific detyrosination reaction occurs at the C-terminus of α-tubulin which could be used to assess efficacy. A fluorescence resonance energy transfer (FRET) based biosensor was synthesized comprising a short peptide that corresponded to the C-terminus of α-tubulin, a fluorophore (Abz), and a quencher (Dnp). The fluorophore added to the end of the peptide can be released upon enzymatic detyrosination. In addition, a single fluorophore-tagged peptide was also conjugated to mesoporous silica nanoparticles to examine the

  17. Paclitaxel Drug-Eluting Stents in Peripheral Arterial Disease: A Health Technology Assessment

    PubMed Central

    2015-01-01

    Background Peripheral arterial disease is a condition in which atherosclerotic plaques partially or completely block blood flow to the legs. Although percutaneous transluminal angioplasty and metallic stenting have high immediate success rates in treating peripheral arterial disease, long-term patency and restenosis rates in long and complex lesions remain unsatisfactory. Objective The objective of this analysis was to evaluate the clinical effectiveness, safety, cost-effectiveness and budget impact of Zilver paclitaxel self-expanding drug-eluting stents for the treatment of de novo or restenotic lesions in above-the-knee peripheral arterial disease. Data Sources Literature searches were performed using Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid Embase, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), and EBM Reviews. For the economic review, a search filter was applied to limit search results to economics-related literature. Data sources for the budget impact analysis included expert opinion, published literature, and Ontario administrative data. Review Methods Systematic reviews, meta-analyses, randomized controlled trials, and observational studies were included in the clinical effectiveness review, and full economic evaluations were included in the economic literature review. Studies were included if they examined the effect of Zilver paclitaxel drug-eluting stents in de novo or restenotic lesions in above-the-knee arteries. For the budget impact analysis, 3 scenarios were constructed based on different assumptions. Results One randomized controlled trial reported a significantly higher patency rate with Zilver paclitaxel drug-eluting stents for lesions ≤ 14 cm than with angioplasty or bare metal stents. One observational study showed no difference in patency rates between Zilver paclitaxel drug-eluting stents and paclitaxel drug-coated balloons. Zilver paclitaxel drug-eluting stents were associated with

  18. Designing Responsive Buckled Surfaces by Halftone Gel Lithography

    NASA Astrophysics Data System (ADS)

    Kim, Jungwook; Hanna, James A.; Byun, Myunghwan; Santangelo, Christian D.; Hayward, Ryan C.

    2012-03-01

    Self-actuating materials capable of transforming between three-dimensional shapes have applications in areas as diverse as biomedicine, robotics, and tunable micro-optics. We introduce a method of photopatterning polymer films that yields temperature-responsive gel sheets that can transform between a flat state and a prescribed three-dimensional shape. Our approach is based on poly(N-isopropylacrylamide) copolymers containing pendent benzophenone units that allow cross-linking to be tuned by irradiation dose. We describe a simple method of halftone gel lithography using only two photomasks, wherein highly cross-linked dots embedded in a lightly cross-linked matrix provide access to nearly continuous, and fully two-dimensional, patterns of swelling. This method is used to fabricate surfaces with constant Gaussian curvature (spherical caps, saddles, and cones) or zero mean curvature (Enneper’s surfaces), as well as more complex and nearly closed shapes.

  19. Regional and global temperature response to anthropogenic SO2 emissions from China in three climate models

    NASA Astrophysics Data System (ADS)

    Kasoar, Matthew; Voulgarakis, Apostolos; Lamarque, Jean-François; Shindell, Drew T.; Bellouin, Nicolas; Collins, William J.; Faluvegi, Greg; Tsigaridis, Kostas

    2016-08-01

    We use the HadGEM3-GA4, CESM1, and GISS ModelE2 climate models to investigate the global and regional aerosol burden, radiative flux, and surface temperature responses to removing anthropogenic sulfur dioxide (SO2) emissions from China. We find that the models differ by up to a factor of 6 in the simulated change in aerosol optical depth (AOD) and shortwave radiative flux over China that results from reduced sulfate aerosol, leading to a large range of magnitudes in the regional and global temperature responses. Two of the three models simulate a near-ubiquitous hemispheric warming due to the regional SO2 removal, with similarities in the local and remote pattern of response, but overall with a substantially different magnitude. The third model simulates almost no significant temperature response. We attribute the discrepancies in the response to a combination of substantial differences in the chemical conversion of SO2 to sulfate, translation of sulfate mass into AOD, cloud radiative interactions, and differences in the radiative forcing efficiency of sulfate aerosol in the models. The model with the strongest response (HadGEM3-GA4) compares best with observations of AOD regionally, however the other two models compare similarly (albeit poorly) and still disagree substantially in their simulated climate response, indicating that total AOD observations are far from sufficient to determine which model response is more plausible. Our results highlight that there remains a large uncertainty in the representation of both aerosol chemistry as well as direct and indirect aerosol radiative effects in current climate models, and reinforces that caution must be applied when interpreting the results of modelling studies of aerosol influences on climate. Model studies that implicate aerosols in climate responses should ideally explore a range of radiative forcing strengths representative of this uncertainty, in addition to thoroughly evaluating the models used against

  20. Temperature response functions introduce high uncertainty in modelled carbon stocks in cold temperature regimes

    NASA Astrophysics Data System (ADS)

    Portner, H.; Bugmann, H.; Wolf, A.

    2010-11-01

    Models of carbon cycling in terrestrial ecosystems contain formulations for the dependence of respiration on temperature, but the sensitivity of predicted carbon pools and fluxes to these formulations and their parameterization is not well understood. Thus, we performed an uncertainty analysis of soil organic matter decomposition with respect to its temperature dependency using the ecosystem model LPJ-GUESS. We used five temperature response functions (Exponential, Arrhenius, Lloyd-Taylor, Gaussian, Van't Hoff). We determined the parameter confidence ranges of the formulations by nonlinear regression analysis based on eight experimental datasets from Northern Hemisphere ecosystems. We sampled over the confidence ranges of the parameters and ran simulations for each pair of temperature response function and calibration site. We analyzed both the long-term and the short-term heterotrophic soil carbon dynamics over a virtual elevation gradient in southern Switzerland. The temperature relationship of Lloyd-Taylor fitted the overall data set best as the other functions either resulted in poor fits (Exponential, Arrhenius) or were not applicable for all datasets (Gaussian, Van't Hoff). There were two main sources of uncertainty for model simulations: (1) the lack of confidence in the parameter estimates of the temperature response, which increased with increasing temperature, and (2) the size of the simulated soil carbon pools, which increased with elevation, as slower turn-over times lead to higher carbon stocks and higher associated uncertainties. Our results therefore indicate that such projections are more uncertain for higher elevations and hence also higher latitudes, which are of key importance for the global terrestrial carbon budget.

  1. Studies on the application of temperature-responsive ion exchange polymers with whey proteins.

    PubMed

    Maharjan, Pankaj; Campi, Eva M; De Silva, Kirthi; Woonton, Brad W; Jackson, W Roy; Hearn, Milton T W

    2016-03-18

    Several new types of temperature-responsive ion exchange resins of different polymer composition have been prepared by grafting the products from the co-polymerisation of N-phenylacrylamide, N-iso-propylacrylamide and acrylic acid derivatives onto cross-linked agarose. Analysis of the binding isotherms for these different resins obtained under batch adsorption conditions indicated that the resin based on N-iso-propylacrylamide containing 5% (w/w) N-phenylacrylamide and 5% (w/w) acrylic acid resulted in the highest adsorption capacity, Bmax, for the whey protein, bovine lactoferrin, e.g. 14 mg bovine lactoferrin/mL resin at 4 °C and 62 mg bovine lactoferrin/mL resin at 40 °C, respectively. Under dynamic loading conditions at 40 °C, 94% of the loaded bovine lactoferrin on a normalised mg protein per mL resin basis was adsorbed by this new temperature-responsive ion-exchanger, and 76% was eluted by a single cycle temperature shift to 4 °C without varying the composition of the 10mM sodium dihydrogen phosphate buffer, pH 6.5, or the flow rate. The binding characteristics of these different ion exchange resins with bovine lactoferrin were also compared to results obtained using other resins based on N-isopropylacrylamide but contained N-tert-butylacrylamide rather than N-phenylacrylamide, where the corresponding dynamic capture and release properties for bovine lactoferrin required different temperature conditions of 20 °C and 50 °C, respectively for optimal desorption/adsorption. The cationic protein, bovine lactoperoxidase, was also adsorbed and desorbed with these temperature-responsive resins under similar conditions of changing temperature, whereas the anionic protein, bovine β-lactoglobulin, was not adsorbed under this regime of temperature conditions but instead eluted in the flow-through.

  2. Long- and short-term temperature responses of microbially-mediated boreal soil organic matter transformations

    NASA Astrophysics Data System (ADS)

    Min, K.; Buckeridge, K. M.; Edwards, K. A.; Ziegler, S. E.; Billings, S. A.

    2015-12-01

    Microorganisms use exoenzymes to decay soil organic matter into assimilable substrates, some of which are transformed into CO2. Microbial CO2 efflux contributes up to 60% of soil respiration, a feature that can change with temperature due to altered exoenzyme activities (short-term) and microbial communities producing different exoenzymes (longer-term). Often, however, microbial temperature responses are masked by factors that also change with temperature in soil, making accurate projections of microbial CO2 efflux with warming challenging. Using soils along a natural climate gradient similar in most respects except for temperature regime (Newfoundland Labrador Boreal Ecosystem Latitudinal Transect), we investigated short-vs. long-term temperature responses of microbially-mediated organic matter transformations. While incubating soils at 5, 15, and 25°C for 84 days, we measured exoenzyme activities, CO2 efflux rates and biomass, and extracted DNA at multiple times. We hypothesized that short-term, temperature-induced increases in exoenzyme activities and CO2 losses would be smaller in soils from warmer regions, because microbes presumably adapted to warmer regions should use assimilable substrates more efficiently and thus produce exoenzymes at a lower rate. While incubation temperature generally induced greater exoenzyme activities (p<0.001), exoenzymes' temperature responses depended on enzymes and regions (p<0.001). Rate of CO2 efflux was affected by incubation temperature (P<0.001), but not by region. Microbial biomass and DNA sequencing will reveal how microbial community abundance and composition change with short-vs. longer-term temperature change. Though short-term microbial responses to temperature suggest higher CO2 efflux and thus lower efficiency of resource use with warming, longer-term adaptations of microbial communities to warmer climates remain unknown; this work helps fill that knowledge gap.

  3. Differences between rice and wheat in temperature responses of photosynthesis and plant growth.

    PubMed

    Nagai, Takeshi; Makino, Amane

    2009-04-01

    The temperature responses of photosynthesis (A) and growth were examined in rice and wheat grown hydroponically under day/night temperature regimes of 13/10, 19/16, 25/19, 30/24 and 37/31 degrees C. Irrespective of growth temperature, the maximal rates of A were found to be at 30-35 degrees C in rice and at 25-30 degrees C in wheat. Below 25 degrees C the rates were higher in wheat, while above 30 degrees C they were higher in rice. However, in both species, A measured at the growth temperature remained almost constant irrespective of temperature. Biomass production and relative growth rate (RGR) were greatest in rice grown at 30/24 degrees C and in wheat grown at 25/19 degrees C. Although there was no difference between the species in the optimal temperature of the leaf area ratios (LARs), the net assimilation rate (NAR) in rice decreased at low temperature (19/16 degrees C) while the NAR in wheat decreased at high temperature (37/31 degrees C). For both species, the N-use efficiency (NUE) for growth rate (GR), estimated by dividing the NAR by leaf-N content, correlated with GR and with biomass production. Similarly, when NUE for A at growth temperature was estimated, the temperature response of NUE for A was similar to that of NUE for GR in both species. The results suggest that the difference between rice and wheat in the temperature response of biomass production depends on the difference in temperature dependence of NUE for A.

  4. Modeling the Temperature Responses to Spectral Solar Variability on Decadal and Centennial Time Scales

    NASA Astrophysics Data System (ADS)

    Cahalan, R. F.; Wen, G.; Pilewskie, P.; Harder, J. W.

    2010-12-01

    Atmospheric temperature responses to decadal solar variations are computed for two scenarios of solar spectral irradiance (SSI), SIM-based out-of-phase and proxy-based in-phase variations, using a time-dependent radiative-convective model (RCM), and also GISS modelE (GCM.) For both scenarios and both models, maximum responses occur in upper stratosphere, decreasing downward to the surface. Upper stratospheric temperature peak-to-peak responses to out-of-phase forcing are ~0.6 K in RCM and ~0.9 K over tropics in GCM, ~5x as large as responses to in-phase forcing. Stratospheric responses are in-phase with TSI (Total Solar Irradiance). Modeled upper stratospheric temperature responses to SIM-based forcing are similar to 11-year temperature variations observed with HALOE (Halogen Occultation Experiment). For both RCM and GCM, surface responses to the two scenarios are significantly smaller than stratospheric responses. On centennial timescales, SSI variations are poorly known. However, two scenarios of reconstructed TSI, one based on 11-year cycle with background [Lean 2000] and the other on flux transport with much less background [Wang, Lean, and Sheeley, 2005], provide a potential range of TSI variations. We apply phase relations among different SSI bands both from SIM observations and proxy reconstructions to the two scenarios of historical TSI to derive associated historical SSI, which then drives the RCM. The updated atmosphere and ocean mixed coupled RCM including diffusion to deep-ocean provide a first order estimate of temperature responses to SSI variations on centennial time scales. We discuss potential mechanisms for atmosphere-ocean and stratosphere-troposphere couplings responsible for the climate responses to spectral solar variations.

  5. Altitudinal changes in temperature responses of net photosynthesis and dark respiration in tropical bryophytes

    PubMed Central

    Wagner, Sebastian; Zotz, Gerhard; Salazar Allen, Noris; Bader, Maaike Y.

    2013-01-01

    Background and Aims There is a conspicuous increase of poikilohydric organisms (mosses, liverworts and macrolichens) with altitude in the tropics. This study addresses the hypothesis that the lack of bryophytes in the lowlands is due to high-temperature effects on the carbon balance. In particular, it is tested experimentally whether temperature responses of CO2-exchange rates would lead to higher respiratory carbon losses at night, relative to potential daily gains, in lowland compared with lower montane forests. Methods Gas-exchange measurements were used to determine water-, light-, CO2- and temperature-response curves of net photosynthesis and dark respiration of 18 tropical bryophyte species from three altitudes (sea level, 500 m and 1200 m) in Panama. Key Results Optimum temperatures of net photosynthesis were closely related to mean temperatures in the habitats in which the species grew at the different altitudes. The ratio of dark respiration to net photosynthesis at mean ambient night and day temperatures did not, as expected, decrease with altitude. Water-, light- and CO2-responses varied between species but not systematically with altitude. Conclusions Drivers other than temperature-dependent metabolic rates must be more important in explaining the altitudinal gradient in bryophyte abundance. This does not discard near-zero carbon balances as a major problem for lowland species, but the main effect of temperature probably lies in increasing evaporation rates, thus restricting the time available for photosynthetic carbon gain, rather than in increasing nightly respiration rates. Since optimum temperatures for photosynthesis were so fine tuned to habitat temperatures we analysed published temperature responses of bryophyte species worldwide and found the same pattern on the large scale as we found along the tropical mountain slope we studied. PMID:23258418

  6. Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles

    PubMed Central

    Shiozaki, Afonso A.; Senra, Tiago; Morikawa, Aleksandra T.; Deus, Débora F.; Paladino, Antonio T; Pinto, Ibraim M.F.; Maranhão, Raul C.

    2016-01-01

    OBJECTIVE: The toxicity of anti-cancer chemotherapeutic agents can be reduced by associating these compounds, such as the anti-proliferative agent paclitaxel, with a cholesterol-rich nanoemulsion (LDE) that mimics the lipid composition of low-density lipoprotein (LDL). When injected into circulation, the LDE concentrates the carried drugs in neoplastic tissues and atherosclerotic lesions. In rabbits, atherosclerotic lesion size was reduced by 65% following LDE-paclitaxel treatment. The current study aimed to test the effectiveness of LDE-paclitaxel on inpatients with aortic atherosclerosis. METHODS: This study tested a 175 mg/m2 body surface area dose of LDE-paclitaxel (intravenous administration, 3/3 weeks for 6 cycles) in patients with aortic atherosclerosis who were aged between 69 and 86 yrs. A control group of 9 untreated patients with aortic atherosclerosis (72-83 yrs) was also observed. RESULTS: The LDE-paclitaxel treatment elicited no important clinical or laboratory toxicities. Images were acquired via multiple detector computer tomography angiography (64-slice scanner) before treatment and at 1-2 months after treatment. The images showed that the mean plaque volume in the aortic artery wall was reduced in 4 of the 8 patients, while in 3 patients it remained unchanged and in one patient it increased. In the control group, images were acquired twice with an interval of 6-8 months. None of the patients in this group exhibited a reduction in plaque volume; in contrast, the plaque volume increased in three patients and remained stable in four patients. During the study period, one death unrelated to the treatment occurred in the LDE-paclitaxel group and one death occurred in the control group. CONCLUSION: Treatment with LDE-paclitaxel was tolerated by patients with cardiovascular disease and showed the potential to reduce atherosclerotic lesion size. PMID:27626473

  7. Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles

    PubMed Central

    Shiozaki, Afonso A.; Senra, Tiago; Morikawa, Aleksandra T.; Deus, Débora F.; Paladino, Antonio T; Pinto, Ibraim M.F.; Maranhão, Raul C.

    2016-01-01

    OBJECTIVE: The toxicity of anti-cancer chemotherapeutic agents can be reduced by associating these compounds, such as the anti-proliferative agent paclitaxel, with a cholesterol-rich nanoemulsion (LDE) that mimics the lipid composition of low-density lipoprotein (LDL). When injected into circulation, the LDE concentrates the carried drugs in neoplastic tissues and atherosclerotic lesions. In rabbits, atherosclerotic lesion size was reduced by 65% following LDE-paclitaxel treatment. The current study aimed to test the effectiveness of LDE-paclitaxel on inpatients with aortic atherosclerosis. METHODS: This study tested a 175 mg/m2 body surface area dose of LDE-paclitaxel (intravenous administration, 3/3 weeks for 6 cycles) in patients with aortic atherosclerosis who were aged between 69 and 86 yrs. A control group of 9 untreated patients with aortic atherosclerosis (72-83 yrs) was also observed. RESULTS: The LDE-paclitaxel treatment elicited no important clinical or laboratory toxicities. Images were acquired via multiple detector computer tomography angiography (64-slice scanner) before treatment and at 1-2 months after treatment. The images showed that the mean plaque volume in the aortic artery wall was reduced in 4 of the 8 patients, while in 3 patients it remained unchanged and in one patient it increased. In the control group, images were acquired twice with an interval of 6-8 months. None of the patients in this group exhibited a reduction in plaque volume; in contrast, the plaque volume increased in three patients and remained stable in four patients. During the study period, one death unrelated to the treatment occurred in the LDE-paclitaxel group and one death occurred in the control group. CONCLUSION: Treatment with LDE-paclitaxel was tolerated by patients with cardiovascular disease and showed the potential to reduce atherosclerotic lesion size.

  8. Paclitaxel attenuates renal interstitial fibroblast activation and interstitial fibrosis by inhibiting STAT3 signaling

    PubMed Central

    Zhang, Lei; Xu, Xuan; Yang, Ruhao; Chen, Jingwen; Wang, Shixuan; Yang, Junqin; Xiang, Xudong; He, Zhibiao; Zhao, Yu; Dong, Zheng; Zhang, Dongshan

    2015-01-01

    Recent studies have demonstrated that paclitaxel might inhibit renal fibrosis. However, the underlying molecular mechanism remains unclear. In this study, we hypothesized that low-dose paclitaxel may block the STAT3 (signal transducer and activator of transcription 3) signaling to attenuate fibrosis in a mouse model with unilateral ureteral obstruction. Both NRK-49F cells and mice with unilateral ureteral obstruction were treated with paclitaxel. The results showed that paclitaxel treatment resulted in a dose- and time-dependent decrease in tyrosine-phosphorylated STAT3, and inhibited the expression of fibronectin, alpha-smooth muscle actin (α-SMA), and collagen I in cultured NRK-49F cells. S3I-201, an STAT3 inhibitor, also suppressed the expression of fibronectin, α-SMA, and collagen I in cultured NRK-49F cells. Mechanistically, paclitaxel treatment blocked the STAT3 activity by disrupting the association of STAT3 with tubulin and inhibiting STAT3 nucleus translocation. Furthermore, paclitaxel also ameliorated renal fibrosis by down-regulating the expression of fibronectin, α-SMA, and collagen I, and suppressed the infiltration of macrophages and production of TNF-α, IL-1β, TGF-β, and ICAM-1 (intercellular adhesion molecule 1) by inhibition of STAT3 activity in obstructive nephropathy. These results suggest that paclitaxel may block the STAT3 activity by disrupting the association of STAT3 with tubulin and inhibiting STAT3 nucleus translocation, consequently leading to the suppression of renal interstitial fibroblast activation and the development of renal fibrosis, and inhibition of proinflammatory cytokine production. PMID:25931810

  9. Dasatinib enhances antitumor activity of paclitaxel in ovarian cancer through Src signaling

    PubMed Central

    XIAO, JUAN; XU, MANMAN; HOU, TENG; HUANG, YONGWEN; YANG, CHENLU; LI, JUNDONG

    2015-01-01

    Src family tyrosine kinase (SFK) activation is associated with ovarian cancer progression. Therefore, SFKs are targets for the development of potential treatments of ovarian cancer. Dasatinib is a tyrosine kinase inhibitor that targets SFK activity, and is used for the treatment of B cell and Abelson lymphomas. At the present time, the potential effect of dasatinib on ovarian cancer is not clear. The aim of the present study was to investigate the antitumor activity of dasatinib, alone and in combination with paclitaxel, in ovarian cancer in vitro and in vivo. In the present study, the expression of Src and phospho-Src-Y416 (p-Src) was measured in six ovarian cancer cell lines using western blotting and immunohistochemistry. In addition, cell viability and apoptosis were measured using an MTT assay and annexin V-fluorescein isothiocyanate staining. An ovarian cancer murine xenograft model was established, in order to evaluate the antitumor effect of dasatinib alone and in combination with paclitaxel in ovarian cancer. High levels of p-Src protein expression were observed in all cell lines, as compared with healthy cells, which indicated activation of the Src signaling pathway. p-Src expression increased in ovarian cancer cells following paclitaxel treatment. Dasatinib treatment demonstrated anti-ovarian cancer properties, by downregulating p-Src expression and by inducing cancer cell apoptosis. Combined treatment with dasatinib and paclitaxel markedly inhibited proliferation and promoted apoptosis of ovarian cancer cells, compared with control cells. Combined dasatinib and paclitaxel treatment exhibited antitumor activities in vivo and in vitro (combination indices, 0.25–0.93 and 0.31–0.75; and tumor growth inhibitory rates, 76.7% and 58.5%, in A2780 and HO8910 cell lines, respectively), compared with paclitaxel treatment alone. Dasatinib monotherapy demonstrated anti-ovarian cancer activities. The effects of dasatinib and paclitaxel treatments on ovarian

  10. Simulation of pressure and temperature responses for the 20 Inch Supersonic Wind Tunnel

    NASA Technical Reports Server (NTRS)

    Motter, Mark A.

    1990-01-01

    A simulation of the pressure and temperature responses of the 20 inch Supersonic Wind Tunnel (SWT) is developed. The simulation models the tunnel system as a set of lumped parameter volumes connected by flow regulating elements such as valves and nozzles. Simulated transient responses of temperature and pressure for the five boundary points of the 20 inch SWT operating map are produced from their respective initial conditions, tunnel operating conditions, heater input power, and valve positions. Upon reaching steady state, a linearized model for each operating point is determined. Both simulated and actual tunnel responses are presented for comparison.

  11. Surveying Rubisco Diversity and Temperature Response to Improve Crop Photosynthetic Efficiency1[OPEN

    PubMed Central

    Andralojc, P. John

    2016-01-01

    The threat to global food security of stagnating yields and population growth makes increasing crop productivity a critical goal over the coming decades. One key target for improving crop productivity and yields is increasing the efficiency of photosynthesis. Central to photosynthesis is Rubisco, which is a critical but often rate-limiting component. Here, we present full Rubisco catalytic properties measured at three temperatures for 75 plants species representing both crops and undomesticated plants from diverse climates. Some newly characterized Rubiscos were naturally “better” compared to crop enzymes and have the potential to improve crop photosynthetic efficiency. The temperature response of the various catalytic parameters was largely consistent across the diverse range of species, though absolute values showed significant variation in Rubisco catalysis, even between closely related species. An analysis of residue differences among the species characterized identified a number of candidate amino acid substitutions that will aid in advancing engineering of improved Rubisco in crop systems. This study provides new insights on the range of Rubisco catalysis and temperature response present in nature, and provides new information to include in models from leaf to canopy and ecosystem scale. PMID:27342312

  12. Global Temperature Response to the Major Volcanic Eruptions in Multiple Reanalysis Datasets

    NASA Astrophysics Data System (ADS)

    Fujiwara, M.; Hibino, T.; Mehta, S. K.; Gray, L. J.; Mitchell, D.; Anstey, J.

    2015-12-01

    Global temperature response to the eruptions of Mount Agung in 1963, El Chichón in 1982 and Mount Pinatubo in 1991 is investigated using nine reanalysis datasets (JRA-55, MERRA, ERA-Interim, NCEP-CFSR, JRA-25, ERA-40, NCEP-1, NCEP-2, and 20CR). Multiple linear regression is applied to the zonal and monthly mean time series of temperature for two periods, 1979-2009 (for eight reanalysis datasets) and 1958-2001 (for four reanalysis datasets), by considering explanatory factors of seasonal harmonics, linear trends, Quasi-Biennial Oscillation, solar cycle, and El Niño Southern Oscillation. The residuals are used to define the volcanic signals for the three eruptions separately. In response to the Mount Pinatubo eruption, most reanalysis datasets show strong warming signals (up to 2-3 K for one-year average) in the tropical lower stratosphere and weak cooling signals (down to -1 K) in the subtropical upper troposphere. For the El Chichón eruption, warming signals in the tropical lower stratosphere are somewhat smaller than those for the Mount Pinatubo eruption. The response to the Mount Agung eruption is asymmetric about the equator with strong warming in the Southern Hemisphere midlatitude upper troposphere to lower stratosphere. Comparison of the results from several different reanalysis datasets confirms the atmospheric temperature response to these major eruptions qualitatively, but also shows quantitative differences even among the most recent reanalysis datasets.

  13. Modeling and Experimental Analysis on the Temperature Response of AlN-Film Based SAWRs

    PubMed Central

    Chen, Shuo; You, Zheng

    2016-01-01

    The temperature responses of aluminum nitride (AlN) based surface acoustic wave resonator (SAWR) are modeled and tested. The modeling of the electrical performance is based on a modified equivalent circuit model introduced in this work. For SAWR consisting of piezoelectric film and semiconducting substrate, parasitic parameters from the substrate is taken into consideration for the modeling. By utilizing the modified model, the high temperature electrical performance of the AlN/Si and AlN/6H-SiC based SAWRs can be predicted, indicating that a substrate with a wider band gap will lead to a more stable high temperature behavior, which is further confirmed experimentally by high temperature testing from 300 K to 725 K with SAWRs having a wavelength of 12 μm. Temperature responses of SAWR’s center frequency are also calculated and tested, with experimental temperature coefficient factors (TCF) of center frequency being −29 ppm/K and −26 ppm/K for the AlN/Si and AlN/6H-SiC based SAWRs, which are close to the predicted values. PMID:27483286

  14. Temperature-responsive polymers and brushes with tunable onset of response

    NASA Astrophysics Data System (ADS)

    Foley, Theresa; Efimenko, Kiril; Genzer, Jan; Manias, Evangelos

    2006-03-01

    Temperature-responsive polymers are of high interest in the scientific field of stimuli responsive materials, in particular water soluble polymers with a response at ˜36.5^oC. However, difficulties in tailoring this T-response, as illustrated for example from studies of PNIPAM in numerous functionalized and copolymer forms, has hampered their proliferation. Here we present a systematic series of temperature-responsive polymers, which were designed, synthesized, and studied, and we show that we can tailor with high sensitivity their onset of T-response via the design of their monomer. Specifically, we demonstrate lower critical solution temperature (LCST) in water finely tuned between 5 and 70^oC, by controlling the hydrophilic/hydrophobic balance in the monomer (closely following predictions of phase behavior theories). In addition, we will also show that these polymers maintain their T-responsive characteristics when end-tethered to solid surfaces, over a wide range of grafting densities in combinatorial brushes. This approach allows for controlling contact angle, adhesion and tackiness as a function of temperature.

  15. Modeling and Experimental Analysis on the Temperature Response of AlN-Film Based SAWRs.

    PubMed

    Chen, Shuo; You, Zheng

    2016-01-01

    The temperature responses of aluminum nitride (AlN) based surface acoustic wave resonator (SAWR) are modeled and tested. The modeling of the electrical performance is based on a modified equivalent circuit model introduced in this work. For SAWR consisting of piezoelectric film and semiconducting substrate, parasitic parameters from the substrate is taken into consideration for the modeling. By utilizing the modified model, the high temperature electrical performance of the AlN/Si and AlN/6H-SiC based SAWRs can be predicted, indicating that a substrate with a wider band gap will lead to a more stable high temperature behavior, which is further confirmed experimentally by high temperature testing from 300 K to 725 K with SAWRs having a wavelength of 12 μm. Temperature responses of SAWR's center frequency are also calculated and tested, with experimental temperature coefficient factors (TCF) of center frequency being -29 ppm/K and -26 ppm/K for the AlN/Si and AlN/6H-SiC based SAWRs, which are close to the predicted values. PMID:27483286

  16. Mathematical model of cycad cones' thermogenic temperature responses: inverse calorimetry to estimate metabolic heating rates.

    PubMed

    Roemer, R B; Booth, D; Bhavsar, A A; Walter, G H; Terry, L I

    2012-12-21

    A mathematical model based on conservation of energy has been developed and used to simulate the temperature responses of cones of the Australian cycads Macrozamia lucida and Macrozamia. macleayi during their daily thermogenic cycle. These cones generate diel midday thermogenic temperature increases as large as 12 °C above ambient during their approximately two week pollination period. The cone temperature response model is shown to accurately predict the cones' temperatures over multiple days as based on simulations of experimental results from 28 thermogenic events from 3 different cones, each simulated for either 9 or 10 sequential days. The verified model is then used as the foundation of a new, parameter estimation based technique (termed inverse calorimetry) that estimates the cones' daily metabolic heating rates from temperature measurements alone. The inverse calorimetry technique's predictions of the major features of the cones' thermogenic metabolism compare favorably with the estimates from conventional respirometry (indirect calorimetry). Because the new technique uses only temperature measurements, and does not require measurements of oxygen consumption, it provides a simple, inexpensive and portable complement to conventional respirometry for estimating metabolic heating rates. It thus provides an additional tool to facilitate field and laboratory investigations of the bio-physics of thermogenic plants. PMID:22995822

  17. Modeling and Experimental Analysis on the Temperature Response of AlN-Film Based SAWRs.

    PubMed

    Chen, Shuo; You, Zheng

    2016-07-30

    The temperature responses of aluminum nitride (AlN) based surface acoustic wave resonator (SAWR) are modeled and tested. The modeling of the electrical performance is based on a modified equivalent circuit model introduced in this work. For SAWR consisting of piezoelectric film and semiconducting substrate, parasitic parameters from the substrate is taken into consideration for the modeling. By utilizing the modified model, the high temperature electrical performance of the AlN/Si and AlN/6H-SiC based SAWRs can be predicted, indicating that a substrate with a wider band gap will lead to a more stable high temperature behavior, which is further confirmed experimentally by high temperature testing from 300 K to 725 K with SAWRs having a wavelength of 12 μm. Temperature responses of SAWR's center frequency are also calculated and tested, with experimental temperature coefficient factors (TCF) of center frequency being -29 ppm/K and -26 ppm/K for the AlN/Si and AlN/6H-SiC based SAWRs, which are close to the predicted values.

  18. Paclitaxel tumor priming promotes delivery and transfection of intravenous lipid-siRNA in pancreatic tumors.

    PubMed

    Wang, Jie; Lu, Ze; Wang, Junfeng; Cui, Minjian; Yeung, Bertrand Z; Cole, David J; Wientjes, M Guillaume; Au, Jessie L-S

    2015-10-28

    The major barrier for using small interfering RNA (siRNA) as cancer therapeutics is the inadequate delivery and transfection in solid tumors. We have previously shown that paclitaxel tumor priming, by inducing apoptosis, expands the tumor interstitial space, improves the penetration and dispersion of nanoparticles and siRNA-lipoplexes in 3-dimensional tumor histocultures, and promotes the delivery and transfection efficiency of siRNA-lipoplexes under the locoregional setting in vivo (i.e., intraperitoneal treatment of intraperitoneal tumors). The current study evaluated whether tumor priming is functional for systemically delivered siRNA via intravenous injection, which would subject siRNA to several additional delivery barriers and elimination processes. We used the same pegylated cationic (PCat)-siRNA lipoplexes as in the intraperitoneal study to treat mice bearing subcutaneous human pancreatic Hs766T xenograft tumors. The target gene was survivin, an inducible chemoresistance gene. The results show single agent paclitaxel delayed tumor growth but also significantly induced the survivin protein level in residual tumors, whereas addition of PCat-siSurvivin completely reversed the paclitaxel-induced survivin and enhanced the paclitaxel activity (p<0.05). In comparison, PCat-siSurvivin alone did not yield survivin knockdown or antitumor activity, indicating the in vivo effectiveness of intravenous siRNA-mediated gene silencing requires paclitaxel cotreatment. Additional in vitro studies showed that paclitaxel promoted the cytoplasmic release of siGLO, a 22 nucleotide double-stranded RNA that has no mRNA targets, from its PCat lipoplex and/or endosomes/lysosomes. Taken together, our earlier and current data show paclitaxel tumor priming, by promoting the interstitial transport and cytoplasmic release, is critical to promote the delivery and transfection of siRNA in vivo. In addition, because paclitaxel has broad spectrum activity and is used to treat multiple types

  19. Combination treatment with paclitaxel and doxorubicin inhibits growth of human esophageal squamous cancer cells by inactivation of Akt.

    PubMed

    Lee, Hwan Hee; Ye, Shuai; Li, Xiu Juan; Lee, Kwang Bok; Park, Man Hee; Kim, Soo Mi

    2014-01-01

    Despite the fact that paclitaxel and doxorubicin are widely used as chemotherapy agents against several types of cancer, their combined effects on esophageal squamous cell carcinoma (ESCC) have never been fully elucidated. The present study was designed to investigate the biological effects of paclitaxel and doxorubicin in ESCC cells. Combination treatment with paclitaxel and doxorubicin significantly inhibited the proliferation of TE-12 cells in a dose-and time-dependent manner compared to treatment with paclitaxel or doxorubicin alone. FACS analysis showed that the percentage of cells in the G2/M phase was significantly increased at 12 h after treatment with the combination. Increased p-cdc2, p-Wee1 and p53 protein levels were observed, while Akt activation was suppressed by combination treatment with paclitaxel and doxorubicin. In addition, treatment with paclitaxel plus doxorubicin significantly increased apoptosis as indicated by increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-7 and -9 levels. These results suggest that combination treatment with paclitaxel and doxorubicin induced G2/M cell cycle arrest and apoptosis in human ESCC cells by suppressing Akt activity. These findings highlight the potent apoptotic effect of combination therapy with paclitaxel and doxorubicin in ESCC cells and the potential clinical benefits of these two drugs in esophageal cancer. PMID:24247637

  20. MiR-634 sensitizes nasopharyngeal carcinoma cells to paclitaxel and inhibits cell growth both in vitro and in vivo.

    PubMed

    Peng, Xiaowei; Cao, Peiguo; He, Dong; Han, Shuang; Zhou, Jianda; Tan, Guolin; Li, Wei; Yu, Fenghui; Yu, Jianjun; Li, Zan; Cao, Ke

    2014-01-01

    Resistance to chemotherapy is one of the key causal factors in cancer death and increasing evidence has revealed that microRNAs (miRNAs) are involved in chemoresistance in many kinds of human cancers. Paclitaxel has been used for treatment of advanced nasopharyngeal carcinoma (NPC); however, treatment failure often occurs due to development of acquired paclitaxel resistance. In this study, based on miRNA microarray screening and qRT-PCR validation, we found six differentially expressed miRNAs in our induced paclitaxel-resistant NPC CNE-1/Taxol cells. Furthermore, we clarified the role of miR-634, most significantly downregulated in the paclitaxel-resistant CNE-1/Taxol, in regulating the paclitaxel sensitivity in NPC cells. We restored miR-634 expression in the CNE-1/Taxol cells by lentivirus infection, and found restoration of miR-634 re-sensitized the CNE-1/Taxol cells to paclitaxel in vitro by MTT assay and colony formation assay. In xenograft mouse model, we found that miR-634 inhibited tumor growth and enhanced paclitaxel sensitivity. Thus, our findings provide important information for the development of targeted gene therapy for reversing paclitaxel resistance in NPC.

  1. Paclitaxel/Taxol sensitivity in human renal cell carcinoma is not determined by the p53 status.

    PubMed

    Reinecke, Petra; Kalinski, Thomas; Mahotka, Csaba; Schmitz, Michael; Déjosez, Marion; Gabbert, Helmut Erich; Gerharz, Claus Dieter

    2005-05-26

    In this study, we analyzed the role of the p53 status for paclitaxel/Taxol sensitivity in renal cell carcinomas (RCCs) of the clear cell type. Using immunohistochemistry, nuclear p53 accumulation could not be correlated to the paclitaxel/Taxol sensitivity. DNA sequencing detected a p53 gene mutation in two out of eight RCC cell lines, i.e. in exon 8 (cell line clearCa-6), and in exon 9 (cell line clearCa-5). No correlation, however, was found between the p53 status of our RCC cell lines and their paclitaxel/Taxol sensitivity as indicated by the IC50 values. However, paclitaxel-induced growth inhibition in paclitaxel-sensitive RCC cell lines was accompanied by an increase in apoptosis, irrespective of their p53 status. Although CD95 up-regulation was observed in renal cell carcinoma with wild-type p53 upon paclitaxel treatment, paclitaxel-induced apoptosis itself is triggered independently from the CD95 system. In conclusion, the p53 status cannot predict paclitaxel/Taxol sensitivity in RCC cell lines of the clear cell type.

  2. IRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to paclitaxel

    PubMed Central

    Wee, Zhen Ning; Yatim, Siti Maryam J. M.; Kohlbauer, Vera K; Feng, Min; Goh, Jian Yuan; Yi, Bao; Lee, Puay Leng; Zhang, Songjing; Wang, Pan Pan; Lim, Elgene; Tam, Wai Leong; Cai, Yu; Ditzel, Henrik J; Hoon, Dave S. B.; Tan, Ern Yu; Yu, Qiang

    2015-01-01

    Metastatic tumour recurrence due to failed treatments remains a major challenge of breast cancer clinical management. Here we report that interleukin-1 receptor-associated kinase 1 (IRAK1) is overexpressed in a subset of breast cancers, in particular triple-negative breast cancer (TNBC), where it acts to drive aggressive growth, metastasis and acquired resistance to paclitaxel treatment. We show that IRAK1 overexpression confers TNBC growth advantage through NF-κB-related cytokine secretion and metastatic TNBC cells exhibit gain of IRAK1 dependency, resulting in high susceptibility to genetic and pharmacologic inhibition of IRAK1. Importantly, paclitaxel treatment induces strong IRAK1 phosphorylation, an increase in inflammatory cytokine expression, enrichment of cancer stem cells and acquired resistance to paclitaxel treatment. Pharmacologic inhibition of IRAK1 is able to reverse paclitaxel resistance by triggering massive apoptosis at least in part through inhibiting p38-MCL1 pro-survival pathway. Our study thus demonstrates IRAK1 as a promising therapeutic target for TNBC metastasis and paclitaxel resistance. PMID:26503059

  3. Paclitaxel Induced MDS and AML: A Case Report and Literature Review

    PubMed Central

    Bhatnagar, Udit Bhaskar; Singh, Daulath; Glazyrin, Alexy; Moormeier, Jill

    2016-01-01

    Therapy related acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) have been classically linked to alkylating agents and topoisomerase inhibitors. They constitute about 1% of all AMLs. There is less evidence on association of taxanes (paclitaxel and docetaxel) with these myeloid neoplasms. We present a case of paclitaxel therapy related acute myelogenous leukemia after treatment of endometrial cancer with a regimen containing paclitaxel and carboplatin. A 63-year-old female underwent surgery followed by a total of 6 cycles of chemotherapy with carboplatin and paclitaxel. Six months after last cycle of chemotherapy, she was diagnosed with myelodysplastic syndrome with refractory anemia and excess blasts. Six weeks later, she had worsening anemia and thrombocytopenia which prompted a bone marrow biopsy which revealed acute myelomonocytic leukemia. A thorough literature review revealed 12 other case reports where taxanes have been implicated in the development of therapy related myeloid neoplasm. Based on the timeline of events in our patient, paclitaxel is the likely culprit in the pathogenesis of this myeloid neoplasm. This rare but significantly grave adverse effect should be kept in consideration when deciding on treatment options for gynecological malignancies. PMID:27057370

  4. Paclitaxel reduces formation of hypertrophic scars in the rabbit ear model

    PubMed Central

    Huang, Li-ping; Wang, Guo-qi; Jia, Zi-shan; Chen, Jing-wen; Wang, Gang; Wang, Xing-lin

    2015-01-01

    Background and objective The onset and progression of pathological scarring involves multiple cytokines and complex mechanisms. However, hyperplasia of fibroblasts and neovascularization plays important roles, which can be inhibited by paclitaxel. The aim of this study was to investigate the efficacy of paclitaxel in the treatment of hypertrophic scars on rabbit ears. Methods Rabbit ear models of hypertrophic scars were established to observe the therapeutic effects of paclitaxel at different concentrations (12 mg/L, 24 mg/L, 48 mg/L, 96 mg/L, 18 mg/L, 54 mg/L, 162 mg/L, 486 mg/L, 30 mg/L, 150 mg/L, 750 mg/L, 3,750 mg/L). The outcome measures included hypertrophic index (HI), density of fibroblasts, density of collagenous fibers, and microvessel density. Results In comparison with the control group, the concentrations of 96 mg/L, 150 mg/L, and 162 mg/L significantly reduce the formation of hypertrophic scars in the rabbit ear models. However, local necrosis was found in the rabbit ear models treated with paclitaxel solution >400 mg/L. Conclusion Paclitaxel has strong inhibitory effects on the hyperplasia of fibroblasts, deposition of collagen, and microangiogenesis in hypertrophic scars on rabbit ears within the concentration range from 48 mg/L to 162 mg/L, without causing local necrosis. PMID:26251604

  5. Paclitaxel Through the Ages of Anticancer Therapy: Exploring Its Role in Chemoresistance and Radiation Therapy

    PubMed Central

    Barbuti, Anna Maria; Chen, Zhe-Sheng

    2015-01-01

    Paclitaxel (Taxol®) is a member of the taxane class of anticancer drugs and one of the most common chemotherapeutic agents used against many forms of cancer. Paclitaxel is a microtubule-stabilizer that selectively arrests cells in the G2/M phase of the cell cycle, and found to induce cytotoxicity in a time and concentration-dependent manner. Paclitaxel has been embedded in novel drug formulations, including albumin and polymeric micelle nanoparticles, and applied to many anticancer treatment regimens due to its mechanism of action and radiation sensitizing effects. Though paclitaxel is a major anticancer drug which has been used for many years in clinical treatments, its therapeutic efficacy can be limited by common encumbrances faced by anticancer drugs. These encumbrances include toxicities, de novo refraction, and acquired multidrug resistance (MDR). This article will give a current and comprehensive review of paclitaxel, beginning with its unique history and pharmacology, explore its mechanisms of drug resistance and influence in combination with radiation therapy, while highlighting current treatment regimens, formulations, and new discoveries. PMID:26633515

  6. Ferulic acid reverses ABCB1-mediated paclitaxel resistance in MDR cell lines.

    PubMed

    Muthusamy, Ganesan; Balupillai, Agilan; Ramasamy, Karthikeyan; Shanmugam, Mohana; Gunaseelan, Srithar; Mary, Beaulah; Prasad, N Rajendra

    2016-09-01

    Multidrug resistance (MDR) remains a major obstacle in cancer chemotherapy. The use of the dietary phytochemicals as chemosensitizing agents to enhance the efficacy of conventional cytostatic drugs has recently gained the attention as a plausible approach for overcoming the drug resistance. The aim of this study was to investigate whether a naturally occurring diet-based phenolic acid, ferulic acid, could sensitize paclitaxel efficacy in ABCB1 overexpressing (P-glycoprotein) colchicine selected KB Ch(R)8-5 cell line. In vitro drug efflux assays demonstrated that ferulic acid inhibits P-glycoprotein transport function in drug resistant KB Ch(R)8-5 cell lines. However, ferulic acid significantly downregulates ABCB1 expression in a concentration dependent manner. Cytotoxicity assay reveals that ferulic acid decreased paclitaxel resistance in KBCh(R)8-5 and HEK293/ABCB1 cells, which indicates its chemosensitizing potential. Clonogenic cell survival assay and apoptotic morphological staining further confirm the chemosensitizing potential of ferulic acid in drug resistant KB Ch(R)8-5 cell lines. Ferulic acid treatment enhances paclitaxel mediated cell cycle arrest and upregulates paclitaxel-induced apoptotic signaling in KB resistant cells. Hence, it has been concluded that downregulation of ABCB1 and subsequent induction of paclitaxel-mediated cell cycle arrest and apoptotic signaling may be the cause for the chemosensitizing potential of ferulic acid in P-gp overexpressing cell lines. PMID:27262378

  7. Synergistic interaction of paclitaxel and curcumin with cyclodextrin polymer complexation in human cancer cells.

    PubMed

    Boztas, Ali O; Karakuzu, Ozgur; Galante, Gabriela; Ugur, Zafer; Kocabas, Fatih; Altuntas, Cengiz Z; Yazaydin, A Ozgur

    2013-07-01

    The use of cytotoxic chemotherapic agents is the most common method for the treatment of metastatic cancers. Poor water solubility and low efficiency of chemotherapic agents are among the major hurdles of effective chemotherapy treatments. Curcumin and paclitaxel are well-known chemotherapic agents with poor water solubility and undesired side effects. In this study, a novel drug nanocarrier system was formulated by encapsulating curcumin and paclitaxel in poly(β-cyclodextrin triazine) (PCDT) for the therapy of four cancer models; ovarian, lung, prostate, and breast cancer. Cell viability and colony formation assays revealed enhanced curcumin cytotoxicity upon complexation. Annexin V apoptotic studies showed that the PCDT complexation improved curcumin induced apoptosis in human ovarian cancer cell lines A2780 and SKOV-3, human nonsmall cell lung carcinoma cell line H1299, and human prostate cancer line DU-145, while no significant effect was observed with paclitaxel/PCDT complexation. The bioactivity of combining curcumin and paclitaxel was also investigated. A synergism was found between curcumin and paclitaxel, particularly when complexed with PCDT on A2780, SKOV-3, and H1299 cancer cell lines.

  8. Paclitaxel sensitivity in relation to ABCB1 expression, efflux and single nucleotide polymorphisms in ovarian cancer

    PubMed Central

    Gao, Bo; Russell, Amanda; Beesley, Jonathan; Chen, Xiao Qing; Healey, Sue; Henderson, Michelle; Wong, Mark; Emmanuel, Catherine; Galletta, Laura; Johnatty, Sharon E.; Bowtell, David; Bowtell, David; Chenevix-Trench, Georgia; deFazio, Anna; Gertig, Dorota; Green, Adle; Webb, Penelope; Hung, Jillian; Moore, Sue; Traficante, Nadia; Fereday, Sian; Harrap, Karen; Sadkowsky, Troy; Pandeya, Nirmala; Stuart-Harris, Robin; Kirsten, Fred; Rutovitz, Josie; Clingan, Peter; Glasgow, Amanda; Proietto, Anthony; Braye, Stephen; Otton, Greg; Shannon, Jennifer; Bonaventura, Tony; Stewart, James; Begbie, Stephen; Friedlander, Michael; Bell, David; Baron-Hay, Sally; Ferrier, Alan; Gard, Greg; Nevell, David; Pavlakis, Nick; Valmadre, Sue; Young, Barbara; Camaris, Catherine; Crouch, Roger; Edwards, Lyndal; Hacker, Neville; Marsden, Donald; Robertson, Greg; Beale, Phillip; Beith, Jane; Carter, Jonothan; Dalrymple, Chris; Hamilton, Anne; Houghton, Roger; Russell, Peter; Links, Matthew; Grygiel, John; Hill, Jane; Brand, Alison; Byth, Karen; Jaworski, Richard; Harnett, Paul; Sharma, Raghwa; Achen, Anita; Wain, Gerard; Ward, Bruce; Papadimos, David; Crandon, Alex; Cummings, Margaret; Horwood, Ken; Obermair, Andreas; Perrin, Lew; Wyld, David; Nicklin, Jim; Davy, Margaret; Oehler, Martin K; Hall, Chris; Dodd, Tom; Healy, Tabitha; Pittman, Ken; Henderson, Doug; Miller, John; Pierdes, John; Blomfield, Penny; Challis, David; McIntosh, Robert; Parker, Andrew; Brown, Bob; Rome, Robert; Allen, David; Grant, Peter; Hyde, Simon; Laurie, Rohan; Robbie, Melissa; Healy, David; Jobling, Tom; Manolitsas, Tom; McNealage, Jane; Rogers, Peter; Susil, Beatrice; Sumithran, Eric; Simpson, Ian; Phillips, Kelly; Rischin, Danny; Fox, Stephen; Johnson, Daryl; Waring, Paul; Lade, Stephen; Loughrey, Maurice; O’Callaghan, Neil; Murray, William; Billson, Virginia; Pyman, Jan; Neesham, Debra; Quinn, Michael; Underhill, Craig; Bell, Richard; Ng, Leong-Fook; Blum, Robert; Ganju, Vinod; Hammond, Ian; Leung, Yee; McCartney, Anthony; Buck, Martin; Haviv, Izak; Purdie, David; Whiteman, David; Zeps, Nikolajs; Malt, Mary-Rose; Mellon, Anne; Robertson, Randall; Bergh, Trish Vanden; Jones, Marian; Mackenzie, Patricia; Maidens, Jane; Nattress, Kath; Chiew, Yoke-Eng; Stenlake, Annie; Sullivan, Helen; Alexander, Barbara; Ashover, Pat; Brown, Sue; Corrish, Tracy; Green, Lyn; Jackman, Leah; Ferguson, Kaltin; Martin, Karen; Martyn, Adam; Ranieri, Barbara; White, Jo; Jayde, Victoria; Bowes, Leanne; Mamers, Pamela; Galletta, Laura; Giles, Debra; Hendley, Joy; Alsop, Katherine; Schmidt, Trudy; Shirley, Helen; Ball, Colleen; Young, Cherry; Viduka, Suzanna; Tran, Hoa; Bilic, Sanela; Glavinas, Lydia; Brooks, Julia; Haber, Michelle; Norris, Murray; Harnett, Paul; Chenevix-Trench, Georgia; Balleine, Rosemary L.; deFazio, Anna

    2014-01-01

    ABCB1 (adenosine triphosphate-binding cassette transporter B1) mediates cellular elimination of many chemotherapeutic agents including paclitaxel, which is commonly used to treat ovarian cancer. A significant association between common single nucleotide polymorphisms (SNPs) in ABCB1 and progression-free survival has been reported in patients with ovarian cancer. Variable paclitaxel clearance due to genotype specific differences in ABCB1 activity in cancer cells and/or normal tissues may underlie the association. Using cell-based models, we evaluated the correlations between ABCB1 expression, polymorphisms, transporter activity and paclitaxel sensitivity in ovarian cancer (n = 10) and lymphoblastoid (n = 19) cell lines. Close associations between ABCB1 expression, transporter function and paclitaxel sensitivity were found in lymphoblastoid cell lines, although we could not demonstrate an association with common SNPs. In ovarian cancer cell lines, ABCB1 expression was low and the association between expression and function was lost. These results suggest that ABCB1 related survival difference in ovarian cancer patients is more likely to be due to differential whole body paclitaxel clearance mediated by normal cells rather than a direct effect on cancer cells. PMID:24810093

  9. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer

    PubMed Central

    SIDERIS, SPYRIDON; AOUN, FOUAD; ZANATY, MARC; MARTINEZ, NIEVES CHANZA; LATIFYAN, SOFIA; AWADA, AHMAD; GIL, THIERRY

    2016-01-01

    The aim of the present study was to investigate the efficacy of paclitaxel following a first-line cisplatin regimen in patients with metastatic bladder cancer. The present study retrospectively evaluated the clinical effects and toxicities of second-line paclitaxel regimens following first-line cisplatin treatment in metastatic bladder cancer. A total of 42 patients with progressing metastatic urothelial bladder cancer following cisplatin-based chemotherapy were enrolled. The patients received weekly treatment with paclitaxel (80 mg/m2) with a median duration of 3 months. The overall response rate, disease control rate and median progression free survival were 9.5, 45.2 and 6.4 months, respectively. Weekly paclitaxel was well-tolerated with rare grade III or IV toxicities. Second-line weekly paclitaxel treatment following first-line cisplatin-based chemotherapy is an effective and well-tolerated regimen in urothelial metastatic bladder cancer. PMID:27284445

  10. Temperature Responses to Spectral Solar Variability on Decadal and Centennial Time Scales

    NASA Astrophysics Data System (ADS)

    Cahalan, Robert; Wen, Guoyong; Pilewskie, Peter; Harder, Jerald

    2010-05-01

    We apply two scenarios of 11-year solar spectral forcing, namely SIM-based out-of-phase variations and proxy-based in-phase variations, as input to a time-dependent radiative-convective model (RCM), and also to the GISS modelE GCM. For both scenarios, and both models, we find that the maximum temperature response occurs in the upper stratosphere, and temperature responses decrease downward to the surface. The upper stratospheric temperature peak-to-peak responses to out-of-phase solar forcing are ~0.6 K in RCM and ~0.9 K over the tropical region in GCM simulations, a factor of ~5 times as large as responses to in-phase solar forcing. Stratospheric responses are in-phase with TSI (Total Solar Irradiance) variations. The modeled upper stratospheric temperature response to the SORCE SIM observed SSI (Spectral Solar Irradiance) forcing resembles 11-year temperature variations observed with HALOE (Halogen Occultation Experiment). Surface responses to the two SSI scenarios are small for both RCM and GCM studies, as compared to stratospheric responses. Though solar irradiance variations on centennial time scale are not well known, the two scenarios of reconstructed TSI time series (i.e., one based on 11-year cycles with background [Lean 2000] and the second from flux transport that has much less background change [Wang, Lean, and Sheeley, 2005]) provide a range of variations of TSI on centennial time scales. We apply phase relations among different spectral irradiance bands both from SIM observation and proxy reconstructions to the two scenarios of historical TSI. The spectral solar forcing is used to drive the RCM. The updated atmosphere and ocean mixed coupled RCM including diffusion to deep-ocean provides a first-order estimate of climate response. We report the different responses of stratosphere, troposphere, and ocean surface to these 4 scenarios of centennial spectral solar forcing. We further discuss the mechanisms for atmosphere-ocean and stratosphere

  11. A PEG-Fmoc conjugate as a nanocarrier for paclitaxel

    PubMed Central

    Zhang, Peng; Huang, Yixian; Liu, Hao; Marquez, Rebecca; Lu, Jianqin; Zhao, Wenchen; Zhang, Xiaolan; Gao, Xiang; Li, Jiang; Venkataramanan, Raman; Xu, Liang; Li, Song

    2014-01-01

    We report here that a simple, well-defined, and easy-to-scale up nanocarrier, PEG5000-lysyl-(α-Fmoc-ε-t-Boc-lysine)2 conjugate (PEG-Fmoc), provides high loading capacity, excellent formulation stability and low systemic toxicity for paclitaxel (PTX), a first-line chemotherapeutic agent for various types of cancers. 9-Fluorenylmethoxycarbonyl (Fmoc) was incorporated into the nanocarrier as a functional building block to interact with drug molecules. PEG-Fmoc was synthesized via a three-step synthetic route, and it readily interacted with PTX to form mixed nanomicelles of small particle size (25–30 nm). The PTX loading capacity was about 36%, which stands well among the reported micellar systems. PTX entrapment in this micellar system is achieved largely via an Fmoc/PTX π-π stacking interaction, which was demonstrated by fluorescence quenching studies and 13C-NMR. PTX formulated in PEG-Fmoc micelles demonstrated sustained release kinetics, and in vivo distribution study via near infrared fluorescence imaging demonstrated an effective delivery of Cy5.5-labled PTX to tumor sites. The maximal tolerated dose for PTX/PEG-Fmoc (MTD > 120 mg PTX/kg) is higher than those for most reported PTX formulations, and in vivo therapeutic study exhibited a significantly improved antitumor activity than Taxol, a clinically used formulation of PTX. Our system may hold promise as a simple, safe, and effective delivery system for PTX with a potential for rapid translation into clinical study. PMID:24856103

  12. Stable and Efficient Paclitaxel Nanoparticles for Targeted Glioblastoma Therapy

    PubMed Central

    Mu, Qingxin; Jeon, Mike; Hsiao, Meng-Hsuan; Patton, Victoria K.; Wang, Kui; Press, Oliver W.

    2015-01-01

    Development of efficient nanoparticles (NPs) for cancer therapy remains a challenge. NPs are required to have high stability, uniform size, sufficient drug loading, targeting capability, and ability to overcome drug resistance. In this study, we report the development of a nanoparticle formulation that can meet all these challenging requirements for targeted glioblastoma multiform (GBM) therapy. This multifunctional nanoparticle is composed of a polyethylene glycol (PEG) coated magnetic iron oxide NP conjugated with cyclodextrin (CD) and chlorotoxin (CTX) and loaded with fluorescein and paclitaxel (PTX) (IONP-PTX-CTX-FL). The physicochemical properties of the IONP-PTX-CTX-FL were characterized by TEM, dynamic light scattering (DLS), and HPLC. The cellular uptake of NPs was studied using flow cytometry and confocal microscopy. Cell viability and apoptosis were assessed with the Alamar Blue viability assay and flow cytometry, respectively. The IONP-PTX-CTX-FL had a uniform size of ~44 nm and high stability in cell culture medium. Importantly, the presence of CTX on NPs enhanced the uptake of the NPs by GBM cells and improved the efficacy of PTX in killing both GBM and GBM drug-resistant cells. The IONP-PTX-CTX-FL has demonstrated its great potential for brain cancer therapy and may also be used to deliver PTX to treat other cancers. PMID:25761648

  13. Stable and efficient Paclitaxel nanoparticles for targeted glioblastoma therapy.

    PubMed

    Mu, Qingxin; Jeon, Mike; Hsiao, Meng-Hsuan; Patton, Victoria K; Wang, Kui; Press, Oliver W; Zhang, Miqin

    2015-06-01

    Development of efficient nanoparticles (NPs) for cancer therapy remains a challenge. NPs are required to have high stability, uniform size, sufficient drug loading, targeting capability, and ability to overcome drug resistance. In this study, the development of a NP formulation that can meet all these challenging requirements for targeted glioblastoma multiform (GBM) therapy is reported. This multifunctional NP is composed of a polyethylene glycol-coated magnetic iron oxide NP conjugated with cyclodextrin and chlorotoxin (CTX) and loaded with fluorescein and paclitaxel (PTX) (IONP-PTX-CTX-FL). The physicochemical properties of the IONP-PTX-CTX-FL are characterized by transmission electron microscope, dynamic light scattering, and high-performance liquid chromatography. The cellular uptake of NPs is studied using flow cytometry and confocal microscopy. Cell viability and apoptosis are assessed with the Alamar Blue viability assay and flow cytometry, respectively. The IONP-PTX-CTX-FL had a uniform size of ≈44 nm and high stability in cell culture medium. Importantly, the presence of CTX on NPs enhanced the uptake of the NPs by GBM cells and improved the efficacy of PTX in killing both GBM and GBM drug-resistant cells. The IONP-PTX-CTX-FL demonstrated its great potential for brain cancer therapy and may also be used to deliver PTX to treat other cancers.

  14. Paclitaxel inhibits selenoprotein S expression and attenuates endoplasmic reticulum stress.

    PubMed

    Qin, Hong-Shuang; Yu, Pei-Pei; Sun, Ying; Wang, Dan-Feng; Deng, Xiao-Fen; Bao, Yong-Li; Song, Jun; Sun, Lu-Guo; Song, Zhen-Bo; Li, Yu-Xin

    2016-06-01

    The primary effect of the endoplasmic reticulum (ER) stress response or unfolded protein response (UPR) is to reduce the load of unfolded protein and promote survival. However, prolonged and severe ER stress leads to tissue injury and serious diseases. Thus, it is important to identify drugs that can attenuate ER stress for the treatment of diseases. Natural products continue to provide lead compounds for drug discovery and front‑line pharmacotherapy for people worldwide. Previous studies have indicated that selenoprotein S (SelS) is a sensitive and ideal maker of ER stress. In the present study, a firefly luciferase reporter driven by the SelS gene promoter was used to screen for natural compounds capable of attenuating ER stress. From this, paclitaxel (PTX) was identified to efficiently inhibit the promoter activity of the SelS gene, and further results revealed that PTX significantly inhibited the tunicamycin‑induced upregulation of SelS at the mRNA and protein levels in HepG2 and HEK293T cells. In addition, PTX was able to efficiently inhibit the expression of the ER stress marker, glucose‑regulated protein 78, in ER stress, indicating that PTX may reverse ER stress. Taken together, these results suggest that PTX is able to inhibit SelS expression during ER stress and attenuate ER stress. PMID:27109260

  15. Radiation recall phenomenon presenting as myositis triggered by carboplatin plus paclitaxel and related literature review.

    PubMed

    Maeng, Chi Hoon; Park, Jun Sang; Lee, Seung Ah; Kim, Dong Hwan; Yun, Dong Hwan; Yoo, Seung-Don; Kim, Hee-Sang; Chon, Jinmann

    2014-01-01

    While most case reports to date are radiation recall dermatitis, radiation recall myositis, which is a distinct form of radiation recall phenomenon caused by carboplatin plus paclitaxel, has not been reported. We treated a 57-year-old female patient who suffered from recurrent cervical cancer. When the patient developed a new left sacral metastasis, salvage radiotherapy (total dose 60 Gy) was administered. Four weeks later, chemotherapy using carboplatin plus paclitaxel was initiated. Four months after chemotherapy, the patient complained of severe pain in her left buttock. On magnetic resonance imaging (MRI), edematous changes and increased signal densities of left gluteus maximus and medius muscles were noted suggesting myositis. The border of the high signal intensity territory of the muscles was sharp and clearly corresponded with the recent irradiation field. We concluded that the patient had radiation recall myositis triggered by paclitaxel-carboplatin. Symptoms were controlled by analgesics, and there was no recurrence.

  16. Well-Defined Polymer-Paclitaxel Prodrugs by a Grafting-from-Drug Approach.

    PubMed

    Louage, Benoit; Nuhn, Lutz; Risseeuw, Martijn D P; Vanparijs, Nane; De Coen, Ruben; Karalic, Izet; Van Calenbergh, Serge; De Geest, Bruno G

    2016-09-19

    We report on the design of a polymeric prodrug of the anticancer agent paclitaxel (PTX) by a grafting-from-drug approach. A chain transfer agent for reversible addition fragmentation chain transfer (RAFT) polymerization was efficiently and regioselectively linked to the C2' position of paclitaxel, which is crucial for its bioactivity. Subsequent RAFT polymerization of a hydrophilic monomer yielded well-defined paclitaxel-polymer conjugates with high drug loading, water solubility, and stability. The versatility of this approach was further demonstrated by ω-end post-functionalization with a fluorescent tracer. In vitro experiments showed that these conjugates are readily taken up into endosomes where native PTX is efficiently cleaved off and then reaches its subcellular target. This was confirmed by the cytotoxicity profile of the conjugate, which matches those of commercial PTX formulations based on mere physical encapsulation. PMID:27560940

  17. [A case of secondary sclerosing cholangitis caused by chemotherapy with nab-paclitaxel].

    PubMed

    Matsuo, Taku; Nakamura, Yukiko; Suzuki, Koji

    2015-05-01

    A 73-year-old woman had received 9 months of chemotherapy with nab-paclitaxel for locally advanced breast cancer. During the treatment, she was well and showed no major side effects except for alopecia and arthralgia. The tumor showed a tendency to reduction. However, chemotherapy was discontinued because of liver dysfunction. MRCP and ERCP demonstrated multiple stenoses of the hepatic ducts and the intrahepatic bile ducts. We diagnosed chemotherapy-induced sclerosing cholangitis caused by nab-paclitaxel. Treatment with ursodeoxycholic acid and steroid was ineffective. We added bezafibrate, which resulted in a gradual improvement in liver function. To the best of our knowledge, this is the first reported case of nab-paclitaxel-induced secondary sclerosing cholangitis. PMID:25947025

  18. Low Levels of NDRG1 in Nerve Tissue Are Predictive of Severe Paclitaxel-Induced Neuropathy

    PubMed Central

    Sundar, Raghav; Jeyasekharan, Anand D.; Pang, Brendan; Soong, Richie Chuan Teck; Kumarakulasinghe, Nesaretnam Barr; Ow, Samuel Guan Wei; Ho, Jingshan; Lim, Joline Si Jing; Tan, David Shao Peng; Wilder-Smith, Einar P. V.; Bandla, Aishwarya; Tan, Stacey Sze Hui; Asuncion, Bernadette Reyna; Fazreen, Zul; Hoppe, Michal Marek; Putti, Thomas Choudary; Poh, Lay Mui; Goh, Boon Cher; Lee, Soo-Chin

    2016-01-01

    Introduction Sensory peripheral neuropathy caused by paclitaxel is a common and dose limiting toxicity, for which there are currently no validated predictive biomarkers. We investigated the relationship between the Charcot-Marie-Tooth protein NDRG1 and paclitaxel-induced neuropathy. Methods/Materials Archived mammary tissue specimen blocks of breast cancer patients who received weekly paclitaxel in a single centre were retrieved and NDRG1 immunohistochemistry was performed on normal nerve tissue found within the sample. The mean nerve NDRG1 score was defined by an algorithm based on intensity of staining and percentage of stained nerve bundles. NDRG1 scores were correlated with paclitaxel induced neuropathy Results 111 patients were studied. 17 of 111 (15%) developed severe paclitaxel-induced neuropathy. The mean nerve NDRG1 expression score was 5.4 in patients with severe neuropathy versus 7.7 in those without severe neuropathy (p = 0.0019). A Receiver operating characteristic (ROC) curve analysis of the mean nerve NDRG1 score revealed an area under the curve of 0.74 (p = 0.0013) for the identification of severe neuropathy, with a score of 7 being most discriminative. 13/54 (24%) subjects with an NDRG1 score < = 7 developed severe neuropathy, compared to only 4/57 (7%) in those with a score >7 (p = 0.017). Conclusion Low NDRG1 expression in nerve tissue present within samples of surgical resection may identify subjects at risk for severe paclitaxel-induced neuropathy. Since nerve biopsies are not routinely feasible for patients undergoing chemotherapy for early breast cancer, this promising biomarker strategy is compatible with current clinical workflow. PMID:27716814

  19. Akt Phosphorylation at Ser473 Predicts Benefit of Paclitaxel Chemotherapy in Node-Positive Breast Cancer

    PubMed Central

    Yang, Sherry X.; Costantino, Joseph P.; Kim, Chungyeul; Mamounas, Eleftherios P.; Nguyen, Dat; Jeong, Jong-Hyeon; Wolmark, Norman; Kidwell, Kelley; Paik, Soonmyung; Swain, Sandra M.

    2010-01-01

    Purpose We tested the hypothesis that Akt-Ser473 phosphorylation (pAkt) predicts benefit from the sequential addition of paclitaxel to adjuvant doxorubicin plus cyclophosphamide (AC) chemotherapy in patients with node-positive breast cancer participating in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial. Patients and Methods Primary tumors from the NSABP B-28 trial tissue microarray were available from 1,581 of 3,060 patients who were randomly assigned to receive either four cycles of AC alone or followed by four cycles of paclitaxel. Immunohistochemistry and quantitative analysis of pAkt were performed at the National Cancer Institute blinded to clinical outcome. Association between pAkt and clinical outcome was assessed using multivariate Cox modeling adjusting for age, tumor size, number of positive nodes, tumor grade, estrogen receptor status, and human epidermal growth factor receptor 2 status. Results With a median follow-up of 9.1 years, there were no differences in disease-free survival (adjusted hazard ratio [HR], 1.02; P = .81) or overall survival (HR, 0.97; P = .80) with and without receiving paclitaxel among 975 patients with pAkt-negative tumors. In 606 patients with pAkt-positive tumors, the sequential addition of paclitaxel resulted in a 26% improvement in disease-free survival (HR, 0.74; P = .02) or a 20% improvement in overall survival (HR, 0.80; P = .17). Conclusion pAkt significantly predicts disease-free benefit from the sequential addition of paclitaxel to AC chemotherapy in patients with node-positive breast cancer. Patients with pAkt-negative breast tumors do not appear to benefit from the addition of paclitaxel. PMID:20479407

  20. Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy.

    PubMed

    Duggett, Natalie A; Griffiths, Lisa A; McKenna, Olivia E; de Santis, Vittorio; Yongsanguanchai, Nutcha; Mokori, Esther B; Flatters, Sarah J L

    2016-10-01

    Paclitaxel is a first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Previous preclinical studies indicate mitochondrial dysfunction and oxidative stress are associated with this disorder; however no direct assessment of reactive oxygen species (ROS) levels and antioxidant enzyme activity in sensory neurons following paclitaxel has been undertaken. As expected, repeated low doses of systemic paclitaxel in rats induced long-lasting pain behaviour with a delayed onset, akin to the clinical scenario. To elucidate the role of ROSinthe development and maintenance ofpaclitaxel-inducedpainful neuropathy, we have assessed ROS and antioxidant enzyme activity levels in the nociceptive system in vivo at three key behavioural time-points; prior to pain onset (day 7), peak pain severity and pain resolution. In isolated dorsal root ganglia (DRG) neurons, ROS levels were unchanged following paclitaxel-exposure in vitro or in vivo. ROS levels were further assessed in DRG and spinal cord in vivo following intrathecal MitoTracker®RedCM-H2XRos administration in paclitaxel-/vehicle-treated rats. ROS levels were increased at day 7, specifically in non-peptidergic DRG neurons. In the spinal cord, neuronally-derived ROS was increased at day 7, yet ROS levels in microglia and astrocytes were unaltered. In DRG, CuZnSOD and glutathione peroxidase (GPx) activity were increased at day 7 and peak pain time-points, respectively. In peripheral sensory nerves, CuZnSOD activity was increased at day 7, and at peak pain, MnSOD, CuZnSOD and GPx activity were increased. Catalase activity was unaltered in DRG and saphenous nerves. These data suggest that neuronally-derived mitochondrial ROS, accompanied with an inadequate endogenous antioxidant enzyme response, are contributory factors in paclitaxel-induced painful neuropathy.

  1. PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer.

    PubMed

    Martín, Miguel; Prat, Aleix; Rodríguez-Lescure, Alvaro; Caballero, Rosalía; Ebbert, Mark T W; Munárriz, Blanca; Ruiz-Borrego, Manuel; Bastien, Roy R L; Crespo, Carmen; Davis, Carole; Rodríguez, César A; López-Vega, José M; Furió, Vicente; García, Ana M; Casas, Maribel; Ellis, Matthew J; Berry, Donald A; Pitcher, Brandelyn N; Harris, Lyndsay; Ruiz, Amparo; Winer, Eric; Hudis, Clifford; Stijleman, Inge J; Tuck, David P; Carrasco, Eva; Perou, Charles M; Bernard, Philip S

    2013-04-01

    To identify a group of patients who might benefit from the addition of weekly paclitaxel to conventional anthracycline-containing chemotherapy as adjuvant therapy of node-positive operable breast cancer. The predictive value of PAM50 subtypes and the 11-gene proliferation score contained within the PAM50 assay were evaluated in 820 patients from the GEICAM/9906 randomized phase III trial comparing adjuvant FEC to FEC followed by weekly paclitaxel (FEC-P). Multivariable Cox regression analyses of the secondary endpoint of overall survival (OS) were performed to determine the significance of the interaction between treatment and the (1) PAM50 subtypes, (2) PAM50 proliferation score, and (3) clinical and pathological variables. Similar OS analyses were performed in 222 patients treated with weekly paclitaxel versus paclitaxel every 3 weeks in the CALGB/9342 and 9840 metastatic clinical trials. In GEICAM/9906, with a median follow up of 8.7 years, OS of the FEC-P arm was significantly superior compared to the FEC arm (unadjusted HR = 0.693, p = 0.013). A benefit from paclitaxel was only observed in the group of patients with a low PAM50 proliferation score (unadjusted HR = 0.23, p < 0.001; and interaction test, p = 0.006). No significant interactions between treatment and the PAM50 subtypes or the various clinical-pathological variables, including Ki-67 and histologic grade, were identified. Finally, similar OS results were obtained in the CALGB data set, although the interaction test did not reach statistical significance (p = 0.109). The PAM50 proliferation score identifies a subset of patients with a low proliferation status that may derive a larger benefit from weekly paclitaxel.

  2. Tubulin polymerization by paclitaxel (taxol) phosphate prodrugs after metabolic activation with alkaline phosphatase.

    PubMed

    Mamber, S W; Mikkilineni, A B; Pack, E J; Rosser, M P; Wong, H; Ueda, Y; Forenza, S

    1995-08-01

    Paclitaxel (taxol) phosphate derivatives BMY46366, BMY-46489, BMS180661 and BMS180820 were used to determine the ability of alkaline phosphatase to convert these water-soluble potential prodrugs to tubulin-polymerizing metabolites (i.e., paclitaxel). Compounds were treated up to 180 min with an in vitro metabolic activation system composed of 10% bovine alkaline phosphatase in 0.2 M tris, pH 7.4, or in 0.2 M glycine, pH 8.8, plus 0.05 M MgCl2. Samples were tested (either by direct addition or after methylene chloride extraction/dimethyl-sulfoxide resuspension) in spectrophotometric tubulin polymerization assays utilizing bovine-derived microtubule protein. Pretreatment of 2'- and 7-phosphonoxyphenylpropionate prodrugs BMS180661 and BMS180820 with alkaline phosphatase for 30 to 120 min yielded relative initial slopes of about 20 to 100% at test concentrations equimolar to paclitaxel. High-performance liquid chromatography/mass spectrometry of BMS180661 treated with alkaline phosphatase confirmed the production of paclitaxel from the prodrug. In contrast, 2'- and 7-phosphate analogs BMY46366 and BMY46489 treated with alkaline phosphatase were not active in tubulin assays. None of the paclitaxel phosphate prodrugs polymerized tubulin in the absence of metabolic activation. The differences in tubulin polymerization with metabolic activation may be related both to accessibility of the phosphate group to the enzyme and to anionic charge effects. These results demonstrate that certain paclitaxel phosphate prodrugs can be metabolized by alkaline phosphatase to yield effective tubulin polymerization. PMID:7636751

  3. Biocompatible zwitterionic sulfobetaine copolymer-coated mesoporous silica nanoparticles for temperature-responsive drug release.

    PubMed

    Sun, Jiao-Tong; Yu, Zhi-Qiang; Hong, Chun-Yan; Pan, Cai-Yuan

    2012-05-14

    A novel nanocontainer, which could regulate the release of payloads, has been successfully fabricated by attaching zwitterionic sulfobetaine copolymer onto the mesoporous silica nanoparticles (MSNs). RAFT polymerization is employed to prepare the hybrid poly(2-(dimethylamino)ethyl methacrylate)-coated MSNs (MSN-PDMAEMA). Subsequently, the tertiary amine groups in PDMAEMA are quaternized with 1,3-propanesultone to get poly(DMAEMA-co-3-dimethyl(methacryloyloxyethyl)ammonium propanesulfonate)-coated MSNs [MSN-Poly(DMAEMA-co-DMAPS)]. The zwitterionic PDMAPS component endows the nanocarrier with biocompatibility, and the PDMAEMA component makes the copolymer shell temperature-responsive. Controlled release of loaded rhodamine B has been achieved in the saline solutions. PMID:22488562

  4. The High Temperature Response of the TRACE 171 Angstrom and 195 Angstrom Channels

    NASA Technical Reports Server (NTRS)

    Phillips, K. J. H.; Chifor, C.; Landi, E.

    2005-01-01

    The CHIANTI spectral code is used to estimate line and continuum intensity contributions to the TRACE 171 Angstrom and 195 Angstrom channels, widely used for imaging a variety of solar features and phenomena, including quiet Sun and active region loops and solar flares. It is shown that the 171 Angstrom channel has a high-temperature response, so high-temperature (approx. 10 MK) features in flares, prominent in TRACE 195 approx.\\AA\\ images as well as X-ray images from Yohkoh and RHESSI, are sometimes visible in images made in the 171 Angstrom channel. Such features consist of hot loop-top emission, either confined spots or 'spine' structures in loop arcades. This is illustrated with TRACE and X-ray flare images.

  5. Overview of the Temperature Response in the Mesosphere and Lower Thermosphere to Solar Activity

    NASA Technical Reports Server (NTRS)

    Beig, Gufran; Scheer, Juergen; Mlynczak, Martin G.; Keckhut, Philippe

    2008-01-01

    The natural variability in the terrestrial mesosphere needs to be known to correctly quantify global change. The response of the thermal structure to solar activity variations is an important factor. Some of the earlier studies highly overestimated the mesospheric solar response. Modeling of the mesospheric temperature response to solar activity has evolved in recent years, and measurement techniques as well as the amount of data have improved. Recent investigations revealed much smaller solar signatures and in some case no significant solar signal at all. However, not much effort has been made to synthesize the results available so far. This article presents an overview of the energy budget of the mesosphere and lower thermosphere (MLT) and an up-to-date status of solar response in temperature structure based on recently available observational data. An objective evaluation of the data sets is attempted and important factors of uncertainty are discussed.

  6. Preparation and characterization of temperature-responsive magnetic composite particles for multi-modal cancer therapy.

    PubMed

    Yao, Aihua; Chen, Qi; Ai, Fanrong; Wang, Deping; Huang, Wenhai

    2011-10-01

    The temperature-responsive magnetic composite particles were synthesized by emulsion-free polymerization of N-isopropylacrylamide (NIPAAm) and acrylamide (Am) in the presence of oleic acid-modified Fe(3)O(4) nanoparticles. The magnetic properties and heat generation ability of the composite particles were characterized. Furthermore, temperature and alternating magnetic field (AMF) triggered drug release behaviors of vitamin B(12)-loaded composite particles were also examined. It was found that composite particles enabled drug release to be controlled through temperature changes in the neighborhood of lower critical solution temperature. Continuous application of AMF resulted in an accelerated release of the loaded drug. On the other hand, intermittent AMF application to the composite particles resulted in an "on-off", stepwise release pattern. Longer release duration and larger overall release could be achieved by intermittent application of AMF as compared to continuous magnetic field. Such composite particles may be used for magnetic drug targeting followed by simultaneous hyperthermia and drug release.

  7. Construction of a chondrocyte cell sheet using temperature-responsive poly(N-isopropylacrylamide)-co-acrylamide.

    PubMed

    Viravaidya-Pasuwat, Kwanchanok; Wong-in, Sopita; Sakulaue, Phongphot; Siriwatwechakul, Wanwipa

    2013-01-01

    In this study, a novel temperature-responsive poly(N-isopropylacrylamide)-co-acrylamide was used to prepare a chondrocyte cell sheet. Chondrocytes were isolated from human articular cartilage and plated on the copolymer film grafted tissue culture plates. The cell attachment on the copolymer film was shown to be similar to that of the ungrafted surface. To harvest a cell sheet, the incubation temperature was reduced to 10°C for 30 minutes to allow the polymer chain to fully extend, changing the copolymer's phase from hydrophobicity to hydrophilicity. Additional incubation at 20°C for 60 minutes was necessary to activate the cellular metabolism required for cytoskeletal organization and cell detachment. A complete cell sheet recovery was achieved when a PVDF membrane was used as a cell sheet carrier. Unfortunately, the shrinkage of the cell sheet was observed. Nonetheless, the harvested cell sheet was shown to be viable and healthy. PMID:24111348

  8. Temperature response functions introduce high uncertainty in modelled carbon stocks in cold temperature regimes

    NASA Astrophysics Data System (ADS)

    Portner, H.; Bugmann, H.; Wolf, A.

    2009-08-01

    Models of carbon cycling in terrestrial ecosystems contain formulations for the dependence of respiration on temperature, but the sensitivity of predicted carbon pools and fluxes to these formulations and their parameterization is not understood. Thus, we made an uncertainty analysis of soil organic matter decomposition with respect to its temperature dependency using the ecosystem model LPJ-GUESS. We used five temperature response functions (Exponential, Arrhenius, Lloyd-Taylor, Gaussian, Van't Hoff). We determined the parameter uncertainty ranges of the functions by nonlinear regression analysis based on eight experimental datasets from northern hemisphere ecosystems. We sampled over the uncertainty bounds of the parameters and run simulations for each pair of temperature response function and calibration site. The uncertainty in both long-term and short-term soil carbon dynamics was analyzed over an elevation gradient in southern Switzerland. The function of Lloyd-Taylor turned out to be adequate for modelling the temperature dependency of soil organic matter decomposition, whereas the other functions either resulted in poor fits (Exponential, Arrhenius) or were not applicable for all datasets (Gaussian, Van't Hoff). There were two main sources of uncertainty for model simulations: (1) the uncertainty in the parameter estimates of the response functions, which increased with increasing temperature and (2) the uncertainty in the simulated size of carbon pools, which increased with elevation, as slower turn-over times lead to higher carbon stocks and higher associated uncertainties. The higher uncertainty in carbon pools with slow turn-over rates has important implications for the uncertainty in the projection of the change of soil carbon stocks driven by climate change, which turned out to be more uncertain for higher elevations and hence higher latitudes, which are of key importance for the global terrestrial carbon budget.

  9. Global temperature response to the major volcanic eruptions in multiple reanalysis datasets

    NASA Astrophysics Data System (ADS)

    Fujiwara, M.; Hibino, T.; Mehta, S. K.; Gray, L.; Mitchell, D.; Anstey, J.

    2015-05-01

    Global temperature response to the eruptions of Mount Agung in 1963, El Chichón in 1982 and Mount Pinatubo in 1991 is investigated using nine reanalysis datasets (JRA-55, MERRA, ERA-Interim, NCEP-CFSR, JRA-25, ERA-40, NCEP-1, NCEP-2, and 20CR). Multiple linear regression is applied to the zonal and monthly mean time series of temperature for two periods, 1979-2009 (for eight reanalysis datasets) and 1958-2001 (for four reanalysis datasets), by considering explanatory factors of seasonal harmonics, linear trends, Quasi-Biennial Oscillation, solar cycle, and El Niño Southern Oscillation. The residuals are used to define the volcanic signals for the three eruptions separately. In response to the Mount Pinatubo eruption, most reanalysis datasets show strong warming signals (up to 2-3 K for one-year average) in the tropical lower stratosphere and weak cooling signals (down to -1 K) in the subtropical upper troposphere. For the El Chichón eruption, warming signals in the tropical lower stratosphere are somewhat smaller than those for the Mount Pinatubo eruption. The response to the Mount Agung eruption is asymmetric about the equator with strong warming in the Southern Hemisphere midlatitude upper troposphere to lower stratosphere. The response to three other smaller-scale eruptions in the 1960s and 1970s is also investigated. Comparison of the results from several different reanalysis datasets confirms the atmospheric temperature response to these major eruptions qualitatively, but also shows quantitative differences even among the most recent reanalysis datasets.

  10. Acute Effects of Normobaric Hypoxia on Hand-Temperature Responses During and After Local Cold Stress

    PubMed Central

    Kölegård, Roger; Mekjavic, Igor B.; Eiken, Ola

    2014-01-01

    Abstract Keramidas, Michail E, Roger Kölegård, Igor B. Mekjavic, and Ola Eiken. Acute effects of normobaric hypoxia on hand-temperature responses during and after local cold stress. High Alt Med Biol. 15:183–191, 2014.—The purpose was to investigate acute effects of normobaric hypoxia on hand-temperature responses during and after a cold-water hand immersion test. Fifteen males performed two right-hand immersion tests in 8°C water, during which they were inspiring either room air (Fio2: 0.21; AIR), or a hypoxic gas mixture (Fio2: 0.14; HYPO). The tests were conducted in a counterbalanced order and separated by a 1-hour interval. Throughout the 30-min cold-water immersion (CWI) and the 15-min spontaneous rewarming (RW) phases, finger-skin temperatures were measured continuously with thermocouple probes; infrared thermography was also employed during the RW phase to map all segments of the hand. During the CWI phase, the average skin temperature (Tavg) of the fingers did not differ between the conditions (AIR: 10.2±0.5°C, HYPO: 10.0±0.5°C; p=0.67). However, Tavg was lower in the HYPO than the AIR RW phase (AIR: 24.5±3.4°C; HYPO: 22.0±3.8°C; p=0.002); a response that was alike in all regions of the immersed hand. Accordingly, present findings suggest that acute exposure to normobaric hypoxia does not aggravate the cold-induced drop in hand temperature of normothermic males. Still, hypoxia markedly impairs the rewarming responses of the hand. PMID:24666109

  11. A temperature-responsive network links cell shape and virulence traits in a primary fungal pathogen.

    PubMed

    Beyhan, Sinem; Gutierrez, Matias; Voorhies, Mark; Sil, Anita

    2013-07-01

    Survival at host temperature is a critical trait for pathogenic microbes of humans. Thermally dimorphic fungal pathogens, including Histoplasma capsulatum, are soil fungi that undergo dramatic changes in cell shape and virulence gene expression in response to host temperature. How these organisms link changes in temperature to both morphologic development and expression of virulence traits is unknown. Here we elucidate a temperature-responsive transcriptional network in H. capsulatum, which switches from a filamentous form in the environment to a pathogenic yeast form at body temperature. The circuit is driven by three highly conserved factors, Ryp1, Ryp2, and Ryp3, that are required for yeast-phase growth at 37°C. Ryp factors belong to distinct families of proteins that control developmental transitions in fungi: Ryp1 is a member of the WOPR family of transcription factors, and Ryp2 and Ryp3 are both members of the Velvet family of proteins whose molecular function is unknown. Here we provide the first evidence that these WOPR and Velvet proteins interact, and that Velvet proteins associate with DNA to drive gene expression. Using genome-wide chromatin immunoprecipitation studies, we determine that Ryp1, Ryp2, and Ryp3 associate with a large common set of genomic loci that includes known virulence genes, indicating that the Ryp factors directly control genes required for pathogenicity in addition to their role in regulating cell morphology. We further dissect the Ryp regulatory circuit by determining that a fourth transcription factor, which we name Ryp4, is required for yeast-phase growth and gene expression, associates with DNA, and displays interdependent regulation with Ryp1, Ryp2, and Ryp3. Finally, we define cis-acting motifs that recruit the Ryp factors to their interwoven network of temperature-responsive target genes. Taken together, our results reveal a positive feedback circuit that directs a broad transcriptional switch between environmental and

  12. Temperature response of methane production in liquid manures and co-digestates.

    PubMed

    Elsgaard, Lars; Olsen, Anne B; Petersen, Søren O

    2016-01-01

    Intensification of livestock production makes correct estimation of methanogenesis in liquid manure increasingly important for inventories of CH4 emissions. Such inventories currently rely on fixed methane conversion factors as knowledge gaps remain with respect to detailed temperature responses of CH4 emissions from liquid manure. Here, we describe the temperature response of CH4 production in liquid cattle slurry, pig slurry, and fresh and stored co-digested slurry from a thermophilic biogas plant. Subsamples of slurry were anoxically incubated at 20 temperatures from 5-52°C in a temperature gradient incubator and CH4 production was measured by gas chromatographic analysis of headspace gas after a 17-h incubation period. Methane production potentials at 5-37°C were described by the Arrhenius equation (modelling efficiencies, 79.2-98.1%), and the four materials showed a consistent activation energy (Ea) which averaged 81.0kJmol(-1) (95% confidence interval, 74.9-87.1kJmol(-1)) corresponding to a temperature sensitivity (Q10) of 3.4. In contrast, the frequency factor (A) differed among the slurry materials (30.1

  13. Randomized Phase III Trial of Paclitaxel Once Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel Once Per Week or Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally Recurrent or Metastatic Breast Cancer: CALGB 40502/NCCTG N063H (Alliance)

    PubMed Central

    Rugo, Hope S.; Barry, William T.; Moreno-Aspitia, Alvaro; Lyss, Alan P.; Cirrincione, Constance; Leung, Eleanor; Mayer, Erica L.; Naughton, Michael; Toppmeyer, Deborah; Carey, Lisa A.; Perez, Edith A.; Hudis, Clifford; Winer, Eric P.

    2015-01-01

    Purpose We compared nab-paclitaxel or ixabepilone once per week to paclitaxel with bevacizumab as first-line therapy for patients with advanced breast cancer (BC) to evaluate progression-free survival (PFS) for nab-paclitaxel or ixabepilone versus paclitaxel. Patients and Methods Eligible patients were age ≥ 18 years with chemotherapy-naive advanced BC. Patients were randomly assigned to bevacizumab with paclitaxel 90 mg/m2 (arm A), nab-paclitaxel 150 mg/m2 (arm B), or ixabepilone 16 mg/m2 (arm C), once per week for 3 of 4 weeks. Planned enrollment was 900 patients, which would give 88% power to detect a hazard ratio of 0.73. Results In all, 799 patients were enrolled, and 783 received treatment (97% received bevacizumab). Arm C was closed for futility at the first interim analysis (n = 241), and arm A (n = 267) and arm B (n = 275) were closed for futility at the second interim analysis. Median PFS for paclitaxel was 11 months, ixabepilone was inferior to paclitaxel (PFS, 7.4 months; hazard ratio, 1.59; 95% CI, 1.31 to 1.93; P < .001), and nab-paclitaxel was not superior to paclitaxel (PFS, 9.3 months; hazard ratio, 1.20; 95% CI, 1.00 to 1.45; P = .054). Results were concordant with overall survival; time to treatment failure was significantly shorter in both experimental arms v paclitaxel. Hematologic and nonhematologic toxicity, including peripheral neuropathy, was increased with nab-paclitaxel, with more frequent and earlier dose reductions. Conclusion In patients with chemotherapy-naive advanced BC, ixabepilone once per week was inferior to paclitaxel, and nab-paclitaxel was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms, particularly for nab-paclitaxel. Paclitaxel once per week remains the preferred palliative chemotherapy in this setting. PMID:26056183

  14. MAGIC Gel Dosimetry

    NASA Astrophysics Data System (ADS)

    Mifflin, Rachel; Shahnazi, Kambiz; Jesseph, Rick

    2008-10-01

    Proton therapy has proven a very successful tool in treating certain tumors, but a three dimensional view of this fact has not yet been clearly demonstrated. In this experiment we have used MAGIC (Methacrylic and Ascorbic Acid in Gelatin Initiated by Copper) gel to represent brain tissue and gone through normal treatment planning for an Acoustic Neuroma to show the three dimensional dose distributions associated with such a tumor.

  15. Superior Antitumor Activity of Nanoparticle Albumin-Bound Paclitaxel in Experimental Gastric Cancer

    PubMed Central

    Zhang, Changhua; Awasthi, Niranjan; Schwarz, Margaret A.; Hinz, Stefan; Schwarz, Roderich E.

    2013-01-01

    Gastric cancer is the second common cause of cancer related death worldwide and lacks highly effective treatment for advanced disease. Nab-paclitaxel is a novel microtubule-inhibitory cytotoxic agent that has not been tested in gastric cancer as of yet. In this study, human gastric cancer cell lines AGS, NCI-N87 and SNU16 were studied. Nab-paclitaxel inhibited cell proliferation with an IC50 of 5 nM in SNU16, 23 nM in AGS and 49 nM in NCI-N87 cells after 72-hour treatment, which was lower than that of oxaliplatin (1.05 μM to 1.51 μM) and epirubicin (0.12 μM to 0.25 μM). Nab-paclitaxel treatment increased expression of the mitotic-spindle associated phospho-stathmin irrespective of the baseline total or phosphorylated stathmin level, and induced mitotic cell death as confirmed through increased expression of cleaved-PARP and caspase-3. After a two-week nab-paclitaxel, oxaliplatin or epirubicin treatment, the average in vivo local tumor growth inhibition rate was 77, 17.2 and 21.4 percent, respectively (p = 0.002). Effects of therapy on tumoral proliferative and apoptotic indices corresponded with tumor growth inhibition data, while expression of phospho-stathmin also increased in tissues. There was an increase in median animal survival after nab-paclitaxel treatment (93 days) compared to controls (31 days, p = 0.0007), oxaliplatin (40 days, p = 0.0007) or to docetaxel therapy (81 days, p = 0.0416). The strong antitumor activity of nab-paclitaxel in experimental gastric cancer supports such microtubule-inhibitory strategy for clinical application. Nab-paclitaxel benefits were observed independent from phosphorylated stathmin expression at baseline, putting into question the consideration of nab-paclitaxel use in gastric cancer based on this putative biomarker. PMID:23460921

  16. A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: A Gynecologic Oncology Group study☆,☆☆,★

    PubMed Central

    Gould, Natalie; Sill, Michael W.; Mannel, Robert S.; Thaker, P.H.; DiSilvestro, Paul; Waggoner, Steve; Yamada, S. Diane; Armstrong, Deborah K.; Wenzel, Lari; Huang, Helen; Fracasso, Paula M.; Walker, Joan L.

    2013-01-01

    Objective To define the maximum tolerated dose (MTD) and assess the feasibility of intravenous (IV) paclitaxel, intraperitoneal (IP) carboplatin, and IP paclitaxel in women with newly diagnosed Stages II–IV ovarian, fallopian tube, or primary peritoneal carcinoma. Methods Patients received escalating doses of paclitaxel IV and carboplatin IP on day 1 and paclitaxel IP 60 mg/m2 on day 8. A standard 3+3 design was used in the escalation phase. A two-stage group sequential design with 20 patients at the MTD was used in the feasibility phase. Patient-reported neurotoxicity was assessed pre and post treatment. Results Patients were treated with paclitaxel 175 mg/m2 IV and carboplatin IP from AUC 5–7 on day 1 and paclitaxel 60 mg/m2 IP on day 8. The MTD was estimated at carboplatin AUC 6 IP and 25 patients enrolled at this dose level. Within the first 4 cycles, seven (35%) of twenty evaluable patients had dose-limiting toxicities (DLTs) including grade 4 thrombocytopenia (1), grade 3 neutropenic fever (3), >2 week delay due to ANC recovery (1), grade 3 LFT (1), and grade 3 infection (1). De-escalation to paclitaxel 135 mg/m2 IV was given to improve the safety. After six evaluable patients completed 4 cycles without a DLT, bevacizumab was added and six evaluable patients completed 4 cycles with one DLT (grade 3 hyponatremia). Conclusions Paclitaxel at 175 mg/m2 IV, carboplatin AUC 6 IP day 1 and paclitaxel 60 mg/m2 IP day 8 yield 18–56% patients with DLTs. The tolerability of the regimen in combination with bevacizumab was indicated in a small cohort. PMID:22155262

  17. The potent microtubule-stabilizing agent (+)-discodermolide induces apoptosis in human breast carcinoma cells--preliminary comparisons to paclitaxel.

    PubMed

    Balachandran, R; ter Haar, E; Welsh, M J; Grant, S G; Day, B W

    1998-01-01

    (+)-Discodermolide, a sponge-derived natural product, stabilizes microtubules more potently than paclitaxel despite the lack of any obvious structural similarities between the drugs. It competitively inhibits the binding of paclitaxel to tubulin polymers, hypernucleates microtubule assembly more potently than paclitaxel, and inhibits the growth of paclitaxel-resistant ovarian and colon carcinoma cells. Because paclitaxel shows clinical promise for breast cancer treatment, its effects in a series of human breast cancer cells were compared to those of (+)-discodermolide. Growth inhibition, cell and nuclear morphological, and electrophoretic and flow cytometric analyses were performed on (+)-discodermolide-treated MCF-7 and MDA-MB231 cells. (+)-Discodermolide potently inhibited the growth of both cell types (IC50 < 2.5 nM) at concentrations similar to those observed with paclitaxel. Complete inhibition of growth occurred with 10 nM or greater of each drug and was not reversed by removal. (+)-Discodermolide-treated cells exhibited condensed and highly fragmented nuclei. Flow cytometric comparison of cells treated with either drug at 10 nM, a concentration well below that achieved clinically with paclitaxel, showed both caused cell cycle perturbation and induction of a hypodiploid cell population. (+)-Discodermolide caused these effects more extensively and at earlier time points. The timing and type of high molecular weight DNA fragmentation induced by the two agents was consistent with induction of apoptosis. The results suggest that (+)-discodermolide has promise as a new chemotherapeutic agent against breast and other cancers.

  18. Combination Therapy of Albumin-Bound Paclitaxel and Carboplatin as First Line Therapy in a Patient with Ovarian Cancer

    PubMed Central

    Srinivasan, K. N; Rauthan, Amit; Gopal, R.

    2014-01-01

    Background. Ovarian cancer is the ninth most common cancer among women and causes more deaths than any other type of female reproductive cancer. Albumin-bound paclitaxel is known to increase intratumoral concentration of the paclitaxel by a receptor-mediated transport process across the endothelial cell wall, thereby breaching the blood/tumor interface. We present below three cases in which nab-paclitaxel based chemotherapy has been used in different settings for patients with ovarian cancer. Case Presentation. In the first case nab-paclitaxel was used along with carboplatin in adjuvant setting, in the second case, nab-paclitaxel was used along with carboplatin and bevacizumab as second line chemotherapy in a relapsed ovarian cancer case, and the third case delineates the use of nab-paclitaxel along with cisplatin as third line chemotherapy. Conclusion. In all the three scenarios, patients tolerated the chemotherapy well, as well as responding well to nab-paclitaxel based chemotherapy. The patients are currently on long-term follow-up and have been having an uneventful postchemotherapy. PMID:24804130

  19. Enhanced oral bioavailability of paclitaxel by solid dispersion granulation.

    PubMed

    Shanmugam, Srinivasan; Im, Ho Taek; Sohn, Young Taek; Kim, Yong-Il; Park, Jae-Hyun; Park, Eun-Seok; Woo, Jong Soo

    2015-01-01

    The main objective of this study was to develop novel orally administrable tablets containing solid dispersion granules (SDG) of amorphous paclitaxel (PTX) prepared by fluid bed technology, and to evaluate its in vitro dissolution and in vivo pharmacokinetics (PK) in beagle dogs. The SDG were prepared using optimized composition by fluid bed technology, and characterized for solid-state properties. The release study of SDG tablet (SDG-T) in simulated gastric fluid showed a rapid release of PTX, reaching maximum dissolution within 20 min. Finally, the PK profile of SDG-T and a reference formulation Oraxol™ (oral solution formulation used in Phase I clinical study) at a dose of 60 mg orally with co-administration of P-gp inhibitor HM38101, and Taxol® at a dose of 10 mg intravenously (i.v.) was investigated in beagle dogs. The mean absolute BA% of PTX following SDG-T and Oraxol™ solution was 8.23 and 6.22% in comparison to i.v. administration of Taxol®. The relative BA% of PTX from SDG-T in comparison to Oraxol™ solution was 132.25% at a dose of 60 mg following oral administration. In conclusion, we have successfully prepared PTX tablets with solid dispersion granules (SDG) of amorphous PTX using fluid bed technology that could provide plasma PTX concentration in the range of 10-150 ng/mL for a period of 24 h following oral administration in dogs with a P-gp inhibitor. Hence, this could be a promising formulation for PTX oral delivery and could be used in our intended clinical studies following pre-clinical efficacy studies.

  20. Drug-drug Interaction between Losartan and Paclitaxel in Human Liver Microsomes with Different CYP2C8 Genotypes.

    PubMed

    Mukai, Yuji; Senda, Asuna; Toda, Takaki; Hayakawa, Toru; Eliasson, Erik; Rane, Anders; Inotsume, Nobuo

    2015-06-01

    The cytochrome P450 (CYP) 2C8*3 allele is associated with reduced metabolic activity of paclitaxel. This study was aimed to investigate the inhibitory effect of losartan on paclitaxel metabolism in human liver microsomes (HLMs) and to determine the impact of the CYP2C8*3 polymorphism. HLMs that contained the CYP2C8*1 homozygote (HL60) or CYP2C8*3 heterozygote (HL54) genotype were used for the inhibition study. Losartan, at a concentration of 50 μmol/L, significantly inhibited paclitaxel metabolism by 29% and 57% in the HL60 (p < 0.001) and HL54 (p < 0.01), respectively. When using HL60, losartan and the CYP3A4-selective inhibitors, erythromycin and ketoconazole, caused a greater inhibition of the paclitaxel metabolism than quercetin, a CYP2C8-selective inhibitor. This demonstrated that the paclitaxel metabolism was mainly catalysed by CYP3A4 in HL60. There were no significant differences found for the inhibitory effects caused by the four inhibitors of the paclitaxel metabolism in HL54, indicating that both CYP2C8 and CYP3A4 play important roles in paclitaxel metabolism in HL54. These findings suggest that 50 μmol/L of losartan inhibits both CYP2C8 and CYP3A4 in HLMs. In summary, losartan inhibited paclitaxel metabolism, with concentrations over 50 μmol/L in HLMs. The CYP2C8*3 allele carriers are likely susceptible to the interactions of losartan and CYP3A4 inhibitors to paclitaxel metabolism.

  1. Induction chemotherapy with carboplatin-paclitaxel followed by standard radiotherapy with concurrent daily low-dose cisplatin plus weekly paclitaxel for inoperable non-small-cell lung cancer.

    PubMed

    Ardizzoni, Andrea; Scolaro, Tindaro; Mereu, Carlo; Cafferata, Mara Argenide; Tixi, Lucia; Bacigalupo, Almalina; Tiseo, Marcello; Monetti, Francesco; Rosso, Riccardo

    2005-02-01

    Both induction chemotherapy and concurrent platinating agents have been shown to improve results of thoracic irradiation in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This phase II study investigated activity and feasibility of a novel chemoradiation regimen, including platinum and paclitaxel, both as induction chemotherapy and concurrently with thoracic radiotherapy. Previously untreated patients with histologically/cytologically proven unresectable stage I-III NSCLC were eligible. Induction chemotherapy consisted of 2 courses of 200 mg/m2 paclitaxel and carboplatin at AUC of 6 mg/mL/min every 3 weeks. From day 43, continuous thoracic irradiation (60 Gy in 30 fractions radiotherapy for 6 weeks) was given concurrently with daily cisplatin at a dose of 5 mg/m2 intravenously and weekly paclitaxel at a dose of 45 mg/m2 for 6 weeks. Fifteen patients were accrued in the first stage of the trial. According to the previous statistical considerations, accrual at the second stage of the study was halted as a result of the achievement an insufficient number of successes. Major toxicity of combined chemoradiation was grade III-IV esophagitis requiring hospitalization for artificial nutrition, which occurred in 58% of patients. Other toxicities included grade II-IV fatigue in 75% of patients and grade I-IV neuromuscular toxicity in 67%. Only 7 patients completed the treatment program as scheduled. Eight patients (53.3%; 95% confidence interval, 26.5-78.7%) had a major response (5 partial response, 3 complete response), 2 patients had disease progression, and 1 was stable at the end of treatment. Four patients died early. With a median follow up of 38 months, the median survival was 12 months. A combined chemoradiation program, including platinum and paclitaxel, appears difficult to deliver at full dose as a result of toxicity, mainly esophagitis. More active and less toxic combined modality treatments need to be developed for inoperable NSCLC.

  2. A phase II randomised clinical trial comparing cisplatin, paclitaxel and ifosfamide with cisplatin, paclitaxel and epirubicin in newly diagnosed advanced epithelial ovarian cancer: long-term survival analysis

    PubMed Central

    Fruscio, R; Colombo, N; Lissoni, A A; Garbi, A; Fossati, R; Ieda', N; Torri, V; Mangioni, C

    2008-01-01

    To test the feasibility and efficacy of epirubicin and ifosfamide added to first-line chemotherapy with cisplatin and paclitaxel in a phase II randomised clinical trial. Patients with histologically proven epithelial ovarian cancer were randomly assigned to receive first-line polychemotherapy with cisplatin/paclitaxel/epirubicin (CEP) or cisplatin/paclitaxel/ifosfamide (CIP) for six cycles every 21 days. Two hundred and eight patients were randomised between the two treatment arms and the median number of cycles per patient was six. Toxicity was predominantly haematological with both regimens; however, anaemia, leucopaenia, neutropaenic fever and use of granulocyte colony-stimulating factors and transfusion were significantly more frequent in the CIP treatment arm. Response rates were 85% (95% confidence interval (CI) 77–93%) in the CIP arm and 90% (95% CI 84–96%) in the CEP arm; complete response rates were 48 and 52%. After a median follow-up of 82 months, median overall survival (OS) was 51 and 65 months; 5-year survival rates were respectively 43 and 50%. In this clinical trial, both regimens showed good efficacy, but toxicity was heavier with the CIP regimen. Considering that more than 50% of patients were suboptimally debulked after the first surgery, OS seems to be longer than is commonly reported. This unexpected finding might be a consequence of the close surgical surveillance and aggressive chemotherapeutic approach. PMID:18253120

  3. Global temperature response to the major volcanic eruptions in multiple reanalysis data sets

    NASA Astrophysics Data System (ADS)

    Fujiwara, M.; Hibino, T.; Mehta, S. K.; Gray, L.; Mitchell, D.; Anstey, J.

    2015-12-01

    The global temperature responses to the eruptions of Mount Agung in 1963, El Chichón in 1982, and Mount Pinatubo in 1991 are investigated using nine currently available reanalysis data sets (JRA-55, MERRA, ERA-Interim, NCEP-CFSR, JRA-25, ERA-40, NCEP-1, NCEP-2, and 20CR). Multiple linear regression is applied to the zonal and monthly mean time series of temperature for two periods, 1979-2009 (for eight reanalysis data sets) and 1958-2001 (for four reanalysis data sets), by considering explanatory factors of seasonal harmonics, linear trends, Quasi-Biennial Oscillation, solar cycle, and El Niño Southern Oscillation. The residuals are used to define the volcanic signals for the three eruptions separately, and common and different responses among the older and newer reanalysis data sets are highlighted for each eruption. In response to the Mount Pinatubo eruption, most reanalysis data sets show strong warming signals (up to 2-3 K for 1-year average) in the tropical lower stratosphere and weak cooling signals (down to -1 K) in the subtropical upper troposphere. For the El Chichón eruption, warming signals in the tropical lower stratosphere are somewhat smaller than those for the Mount Pinatubo eruption. The response to the Mount Agung eruption is asymmetric about the equator with strong warming in the Southern Hemisphere midlatitude upper troposphere to lower stratosphere. Comparison of the results from several different reanalysis data sets confirms the atmospheric temperature response to these major eruptions qualitatively, but also shows quantitative differences even among the most recent reanalysis data sets. The consistencies and differences among different reanalysis data sets provide a measure of the confidence and uncertainty in our current understanding of the volcanic response. The results of this intercomparison study may be useful for validation of climate model responses to volcanic forcing and for assessing proposed geoengineering by stratospheric

  4. A pH- and Temperature-Responsive Magnetic Composite Adsorbent for Targeted Removal of Nonylphenol.

    PubMed

    Zhen, Yang; Ning, Zhuo; Shaopeng, Zhang; Yayi, Dong; Xuntong, Zhang; Jiachun, Shen; Weiben, Yang; Yuping, Wang; Jianqiang, Chen

    2015-11-11

    A pH- and temperature-responsive magnetic adsorbent [poly(N-isopropylacrylamide) grafted chitosan/Fe3O4 composite particles, CN-MCP], was synthesized for the removal of the endocrine-disrupting chemical nonylphenol. According to the structural characteristics (changeable surface-charge and hydrophilic/hydrophobic properties) of the targeted contaminant, CN-MCP was designed owning special structure (pH- and temperature-responsiveness for the changeable surface-charge and adjustable hydrophilic/hydrophobic properties, respectively). Compared to chitosan magnetic composite particles without grafting modification (CS-MCP) and several other reported adsorbents, CN-MCP exhibited relatively high adsorption capacity for nonylphenol under corresponding optimal conditions (123 mg/g at pH 9 and 20 °C; 116 mg/g at pH 5 and 40 °C). Meanwhile, high selectivity of the novel adsorbent in selective adsorption of nonylphenol from bisolute solution of nonylphenol and phenol was found. Effects of grafting ratio of the grafted polymer branches and coexisting inorganic salts on the adsorption were systematically investigated. Moreover, CN-MCP demonstrated desired reusability during 20 times of adsorption-desorption recycling. The high adsorption capacity, high selectivity, and desired reusability aforementioned revealed the significant application potential of CN-MCP in the removal of NP. On the basis of the adsorption behaviors, isotherms equilibrium, thermodynamics and kinetics studies, and instrumental analyses including X-ray photoelectron spectroscopy, BET specific surface area, zeta potential, and static water contact angle measurements, distinct adsorption mechanisms were found under various conditions: charge attraction between CN-MCP and the contaminant, as well as binding between polymeric branches of CN-MCP and nonyls, contributed to the adsorption at pH 9 and 20 °C; whereas hydrophobic interaction between CN-MCP and nonylphenol played a dominant role at pH 5 and 40

  5. Factors influencing alginate gel biocompatibility.

    PubMed

    Tam, Susan K; Dusseault, Julie; Bilodeau, Stéphanie; Langlois, Geneviève; Hallé, Jean-Pierre; Yahia, L'Hocine

    2011-07-01

    Alginate remains the most popular polymer used for cell encapsulation, yet its biocompatibility is inconsistent. Two commercially available alginates were compared, one with 71% guluronate (HiG), and the other with 44% (IntG). Both alginates were purified, and their purities were verified. After 2 days in the peritoneal cavity of C57BL/6J mice, barium (Ba)-gel and calcium (Ca)-gel beads of IntG alginate were clean, while host cells were adhered to beads of HiG alginate. IntG gel beads, however, showed fragmentation in vivo while HiG gel beads stayed firm. The physicochemical properties of the sodium alginates and their gels were thoroughly characterized. The intrinsic viscosity of IntG alginate was 2.5-fold higher than that of HiG alginate, suggesting a greater molecular mass. X-ray photoelectron spectroscopy indicated that both alginates were similar in elemental composition, including low levels of counterions in all gels. The wettabilities of the alginates and gels were also identical, as measured by contact angles of water on dry films. Ba-gel beads of HiG alginate resisted swelling and degradation when immersed in water, much more than the other gel beads. These results suggest that the main factors contributing to the biocompatibility of gels of purified alginate are the mannuronate/guluronate content and/or intrinsic viscosity.

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

    PubMed Central

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

    2015-01-01

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

  7. Survivin-specific small interfering RNAs enhance sensitivity of glioma U-87MG cells to paclitaxel by promoting apoptosis☆

    PubMed Central

    Xie, Yunliang; Liu, Yanbo; Shen, Weigao; Zhang, Bo; Liu, Qun

    2012-01-01

    A survivin siRNA expression vector was transfected into glioma U-87MG cells and these cells were then treated with paclitaxel. The results showed that survivin-specific siRNA combined with paclitaxel treatment synergistically inhibited glioma U-87MG cell proliferation and promoted apoptosis. This treatment also inhibited the expression of the cell cycle regulatory proteins, survivin, cyclinD1, c-Myc and CDK4 and enhanced the sensitivity of U-87MG cells to paclitaxel. PMID:25722690

  8. Weekly paclitaxel therapy for gastric cancer in patients with renal dysfunction: A case report.

    PubMed

    Kanematsu, Kyohei; Tsujimoto, Hironori; Nomura, Shinsuke; Horiguchi, Hiroyuki; Ito, Nozomi; Yamazaki, Kenji; Hiraki, Shuichi; Aosasa, Suefumi; Yamamoto, Junji; Hase, Kazuo

    2016-11-01

    A 57-year-old woman was admitted to National Defense Medical College hospital for treatment of gastric cancer with pyloric stenosis. She had been diagnosed with chronic kidney disease (CKD) 10 years prior, but received no hemodialysis. Because of peritoneal dissemination, a palliative distal gastrectomy was performed. In consideration of renal dysfunction, we decided for chemotherapy with paclitaxel, but not S-1 plus cisplatin regimen which is renal toxic agents. On the 29th postoperative day, chemotherapy using paclitaxel was initiated at a dose of 80 mg/m(2). Paclitaxel was administered weekly on days 1, 8, and 15 on a 28-day cycle. The patient tolerated 13 courses of this treatment without any severe adverse effect, such as exacerbation of renal function. Despite the gradual increase in the level of tumor markers, metastases were not detected via radiography during the clinical course. Moreover, renal function was maintained for the duration of the clinical course. To date, standard chemotherapeutic treatment for patients with CKD has not been established. We conclude that weekly paclitaxel is a suitable treatment regimen for patients with renal failure requiring chemotherapy for advanced gastric cancer. PMID:27656282

  9. Investigation of Paclitaxel Resistant R306C Mutation in β-Tubulin—A Computational Approach.

    PubMed

    Verma, Kanika; Ramanathan, K

    2015-07-01

    Paclitaxel is the most effective chemotherapeutic agent used for the treatment of a broad spectrum of solid tumors. However, observed paclitaxel resistance in clinical trials presents one of the major obstacles for cancer chemotherapy. Most importantly, resistance due to β-tubulin mutations (R306C) has been intensely debated in recent years. Despite all efforts, mechanism of resistance is still not well understood. In this study, computational techniques were employed to uncover the effect of R306C mutation in the β-tubulin structure and its function. The tools such as I-Mutant, CUPSAT and Fold-X were employed to address the consequence of R306C mutation in the structural stability of β-tubulin. Further, molecular docking and molecular dynamics study was employed to understand the functional impact of β-tubulin mutation. Our results suggest that the R306C mutation causes a significant reduction in the binding affinity between β-tubulin and paclitaxel. Further, docked complex analysis indicates that destruction of conservative hydrogen bond maintained by the residues Arg282 and Gly360 should be responsible for the large conformation changes of the binding pocket in R306C mutant. Finally, molecular dynamics simulations study confirms the stable binding of paclitaxel with native type β-tubulin structure rather than mutant (R306C) type. We certainly believe that this study will provide useful guidance for the development of novel inhibitors that are less susceptible to drug resistance.

  10. Exploration of paclitaxel (Taxol) as a treatment for malignant tumors in cats: a descriptive case series.

    PubMed

    Kim, Jennifer; Doerr, Mary; Kitchell, Barbara E

    2015-02-01

    Paclitaxel, an effective chemotherapeutic agent in human oncology, has received little evaluation in feline patients. The diluent used to solubilize paclitaxel, polyoxyethylated castor oil (Cremophor EL), causes anaphylactoid reactions in human and dogs, which limits enthusiasm for use of this agent in veterinary oncology. Nine feline patients with measurable malignant tumors were treated with paclitaxel at a dosage of 80 mg/m(2) intravenously every 21 days for up to two doses. Adverse effects, including evidence of toxicity and anaphylactoid reactions, were assessed. Tumor response, progression and patient time to progression (TTP) were also recorded. Adverse effects included grade III and IV thrombocytopenia, grade III gastrointestinal signs (vomiting and constipation) and hypersensitivity reactions, seen in a total of five patients. Anaphylactoid reactions resolved with appropriate management. Stable disease and partial response were observed in 56% of feline patients. Median TTP was 28 days (range 15-45 days). Intravenous paclitaxel is a safe treatment option for feline malignant tumor patients. Future investigation is warranted to explore the effectiveness and appropriate application of this agent for specific tumor types.

  11. [Nab-Paclitaxel plus gemcitabine in patients with metastatic pancreatic adenocarcinoma: experience of use].

    PubMed

    Ferris Villanueva, Elena; Martínez Penella, Mónica; Cerezuela Fuentes, Pablo; Guerrero Bautista, Rocío; García Márquez, Andrés; Mira Sirvent, María Del Carmen

    2015-05-01

    Objetivo: Describir los resultados obtenidos en el uso de nab-paclitaxel y gemcitabina en el tratamiento de pacientes con adenocarcinoma de páncreas metastático. Material y métodos: Estudio observacional retrospectivo. Se seleccionaron pacientes en tratamiento con nab-paclitaxel asociado a gemcitabina entre enero 2013 y enero 2014. Se recogieron datos demográficos y clínicos. Resultados: Se incluyeron 15 pacientes (edad media: 59,4 ± 10,3 años). Todos ellos recibieron la combinación de nab-paclitaxel y gemcitabina en primera línea para la enfermedad metastásica. Nueve recibieron tratamiento adyuvante antes de que la enfermedad fuera metastásica, siendo la media de líneas de tratamiento previamente al uso de la combinación de 1,1. La mediana de supervivencia libre de progresión fue de 5,6 meses (IC 95%: 4,44 - 8,03). Sólo dos pacientes suspendieron el tratamiento por toxicidad. Conclusiones: El tratamiento con nab-paclitaxel y gemcitabina en nuestros pacientes ha resultado en una supervivencia libre de progresión similar a la de los ensayos clínicos publicados, presentando además una buena tolerancia.

  12. A process optimization study on ultrasonic extraction of paclitaxel from Taxus cuspidata.

    PubMed

    Wang, Shujie; Li, Chun; Wang, Hujun; Zhong, Xiangmei; Zhao, Jing; Zhou, Yajun

    2016-01-01

    This study aimed to improve the extraction rate of paclitaxel from Taxus cuspidata in order to determine the most effective combination of ultrasonic extraction and thin-layer chromatography-ultraviolet (TLC-UV) rapid separation method. The study was performed using the Box-Behnken test design to conduct single-factor experiments using ultrasonic extraction of paclitaxel from Taxus cuspidata. The study showed ethanol to be the best extraction solvent. When mixed with dichloromethane (1:1), the ratio of material to liquid was 1:50 when using an ultrasonic time of 1 hr at a power of 200 W. The correction coefficient K for the separation and detection of paclitaxel using the TLC-UV spectrophotometric method was 0.009152. Multifactor experiments determined the effect of the rate of liquid to material (X1), ultrasonic time (X2), and ultrasonic power (X3) on extraction using extraction volume as the dependent variable. Response surface analysis allowed a regression equation to be obtained, with the optimal conditions for extraction when the rate of liquid to material was 53.23 mL/g as an ultrasonic time of 1.11 hr and an ultrasonic power of 207.88 W. Using these parameters, the average amount of extracted paclitaxel was about 130.576 µg/g, which was significantly better than for other extraction methods. PMID:25830908

  13. The effects of narrow-band middle infrared radiation in enhancing the antitumor activity of paclitaxel.

    PubMed

    Tsai, Shang-Ru; Sheu, Bor-Ching; Huang, Pei-Shen; Lee, Si-Chen

    2016-01-01

    Paclitaxel is used as an adjuvant to enhance the effectiveness of ionization radiation therapy; however, high-energy radiation often damages the healthy cells surrounding cancer cells. Low-energy, middle-infrared radiation (MIR) has been shown to prevent tissue damage, and recent studies have begun combining MIR with paclitaxel. However, the cytotoxic effects of this treatment combination remain unclear, and the mechanism underlying its effects on HeLa cells has yet to be elucidated. This study investigated the effectiveness of treating HeLa human cervical cancer cells with a combination of paclitaxel for 48 h in conjunction with narrow-band MIR from 3.0 to 5.0 μm. This combined treatment significantly inhibited the growth of HeLa cells. Specifically, results from Annexin V-FITC/PI apoptosis detection and cell mitochondrial membrane potential analyses revealed an increase in apoptotic cell death and a collapse of mitochondrial membrane potential. One possible mechanism underlying cellular apoptosis is an increase in oxidative stress. These preliminary findings provide evidence to support the combination of narrow-band MIR with paclitaxel as an alternative approach in the treatment of human cervical cancer.

  14. Paclitaxel in platinum-resistant ovarian cancer patients. Argentine Multicenter Taxol Group.

    PubMed

    Ezcurdia, L; Jovtis, S L; Mickiewicz, E; Temperley, G; Rondinón, M; Blajman, C; Cóppola, F S; Lewi, D; Cazap, E; Breier, S; Fasce, H; Fein, L; Polera, J; Triguboff, E; Uranga, G; Pasccón, G; Luchina, A M; Martínez, C A; Politi, P M; Rubio, G; Alvarez, A M

    1997-10-01

    Paclitaxel (Taxol; Bristol-Myers Squibb Company; Princeton, NJ) is an antineoplastic agent that inhibits microtubular function and has shown efficacy in several solid tumors, mainly ovarian tumors, in which 20% to 40% response rates in previously treated patients were observed. We conducted a study to assess survival, response rate, and toxicity associated with paclitaxel treatment in patients with advanced ovarian cancer resistant to platinum therapy. Between September 1994 and November 1996, 38 patients were admitted for study and 37 were evaluable. All had disease progression or relapse within 1 year of receiving platinum-containing first-line chemotherapy. Mean age was 59 years (range, 30 to 75 years), all had bulky disease, and 18 showed increased carbohydrate antigen-125 at admission. They were treated every 3 weeks with paclitaxel 175 mg/m2 as a 3-hour infusion, preceded by standard premedication. Response rate was 51.3%, with a median response duration of 10.0 months and a median survival rate of 16.8 months. Mild to moderate hematologic toxicity was observed with only one episode of grade 4 neutropenia, without fever. Gastrointestinal toxicity was moderate and peripheral neuropathy was mild, except for two patients who had concomitant pathologies or previous treatment, which might have caused some neuropathy. We concluded that paclitaxel given as a 3-hour infusion was easily administered for ambulatory treatment, with mild to moderate toxicity and promising results based on rate and duration of response as well as survival. PMID:9346223

  15. Release Kinetics of Paclitaxel and Cisplatin from Two and Three Layered Gold Nanoparticles

    PubMed Central

    England, Christopher G.; Miller, M. Clarke; Kuttan, Ashani; Trent, John O.; Frieboes, Hermann B.

    2015-01-01

    Gold nanoparticles functionalized with biologically-compatible layers may achieve stable drug release while avoiding adverse effects in cancer treatment. We study cisplatin and paclitaxel release from gold cores functionalized with hexadecanethiol (TL) and phosphatidylcholine (PC) to form two-layer nanoparticles, or TL, PC, and high density lipoprotein (HDL) to form three-layer nanoparticles. Drug release was monitored for 14 days to assess long term effects of the core surface modifications on release kinetics. Release profiles were fitted to previously developed kinetic models to differentiate possible release mechanisms. The hydrophilic drug (cisplatin) showed an initial (5-hr.) burst, followed by a steady release over 14 days. The hydrophobic drug (paclitaxel) showed a steady release over the same time period. Two layer nanoparticles released 64.0 ± 2.5% of cisplatin and 22.3 ± 1.5% of paclitaxel, while three layer nanoparticles released the entire encapsulated drug. The Korsmeyer-Peppas model best described each release scenario, while the simplified Higuchi model also adequately described paclitaxel release from the two layer formulation. We conclude that functionalization of gold nanoparticles with a combination of TL and PC may help to modulate both hydrophilic and hydrophobic drug release kinetics, while the addition of HDL may enhance long term release of hydrophobic drug. PMID:25753197

  16. Percutaneous radial intervention for complex bilateral renal artery stenosis using paclitaxel eluting stents.

    PubMed

    Granillo, Gastón A Rodriguez; van Dijk, Lukas C; McFadden, Eugène P; Serruys, Patrick W

    2005-01-01

    Techniques used in the coronary circulation may be useful in peripheral intervention. We report a case of bilateral renal artery stenosis treated via a radial approach by direct stenting with distal protection at a right ostial lesion and modified crush stenting at a left renal bifurcation lesion using paclitaxel-eluting stents.

  17. Tumor-targeted delivery of paclitaxel using low density lipoprotein-mimetic solid lipid nanoparticles.

    PubMed

    Kim, Jin-Ho; Kim, Youngwook; Bae, Ki Hyun; Park, Tae Gwan; Lee, Jung Hee; Park, Keunchil

    2015-04-01

    Water-insoluble anticancer drugs, including paclitaxel, present severe clinical side effects when administered to patients, primarily associated with the toxicity of reagents used to solubilize the drugs. In efforts to develop alternative formulations of water-insoluble anticancer drugs suitable for intravenous administration, we developed biocompatible anticancer therapeutic solid lipid nanoparticles (SLNs), mimicking the structure and composition of natural particles, low-density lipoproteins (LDLs), for tumor-targeted delivery of paclitaxel. These therapeutic nanoparticles contained water-insoluble paclitaxel in the core with tumor-targeting ligand covalently conjugated on the polyethylene glycol (PEG)-modified surface (targeted PtSLNs). In preclinical human cancer xenograft mouse model studies, the paclitaxel-containing tumor-targeting SLNs exhibited pronounced in vivo stability and enhanced biocompatibility. Furthermore, these SLNs had superior antitumor activity to in-class nanoparticular therapeutics in clinical use (Taxol and Genexol-PM) and yielded long-term complete responses. The in vivo targeted antitumor activities of the SLN formulations in a mouse tumor model suggest that LDL-mimetic SLN formulations can be utilized as a biocompatible, tumor-targeting platform for the delivery of various anticancer therapeutics.

  18. Nab-Paclitaxel in Metastatic Breast Cancer: Defining the Best Patient Profile.

    PubMed

    González-Martín, Antonio; Alba, Emilio; Ciruelos, Eva; Cortés, Javier; Llombart, Antonio; Lluch, Ana; Andrés, Raquel; Álvarez, Isabel; Aramendía, José Manuel; de la Peña, Francisco Ayala; Barnadas, Agustí; Batista, Norberto; Calvo, Lourdes; Galve, Elena; García-Palomo, Andrés; García-Sáenz, José Ángel; de la Haba, Juan; López, Rafael; López-Vivanco, Guillermo; Martínez-Jáñez, Noelia; de Dueñas, Eduardo Martínez; Plazaola, Arrate; Rodríguez-Lescure, Álvaro; Ruiz, Manuel; Sánchez-Rovira, Pedro; Santaballa, Ana; Seguí, Miguel Ángel; Tusquets, Ignasi; Zamora, Pilar; Martín, Miguel

    2016-01-01

    Around 40% of patients with breast cancer will present with a recurrence of the disease. Chemotherapy is recommended for patients with recurrent hormone-independent or hormone-refractory breast cancer and almost all patients with metastatic breast cancer (MBC) receive chemotherapy during their medical history. Nanoparticle albuminbound (nab)-paclitaxel is a solvent-free, 130-nanometer particle formulation of paclitaxel. Nab-paclitaxel can be administered to all patients for whom the treatment choice is a taxane. In this review, 6 patient profiles for which nabpaclitaxel may be particularly useful are described and analyzed: (i) as first-line treatment of MBC, (ii) as second-line treatment of MBC after oral chemotherapy, (iii) after a standard taxane, (iv) as third-line treatment after a standard taxane and oral chemotherapy, (v) for patients with HER2-positive MBC and (vi) for patients with intolerance to standard taxanes. Nab-paclitaxel is a rational treatment choice for patients with MBC in different settings, as well as for those with prior exposure to a standard taxane. PMID:26278712

  19. Acquisition of Paclitaxel Resistance Is Associated With a More Aggressive and Invasive Phenotype in Prostate Cancer

    PubMed Central

    Kim, John J.; Yin, Bo; Christudass, Christhunesa S.; Terada, Naoki; Rajagopalan, Krithika; Fabry, Ben; Lee, Danielle Y.; Shiraishi, Takumi; Getzenberg, Robert H.; Veltri, Robert W.; An, Steven S.; Mooney, Steven M.

    2014-01-01

    Drug resistance is a major limitation to the successful treatment of advanced prostate cancer (PCa). Patients who have metastatic, castration-resistant PCa (mCRPC) are treated with chemotherapeutics. However, these standard therapy modalities culminate in the development of resistance. We established paclitaxel resistance in a classic, androgen-insensitive mCRPC cell line (DU145) and, using a suite of molecular and biophysical methods, characterized the structural and functional changes in vitro and in vivo that are associated with the development of drug resistance. After acquiring paclitaxel-resistance, cells exhibited an abnormal nuclear morphology with extensive chromosomal content, an increase in stiffness, and faster cytoskeletal remodeling dynamics. Compared with the parental DU145, paclitaxel-resistant (DU145-TxR) cells became highly invasive and motile in vitro, exercised greater cell traction forces, and formed larger and rapidly growing tumors in mouse xenografts. Furthermore, DU145-TxR cells showed a discrete loss of keratins but a distinct gain of ZEB1, Vimentin and Snail, suggesting an epithelial-to-mesenchymal transition. These findings demonstrate, for the first time, that paclitaxel resistance in PCa is associated with a trans-differentiation of epithelial cell machinery that enables more aggressive and invasive phenotype and portend new strategies for developing novel biomarkers and effective treatment modalities for PCa patients. PMID:23192682

  20. Effect of Combined Treatment Using Wilfortrine and Paclitaxel in Liver Cancer and Related Mechanism

    PubMed Central

    Li, Shuzhen; Zheng, Lei

    2016-01-01

    Background Liver cancer is a common malignant tumor with high mortality. Currently, effective medicines against liver cancer are still lacking. Paclitaxel is a wide-spectrum anti-tumor agent, while wilfortrine has been shown to have an inhibitory effect on the proliferation of liver cancer cells. This study thus investigated the potential effect of paclitaxel combined with wilfortrine on cultured liver cancer cells and related mechanisms, in order to provide evidence for pathogenesis and treatment of liver cancer. Material/Methods Liver cancer cell line HpeG2 was divided into control, paclitaxel, wilfortrine, and combined treatment groups. Cell proliferation was tested by MTT, while invasion was detected in Transwell chamber assay. Apoptotic protein Bcl-2 and Bax expression levels were further quantified using real-time PCR and Western blotting. Results Both of those 2 drugs can effectively inhibit cancer cell proliferation, depress invasion ability, increase Bcl-2 expression, and elevate Bax expression levels (p<0.05 in all cases). The combined therapy had better treatment efficacy compared to either of those drugs alone (p<0.05). Conclusions The combined treatment using wilfortrine and paclitaxel can inhibit proliferation and invasion of liver cancer cells via down-regulating Bcl-2 and up-regulating Bax, with better efficacy than single use of either drug. PMID:27043783

  1. Dicer Elicits Paclitaxel Chemosensitization and Suppresses Cancer Stemness in Breast Cancer by Repressing AXL.

    PubMed

    Chang, Ting-Yu; Chen, Hsin-An; Chiu, Ching-Feng; Chang, Yi-Wen; Kuo, Tsang-Chih; Tseng, Po-Chun; Wang, Weu; Hung, Mien-Chie; Su, Jen-Liang

    2016-07-01

    Paclitaxel is a standard-of-care chemotherapy for breast cancer, despite the increasing recognition of its poor effectiveness in the treatment of patients with advanced disease. Here, we report that adenovirus-type 5 E1A-mediated elevation of the miRNA-processing enzyme Dicer is sufficient to enhance paclitaxel sensitization and reduce cancer stem-like cell properties in this setting. Elevating Dicer expression increased levels of the AXL kinase targeting miRNA miR-494, thereby repressing AXL expression to increase paclitaxel sensitivity. We found that Dicer expression was regulated at the transcription level by E1A, through activation of an MAPK14/CEBPα pathway. Our findings define a mechanism of E1A-mediated chemosensitization for paclitaxel, which is based upon the suppression of breast cancer stem-like cells, with potential implications for the diagnosis and treatment of breast cancer patients. Cancer Res; 76(13); 3916-28. ©2016 AACR. PMID:27216190

  2. Transferrin-Targeted Polymeric Micelles Co-Loaded with Curcumin and Paclitaxel: Efficient Killing of Paclitaxel-Resistant Cancer Cells

    PubMed Central

    Abouzeid, Abraham H.; Patel, Niravkumar R.; Sarisozen, Can

    2014-01-01

    Purpose The ability to successfully treat advanced forms of cancer remains a challenge due to chemotherapy resistance. Numerous studies indicate that NF-κB, a protein complex that controls the expression of numerous genes, as being a key factor in producing chemo-resistant tumors. In this study, the therapeutic potential of transferrin (TF)-targeted mixed micelles, made of PEG-PE and vitamin E co-loaded with curcumin (CUR), a potent NF-κB inhibitor, and paclitaxel (PCL), was examined. Methods The cytotoxicity of non-targeted and TF-targeted CUR and PCL micelles as a single agent or in combination was investigated against SK-OV-3 human ovarian adenocarcinoma along with its multi-drug resistant (MDR) version SK-OV-3-PCL-resistant (SK-OV-3TR) cells in vitro. Results Our results indicated that the TF-targeted combination micelles were able to improve the net cytotoxic effect of CUR and PCL to clear synergistic one against the SK-OV-3 cells. In addition, even though the non-targeted combination treatment demonstrated a synergistic effect against the SK-OV-3TR cells, the addition of the TF-targeting moiety significantly increased this cytotoxic effect. While keeping CUR constant at 5 and 10 μM and varying the PCL concentration, the PCL IC50 decreased from ~ 1.78 and 0.68 μM for the non-targeted formulations to ~ 0.74 and 0.1 μM for the TF-targeted ones, respectively. Conclusion Our results indicate that such co-loaded targeted mixed micelles could have significant clinical advantages for the treatment of resistant ovarian cancer and provide a clear rational for further in vivo investigation. PMID:24522815

  3. Digitoxin activates EGR1 and synergizes with paclitaxel on human breast cancer cells

    PubMed Central

    Einbond, Linda Saxe; Wu, Hsan-au; Su, Tao; Chang, Tangel; Panjikaran, Maya; Wang, Xiaomei; Goldsberry, Sarah

    2010-01-01

    Background: Numerous studies have suggested that digitalis derivatives promise to be superior to existing adjuvant therapy for breast cancer as to effects and side-effects. In the present study, we have used gene expression analysis to determine the molecular action of digitoxin on breast cancer cells and assessed digitoxin’s ability to synergize with the chemotherapy agent paclitaxel with respect to inhibition of cell proliferation Materials and Methods: We treated (Her2 overexpressing, ER low) MDA-MB-453 human breast cancer cells with digitoxin at four doses {20 ng/ml (26 nM) to 1 μg/ml} and collected RNA at 6 h and 24 h for gene expression analysis. To examine the effects on ER positive cells, we treated MCF7 cells with digitoxin at 1 μg/ml and collected RNA for RT-PCR analysis. In addition, we assayed the growth inhibitory effect of low doses of digitoxin combined with paclitaxel and determined combination index values. Results: To reveal primary effects, we examined digitoxin’s effect 6 h post-treatment with the highest dose, 1μg/ml, and found upregulation of the stress response genes EGR-1 and NAB2, lipid biosynthetic genes and the tumor suppressor gene p21, and downregulation of the mitotic cell cycle gene CDC16 and the replication gene PolR3B. RT-PCR analysis validated effects on stress response, apoptotic and cell cycle genes on MDA-MB-453 and MCF7 cells. Western blot analysis confirmed induction of EGR1 protein at 1 h and ATF3 at 24 h. Paclitaxel, as well as digitoxin, inhibited the in vitro activity of the purified Na+-K+-ATPase; digitoxin enhanced the growth inhibitory effects of paclitaxel on Her2 overexpressing breast cancer cells. Conclusions: Our studies show the potential of digitoxin to prevent and treat breast cancer and indicate that the combination of digitoxin and paclitaxel is a promising treatment for ER negative breast cancer. These findings are the first to alert physicians to the possible dangers to patients who take a combination

  4. Polymeric nanoparticles for the intracellular delivery of paclitaxel in lung and breast cancer

    NASA Astrophysics Data System (ADS)

    Zubris, Kimberly Ann Veronica

    Nanoparticles are useful for addressing many of the difficulties encountered when administering therapeutic compounds. Nanoparticles are able to increase the solubility of hydrophobic drugs, improve pharmacokinetics through sustained release, alter biodistribution, protect sensitive drugs from low pH environments or enzymatic alteration, and, in some cases, provide targeting of the drug to the desired tissues. The use of functional nanocarriers can also provide controlled intracellular delivery of a drug. To this end, we have developed functional pH-responsive expansile nanoparticles for the intracellular delivery of paclitaxel. The pH-responsiveness of these nanoparticles occurs due to a hydrophobic to hydrophilic transition of the polymer occurring under mildly acidic conditions. These polymeric nanoparticles were systematically evaluated for the delivery of paclitaxel in vitro and in vivo to improve local therapy for lung and breast cancers. Nanoparticles were synthesized using a miniemulsion polymerization process and were subsequently characterized and found to swell when exposed to acidic environments. Paclitaxel was successfully encapsulated within the nanoparticles, and the particles exhibited drug release at pH 5 but not at pH 7.4. In addition, the uptake of nanoparticles was observed using flow cytometry, and the anticancer efficacy of the paclitaxel-loaded nanoparticles was measured using cancer cell lines in vitro. The potency of the paclitaxel-loaded nanoparticles was close to that of free drug, demonstrating that the drug was effectively delivered by the particles and that the particles could act as an intracellular drug depot. Following in vitro characterization, murine in vivo studies demonstrated the ability of the paclitaxel-loaded responsive nanoparticles to delay recurrence of lung cancer and to prevent establishment of breast cancer in the mammary fat pads with higher efficacy than paclitaxel alone. In addition, the ability of nanoparticles to

  5. Curcumin improves the paclitaxel-induced apoptosis of HPV-positive human cervical cancer cells via the NF-κB-p53-caspase-3 pathway

    PubMed Central

    DANG, YU-PING; YUAN, XIAO-YING; TIAN, RONG; LI, DONG-GUANG; LIU, WEI

    2015-01-01

    Paclitaxel, isolated from Taxus brevifolia, is considered to be an efficacious agent against a wide spectrum of human cancers, including human cervical cancer. However, dose-limiting toxicity and high cost limit its clinical application. Curcumin, a nontoxic food additive, has been reported to improve paclitaxel chemotherapy in mouse models of cervical cancer. However, the underlying mechanisms remain unclear. In this study, two human cervical cancer cell lines, CaSki [human papilloma virus (HPV)16-positive] and HeLa (HPV18-positive), were selected in which to investigate the effect of curcumin on the anticancer action of paclitaxel and further clarify the mechanisms. Flow cytometry and MTT analysis demonstrated that curcumin significantly promoted paclitaxel-induced apoptosis and cytotoxicity in the two cervical cell lines compared with that observed with paclitaxel alone (P<0.05). Reverse transcription-polymerase chain reaction indicated that the decline of HPV E6 and E7 gene expression induced by paclitaxel was also assisted by curcumin. The expression levels of p53 protein and cleaved caspase-3 were increased significantly in the curcumin plus paclitaxel-treated HeLa and CaSki cells compared with those in the cells treated with paclitaxel alone (P<0.01). Significant reductions in the levels of phosphorylation of IκBα and the p65-NF-κB subunit in CaSki cells treated with curcumin and paclitaxel were observed compared with those in cells treated with paclitaxel alone (P<0.05). This suggests that the combined effect of curcumin and paclitaxel was associated with the NF-κB-p53-caspase-3 pathway. In conclusion, curcumin has the ability to improve the paclitaxel-induced apoptosis of HPV-positive human cervical cancer cell lines via the NF-κB-p53-caspase-3 pathway. Curcumin in combination with paclitaxel may provide a superior therapeutic effect on human cervical cancer. PMID:25780454

  6. Hyaluronic acid-paclitaxel conjugate inhibits growth of human squamous cell carcinomas of the head and neck via a hyaluronic acid-mediated mechanism.

    PubMed

    Galer, Chad E; Sano, Daisuke; Ghosh, Sukhen C; Hah, Jeong H; Auzenne, Edmund; Hamir, Amirali N; Myers, Jeffrey N; Klostergaard, Jim

    2011-11-01

    Chemotherapeutic regimens incorporating taxanes significantly improve outcomes for patients with squamous cell carcinomas of the head and neck (SCCHN). However, treatment with taxanes is limited by toxicities, including bone marrow suppression and peripheral neuropathies. We proposed that conjugating taxanes to targeting carrier molecules would increase antitumor efficacy and decrease toxicity. The cell surface proteoglycan, CD44, is expressed on most SCCHNs, and we hypothesized that it is an attractive candidate for targeted therapy via its natural ligand, hyaluronic acid (HA). We determined whether HA-paclitaxel conjugates were able to decrease tumor growth and improve survival in orthotopic nude mouse human SCCHN xenograft models. HA-paclitaxel concentration-dependent growth inhibition of human SCCHN cell lines OSC-19 and HN5 in vitro, very similarly to free paclitaxel treatment. Tumor cell uptake of FITC-labeled HA-paclitaxel was significantly blocked with free HA, indicating the dependence of uptake on CD44. HA-paclitaxel administered intravenously once per week for three weeks at 120 mg/kg paclitaxel equivalents, far above the paclitaxel maximum tolerated dose, exerted superior tumor growth control to that of paclitaxel in both orthotopic OSC-19-luciferase and HN5 xenograft models in vivo. Mouse survival following HA-paclitaxel administration was prolonged compared with that of controls in mice implanted with either of these xenografts. Mice treated with HA-paclitaxel displayed increased TUNEL(+) cells in tumor tissue, as well as markedly reduced microvessel density compared to those treated with free paclitaxel. No acute histopathological changes were observed in mice treated with HA-paclitaxel. Thus, we conclude that HA-paclitaxel effectively inhibits tumor growth in human SCCHN xenografts via an HA-mediated mechanism and this conjugate should be considered for further preclinical development for this disease.

  7. Tunable temperature responsive liquid chromatography through thiolactone-based immobilization of poly(N-isopropylacrylamide).

    PubMed

    Satti, Angel J; Espeel, Pieter; Martens, Steven; Van Hoeylandt, Tim; Du Prez, Filip E; Lynen, Frederic

    2015-12-24

    A straightforward and efficient functionalization of aminopropylsilica with polymeric structures is described for the development of temperature responsive stationary phases applicable in purely aqueous liquid chromatography. The immobilization of the thermoresponsive polymers involves a thiolactone-based ring opening using the primary amines in aminopropylsilica, with a simultaneous one-pot, thiol-ene functionalization with an acrylate of choice. This mild, straightforward and modular grafting process results in high polymer coupling yields. By variation of the acrylate for the thiol-ene reaction, different stationary phases can be readily obtained. Two stationary phases as a result of the modular modification of aminopropylsilica were evaluated with test mixtures of hydrophobic analytes and a mixture of di- and tripeptides. Analyses using the 5μm material packed in 10cm×4.6mm columns revealed high hydrophobic retention, which proved adaptable as a function of the temperature in aqueous mobile phases. High versus low retention were obtained at temperatures above and below the lower critical solution temperature of the polymer, respectively. Moreover, the columns depict potential for diastereoisomeric peptide separation. Finally, the lower retention, observed when using PEGylated silica, illustrates the potential of the approach for modular stationary phase tuning. PMID:26655790

  8. Application of polymeric macroporous supports for temperature-responsive chromatography of pharmaceuticals.

    PubMed

    Lamprou, Alexandros; Gavriilidou, Agni-Faviola-Mika; Storti, Giuseppe; Soos, Miroslav; Morbidelli, Massimo

    2015-08-14

    A macroporous particulate support prepared previously by reactive gelation under shear and functionalized with poly(N-isopropylacrylamide), PNIPAM, brushes of variable length is applied for temperature-responsive chromatography, whereby temperature modulates hydrophobic interactions. Several different analytes, including small pharmaceuticals, peptides, proteins and monoclonal antibodies are employed. Contrary to the most commonly observed behavior in conventional chromatography, increasing retention is observed at elevated temperatures. Peak broadening is quantified using the peak standard deviation, which depends on both the polymer chain conformation and analyte adsorptivity. The favorable effect of grafted polymer thickness on retention becomes progressively less pronounced for thicker grafted PNIPAM layers. The effect of eluent composition on solute-sorbent interactions was investigated by introducing NaCl, methanol, dioxane and by varying the pH. Salt or organic solvent addition affects apart from the analytes solution properties, the hydrophobicity of the stationary phase itself. Frontal analyses performed at different temperatures to determine dynamic binding capacities, indicate small mass transfer resistances imposed by this novel packing material.

  9. Temperature responsive complex coacervate core micelles with a PEO and PNIPAAm corona.

    PubMed

    Voets, Ilja K; Moll, Puck M; Aqil, Abdelhafid; Jérôme, Christine; Detrembleur, Christophe; Waard, Pieter de; Keizer, Arie de; Stuart, Martien A Cohen

    2008-09-01

    In aqueous solutions at room temperature, poly( N-methyl-2-vinyl pyridinium iodide)- block-poly(ethylene oxide), P2MVP 38- b-PEO 211 and poly(acrylic acid)- block-poly(isopropyl acrylamide), PAA 55- b-PNIPAAm 88 spontaneously coassemble into micelles, consisting of a mixed P2MVP/PAA polyelectrolyte core and a PEO/PNIPAAm corona. These so-called complex coacervate core micelles (C3Ms), also known as polyion complex (PIC) micelles, block ionomer complexes (BIC), and interpolyelectrolyte complexes (IPEC), respond to changes in solution pH and ionic strength as their micellization is electrostatically driven. Furthermore, the PNIPAAm segments ensure temperature responsiveness as they exhibit lower critical solution temperature (LCST) behavior. Light scattering, two-dimensional 1H NMR nuclear Overhauser effect spectrometry, and cryogenic transmission electron microscopy experiments were carried out to investigate micellar structure and solution behavior at 1 mM NaNO 3, T = 25, and 60 degrees C, that is, below and above the LCST of approximately 32 degrees C. At T = 25 degrees C, C3Ms were observed for 7 < pH < 12 and NaNO 3 concentrations below approximately 105 mM. The PEO and PNIPAAm chains appear to be (randomly) mixed within the micellar corona. At T = 60 degrees C, onion-like complexes are formed, consisting of a PNIPAAm inner core, a mixed P2MVP/PAA complex coacervate shell, and a PEO corona.

  10. Effects of temperature-responsive hydrogel on viscosity of denture adhesives.

    PubMed

    Zhao, Huizi; Akiba, Norihisa; Tanimoto, Hiroyuki; Yoshizaki, Taro; Yalikun, Kaidiliya; Minakuchi, Shunsuke

    2016-01-01

    The cream type of denture adhesives after use cannot be easily removed from oral mucosa and have the potential risk to change the oral flora. The effects of the temperature-responsive hydrogel Pluronic F-127 (PF) on the complex viscosity of denture adhesives were evaluated. Carboxy methylcellulose (CMC) mass fractions (1, 2, 3 and 4%) were added to 20 and 25% PF hydrogels. Complex viscosity was measured over a temperature cycle (40→10→40°C) and fixed temperature points (23 and 37°C). Adhesive strength tests were performed with 2 resin plates at 23 and 37°C. One commercial cream-type denture adhesive, New Poligrip® (NP), was evaluated as a control. Complex viscosity values for PF20% groups at 23°C were lower than those for NP at 37°C. Adhesive strength of PF20% with CMC2%, was higher at 23°C when compared to NP at 37°C, which suggests that PF20%CMC2% is an effective adhesive and is easily removed after mouth rinsing.

  11. Body temperature responses of Savanna Brown goat to the harmattan and hot-dry season

    NASA Astrophysics Data System (ADS)

    Igono, M. O.; Molokwu, E. C. I.; Aliu, Y. O.

    1982-09-01

    Rectal and vaginal temperature responses of the Savanna Brown goat indigenous to the Nigerian guinea savanna were determined during the harmattan and the hot-dry season. Measurements were made at 06:00h and at 14:00h after 8h exposure to field conditions. At the 06:00h measurements during the harmattan, all animals were observed to shiver. A significant (P<0.01) positive correlation was found between rectal (Tre) and vaginal temperatures. During the harmattan, mean Tre was 38.2‡C at 06:00h and 39.7‡C at 14:00h; the mean difference, δTre was 1.5‡C. During the hot-dry season, Tre at 06:00h was 38.1‡C, and at 14:00h, 38.7; δTre was 0.6‡C. It is concluded that the harmattan is thermally more stressful than the hot-dry season and that passive thermolability may not be an important mechanism in the Savanna Brown goat in adaptation to thermal stress.

  12. Seasonal temperature responses to land-use change in the western United States

    USGS Publications Warehouse

    Kueppers, L.M.; Snyder, M.A.; Sloan, L.C.; Cayan, D.; Jin, J.; Kanamaru, H.; Kanamitsu, M.; Miller, N.L.; Tyree, Mary; Du, H.; Weare, B.

    2008-01-01

    In the western United States, more than 79 000??km2 has been converted to irrigated agriculture and urban areas. These changes have the potential to alter surface temperature by modifying the energy budget at the land-atmosphere interface. This study reports the seasonally varying temperature responses of four regional climate models (RCMs) - RSM, RegCM3, MM5-CLM3, and DRCM - to conversion of potential natural vegetation to modern land-cover and land-use over a 1-year period. Three of the RCMs supplemented soil moisture, producing large decreases in the August mean (- 1.4 to - 3.1????C) and maximum (- 2.9 to - 6.1????C) 2-m air temperatures where natural vegetation was converted to irrigated agriculture. Conversion to irrigated agriculture also resulted in large increases in relative humidity (9% to 36% absolute change). Modeled changes in the August minimum 2-m air temperature were not as pronounced or consistent across the models. Converting natural vegetation to urban land-cover produced less pronounced temperature effects in all models, with the magnitude of the effect dependent upon the preexisting vegetation type and urban parameterizations. Overall, the RCM results indicate that the temperature impacts of land-use change are most pronounced during the summer months, when surface heating is strongest and differences in surface soil moisture between irrigated land and natural vegetation are largest. ?? 2007 Elsevier B.V. All rights reserved.

  13. Novel temperature-responsive polymer brushes with carbohydrate residues facilitate selective adhesion and collection of hepatocytes

    NASA Astrophysics Data System (ADS)

    Idota, Naokazu; Ebara, Mitsuhiro; Kotsuchibashi, Yohei; Narain, Ravin; Aoyagi, Takao

    2012-12-01

    Temperature-responsive glycopolymer brushes were designed to investigate the effects of grafting architectures of the copolymers on the selective adhesion and collection of hypatocytes. Homo, random and block sequences of N-isopropylacrylamide and 2-lactobionamidoethyl methacrylate were grafted on glass substrates via surface-initiated atom transfer radical polymerization. The galactose/lactose-specific lectin RCA120 and HepG2 cells were used to test for specific recognition of the polymer brushes containing galactose residues over the lower critical solution temperatures (LCSTs). RCA120 showed a specific binding to the brush surfaces at 37 °C. These brush surfaces also facilitated the adhesion of HepG2 cells at 37 °C under nonserum conditions, whereas no adhesion was observed for NIH-3T3 fibroblasts. When the temperature was decreased to 25 °C, almost all the HepG2 cells detached from the block copolymer brush, whereas the random copolymer brush did not release the cells. The difference in releasing kinetics of cells from the surfaces with different grafting architectures can be explained by the correlated effects of significant changes in LCST, mobility, hydrophilicity and mechanical properties of the grafted polymer chains. These findings are important for designing ‘on-off’ cell capture/release substrates for various biomedical applications such as selective cell separation.

  14. Temperature-responsive self-assembled monolayers of oligo(ethylene glycol): control of biomolecular recognition.

    PubMed

    Zareie, Hadi M; Boyer, Cyrille; Bulmus, Volga; Nateghi, Ebrahim; Davis, Thomas P

    2008-04-01

    Self-assembled monolayers (SAMs) of oligo(ethylene glycol) (OEG)-tethered molecules on gold are important for various biorelevant applications ranging from biomaterials to bioanalytical devices, where surface resistance to nonspecific protein adsorption is needed. Incorporation of a stimuli-responsive character to the OEG SAMs enables the creation of nonfouling surfaces with switchable functionality. Here we present an OEG-derived structure that is highly responsive to temperature changes in the vicinity of the physiological temperature, 37 degrees C. The temperature-responsive solution behavior of this new compound was demonstrated by UV-vis and nuclear magnetic resonance spectroscopy. Its chemisorption onto gold(111), and the retention of responsive behavior after chemisorption have been demonstrated by surface plasmon resonance (SPR), X-ray photoelectron spectroscopy (XPS), and atomic force and scanning tunneling microscopy. The OEG-derived SAMs have been shown to reversibly switch the wettability of the surface, as determined by contact angle measurements. More importantly, SPR and AFM studies showed that the OEG SAMs can be utilized to control the affinity binding of streptavidin to the biotin-tethered surface in a temperature-dependent manner while still offering the nonspecific protein-resistance to the surface.

  15. Velocity and Temperature Response Functions of 77 Near-Infrared (800 - 1400 nm) Photospheric Lines - I

    NASA Astrophysics Data System (ADS)

    Penza, V.; Berrilli, F.

    2012-04-01

    We present a new list of solar photospheric lines in the near-infrared (NIR) region obtained by synthesis under local thermodynamic equilibrium (LTE) approximation. We give novel velocity and temperature response functions (RFs) for 77 lines over the spectral range 800 - 1400 nm. Using these RFs, we are able to obtain for each line the core formation height and the range of atmospheric layers where thermodynamic perturbations are dominant. Moreover, by using the depth-integrated RFs, we give an indication of the dependence on the wavelength of the RFs and quantify their sensitivity to thermodynamic variations. The NIR region represents a significant source of interest for spectroscopic and polarimetric studies. Indeed, at these wavelengths we explore the deeper photospheric layers, and the Zeeman splitting is larger than in the visible range. Several research fields in solar astrophysics ( e.g., photospheric and chromospheric dynamics, magnetoconvection in active regions, and interaction between solar plasma and magnetic field) should benefit from using this new line list. Moreover, various new NIR instruments are planned for future space missions or next generation ground-based solar telescopes, such as the European Solar Telescope (EST) or the Advanced Technology Solar Telescope (ATST).

  16. Controllable and switchable drug delivery of ibuprofen from temperature responsive composite nanofibers

    NASA Astrophysics Data System (ADS)

    Tran, Toan; Hernandez, Mariana; Patel, Dhruvil; Burns, Elena; Peterman, Vanessa; Wu, Ji

    2015-08-01

    Composited electrospun nanofibers made of temperature-responsive poly(N-isopropylacrylamide) (pNIPAM) and biodegradable poly (ɛ-caprolactone) (PCL) can be utilized for `on-demand' and controlled drug release of ibuprofen without burst effect for potential pharmaceutical applications. Three types of nanofibers, PCL, pNIPAM and pNIPAM/PCL composite NFs containing ibuprofen were fabricated using electrospinning techniques. Ibuprofen release rates from PCL NFs are not affected by the temperature in the range of 22-34°C (less than 10%). In contrast, the ibuprofen release rates from pNIPAM NFs are very sensitive to the change in temperature, which is five times higher at 22°C compared to 34°C. However, there is a serious burst effect at 22°C. Compared to other two types of NFs, pNIPAM/PCL composite NFs prepared demonstrated a variable and controlled release at both room and higher temperature, due to the extra protection from the hydrophobic poly (ɛ-caprolactone). The rate at 22°C is 75% faster compared to that at 34°C. This kind of composite design can provide a novel approach to suppress the burst effect in drug delivery systems for potential pharmaceutical applications.

  17. The use of infrared thermography to detect the skin temperature response to physical activity

    NASA Astrophysics Data System (ADS)

    Tanda, G.

    2015-11-01

    Physical activity has a noticeable effect on skin blood flow and temperature. The thermal regulatory and hemodynamic processes during physical activity are controlled by two conflicting mechanisms: the skin vasoconstriction induced by the blood flow demand to active muscles and the skin vasodilation required by thermoregulation to increase warm blood flow and heat conduction to the skin. The time-evolution of skin temperature during exercise can give useful information about the adaptation of the subject as a function of specific type, intensity and duration of exercise. In this paper, infrared thermography is used to investigate the thermal response of skin temperature during running exercise on treadmill for a group of seven healthy and trained runners. Two different treadmill exercises are considered: a graded load exercise and a constant load exercise; for both exercises the duration was 30 minutes. Within the limits due to the relatively small size of the sample group, results typically indicate a fall in skin temperature during the initial stage of running exercise. As the exercise progresses, the dynamics of the skin temperature response depends on the type of exercise (graded versus constant load) and probably on the level of training of the subject.

  18. High transparent shape memory gel

    NASA Astrophysics Data System (ADS)

    Gong, Jin; Arai, Masanori; Kabir, M. H.; Makino, Masato; Furukawa, Hidemitsu

    2014-03-01

    Gels are a new material having three-dimensional network structures of macromolecules. They possess excellent properties as swellability, high permeability and biocompatibility, and have been applied in various fields of daily life, food, medicine, architecture, and chemistry. In this study, we tried to prepare new multi-functional and high-strength gels by using Meso-Decoration (Meso-Deco), one new method of structure design at intermediate mesoscale. High-performance rigid-rod aromatic polymorphic crystals, and the functional groups of thermoreversible Diels-Alder reaction were introduced into soft gels as crosslinkable pendent chains. The functionalization and strengthening of gels can be realized by meso-decorating the gels' structure using high-performance polymorphic crystals and thermoreversible pendent chains. New gels with good mechanical properties, novel optical properties and thermal properties are expected to be developed.

  19. Terminal arbor degeneration (TAD): a novel lesion produced by the antineoplastic agent, paclitaxel

    PubMed Central

    Bennett, Gary J.; Liu, Guo Kai; Xiao, Wen Hua; Jin, Hai Wei; Siau, Chiang

    2011-01-01

    The anti-neoplastic agent, paclitaxel, causes a dose-limiting distal, symmetrical, sensory peripheral neuropathy that is often accompanied by a neuropathic pain syndrome. In a low-dose model of paclitaxel-evoked painful peripheral neuropathy in the rat, we have shown that the drug causes degeneration of intraepidermal nerve fibers (IENFs), i.e., the fibers which give rise to the sensory afferent’s terminal receptor arbour. However, we did not find any evidence for axonal degeneration in samples taken at the mid-nerve level. Here we aimed to determine whether the absence of degenerating peripheral nerve axons was due to sampling a level that was too proximal. We used electron microscopy to study the distal-most branches of the nerves innervating the hind paw glabrous skin of normal and paclitaxel-treated rats. We confirmed that we sampled at a time when IENF degeneration was prominent. Because degeneration might be easier to detect with higher paclitaxel doses, we examined a four-fold cumulative dose range (8–32 mg/kg). We found no evidence of degeneration in the superficial subepidermal axon bundles (sSAB) that are located just a few microns below the epidermal basal lamina. Specifically, for all three dose groups there was no change in the number of sSAB per mm of epidermal border, no change in the number of axons per sSAB, and no change in the diameter of sSAB axons. We conclude that paclitaxel produces a novel type of lesion that is restricted to the afferent axon’s terminal arbor; we name this lesion “terminal arbor degeneration (TAD)”. PMID:21395870

  20. Comparative Effects of Ibandronate and Paclitaxel on Immunocompetent Bone Metastasis Model

    PubMed Central

    Chung, Yoon-Sok; Kang, Ho Chul

    2015-01-01

    Purpose Bone metastasis invariably increases morbidity and mortality. This study compares the effects of ibandronate and paclitaxel on bone structure and its mechanical properties and biochemical turnover in resorption markers using an immunocompetent Walker 256-Sprague-Dawley model, which was subjected to tumor-induced osteolysis. Materials and Methods Seventy rats were divided equally into 4 groups: 1) sham group (SHAM), 2) tumor group (CANC), 3) ibandronate treated group (IBAN), and 4) paclitaxel treated group (PAC). Morphological indices [bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp)] and mechanical properties (failure load, stiffness) were evaluated after thirty days of treatment period. Bone resorption rate was analysed using serum deoxypyridinoline (Dpd) concentrations. Results Morphological indices showed that ibandronate (anti-resorptive drug) had a better effect in treating tumor-induced architectural changes in bone than paclitaxel (chemotherapeutic drug). The deterioration in bone architecture was reflected in the biomechanical properties of bone as studied with decreased failure load (Fx) and stiffness (S) of the bone on the 30th day post-surgery. Dpd concentrations were significantly lower in the IBAN group, indicating successful inhibition of bone resorption and destruction. Conclusion Ibandronate was found to be as effective as higher doses of paclitaxel in maintaining stiffness of bone. Paclitaxel treatment did not appear to inhibit osteoclast resorption, which is contrary to earlier in-vitro literature. Emphasis should be placed on the use of immunocompetent models for examining drug efficacy since it adequately reflects bone metastasis in clinical scenarios. PMID:26446649

  1. Transportan in nanocarriers improves skin localization and antitumor activity of paclitaxel

    PubMed Central

    Pepe, Dominique; Carvalho, Vanessa FM; McCall, Melissa; de Lemos, Débora P; Lopes, Luciana B

    2016-01-01

    In this study, the ability of nanocarriers containing protein transduction domains (PTDs) of various classes to improve cutaneous paclitaxel delivery and efficacy in skin tumor models was evaluated. Microemulsions (MEs) were prepared by mixing a surfactant blend (polyoxyethylene 10 oleoyl ether, ethanol and propylene glycol), monocaprylin, and water. The PTD transportan (ME-T), penetratin (ME-P), or TAT (ME-TAT) was added at a concentration of 1 mM to the plain ME. All MEs displayed nanometric size (32.3–40.7 nm) and slight positive zeta potential (+4.1 mV to +6.8 mV). Skin penetration of paclitaxel from the MEs was assessed for 1–12 hours using porcine skin and Franz diffusion cells. Among the PTD-containing formulations, paclitaxel skin (stratum corneum + epidermis and dermis) penetration at 12 hours was maximized with ME-T, whereas ME-TAT provided the lowest penetration (1.6-fold less). This is consistent with the stronger ability of ME-T to increase transepidermal water loss (2.4-fold compared to water) and tissue permeability. The influence of PTD addition on the ME irritation potential was assessed by measuring interleukin-1α expression and viability of bioengineered skin equivalents. A 1.5- to 1.8-fold increase in interleukin-1α expression was induced by ME-T compared to the other formulations, but this effect was less pronounced (5.8-fold) than that mediated by the moderate irritant Triton. Because ME-T maximized paclitaxel cutaneous localization while being safer than Triton, its efficacy was assessed against basal cell carcinoma cells and a bioengineered three-dimensional melanoma model. Paclitaxel-containing ME-T reduced cells and tissue viability by twofold compared to drug solutions, suggesting the potential clinical usefulness of the formulation for the treatment of cutaneous tumors. PMID:27274232

  2. iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes.

    PubMed

    Simón-Gracia, Lorena; Hunt, Hedi; Scodeller, Pablo; Gaitzsch, Jens; Kotamraju, Venkata Ramana; Sugahara, Kazuki N; Tammik, Olav; Ruoslahti, Erkki; Battaglia, Giuseppe; Teesalu, Tambet

    2016-10-01

    Polymersomes are versatile nanoscale vesicles that can be used for cytoplasmic delivery of payloads. Recently, we demonstrated that pH-sensitive polymersomes exhibit an intrinsic selectivity towards intraperitoneal tumor lesions. A tumor homing peptide, iRGD, harbors a cryptic C-end Rule (CendR) motif that is responsible for neuropilin-1 (NRP-1) binding and for triggering extravasation and tumor penetration of the peptide. iRGD functionalization increases tumor selectivity and therapeutic efficacy of systemic drug-loaded nanoparticles in many tumor models. Here we studied whether intraperitoneally administered paclitaxel-loaded iRGD-polymersomes show improved efficacy in the treatment of peritoneal carcinomatosis. First, we demonstrated that the pH-sensitive polymersomes functionalized with RPARPAR (a prototypic CendR peptide) or iRGD internalize in the cells that express NRP-1, and that internalized polymersomes release their cargo inside the cytosol. CendR-targeted polymersomes loaded with paclitaxel were more cytotoxic on NRP-1-positive cells than on NRP-1-negative cells. In mice bearing peritoneal tumors of gastric (MKN-45P) or colon (CT26) origin, intraperitoneally administered RPARPAR and iRGD-polymersomes showed higher tumor-selective accumulation and penetration than untargeted polymersomes. Finally, iRGD-polymersomes loaded with paclitaxel showed improved efficacy in peritoneal tumor growth inhibition and in suppression of local dissemination compared to the pristine paclitaxel-polymersomes or Abraxane. Our study demonstrates that iRGD-functionalization improves efficacy of paclitaxel-polymersomes for intraperitoneal treatment of peritoneal carcinomatosis.

  3. Transportan in nanocarriers improves skin localization and antitumor activity of paclitaxel.

    PubMed

    Pepe, Dominique; Carvalho, Vanessa Fm; McCall, Melissa; de Lemos, Débora P; Lopes, Luciana B

    2016-01-01

    In this study, the ability of nanocarriers containing protein transduction domains (PTDs) of various classes to improve cutaneous paclitaxel delivery and efficacy in skin tumor models was evaluated. Microemulsions (MEs) were prepared by mixing a surfactant blend (polyoxyethylene 10 oleoyl ether, ethanol and propylene glycol), monocaprylin, and water. The PTD transportan (ME-T), penetratin (ME-P), or TAT (ME-TAT) was added at a concentration of 1 mM to the plain ME. All MEs displayed nanometric size (32.3-40.7 nm) and slight positive zeta potential (+4.1 mV to +6.8 mV). Skin penetration of paclitaxel from the MEs was assessed for 1-12 hours using porcine skin and Franz diffusion cells. Among the PTD-containing formulations, paclitaxel skin (stratum corneum + epidermis and dermis) penetration at 12 hours was maximized with ME-T, whereas ME-TAT provided the lowest penetration (1.6-fold less). This is consistent with the stronger ability of ME-T to increase transepidermal water loss (2.4-fold compared to water) and tissue permeability. The influence of PTD addition on the ME irritation potential was assessed by measuring interleukin-1α expression and viability of bioengineered skin equivalents. A 1.5- to 1.8-fold increase in interleukin-1α expression was induced by ME-T compared to the other formulations, but this effect was less pronounced (5.8-fold) than that mediated by the moderate irritant Triton. Because ME-T maximized paclitaxel cutaneous localization while being safer than Triton, its efficacy was assessed against basal cell carcinoma cells and a bioengineered three-dimensional melanoma model. Paclitaxel-containing ME-T reduced cells and tissue viability by twofold compared to drug solutions, suggesting the potential clinical usefulness of the formulation for the treatment of cutaneous tumors. PMID:27274232

  4. Chronic cannabinoid CB2 activation reverses paclitaxel neuropathy without tolerance or CB1-dependent withdrawal

    PubMed Central

    Deng, Liting; Guindon, Josée; Cornett, Benjamin L.; Makriyannis, Alexandros; Mackie, Ken; Hohmann, Andrea G.

    2014-01-01

    Background Mixed cannabinoid CB1/CB2 agonists such as Δ9-tetrahydrocannabinol (Δ9-THC) can produce tolerance, physical withdrawal, and unwanted CB1-mediated central nervous system side effects. Whether repeated systemic administration of a CB2-preferring agonist engages CB1 receptors or produces CB1-mediated side effects is unknown. Methods We evaluated anti-allodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB2-preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB1KO, CB2KO, and WT mice. Comparisons were made with the prototypic classical cannabinoid Δ9-THC. We also explored the site and possible mechanism of action of AM1710. Results Paclitaxel-induced mechanical and cold allodynia developed equivalently in CB1KO, CB2KO, and WT mice. Both AM1710 and Δ9-THC suppressed established paclitaxel-induced allodynia in WT mice. Unlike Δ9-THC, chronic AM1710 did not engage CB1 activity or produce antinociceptive tolerance, CB1-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Anti-allodynic efficacy of systemic AM1710 was absent in CB2KO mice or WT mice receiving the CB2 antagonist AM630, administered either systemically or intrathecally. Intrathecal AM1710 also attenuated paclitaxel-induced allodynia in WT but not CB2KO mice, implicating a possible role for spinal CB2 receptors in AM1710 anti-allodynic efficacy. Finally, both acute and chronic treatment with AM1710 decreased mRNA levels of tumor necrosis factor alpha and monocyte chemoattractant protein-1 in lumbar spinal cord of paclitaxel-treated WT mice. Conclusions Our results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects. PMID:24853387

  5. Timed, sequential administration of paclitaxel improves its cytotoxic effectiveness in a cell culture model

    PubMed Central

    Fisi, Viktória; Kátai, Emese; Bogner, Péter; Miseta, Attila; Nagy, Tamás

    2016-01-01

    ABSTRACT Paclitaxel (taxol) is a chemotherapeutic agent frequently used in combination with other anti-neoplastic drugs. It is most effective during the M phase of the cell-cycle and tends to cause synchronization in malignant cells lines. In this study, we investigated whether timed, sequential treatment based on the cell-cycle characteristics could be exploited to enhance the cytotoxic effect of paclitaxel. We characterized the cell-cycle properties of a rapidly multiplying cell line (Sp2, mouse myeloma cells) by propidium-iodide DNA staining such as the lengths of various cell cycle phases and population duplication time. Based on this we designed a paclitaxel treatment protocol that comprised a primary and a secondary, timed treatment. We found that the first paclitaxel treatment synchronized the cells at the G2/M phase but releasing the block by stopping the treatment allowed a large number of cells to enter the next cell-cycle by a synchronized manner. The second treatment was most effective during the time when these cells approached the next G2/M phase and was least effective when it occurred after the peak time of this next G2/M phase. Moreover, we found that after mixing Sp2 cells with another, significantly slower multiplying cell type (Jurkat human T-cell leukemia) at an initial ratio of 1:1, the ratio of the two different cell types could be influenced by timed sequential paclitaxel treatment at will. Our results demonstrate that knowledge of the cell-cycle parameters of a specific malignant cell type could improve the effectivity of the chemotherapy. Implementing timed chemotherapeutic treatments could increase the cytotoxicity on the malignant cells but also decrease the side-effects since other, non-malignant cell types will have different cell-cycle characteristic and be out of synch during the treatment. PMID:27104236

  6. Carboplatin and paclitaxel as first-line treatment of unresectable or metastatic esophageal or gastric cancer.

    PubMed

    Prithviraj, G K; Baksh, K; Fulp, W; Meredith, K; Hoffe, S; Shridhar, R; Almhanna, K

    2015-01-01

    Survival in patients with metastatic esophageal and gastric cancer is dismal. No standard treatment has been established. Carboplatin/paclitaxel is active in both advanced gastric and esophageal cancer. Here we retrospectively present our single center experience. Between 1998 and 2013, a total of 134 patients with metastatic esophageal and gastric adenocarcinoma treated with carboplatin/paclitaxel (carboplatin predominantly area under the curve 5 and paclitaxel predominantly 175 mg/m(2)) every 3 weeks as first-line therapy were identified. Baseline characteristics, response to therapy, toxicities, and survival in this patient population were evaluated. Overall survival was defined as date from diagnosis to death or last follow up, and progression-free survival was defined at time from cycle 1 to, progression or last follow up. Kaplan-Meier curves were fit to estimate overall and progression-free survival. Of the 134 patients evaluated, the median age at diagnosis was 65 years. Disease control rate was 62.6% (complete response: 11%, partial response: 28%, stable disease: 33%). Median overall survival from date of initial diagnosis was 15.5 months (95% confidence interval [CI] 1.06-1.5). Median progression-free survival from date of initiation of carboplatin and paclitaxel was 5.3 months (95% CI 0.34-0.5). Grade III or greater toxicity occurred in 26.1% of patients. The most common grade III toxicities were neutropenia and neuropathy, present in 14.2% and 3.7% of the total study population, respectively. In patients with metastatic or unresectable esophageal or gastric cancer, the combination of carboplatin and paclitaxel is well tolerated with comparable overall survival and progression-free survival to existing regimens in this population.

  7. Timed, sequential administration of paclitaxel improves its cytotoxic effectiveness in a cell culture model.

    PubMed

    Fisi, Viktória; Kátai, Emese; Bogner, Péter; Miseta, Attila; Nagy, Tamás

    2016-05-01

    Paclitaxel (taxol) is a chemotherapeutic agent frequently used in combination with other anti-neoplastic drugs. It is most effective during the M phase of the cell-cycle and tends to cause synchronization in malignant cells lines. In this study, we investigated whether timed, sequential treatment based on the cell-cycle characteristics could be exploited to enhance the cytotoxic effect of paclitaxel. We characterized the cell-cycle properties of a rapidly multiplying cell line (Sp2, mouse myeloma cells) by propidium-iodide DNA staining such as the lengths of various cell cycle phases and population duplication time. Based on this we designed a paclitaxel treatment protocol that comprised a primary and a secondary, timed treatment. We found that the first paclitaxel treatment synchronized the cells at the G2/M phase but releasing the block by stopping the treatment allowed a large number of cells to enter the next cell-cycle by a synchronized manner. The second treatment was most effective during the time when these cells approached the next G2/M phase and was least effective when it occurred after the peak time of this next G2/M phase. Moreover, we found that after mixing Sp2 cells with another, significantly slower multiplying cell type (Jurkat human T-cell leukemia) at an initial ratio of 1:1, the ratio of the two different cell types could be influenced by timed sequential paclitaxel treatment at will. Our results demonstrate that knowledge of the cell-cycle parameters of a specific malignant cell type could improve the effectivity of the chemotherapy. Implementing timed chemotherapeutic treatments could increase the cytotoxicity on the malignant cells but also decrease the side-effects since other, non-malignant cell types will have different cell-cycle characteristic and be out of synch during the treatment. PMID:27104236

  8. A phase I study of intraperitoneal nanoparticulate paclitaxel (Nanotax®) in patients with peritoneal malignancies

    PubMed Central

    Johnson, Gary A.; Maulhardt, Holly A.; Moore, Kathleen M.; McMeekin, D. S.; Schulz, Thomas K.; Reed, Gregory A.; Roby, Katherine F.; Mackay, Christine B.; Smith, Holly J.; Weir, Scott J.; Wick, Jo A.; Markman, Maurie; diZerega, Gere S.; Baltezor, Michael J.; Espinosa, Jahna; Decedue, Charles J.

    2015-01-01

    Purpose This multicenter, open-label, dose-escalating, phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary tumor response of a nanoparticulate formulation of paclitaxel (Nanotax®) administered intraperitoneally for multiple treatment cycles in patients with solid tumors predominantly confined to the peritoneal cavity for whom no other curative systemic therapy treatment options were available. Methods Twenty-one patients with peritoneal malignancies received Nanotax® in a modified dose-escalation approach utilizing an accelerated titration method. All patients enrolled had previously received chemotherapeutics and undergone surgical procedures, including 33 % with optimal debulking. Six doses (50–275 mg/m2) of Cremophor-free Nanotax® were administered intraperitoneally for one to six cycles (every 28 days). Results Intraperitoneal (IP) administration of Nanotax® did not lead to increases in toxicity over that typically associated with intravenous (IV) paclitaxel. No patient reported ≥Grade 2 neutropenia and/or ≥Grade 3 neurologic toxicities. Grade 3 thrombocytopenia unlikely related to study medication occurred in one patient. The peritoneal concentration–time profile of paclitaxel rose during the 2 days after dosing to peritoneal fluid concentrations 450–2900 times greater than peak plasma drug concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16/21 patients: Four patients were assessed as stable or had no response and twelve patients had increasing disease. Five of 21 patients with advanced cancers survived longer than 400 days after initiation of Nanotax® IP treatment. Conclusions Compared to IV paclitaxel administration, Cremophor-free IP administration of Nanotax® provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity. PMID:25898813

  9. Gel polymer electrolytes for batteries

    DOEpatents

    Balsara, Nitash Pervez; Eitouni, Hany Basam; Gur, Ilan; Singh, Mohit; Hudson, William

    2014-11-18

    Nanostructured gel polymer electrolytes that have both high ionic conductivity and high mechanical strength are disclosed. The electrolytes have at least two domains--one domain contains an ionically-conductive gel polymer and the other domain contains a rigid polymer that provides structure for the electrolyte. The domains are formed by block copolymers. The first block provides a polymer matrix that may or may not be conductive on by itself, but that can soak up a liquid electrolyte, thereby making a gel. An exemplary nanostructured gel polymer electrolyte has an ionic conductivity of at least 1.times.10.sup.-4 S cm.sup.-1 at 25.degree. C.

  10. Electrically controlled polymeric gel actuators

    DOEpatents

    Adolf, D.B.; Shahinpoor, M.; Segalman, D.J.; Witkowski, W.R.

    1993-10-05

    Electrically controlled polymeric gel actuators or synthetic muscles are described capable of undergoing substantial expansion and contraction when subjected to changing pH environments, temperature, or solvent. The actuators employ compliant containers for the gels and their solvents. The gels employed may be cylindrical electromechanical gel fibers such as polyacrylamide fibers or a mixture of poly vinyl alcohol-polyacrylic acid arranged in a parallel aggregate and contained in an electrolytic solvent bath such as salt water. The invention includes smart, electrically activated devices exploiting this phenomenon. These devices are capable of being manipulated via active computer control as large displacement actuators for use in adaptive structure such as robots. 11 figures.

  11. Electrically controlled polymeric gel actuators

    DOEpatents

    Adolf, Douglas B.; Shahinpoor, Mohsen; Segalman, Daniel J.; Witkowski, Walter R.

    1993-01-01

    Electrically controlled polymeric gel actuators or synthetic muscles capable of undergoing substantial expansion and contraction when subjected to changing pH environments, temperature, or solvent. The actuators employ compliant containers for the gels and their solvents. The gels employed may be cylindrical electromechanical gel fibers such as polyacrylamide fibers or a mixture of poly vinyl alcohol-polyacrylic acid arranged in a parallel aggregate and contained in an electrolytic solvent bath such as salt water. The invention includes smart, electrically activated devices exploiting this phenomenon. These devices are capable of being manipulated via active computer control as large displacement actuators for use in adaptive structure such as robots.

  12. A Randomized Phase III Trial of IV Carboplatin and Paclitaxel x 3 Courses Followed by Observation Versus Weekly Maintenance Low Dose Paclitaxel in Patients with Early Stage Ovarian Carcinoma: a Gynecologic Oncology Group Study

    PubMed Central

    Mannel, Robert S; Brady, Mark F; Kohn, Elise C.; Hanjani, Parviz; Hiura, Masamichi; Lee, Roger; DeGeest, Koen; Cohn, David E; Monk, Bradley J.; Michael, Helen

    2011-01-01

    Purpose To compare the recurrence-free interval (RFI), and safety profile in patients with completely resected high-risk early-stage ovarian cancer patients treated with intravenous (IV) carboplatin and paclitaxel with or without maintenance low-dose paclitaxel for 24 weeks. Methods Eligibility was limited to patients with Stage I-A/B (Grade 3 or clear cell), all I-C or II epithelial ovarian cancer. All patients were to receive carboplatin AUC 6 and paclitaxel 175 mg/m2 q 3 wks × 3 courses with random assignment to either observation or maintenance paclitaxel 40 mg/m2/wk × 24 wks. Recurrence required clinical or radiological evidence of new tumor. Results There were 571 patients enrolled onto this study, of whom 29 were deemed ineligible due to inappropriate stage or pathology, leaving 542 patients. At least 3 cycles of treatment were administered to 524/542 (97%) of patients, and among those assigned to maintenance paclitaxel, 80% completed the regimen. The incidence of grade 2 or worse peripheral neuropathy (15.5% vs 6%), infection/fever (19.9% vs 8.7%), and dermatologic events (70.8% vs 52.1%) were higher on the maintenance regimen (p<0.001). The cumulative probability of recurring within 5 years for the maintenance paclitaxel regimen is 20% vs. 23% for surveillance (hazard ratio 0.807; 95% CI: 0.565–1.15). The probability of surviving 5 years was 85.4% and 86.2%, respectively. Conclusion Maintenance paclitaxel at 40 mg/m2/wk × 24 wks added to standard dose AUC6 and paclitaxel 175 mg/m2 × 3 doses provides no significant increase in RFI. PMID:21529904

  13. Temperature response functions introduce high uncertainty in modelled carbon stocks in cold temperature regimes

    NASA Astrophysics Data System (ADS)

    Portner, H.; Wolf, A.; Bugmann, H.

    2009-04-01

    Many biogeochemical models have been applied to study the response of the carbon cycle to changes in climate, whereby the process of carbon uptake (photosynthesis) has usually gained more attention than the equally important process of carbon release by respiration. The decomposition of soil organic matter is driven by a combination of factors with a prominent one being soil temperature [Berg and Laskowski(2005)]. One uncertainty concerns the response function used to describe the sensitivity of soil organic matter decomposition to temperature. This relationship is often described by one out of a set of similar exponential functions, but it has not been investigated how uncertainties in the choice of the response function influence the long term predictions of biogeochemical models. We built upon the well-established LPJ-GUESS model [Smith et al.(2001)]. We tested five candidate functions and calibrated them against eight datasets from different Ameriflux and CarboEuropeIP sites [Hibbard et al.(2006)]. We used a simple Exponential function with a constant Q10, the Arrhenius function, the Gaussian function [Tuomi et al.(2008), O'Connell(1990)], the Van't Hoff function [Van't Hoff(1901)] and the Lloyd&Taylor function [Lloyd and Taylor(1994)]. We assessed the impact of uncertainty in model formulation of temperature response on estimates of present and future long-term carbon storage in ecosystems and hence on the CO2 feedback potential to the atmosphere. We specifically investigated the relative importance of model formulation and the error introduced by using different data sets for the parameterization. Our results suggested that the Exponential and Arrhenius functions are inappropriate, as they overestimated the respiration rates at lower temperatures. The Gaussian, Van't Hoff and Lloyd&Taylor functions all fit the observed data better, whereby the functions of Gaussian and Van't Hoff underestimated the response at higher temperatures. We suggest, that the

  14. Active gel physics

    NASA Astrophysics Data System (ADS)

    Prost, J.; Jülicher, F.; Joanny, J.-F.

    2015-02-01

    The mechanical behaviour of cells is largely controlled by a structure that is fundamentally out of thermodynamic equilibrium: a network of crosslinked filaments subjected to the action of energy-transducing molecular motors. The study of this kind of active system was absent from conventional physics and there was a need for both new theories and new experiments. The field that has emerged in recent years to fill this gap is underpinned by a theory that takes into account the transduction of chemical energy on the molecular scale. This formalism has advanced our understanding of living systems, but it has also had an impact on research in physics per se. Here, we describe this developing field, its relevance to biology, the novelty it conveys to other areas of physics and some of the challenges in store for the future of active gel physics.

  15. Temperature responses of photosynthesis and respiration in Populus balsamifera L.: acclimation versus adaptation.

    PubMed

    Silim, Salim N; Ryan, Natalie; Kubien, David S

    2010-04-01

    To examine the role of acclimation versus adaptation on the temperature responses of CO(2) assimilation, we measured dark respiration (R(n)) and the CO(2) response of net photosynthesis (A) in Populus balsamifera collected from warm and cool habitats and grown at warm and cool temperatures. R(n) and the rate of photosynthetic electron transport (J) are significantly higher in plants grown at 19 versus 27 degrees C; R(n) is not affected by the native thermal habitat. By contrast, both the maximum capacity of rubisco (V(cmax)) and A are relatively insensitive to growth temperature, but both parameters are slightly higher in plants from cool habitats. A is limited by rubisco capacity from 17-37 degrees C regardless of growth temperature, and there is little evidence for an electron-transport limitation. Stomatal conductance (g(s)) is higher in warm-grown plants, but declines with increasing measurement temperature from 17 to 37 degrees C, regardless of growth temperature. The mesophyll conductance (g(m)) is relatively temperature insensitive below 25 degrees C, but g(m) declines at 37 degrees C in cool-grown plants. Plants acclimated to cool temperatures have increased R(n)/A, but this response does not differ between warm- and cool-adapted populations. Primary carbon metabolism clearly acclimates to growth temperature in P. balsamifera, but the ecotypic differences in A suggest that global warming scenarios might affect populations at the northern and southern edges of the boreal forest in different ways.

  16. Linking altitudinal gradients and temperature responses of plant phenology in the Bavarian Alps.

    PubMed

    Cornelius, C; Estrella, N; Franz, H; Menzel, A

    2013-01-01

    Global climate change influences ecosystems across the world. Alpine plant communities have already experienced serious impacts, and will continue to do so as climate change continues. The aim of our study was to determine the sensitivity of woody and herbaceous species to shifts in temperature along an altitudinal gradient. Since 1994, park rangers have been making phenological observations at 24 sites from 680 to 1425 m a.s.l. Each year 21 plant species were observed once or twice weekly from March to July; with a main focus on flowering and leaf unfolding. Our study showed a very high degree of dependence of phenophases and species on inter-annual temperature variation and altitude. Averaged over all species and phenophases, there was a delay of 3.8 days with every 100 m increase in altitude and, across all elevations, an advance of phenophases of 6 days per 1 °C increase in temperature. Temperature lapse rates assessed indirectly by phenology, as the quotient of altitudinal to temperature response coefficients, were higher than directly calculated from March to July mean temperatures, most likely due to snow effects. Furthermore, a significant difference in sensitivity to temperature change was found between growth forms (herbs versus trees). Sensitivity was less pronounced in events occurring later in the season. Our results show that species reactions will differ in magnitude during global warming. Consequently, impacts of shifts in the timing of phenological events on plant migration and plant-pollinator interactions due to rising temperatures should be considered at the species level.

  17. Dual magnetic-/temperature-responsive nanoparticles for microfluidic separations and assays.

    PubMed

    Lai, James J; Hoffman, John M; Ebara, Mitsuhiro; Hoffman, Allan S; Estournès, Claude; Wattiaux, Alain; Stayton, Patrick S

    2007-06-19

    A stimuli-responsive magnetic nanoparticle system for diagnostic target capture and concentration has been developed for microfluidic lab card settings. Telechelic poly(N-isopropylacrylamide) (PNIPAAm) polymer chains were synthesized with dodecyl tails at one end and a reactive carboxylate at the opposite end by the reversible addition fragmentation transfer technique. These PNIPAAm chains self-associate into nanoscale micelles that were used as dimensional confinements to synthesize the magnetic nanoparticles. The resulting superparamagnetic nanoparticles exhibit a gamma-Fe2O3 core ( approximately 5 nm) with a layer of carboxylate-terminated PNIPAAm chains as a corona on the surface. The carboxylate group was used to functionalize the magnetic nanoparticles with biotin and subsequently with streptavidin. The functionalized magnetic nanoparticles can be reversibly aggregated in solution as the temperature is cycled through the PNIPAAm lower critical solution temperature (LCST). While the magnetophoretic mobility of the individual nanoparticles below the LCST is negligible, the aggregates formed above the LCST are large enough to respond to an applied magnetic field. The magnetic nanoparticles can associate with biotinylated targets as individual particles, and then subsequent application of a combined temperature increase and magnetic field can be used to magnetically separate the aggregated particles onto the poly(ethylene glycol)-modified polydimethylsiloxane channel walls of a microfluidic device. When the magnetic field is turned off and the temperature is reversed, the captured aggregates redisperse into the channel flow stream for further downstream processing. The dual magnetic- and temperature-responsive nanoparticles can thus be used as soluble reagents to capture diagnostic targets at a controlled time point and channel position. They can then be isolated and released after the nanoparticles have captured target molecules, overcoming the problem of low

  18. Temperature responses of carbon monoxide and hydrogen uptake by vegetated and unvegetated volcanic cinders

    PubMed Central

    King, Caitlin E; King, Gary M

    2012-01-01

    Ecosystem succession on a large deposit of volcanic cinders emplaced on Kilauea Volcano in 1959 has resulted in a mosaic of closed-canopy forested patches and contiguous unvegetated patches. Unvegetated and unshaded surface cinders (Bare) experience substantial diurnal temperature oscillations ranging from moderate (16 °C) to extreme (55 °C) conditions. The surface material of adjacent vegetated patches (Canopy) experiences much smaller fluctuations (14–25 °C) due to shading. To determine whether surface material from these sites showed adaptations by carbon monoxide (CO) and hydrogen (H2) consumption to changes in ambient temperature regimes accompanying succession, we measured responses of CO and H2 uptake to short-term variations in temperature and long-term incubations at elevated temperature. Based on its broader temperature optimum and lower activation energy, Canopy H2 uptake was less sensitive than Bare H2 uptake to temperature changes. In contrast, Bare and Canopy CO uptake responded similarly to temperature during short-term incubations, indicating no differences in temperature sensitivity. However, during extended incubations at 55 °C, CO uptake increased for Canopy but not Bare material, which indicated that the former was capable of thermal adaptation. H2 uptake for material from both sites was completely inhibited at 55 °C throughout extended incubations. These results indicated that plant development during succession did not elicit differences in short-term temperature responses for Bare and Canopy CO uptake, in spite of previously reported differences in CO oxidizer community composition, and differences in average daily and extreme temperatures. Differences associated with vegetation due to succession did, however, lead to a notable capacity for thermophilic CO uptake by Canopy but not Bare material. PMID:22258097

  19. Highly temperature responsive core-shell magnetic particles: synthesis, characterization and colloidal properties.

    PubMed

    Rahman, Md Mahbubor; Chehimi, Mohamed M; Fessi, Hatem; Elaissari, Abdelhamid

    2011-08-15

    Temperature responsive magnetic polymer submicron particles were prepared by two step seed emulsion polymerization process. First, magnetic seed polymer particles were obtained by emulsion polymerization of styrene using potassium persulfate (KPS) as an initiator and divinylbenzne (DVB) as a cross-linker in the presence of oil-in-water magnetic emulsion (organic ferrofluid droplets). Thereafter, DVB cross-linked magnetic polymer particles were used as seed in the precipitation polymerization of N-isopropylacrylamide (NIPAM) to induce thermosensitive PNIPAM shell onto the hydrophobic polymer surface of the cross-linked magnetic polymer particles. To impart cationic functional groups in the thermosensitive PNIPAM backbone, the functional monomer aminoethylmethacrylate hydrochloride (AEMH) was used to polymerize with NIPAM while N,N'-methylenebisacrylamide (MBA) and 2, 2'-azobis (2-methylpropionamidine) dihydrochloride (V-50) were used as a cross-linker and as an initiator respectively. The effect of seed to monomer (w/w) ratio along with seed nature on the final particle morphology was investigated. Dynamic light scattering (DLS) results demonstrated particles swelling at below volume phase transition temperature (VPTT) and deswelling above the VPTT. The perfect core (magnetic) shell (polymer) structure of the particles prepared was confirmed by Transmission Electron Microscopy (TEM). The chemical composition of the particles were determined by thermogravimetric analysis (TGA). The effect of temperature, pH, ionic strength on the colloidal properties such as size and zeta potential of the micron sized thermo-sensitive magnetic particles were also studied. In addition, a short mechanistic discussion on the formation of core-shell morphology of magnetic polymer particles has also been discussed. PMID:21570083

  20. Antimicrobial Graft Copolymer Gels.

    PubMed

    Harvey, Amanda C; Madsen, Jeppe; Douglas, C W Ian; MacNeil, Sheila; Armes, Steven P

    2016-08-01

    In view of the growing worldwide rise in microbial resistance, there is considerable interest in designing new antimicrobial copolymers. The aim of the current study was to investigate the relationship between antimicrobial activity and copolymer composition/architecture to gain a better understanding of their mechanism of action. Specifically, the antibacterial activity of several copolymers based on 2-(methacryloyloxy)ethyl phosphorylcholine [MPC] and 2-hydroxypropyl methacrylate (HPMA) toward Staphylococcus aureus was examined. Both block and graft copolymers were synthesized using either atom transfer radical polymerization or reversible addition-fragmentation chain transfer polymerization and characterized via (1)H NMR, gel permeation chromatography, rheology, and surface tensiometry. Antimicrobial activity was assessed using a range of well-known assays, including direct contact, live/dead staining, and the release of lactate dehydrogenase (LDH), while transmission electron microscopy was used to study the morphology of the bacteria before and after the addition of various copolymers. As expected, PMPC homopolymer was biocompatible but possessed no discernible antimicrobial activity. PMPC-based graft copolymers comprising PHPMA side chains (i.e. PMPC-g-PHPMA) significantly reduced both bacterial growth and viability. In contrast, a PMPC-PHPMA diblock copolymer comprising a PMPC stabilizer block and a hydrophobic core-forming PHPMA block did not exhibit any antimicrobial activity, although it did form a biocompatible worm gel. Surface tensiometry studies and LDH release assays suggest that the PMPC-g-PHPMA graft copolymer exhibits surfactant-like activity. Thus, the observed antimicrobial activity is likely to be the result of the weakly hydrophobic PHPMA chains penetrating (and hence rupturing) the bacterial membrane. PMID:27409712

  1. Spiro-bicyclo[2.2.2]octane derivatives as paclitaxel mimetics. Synthesis and toxicity evaluation in breast cancer cell lines.

    PubMed

    Manner, Sophie; Oltner, Viveca T; Oredsson, Stina; Ellervik, Ulf; Frejd, Torbjörn

    2013-11-01

    Paclitaxel is one of the most important anti-cancer agents introduced during the last 20 years. However, the use of paclitaxel is limited by undesirable side effects as well as the development of drug resistance. Here, we report a synthetic strategy towards spiro-bicyclo[2.2.2]octane derivatives, which includes double Michael addition and ring-closing metathesis as key synthetic steps. This strategy was used to synthesize a series of spiro-bicyclic compounds designed to be paclitaxel mimetics, which were evaluated in human breast-derived cell lines. One of these paclitaxel mimetics showed toxicity, although at higher concentrations than paclitaxel itself. In addition, two other spiro-bicyclic compounds, lacking the paclitaxel side chain, showed toxicity.

  2. Micro RNA 100 sensitizes luminal A breast cancer cells to paclitaxel treatment in part by targeting mTOR

    PubMed Central

    He, Yuan; Fu, Xing; Fu, Liya; Zhu, Zhengmao; Fu, Li; Dong, Jin-Tang

    2016-01-01

    Luminal A breast cancer usually responds to hormonal therapies but does not benefit from chemotherapies, including microtubule-targeted paclitaxel. MicroRNAs could play a role in mediating this differential response. In this study, we examined the role of micro RNA 100 (miR-100) in the sensitivity of breast cancer to paclitaxel treatment. We found that while miR-100 was downregulated in both human breast cancer primary tumors and cell lines, the degree of downregulation was greater in the luminal A subtype than in other subtypes. The IC50 of paclitaxel was much higher in luminal A than in basal-like breast cancer cell lines. Ectopic miR-100 expression in the MCF-7 luminal A cell line enhanced the effect of paclitaxel on cell cycle arrest, multinucleation, and apoptosis, while knockdown of miR-100 in the MDA-MB-231 basal-like line compromised these effects. Similarly, overexpression of miR-100 enhanced the effects of paclitaxel on tumorigenesis in MCF-7 cells. Rapamycin-mediated inhibition of the mammalian target of rapamycin (mTOR), a target of miR-100, also sensitized MCF-7 cells to paclitaxel. Gene set enrichment analysis showed that genes that are part of the known paclitaxel-sensitive signature had a significant expression correlation with miR-100 in breast cancer samples. In addition, patients with lower levels of miR-100 expression had worse overall survival. These results suggest that miR-100 plays a causal role in determining the sensitivity of breast cancers to paclitaxel treatment. PMID:26744318

  3. Long-circulating PEG-PE micelles co-loaded with paclitaxel and elacridar (GG918) overcome multidrug resistance.

    PubMed

    Sarisozen, Can; Vural, Imran; Levchenko, Tatyana; Hincal, A Atilla; Torchilin, Vladimir P

    2012-11-01

    Overexpression of drug efflux pump P-gp is one of the major reasons to cause multidrug resistance (MDR). To overcome P-gp mediated MDR, modulators, so called P-gp inhibitors, can be used to block efflux pump activity. Elacridar is one of the most potent P-gp inhibitors, which can cause irreversible and total P-gp blockage. Elacridar, among with other P-gp inhibitors, can be used in combination with anticancer drugs to enhance the effectiveness of chemotherapy against resistant tumor cells. On the other hand, P-gp is presented in normal tissues, thus non-selective blockage of P-gp can cause undesired side effects. Therefore, it is important to deliver P-gp inhibitor only to the tumor cells (along with anticancer drug) and limit its distribution in the body. In this study, we have developed PEG-PE-based long-circulating ca. 15 nm micelles co-loaded with elacridar and paclitaxel, and investigated their ability to overcome paclitaxel resistance in two cancer cell lines. Vitamin E, a common solubility enhancer for PEG-PE micelles, was found to have a negative effect on both particle size and encapsulation efficiencies. The human MDR1 gene-transfected and thus paclitaxel-resistant MDCKII-MDR1 P-gp overexpressing cells were used for cytotoxicity evaluation. Even though PEG-PE based micelles itself have a potential to enhance the cytotoxicity of paclitaxel, elacridar/paclitaxel-co-loaded micelles demonstrated the highest cytotoxicity compared to both free and micellar paclitaxel. The obtained results suggest that co-loading of paclitaxel and elacridar into micellar drug carriers results in promising preparations capable of overcoming paclitaxel resistance. PMID:23030458

  4. Nanomedicine-nanoemulsion formulation improves safety and efficacy of the anti-cancer drug paclitaxel according to preclinical assessment.

    PubMed

    Lee, King C; Maturo, Claudia; Rodriguez, Robert; Nguyen, Hoang-Lan; Shorr, Robert

    2011-08-01

    Paclitaxel is an important anticancer drug and is currently used to treat a variety of cancers, including ovarian carcinomas, breast cancer, non-small cell lung cancer, and AIDS-related Kaposi's sarcoma. The objectives of the studies were to assess and compare the safety and efficacy of EmPAC (a newly developed nanoemulsion formulation of paclitaxel) versus Taxol (the injectable formulation of paclitaxel involving the use of polyethylated or polyoxyl castor oil currently used in the clinic). The objectives were also to investigate the mechanism for the improved safety and efficacy of EmPAC over Taxol. These results showed that EmPAC had better anti-tumor efficacy than Taxol, according to in vitro cell culture studies and studies in animal tumor models. EmPAC had improved anti-tumor efficacy even in tumor cell lines that are known to be multi-drug resistant. Part of the mechanism of action for the improved efficacy may be related to EmPAC inducing greater cellular uptake of paclitaxel into tumor cells than Taxol did, according to the in vitro cell culture radioactive-labeled studies and in vitro cell culture antibody studies. It may also partly be because EmPAC delivered more paclitaxel to the tumor mass than Taxol, while the delivery of paclitaxel to other tissues (e.g., blood, muscle, liver, spleen, kidney and lung) were similar between the two formulations of paclitaxel, according to studies in animals with tumor xenograft. EmPAC also had better safety than Taxol according to toxicology studies in rabbits. This may be because EmPAC does not contain the toxic ingredients used in formulating Taxol (such as polyethylated or polyoxyl castor oil). These results support the clinical development of the nanoemulsion formulation of paclitaxel.

  5. [Comparison of the pharmacokinetics and safety of a paclitaxel injection NK and Taxol injection in breast cancer patients].

    PubMed

    Sagara, Yoshiaki; Rai, Yoshiaki; Sagara, Yoshiatsu; Matsuyama, Yoshito; Baba, Shinichi; Tamada, Shugo; Sagara, Yasuaki; Ando, Mitsutake

    2009-02-01

    A paclitaxel injection NK (NK) is a generic product containing the same amount of ingredient as a Taxol Injection. We examined the pharmacokinetics and safety of NK compared to the original product in breast cancer patients. As a result, the transition of plasma paclitaxel concentration and pharmacokinetic parameter in NK and the original drug were almost equal, which suggested that these products were bioequivalent. In adjuvant therapy, there was no significant difference in adverse events reported, and these products were approximately equally safe.

  6. Combination therapy using imatinib and vatalanib improves the therapeutic efficiency of paclitaxel towards a mouse melanoma tumor.

    PubMed

    Kłosowska-Wardęga, Agnieszka; Hasumi, Yoko; Åhgren, Aive; Heldin, Carl-Henrik; Hellberg, Carina

    2011-02-01

    Melanomas respond poorly to chemotherapy. In this study, we investigated the sensitization of B16 mouse melanoma tumors to paclitaxel by a combination of two tyrosine kinase inhibitors: vatalanib, targeting vascular endothelial growth factor receptors, and imatinib, an inhibitor targeting for example, Abl/BCR-ABL, the platelet-derived growth factor receptor, and stem cell factor receptor c-Kit. C57Bl6/J mice carrying B16/PDGF-BB mouse melanoma tumors were treated daily with vatalanib (25 mg/kg), imatinib (100 mg/kg), or a combination of these drugs. Paclitaxel was given subcutaneously twice during the study. The effects of the drugs on tumor cell proliferation in vitro were determined by counting cells. B16/PDGF-BB mouse melanoma tumors were not sensitive to paclitaxel at doses of either 5 or 20 mg/kg. However, the tumor growth was significantly reduced by 58%, in response to paclitaxel (5 mg/kg) when administered with daily doses of both vatalanib and imatinib. Paclitaxel only inhibited the in-vitro growth of B16/PDGF-BB tumor cells when given in combination with imatinib. Imatinib presumably targets c-Kit, as the cells do not express platelet-derived growth factor receptor and as another c-Abl inhibitor was without effect. This was supported by data from three c-Kit-expressing human melanoma cell lines showing varying sensitization to paclitaxel by the kinase inhibitors. In addition, small interfering RNA knockdown of c-Kit sensitized the cells to paclitaxel. These data show that combination of two tyrosine kinase inhibitors, imatinib and vatalanib, increases the effects of paclitaxel on B16/PDGF-BB tumors, thus suggesting a novel strategy for the treatment of melanomas expressing c-Kit. PMID:20975605

  7. Delayed seizure associated with paclitaxel-Cremophor el in a patient with early-stage breast cancer.

    PubMed

    O'Connor, Tracey L; Kossoff, Ellen

    2009-08-01

    Paclitaxel, a microtubule stabilizer, is an effective agent for treating cancer of the breast, ovary, head and neck, and lung. Because paclitaxel is insoluble in water, it is formulated with the micelle-forming Cremophor EL. Neurologic toxicity is well described with both the drug and this carrier, with most toxicities manifesting as peripheral neuropathy, motor neuropathy, autonomic neuropathy, and myopathy. Toxic effects on the central nervous system, such as seizures or encephalopathy, have been rarely reported; however, the seizures reported were closely related to the time of infusion. We describe a 41-year-old woman with no history of seizures who was treated with paclitaxel for breast cancer. Four days after the drug was infused, she developed a generalized tonic-clonic seizure that could not be attributed to other causes. The patient was treated with phenytoin and was able to complete her adjuvant chemotherapy with nab-paclitaxel without further events. Her condition was neurologically stable without phenytoin for the next 6 months. Use of the Naranjo adverse drug reaction probability scale indicated a possible association (score of 3) between the delayed seizure and paclitaxel or its solvent, Cremophor EL. Clinicians should be aware of the potential for seizure activity in patients who receive paclitaxel formulated with Cremophor EL.

  8. Nanocrystal/sol-gel nanocomposites

    DOEpatents

    Petruska, Melissa A.; Klimov, Victor L.

    2012-06-12

    The present invention is directed to solid composites including colloidal nanocrystals within a sol-gel host or matrix and to processes of forming such solid composites. The present invention is further directed to alcohol soluble colloidal nanocrystals useful in formation of sol-gel based solid composites

  9. Nanocrystal/sol-gel nanocomposites

    DOEpatents

    Petruska, Melissa A.; Klimov, Victor L.

    2007-06-05

    The present invention is directed to solid composites including colloidal nanocrystals within a sol-gel host or matrix and to processes of forming such solid composites. The present invention is further directed to alcohol soluble colloidal nanocrystals useful in formation of sol-gel based solid composites.

  10. Hand temperature responses to local cooling after a 10-day confinement to normobaric hypoxia with and without exercise.

    PubMed

    Keramidas, M E; Kölegård, R; Mekjavic, I B; Eiken, O

    2015-10-01

    The study examined the effects of a 10-day normobaric hypoxic confinement (FiO2: 0.14), with [hypoxic exercise training (HT); n = 8)] or without [hypoxic ambulatory (HA; n = 6)] exercise, on the hand temperature responses during and after local cold stress. Before and after the confinement, subjects immersed their right hand for 30 min in 8 °C water [cold water immersion (CWI)], followed by a 15-min spontaneous rewarming (RW), while breathing either room air (AIR), or a hypoxic gas mixture (HYPO). The hand temperature responses were monitored with thermocouples and infrared thermography. The confinement did not influence the hand temperature responses of the HA group during the AIR and HYPO CWI and the HYPO RW phases; but it impaired the AIR RW response (-1.3 °C; P = 0.05). After the confinement, the hand temperature responses were unaltered in the HT group throughout the AIR trial. However, the average hand temperature was increased during the HYPO CWI (+0.5 °C; P ≤ 0.05) and RW (+2.4 °C; P ≤ 0.001) phases. Accordingly, present findings suggest that prolonged exposure to normobaric hypoxia per se does not alter the hand temperature responses to local cooling; yet, it impairs the normoxic RW response. Conversely, the combined stimuli of continuous hypoxia and exercise enhance the finger cold-induced vasodilatation and hand RW responses, specifically, under hypoxic conditions.

  11. Sucrose release from polysaccharide gels.

    PubMed

    Nishinari, Katsuyoshi; Fang, Yapeng

    2016-05-18

    Sucrose release from polysaccharide gels has been studied extensively because it is expected to be useful in understanding flavour release from solid foods and to find a new processing method which produces more palatable and healthier foods. We provide an overview of the release of sucrose and other sugars from gels of agar and related polysaccharides. The addition of sucrose to agar solutions leads to the increase in transparency of the resulting gels and the decrease in syneresis, which is attributed to the decrease in mesh size in gels. The syneresis occurring in the quiescent condition and fluid release induced by compression is discussed. The relationship between the sugar release and the structural, rheological and thermal properties of gels is also discussed. Finally, the future research direction is proposed.

  12. Sucrose release from polysaccharide gels.

    PubMed

    Nishinari, Katsuyoshi; Fang, Yapeng

    2016-05-18

    Sucrose release from polysaccharide gels has been studied extensively because it is expected to be useful in understanding flavour release from solid foods and to find a new processing method which produces more palatable and healthier foods. We provide an overview of the release of sucrose and other sugars from gels of agar and related polysaccharides. The addition of sucrose to agar solutions leads to the increase in transparency of the resulting gels and the decrease in syneresis, which is attributed to the decrease in mesh size in gels. The syneresis occurring in the quiescent condition and fluid release induced by compression is discussed. The relationship between the sugar release and the structural, rheological and thermal properties of gels is also discussed. Finally, the future research direction is proposed. PMID:26952168

  13. Paclitaxel, carboplatin, and oral etoposide in the treatment of small cell lung cancer.

    PubMed

    Greco, F A; Hainsworth, J D

    1996-12-01

    Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is active in previously untreated patients with small cell lung cancer (SCLC). We evaluated the toxicity and efficacy of a 1-hour infusion of paclitaxel added to a combination regimen of carboplatin and etoposide in a phase II trial for the treatment of patients with SCLC. Thirty-eight patients with previously untreated SCLC were treated with paclitaxel 135 mg/m2 (1-hour intravenous infusion), day 1; carboplatin at area under the concentration-time curve of 5, day 1; and oral etoposide 100 and 50 mg (alternating days), days 1 to 10. Treatment cycles were repeated every 21 days for a total of four courses. Patients with limited-stage disease received radiation therapy (4,500 cGy in 25 fractions) concurrently with the last two courses of chemotherapy. This outpatient combination was easily tolerated. Grade 3 or 4 leukopenia was experienced in only 8% of courses; grades 3 and 4 thrombocytopenia and anemia were also infrequent. Nonhematologic toxicity was uncommon, with the exception of transient esophagitis, which occurred in six of 15 patients (grade 3 in five patients, grade 4 in one) receiving concurrent chemoradiotherapy. Of 35 evaluable patients, 29 (83%) achieved a response to treatment. The complete response rate was 29% (40% in patients with limited-stage disease). Median survival was 7 months for patients with extensive-stage disease and 17 months in limited-stage patients. Prophylactic whole brain irradiation was not used, and seven patients developed brain metastases as their initial site of relapse. The combination of 1-hour paclitaxel, carboplatin, and extended oral schedule etoposide is feasible and well tolerated at the doses administered in this phase II trial. This treatment was highly active and the results are comparable to other standard regimens. Increased doses of both paclitaxel and carboplatin could probably be tolerated and are currently being evaluated. Precise definition of the

  14. Combinatorial TGF-β attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells

    PubMed Central

    Park, So-Yeon; Kim, Min-Jin; Park, Sang-A; Kim, Jung-Shin; Min, Kyung-Nan; Kim, Dae-Kee; Lim, Woosung; Nam, Jeong-Seok; Sheen, Yhun Yhong

    2015-01-01

    Distant relapse after chemotherapy is an important clinical issue for treating breast cancer patients and results from the development of cancer stem-like cells (CSCs) during chemotherapy. Here we report that blocking epithelial-to-mesenchymal transition (EMT) suppresses paclitaxel-induced CSCs properties by using a MDA-MB-231-xenografted mice model (in vivo), and breast cancer cell lines (in vitro). Paclitaxel, one of the cytotoxic taxane-drugs such as docetaxel, increases mesenchymal markers (Vimentin and Fibronectin) and decreases an epithelial marker (Zo-1). Blocking TGF-β signaling with the TGF-β type I receptor kinase (ALK5) inhibitor, EW-7197, suppresses paclitaxel-induced EMT and CSC properties such as mammosphere-forming efficiency (MSFE), aldehyde dehydrogenase (ALDH) activity, CD44+/CD24− ratio, and pluripotency regulators (Oct4, Nanog, Klf4, Myc, and Sox2). The combinatorial treatment of EW-7197 improves the therapeutic effect of paclitaxel by decreasing the lung metastasis and increasing the survival time in vivo. We confirmed that Snail is increased by paclitaxel-induced intracellular reactive oxygen species (ROS) and EW-7197 suppresses the paclitaxel-induced Snail and EMT by attenuating paclitaxel-induced intracellular ROS. Knock-down of SNAI1 suppresses paclitaxel-induced EMT and CSC properties. These data together suggest that blocking the Snail-induced EMT with the ALK5 inhibitor attenuates metastasis after paclitaxel-therapy and that this combinatorial approach could prove useful in treating breast cancer. PMID:26462028

  15. Macitentan (ACT-064992), a tissue-targeting endothelin receptor antagonist, enhances therapeutic efficacy of paclitaxel by modulating survival pathways in orthotopic models of metastatic human ovarian cancer.

    PubMed

    Kim, Sun-Jin; Kim, Jang Seong; Kim, Seung Wook; Brantley, Emily; Yun, Seok Joong; He, Junqin; Maya, Marva; Zhang, Fahao; Wu, Qiuyu; Lehembre, François; Regenass, Urs; Fidler, Isaiah J

    2011-02-01

    Potential treatments for ovarian cancers that have become resistant to standard chemotherapies include modulators of tumor cell survival, such as endothelin receptor (ETR) antagonist. We investigated the therapeutic efficacy of the dual ETR antagonist, macitentan, on human ovarian cancer cells, SKOV3ip1 and IGROV1, growing orthotopically in nude mice. Mice with established disease were treated with vehicle (control), paclitaxel (weekly, intraperitoneal injections), macitentan (daily oral administrations), or a combination of paclitaxel and macitentan. Treatment with paclitaxel decreased tumor weight and volume of ascites. Combination therapy with macitentan and paclitaxel reduced tumor incidence and further reduced tumor weight and volume of ascites when compared with paclitaxel alone. Macitentan alone occasionally reduced tumor weight but alone had no effect on tumor incidence or ascites. Immunohistochemical analyses revealed that treatment with macitentan and macitentan plus paclitaxel inhibited the phosphorylation of ETRs and suppressed the survival pathways of tumor cells by decreasing the levels of pVEGFR2, pAkt, and pMAPK. The dose of macitentan necessary for inhibition of phosphorylation correlated with the dose required to increase antitumor efficacy of paclitaxel. Treatment with macitentan enhanced the cytotoxicity mediated by paclitaxel as measured by the degree of apoptosis in tumor cells and tumor-associated endothelial cells. Collectively, these results show that administration of macitentan in combination with paclitaxel prevents the progression of ovarian cancer in the peritoneal cavity of nude mice in part by inhibiting survival pathways of both tumor cells and tumor-associated endothelial cells.

  16. A sandwich-designed temperature-gradient incubator for studies of microbial temperature responses.

    PubMed

    Elsgaard, Lars; Jørgensen, Leif Wagner

    2002-03-01

    A temperature-gradient incubator (TGI) is described, which produces a thermal gradient over 34 aluminium modules (15x30x5 cm) intersected by 2-mm layers of partly insulating graphite foil (SigraFlex Universal). The new, sandwich-designed TGI has 30 rows of six replicate sample wells for incubation of 28-ml test tubes. An electric plate heats one end of the TGI, and the other end is cooled by thermoelectric Peltier elements in combination with a liquid cooling system. The TGI is equipped with 24 calibrated Pt-100 temperature sensors and insulated by polyurethane plates. A PC-operated SCADA (Supervisory Control And Data Acquisition) software (Genesis 4.20) is applied for temperature control using three advanced control loops. The precision of the TGI temperature measurements was better than +/-0.12 degrees C, and for a 0-40 degrees C gradient, the temperature at the six replicate sample wells varied less than +/-0.04 degrees C. Temperatures measured in incubated water samples closely matched the TGI temperatures, which showed a linear relationship to the sample row number. During operation for 8 days with a gradient of 0-40 degrees C, the temperature at the cold end was stable within +/-0.02 degrees C, while the temperatures at the middle and the warm end were stable within +/-0.08 degrees C (n=2370). Using the new TGI, it was shown that the fine-scale (1 degrees C) temperature dependence of S(o) oxidation rates in agricultural soil (0-29 degrees C) could be described by the Arrhenius relationship. The apparent activation energy (E(a)) for S(o) oxidation was 79 kJ mol(-1), which corresponded to a temperature coefficient (Q(10)) of 3.1. These data demonstrated that oxidation of S(o) in soil is strongly temperature-dependent. In conclusion, the new TGI allowed a detailed study of microbial temperature responses as it produced a precise, stable, and certifiable temperature gradient by the new and combined use of sandwich-design, thermoelectric cooling, and advanced

  17. Hydrogeologic controls on baseflow temperature distributions: Implications for stream temperature response to climate variability

    NASA Astrophysics Data System (ADS)

    Boutt, D. F.; Smith, Z.

    2012-12-01

    Ground water temperature distributions in the near surface are not uniform and are the complex result of a variety of near- and sub-surface processes. Heat from the atmosphere is input into the ground via conduction at the ground surface and advection of infiltrating water. These processes produce predictable distributions of temperature that have been used to investigate current and past climatic conditions, determine ground water velocities, and assess basin-scale heat transport in sedimentary systems. The purpose of this investigation is to test a hypothesis that timing and nature of ground water recharge (advection of heat into the subsurface) is a significant control on the temporal and spatial distribution of heat in the shallow subsurface. The advective movement of heat imposes a dominant control on the 3-dimensional subsurface temperature distribution and strongly affects stream baseflow temperatures. We present observational data supporting a strong hydrogeologic control on subsurface water temperatures. These temperature distributions are modified by advection and are significantly different than theoretical distributions in a conduction-dominated environment. The temperature distributions with depth and space are controlled by the aquifers internal hydrogeologic structure and connections to recharge areas. Synthetic modeling is used to address the following questions: (1) how quickly do ground water temperatures respond to a changing climate, and how quickly do they reach a new equilibrium following perturbation; (2) what is the role of recharge water temperature and timing on subsurface temperature distributions; and (3) how do these factors influence baseflow temperatures in stream systems of varying size. Two-dimensional numerical models are developed using Comsol Multiphysics to perform a sensitivity analysis of basin-scale temperature response and coupling to surface water. In nested ground water flow systems, discharge areas farther down the

  18. Bouncing gel balls: Impact of soft gels onto rigid surface

    NASA Astrophysics Data System (ADS)

    Tanaka, Y.; Yamazaki, Y.; Okumura, K.

    2003-07-01

    After being thrown onto a solid substrate, very soft spherical gels bounce repeatedly. Separate rheological measurements suggest that these balls can be treated as nearly elastic. The Hertz contact deformation expected in the static (elastic) limit was observed only at very small impact velocities. For larger velocities, the gel ball deformed into flattened forms like a pancake. We measured the size of the gel balls at the maximal deformation and the contact time as a function of velocities for samples different in the original spherical radius and the Young modulus. The experimental results revealed a number of scaling relations. To interpret these relations, we developed scaling arguments to propose a physical picture.

  19. 212Pb-radioimmunotherapy potentiates paclitaxel-induced cell killing efficacy by perturbing the mitotic spindle checkpoint

    PubMed Central

    Yong, K J; Milenic, D E; Baidoo, K E; Brechbiel, M W

    2013-01-01

    Background: Paclitaxel has recently been reported by this laboratory to potentiate the high-LET radiation therapeutic 212Pb-TCMC-trastuzumab, which targets HER2. To elucidate mechanisms associated with this therapy, targeted α-particle radiation therapeutic 212Pb-TCMC-trastuzumab together with paclitaxel was investigated for the treatment of disseminated peritoneal cancers. Methods: Mice bearing human colon cancer LS-174T intraperitoneal xenografts were pre-treated with paclitaxel, followed by treatment with 212Pb-TCMC-trastuzumab and compared with groups treated with paclitaxel alone, 212Pb-TCMC-HuIgG, 212Pb-TCMC-trastuzumab and 212Pb-TCMC-HuIgG after paclitaxel pre-treatment. Results: 212Pb-TCMC-trastuzumab with paclitaxel given 24 h earlier induced increased mitotic catastrophe and apoptosis. The combined modality of paclitaxel and 212Pb-TCMC-trastuzumab markedly reduced DNA content in the S-phase of the cell cycle with a concomitant increase observed in the G2/M-phase. This treatment regimen also diminished phosphorylation of histone H3, accompanied by an increase in multi-micronuclei, or mitotic catastrophe in nuclear profiles and positively stained γH2AX foci. The data suggests, possible effects on the mitotic spindle checkpoint by the paclitaxel and 212Pb-TCMC-trastuzumab treatment. Consistent with this hypothesis, 212Pb-TCMC-trastuzumab treatment in response to paclitaxel reduced expression and phosphorylation of BubR1, which is likely attributable to disruption of a functional Aurora B, leading to impairment of the mitotic spindle checkpoint. In addition, the reduction of BubR1 expression may be mediated by the association of a repressive transcription factor, E2F4, on the promoter region of BubR1 gene. Conclusion: These findings suggest that the sensitisation to therapy of 212Pb-TCMC-trastuzumab by paclitaxel may be associated with perturbation of the mitotic spindle checkpoint, leading to increased mitotic catastrophe and cell death. PMID:23632482

  20. Clinical pharmacokinetic and in vitro combination studies of nolatrexed dihydrochloride (AG337, ThymitaqTM) and paclitaxel

    PubMed Central

    Hughes, A N; Griffin, M J; Newell, D R; Calvert, A H; Johnston, A; Kerr, B; Lee, C; Liang, B; Boddy, A V

    2000-01-01

    A clinical study of nolatrexed dihydrochloride (AG337, ThymitaqTM) in combination with paclitaxel was performed. The aims were to optimize the schedule of administration and determine any pharmacokinetic (PK) interactions between the two drugs. In vitro combination studies were performed to assist with schedule optimization. Three patients were entered on each of three different schedules of administration of the two drugs: (1) paclitaxel 0–3 h, nolatrexed 24–144 h; (2) nolatrexed 0–120 h, paclitaxel 48–51 h; (3) nolatrexed 0–120 h, paclitaxel 126–129 h. Paclitaxel was administered at a dose of 80 mg m−2over 3 h and nolatrexed at a dose of 500 mg m−2day−1as a 120-h continuous intravenous infusion. Plasma concentrations of both drugs were determined by high performance liquid chromatography. In vitro growth inhibition studies using corresponding schedules were performed using two head and neck cancer cell lines. In both HNX14C and HNX22B cell lines, synergistic growth inhibition was observed on schedule 2, whereas schedules 1 and 3 demonstrated antagonistic effects. In the clinical study, there was no effect of schedule on the pharmacokinetics of nolatrexed. However, patients on schedules 1 and 3 had a higher clearance of paclitaxel (322–520 ml min−1m−2) than those on schedule 2 (165–238 ml min−1m−2). Peak plasma concentrations (1.66–1.93 vs 0.86–1.32 μM) and areas under the curve (392–565 vs 180–291 μM min−1) of paclitaxel were correspondingly higher on schedule 2. The pharmacokinetic interaction was confirmed by studies with human liver microsomes, nolatrexed being an inhibitor of the major routes of metabolism of paclitaxel. Toxicity was not schedule-dependent. Nolatrexed and paclitaxel may be safely given together when administered sequentially at the doses used in this study. Studies in vitro suggest some synergy, however, due to a pharmacokinetic interaction, paclitaxel doses should be reduced when administered during

  1. High-dose paclitaxel in combination with doxorubicin, cyclophosphamide and peripheral blood progenitor cell rescue in patients with high-risk primary and responding metastatic breast carcinoma: toxicity profile, relationship to paclitaxel pharmacokinetics and short-term outcome

    PubMed Central

    Somlo, G; Doroshow, J H; Synold, T; Longmate, J; Reardon, D; Chow, W; Forman, S J; Leong, L A; Margolin, K A; Jr, R J Morgan; Raschko, J W; Shibata, S I; Tetef, M L; Yen, Y; Kogut, N; Schriber, J; Alvarnas, J

    2001-01-01

    We assessed the feasibility and pharmacokinetics of high-dose infusional paclitaxel in combination with doxorubicin, cyclophosphamide, and peripheral blood progenitor cell rescue. Between October 1995 and June 1998, 63 patients with high-risk primary [stage II with ≥ 10 axillary nodes involved, stage IIIA or stage IIIB inflammatory carcinoma (n = 53)] or with stage IV responsive breast cancer (n = 10) received paclitaxel 150–775 mg/m2infused over 24 hours, doxorubicin 165 mg/m2as a continuous infusion over 96 hours, and cyclophosphamide 100 mg kg–1. There were no treatment-related deaths. Dose-limiting toxicity was reversible, predominantly sensory neuropathy following administration of paclitaxel at the 775 mg/m2dose level. Paclitaxel pharmacokinetics were non-linear at higher dose levels; higher paclitaxel dose level, AUC, and peak concentrations were associated with increased incidence of paraesthesias. No correlation between stomatitis, haematopoietic toxicities, and paclitaxel dose or pharmacokinetics was found. Kaplan–Meier estimates of 30-month event-free and overall survival for patients with primary breast carcinoma are 65% (95% CI; 51–83%) and 77% (95% CI; 64–93%). Paclitaxel up to 725 mg/m2infused over 24 hours in combination with with doxorubicin 165 mg/m2and cyclophosphamide 100 mg kg–1is tolerable. A randomized study testing this regimen against high-dose carboplatin, thiotepa and cyclophosphamide (STAMP V) is currently ongoing. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11401310

  2. Paclitaxel- and/or cisplatin-induced ocular neurotoxicity: a case report and literature review

    PubMed Central

    Li, Ying; Li, Yanping; Li, Junyu; Pi, Guoliang; Tan, Wenyong

    2014-01-01

    Paclitaxel (PTX) and/or cisplatin (CDDP), as important cytotoxic anti-cancer agents, are widely used to treat various solid tumors. Both may cause moderate or severe neurotoxicity, but ocular neurotoxicity is also occasionally reported. A patient diagnosed with nasopharyngeal cancer suffering acute ocular neurotoxicity 10 days after paclitaxel and CDDP administration at the recommended dose is described in the present case report, and PTX- and/or CDDP-induced ocular neurotoxicity are summarized according to previous reports. Possible mechanisms and the potential diagnostic, therapeutic and predictive strategies of PTX- and/or CDDP-induced ocular neurotoxicity are reviewed, to help the oncologist to take the infrequent toxicity of cytotoxic drugs into account and improve patient safety during anti-cancer therapy. PMID:25114574

  3. Development and evaluation of paclitaxel loaded PLGA:poloxamer blend nanoparticles for cancer chemotherapy.

    PubMed

    Gupta, Prem N; Jain, Sharad; Nehate, Chetan; Alam, Noor; Khare, Vaibhav; Dubey, Ravindra Dhar; Saneja, Ankit; Kour, Smit; Singh, Shashank K

    2014-08-01

    This investigation described the development of novel PLGA:poloxamer blend nanoparticles for intravenous administration of paclitaxel in order to limit the cremophor-associated adverse effects. The developed formulation was well-characterized using various techniques including scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy and differential scanning calorimetry. The nanoparticles had an average particle size around 180nm and zeta potential of -22.7mV. The in vitro release study of nanoparticles exhibited biphasic release pattern. The non-hemolytic potential of the nanoparticles indicated the suitability of the developed formulation for intravenous administration. The PLGA:poloxamer blend nanoparticles showed significantly improved cytotoxicity in cell lines (MCF-7 and Colo-205), as compared to free drug. Further, the developed formulation was stable under the accelerated storage conditions. In conclusion, the results indicated that the developed polymeric formulation is a novel and potential alternative for the paclitaxel delivery. PMID:24942992

  4. Confocal Raman data analysis enables identifying apoptosis of MCF-7 cells caused by anticancer drug paclitaxel

    NASA Astrophysics Data System (ADS)

    Salehi, Hamideh; Middendorp, Elodie; Panayotov, Ivan; Dutilleul, Pierre-Yves Collard; Vegh, Attila-Gergely; Ramakrishnan, Sathish; Gergely, Csilla; Cuisinier, Frederic

    2013-05-01

    Confocal Raman microscopy is a noninvasive, label-free imaging technique used to study apoptosis of live MCF-7 cells. The images are based on Raman spectra of cells components, and their apoptosis is monitored through diffusion of cytochrome c in cytoplasm. K-mean clustering is used to identify mitochondria in cells, and correlation analysis provides the cytochrome c distribution inside the cells. Our results demonstrate that incubation of cells for 3 h with 10 μM of paclitaxel does not induce apoptosis in MCF-7 cells. On the contrary, incubation for 30 min at a higher concentration (100 μM) of paclitaxel induces gradual release of the cytochrome c into the cytoplasm, indicating cell apoptosis via a caspase independent pathway.

  5. Detection of apoptosis caused by anticancer drug paclitaxel in MCF-7 cells by confocal Raman microscopy

    NASA Astrophysics Data System (ADS)

    Salehi, H.; Middendorp, E.; Végh, A.-G.; Ramakrishnan, S.-K.; Gergely, C.; Cuisinier, F. J. G.

    2013-02-01

    Confocal Raman Microscopy, a non-invasive, label free imaging technique is used to study apoptosis in living MCF-7 cells. The images are based on Raman spectra of cells components. K-mean clustering was used to determine mitochondria position in cells and cytochrome c distribution inside the cells was based on correlation analysis. Cell apoptosis is defined as cytochrome c diffusion in cytoplasm. Co-localization of cytochrome c is found within mitochondria after three hours of incubation with 10 μM paclitaxel. Our results demonstrate that the presence of paclitaxel at this concentration in the culture media for 3 hours does not induce apoptosis of MCF7 cells via a caspase independent pathway.

  6. Mechanical Failure in Colloidal Gels

    NASA Astrophysics Data System (ADS)

    Kodger, Thomas Edward

    When colloidal particles in a dispersion are made attractive, they aggregate into fractal clusters which grow to form a space-spanning network, or gel, even at low volume fractions. These gels are crucial to the rheological behavior of many personal care, food products and dispersion-based paints. The mechanical stability of these products relies on the stability of the colloidal gel network which acts as a scaffold to provide these products with desired mechanical properties and to prevent gravitational sedimentation of the dispersed components. Understanding the mechanical stability of such colloidal gels is thus of crucial importance to predict and control the properties of many soft solids. Once a colloidal gel forms, the heterogeneous structure bonded through weak physical interactions, is immediately subject to body forces, such as gravity, surface forces, such as adhesion to a container walls and shear forces; the interplay of these forces acting on the gel determines its stability. Even in the absence of external stresses, colloidal gels undergo internal rearrangements within the network that may cause the network structure to evolve gradually, in processes known as aging or coarsening or fail catastrophically, in a mechanical instability known as syneresis. Studying gel stability in the laboratory requires model colloidal system which may be tuned to eliminate these body or endogenous forces systematically. Using existing chemistry, I developed several systems to study delayed yielding by eliminating gravitational stresses through density matching and cyclic heating to induce attraction; and to study syneresis by eliminating adhesion to the container walls, altering the contact forces between colloids, and again, inducing gelation through heating. These results elucidate the varied yet concomitant mechanisms by which colloidal gels may locally or globally yield, but then reform due to the nature of the physical, or non-covalent, interactions which form

  7. Adhesive, elastomeric gel impregnating composition

    DOEpatents

    Shaw, David Glenn; Pollard, John Randolph; Brooks, Robert Aubrey

    2002-01-01

    An improved capacitor roll with alternating film and foil layers is impregnated with an adhesive, elastomeric gel composition. The gel composition is a blend of a plasticizer, a polyol, a maleic anhydride that reacts with the polyol to form a polyester, and a catalyst for the reaction. The impregnant composition is introduced to the film and foil layers while still in a liquid form and then pressure is applied to aid with impregnation. The impregnant composition is cured to form the adhesive, elastomeric gel. Pressure is maintained during curing.

  8. CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy.

    PubMed

    Barker, Holly E; Patel, Radhika; McLaughlin, Martin; Schick, Ulrike; Zaidi, Shane; Nutting, Christopher M; Newbold, Katie L; Bhide, Shreerang; Harrington, Kevin J

    2016-09-01

    Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer-related deaths, with increasingly more cases arising due to high-risk human papillomavirus (HPV) infection. Cisplatin-based chemoradiotherapy is a standard-of-care for locally advanced head and neck cancer but is frequently ineffective. Research into enhancing radiation responses as a means of improving treatment outcomes represents a high priority. Here, we evaluated a CHK1 inhibitor (CCT244747) as a radiosensitiser and investigated whether a mechanistically rational triple combination of radiation/paclitaxel/CHK1 inhibitor delivered according to an optimized schedule would provide added benefit. CCT244747 abrogated radiation-induced G2 arrest in the p53-deficient HNSCC cell lines, HN4 and HN5, causing cells to enter mitosis with unrepaired DNA damage. The addition of paclitaxel further increased cell kill and significantly reduced tumor growth in an HN5 xenograft model. Importantly, a lower dose of paclitaxel could be used when CCT244747 was included, therefore potentially limiting toxicity. Triple therapy reduced the expression of several markers of radioresistance. Moreover, the more radioresistant HN5 cell line exhibited greater radiation-mediated CHK1 activation and was more sensitive to triple therapy than HN4 cells. We analyzed CHK1 expression in a panel of head and neck tumors and observed that primary tumors from HPV(+) patients, who went on to recur postradiotherapy, exhibited significantly stronger expression of total, and activated CHK1. CHK1 may serve as a biomarker for identifying tumors likely to recur and, therefore, patients who may benefit from concomitant treatment with a CHK1 inhibitor and paclitaxel during radiotherapy. Clinical translation of this strategy is under development. Mol Cancer Ther; 15(9); 2042-54. ©2016 AACR.

  9. Paclitaxel and Its Evolving Role in the Management of Ovarian Cancer

    PubMed Central

    Kampan, Nirmala Chandralega; Madondo, Mutsa Tatenda; McNally, Orla M.; Quinn, Michael; Plebanski, Magdalena

    2015-01-01

    Paclitaxel, a class of taxane with microtubule stabilising ability, has remained with platinum based therapy, the standard care for primary ovarian cancer management. A deeper understanding of the immunological basis and other potential mechanisms of action together with new dosing schedules and/or routes of administration may potentiate its clinical benefit. Newer forms of taxanes, with better safety profiles and higher intratumoural cytotoxicity, have yet to demonstrate clinical superiority over the parent compound. PMID:26137480

  10. Paclitaxel-Based Chemoradiotherapy in the Treatment of Patients With Operable Esophageal Cancer

    SciTech Connect

    Kelsey, Chris R. Chino, Junzo P.; Willett, Christopher G.; Clough, Robert W.; Hurwitz, Herbert I.; Morse, Michael A.; Bendell, Johanna C.; D'Amico, Thomas A.; Czito, Brian G.

    2007-11-01

    Purpose: To compare a neoadjuvant regimen of cisplatin/5-fluorouracil (5-FU) and concurrent radiation therapy (RT) with paclitaxel-based regimens and RT in the management of operable esophageal (EC)/gastroesophageal junction (GEJ) cancer. Methods and Materials: All patients receiving neoadjuvant chemotherapy (CT) and RT for EC/GEJ cancer at Duke University between January 1995 and December 2004 were included. Clinical end points were compared for patients receiving paclitaxel-based regimens (TAX) vs. alternative regimens (non-TAX). Local control (LC), disease-free survival (DFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Chi-square analysis was performed to test the effect of TAX on pathologic complete response (pCR) rates and toxicity. Results: A total of 109 patients received CT-RT followed by esophagectomy (95 M; 14 F). Median RT dose was 45 Gy (range, 36-66 Gy). The TAX and non-TAX groups comprised 47% and 53% of patients, respectively. Most (83%) TAX patients received three drug regimens including platinum and a fluoropyrimidine. In the non-TAX group, 89% of the patients received cisplatin and 5-FU. The remainder received 5-FU or capecitabine alone. Grade 3-4 toxicity occurred in 41% of patients receiving TAX vs. 24% of those receiving non-TAX (p = 0.19). Overall pCR rate was 39% (39% with TAX vs. 40% with non-TAX, p = 0.9). Overall LC, DFS, and OS at 3 years were 80%, 34%, and 37%, respectively. At 3 years, there were no differences in LC (75% vs. 85%, p = 0.33) or OS (37% vs. 37%, p = 0.32) between TAX and non-TAX groups. Conclusions: In this large experience, paclitaxel-containing regimens did not improve pCR rates or clinical end points compared to non-paclitaxel-containing regimens.

  11. [Comparison of a safety evaluation between paclitaxel injection NK and Taxol®].

    PubMed

    Yamamoto, Daigo; Tsubota, Yu; Sueoka, Noriko; Yokoi, Takashi; Inoue, Kentaro; Ohira, Masumi; Muranaka, Tatsuya

    2013-07-01

    Paclitaxel injection NK(NK)is a generic product containing the same amount of ingredients as a Taxol®Injection. We examined the safety of NK in clinical practice compared to the original drug. Our results suggested that for the cancer patient, most safety profiles between NK and the original drug are similar. However, patients who received Taxol®Injection had significantly more grade 2 neuropathy compared to those who received NK(p<0. 01).

  12. CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy.

    PubMed

    Barker, Holly E; Patel, Radhika; McLaughlin, Martin; Schick, Ulrike; Zaidi, Shane; Nutting, Christopher M; Newbold, Katie L; Bhide, Shreerang; Harrington, Kevin J

    2016-09-01

    Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer-related deaths, with increasingly more cases arising due to high-risk human papillomavirus (HPV) infection. Cisplatin-based chemoradiotherapy is a standard-of-care for locally advanced head and neck cancer but is frequently ineffective. Research into enhancing radiation responses as a means of improving treatment outcomes represents a high priority. Here, we evaluated a CHK1 inhibitor (CCT244747) as a radiosensitiser and investigated whether a mechanistically rational triple combination of radiation/paclitaxel/CHK1 inhibitor delivered according to an optimized schedule would provide added benefit. CCT244747 abrogated radiation-induced G2 arrest in the p53-deficient HNSCC cell lines, HN4 and HN5, causing cells to enter mitosis with unrepaired DNA damage. The addition of paclitaxel further increased cell kill and significantly reduced tumor growth in an HN5 xenograft model. Importantly, a lower dose of paclitaxel could be used when CCT244747 was included, therefore potentially limiting toxicity. Triple therapy reduced the expression of several markers of radioresistance. Moreover, the more radioresistant HN5 cell line exhibited greater radiation-mediated CHK1 activation and was more sensitive to triple therapy than HN4 cells. We analyzed CHK1 expression in a panel of head and neck tumors and observed that primary tumors from HPV(+) patients, who went on to recur postradiotherapy, exhibited significantly stronger expression of total, and activated CHK1. CHK1 may serve as a biomarker for identifying tumors likely to recur and, therefore, patients who may benefit from concomitant treatment with a CHK1 inhibitor and paclitaxel during radiotherapy. Clinical translation of this strategy is under development. Mol Cancer Ther; 15(9); 2042-54. ©2016 AACR. PMID:27422809

  13. Prodigiosin down-regulates survivin to facilitate paclitaxel sensitization in human breast carcinoma cell lines.

    PubMed

    Ho, Tsing-Fen; Peng, Yu-Ta; Chuang, Show-Mei; Lin, Shin-Chang; Feng, Bo-Lin; Lu, Chien-Hsing; Yu, Wan-Ju; Chang, Jo-Shu; Chang, Chia-Che

    2009-03-01

    Prodigiosin is a bacterial metabolite with potent anticancer activity, which is attributed to its proapoptotic effect selectively active in malignant cells. Still, the molecular mechanisms whereby prodigiosin induces apoptosis remain largely unknown. In particular, the role of survivin, a vital inhibitor of apoptosis, in prodigiosin-induced apoptosis has never been addressed before and hence was the primary goal of this study. Our results showed that prodigiosin dose-dependently induced down-regulation of survivin in multiple breast carcinoma cell lines, including MCF-7, T-47D and MDA-MB-231. This down-regulation is mainly regulated at the level of transcription, as prodigiosin reduced the levels of both survivin mRNA and survivin promoter activity but failed to rescue survivin expression when proteasome-mediated degradation is abolished. Importantly, overexpression of survivin rendered cells more resistant to prodigiosin, indicating an essential role of survivin down-regulation in prodigiosin-induced apoptosis. In addition, we found that prodigiosin synergistically enhanced cell death induced by paclitaxel, a chemotherapy drug known to up-regulate survivin that in turn confers its own resistance. This paclitaxel sensitization effect of prodigiosin is ascribed to the lowering of survivin expression, because prodigiosin was shown to counteract survivin induction by paclitaxel and, notably, the sensitization effect was severely abrogated in cells that overexpress survivin. Taken together, our results argue that down-regulation of survivin is an integral component mediating prodigiosin-induced apoptosis in human breast cancer cells, and further suggest the potential of prodigiosin to sensitize anticancer drugs, including paclitaxel, in the treatment of breast cancer.

  14. Prodigiosin down-regulates survivin to facilitate paclitaxel sensitization in human breast carcinoma cell lines

    SciTech Connect

    Ho, T.-F.; Peng, Y.-T.; Chuang, S.-M.; Lin, S.-C.; Feng, B.-L.; Lu, C.-H.; Yu, W.-J.; Chang, J.-S. Chang, C.-C.

    2009-03-01

    Prodigiosin is a bacterial metabolite with potent anticancer activity, which is attributed to its proapoptotic effect selectively active in malignant cells. Still, the molecular mechanisms whereby prodigiosin induces apoptosis remain largely unknown. In particular, the role of survivin, a vital inhibitor of apoptosis, in prodigiosin-induced apoptosis has never been addressed before and hence was the primary goal of this study. Our results showed that prodigiosin dose-dependently induced down-regulation of survivin in multiple breast carcinoma cell lines, including MCF-7, T-47D and MDA-MB-231. This down-regulation is mainly regulated at the level of transcription, as prodigiosin reduced the levels of both survivin mRNA and survivin promoter activity but failed to rescue survivin expression when proteasome-mediated degradation is abolished. Importantly, overexpression of survivin rendered cells more resistant to prodigiosin, indicating an essential role of survivin down-regulation in prodigiosin-induced apoptosis. In addition, we found that prodigiosin synergistically enhanced cell death induced by paclitaxel, a chemotherapy drug known to up-regulate survivin that in turn confers its own resistance. This paclitaxel sensitization effect of prodigiosin is ascribed to the lowering of survivin expression, because prodigiosin was shown to counteract survivin induction by paclitaxel and, notably, the sensitization effect was severely abrogated in cells that overexpress survivin. Taken together, our results argue that down-regulation of survivin is an integral component mediating prodigiosin-induced apoptosis in human breast cancer cells, and further suggest the potential of prodigiosin to sensitize anticancer drugs, including paclitaxel, in the treatment of breast cancer.

  15. Comparative Proteomic Analysis of Advanced Ovarian Cancer Tissue to Identify Potential Biomarkers of Responders and Nonresponders to First-Line Chemotherapy of Carboplatin and Paclitaxel

    PubMed Central

    Sehrawat, Urmila; Pokhriyal, Ruchika; Gupta, Ashish Kumar; Hariprasad, Roopa; Khan, Mohd Imran; Gupta, Divya; Naru, Jasmine; Singh, Sundararajan Baskar; Mohanty, Ashok Kumar; Vanamail, Perumal; Kumar, Lalit; Kumar, Sunesh; Hariprasad, Gururao

    2016-01-01

    Conventional treatment for advanced ovarian cancer is an initial debulking surgery followed by chemotherapy combination of carboplatin and paclitaxel. Despite initial high response, three-fourths of these women experience disease recurrence with a dismal prognosis. Patients with advanced-stage ovarian cancer who underwent cytoreductive surgery were enrolled and tissue samples were collected. Post surgery, these patients were started on chemotherapy and followed up till the end of the cycle. Fluorescence-based differential in-gel expression coupled with mass spectrometric analysis was used for discovery phase of experiments, and real-time polymerase chain reaction, Western blotting, and pathway analysis were performed for expression and functional validation of differentially expressed proteins. While aldehyde reductase, hnRNP, cyclophilin A, heat shock protein-27, and actin are upregulated in responders, prohibitin, enoyl-coA hydratase, peroxiredoxin, and fibrin-β are upregulated in the nonresponders. The expressions of some of these proteins correlated with increased apoptotic activity in responders and decreased apoptotic activity in nonresponders. Therefore, the proteins qualify as potential biomarkers to predict chemotherapy response. PMID:26997873

  16. The role of paclitaxel in the treatment of head and neck cancer.

    PubMed

    Vokes, E E; Haraf, D J; Stenson, K; Stupp, R; Malone, D; Levin, J; Weichselbaum, R R

    1995-10-01

    Current chemotherapeutic approaches to recurrent head and neck cancer have routinely yielded response rates of 10% to 30% (for single agents) and 30% to 50% (for combination chemotherapy). However, median survival times for patients with metastatic and/or recurrent disease have stagnated at around 6 months since the 1970s. The investigation of new drugs and treatment approaches thus continues to be a high priority. One such agent, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), has shown good single-agent activity and is also believed to potentiate the effects of radiation therapy in patients with head and neck cancer. We have focused on the addition of paclitaxel to the previously established combination of 5-fluorouracil, hydroxyurea, and radiation therapy. The study goals are to establish the maximum tolerated dose and dose-limiting toxicity of paclitaxel when added to this combination as a 5-day continuous infusion on a biweekly schedule. Preliminary results of this ongoing study have demonstrated activity in patients with poor-prognosis head and neck cancer. Major dose-limiting toxicities have consisted of neutropenia and mucositis, and definition of a recommended phase II dose is in progress.

  17. Chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells.

    PubMed

    Sen, Zhang; Zhan, Xiao Kai; Jing, Jin; Yi, Zhang; Wanqi, Zhou

    2013-02-01

    Cyclotides comprise a family of circular mini-peptides that have been isolated from various plants and have a wide range of bioactivities. Previous studies have demonstrated that cyclotides have antitumor effects and cause cell death by membrane permeabilization. The present study aimed to evaluate the cytotoxicity and chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells. In this study, a total of seven cyclotides were selected for colorimetric cell viability assay (MTT assay) to evaluate their anticancer and chemosensitizing activities in the lung cancer cell line A549 and its sub-line A549/paclitaxel. Results suggested that certain cyclotides had significant anticancer and chemosensitizing abilities; such cyclotides were capable of causing multi-fold decreases in the half maximal inhibitory concentration (IC(50)) value of cliotides in the presence of paclitaxel. More importantly, their bioactivities were found to be correlated with their net charge status. In conclusion, cyclotides from C. ternatea have potential in chemosensitization application. PMID:23419988

  18. c(RGDyK)-decorated Pluronic micelles for enhanced doxorubicin and paclitaxel delivery to brain glioma

    PubMed Central

    Huang, YuKun; Liu, Wenchao; Gao, Feng; Fang, Xiaoling; Chen, Yanzuo

    2016-01-01

    Brain glioma therapy is an important challenge in oncology. Here, doxorubicin (DOX) and paclitaxel (PTX)-loaded cyclic arginine-glycine-aspartic acid peptide (c(RGDyK))-decorated Pluronic micelles (cyclic arginine-glycine-aspartic acid peptide-decorated Pluronic micelles loaded with doxorubicin and paclitaxel [RGD-PF-DP]) were designed as a potential targeted delivery system to enhance blood–brain barrier penetration and improve drug accumulation via integrin-mediated transcytosis/endocytosis and based on integrin overexpression in blood–brain barrier and glioma cells. The physicochemical characterization of RGD-PF-DP revealed a satisfactory size of 28.5±0.12 nm with uniform distribution and core-shell structure. The transport rates across the in vitro blood–brain barrier model, cellular uptake, cytotoxicity, and apoptosis of U87 malignant glioblastoma cells of RGD-PF-DP were significantly greater than those of non-c(RGDyK)-decorated Pluronic micelles. In vivo fluorescence imaging demonstrated the specificity and efficacy of intracranial tumor accumulation of RGD-PF-DP. RGD-PF-DP displayed an extended median survival time of 39 days, with no serious body weight loss during the regimen. No acute toxicity to major organs was observed in mice receiving treatment doses via intravenous administration. In conclusion, RGD-PF-DP could be a promising vehicle for enhanced doxorubicin and paclitaxel delivery in patients with brain glioma. PMID:27143884

  19. Weekly pegylated liposomal doxorubicin and paclitaxel in patients with metastatic breast carcinoma: A phase II study

    PubMed Central

    LEONARDI, VITA; PALMISANO, VALENTINA; PEPE, ALESSIO; USSET, ANTONELLA; MANUGUERRA, GIOVANNA; SAVIO, GIUSEPPINA; DE BELLA, MANUELA TAMBURO; LAUDANI, AGATA; ALÙ, MASSIMO; CUSIMANO, MARIA PIA; SCIANNA, CATERINA; GIRESI, ARMANDO; AGOSTARA, BIAGIO

    2010-01-01

    Pegylated liposomal doxorubicin (PLD) has the advantage of delivering active anthracycline directly to the tumor site, while exposing the patient to a lesser degree of doxorubicin-associated toxicities. Recently, a regimen in which paclitaxel is infused weekly over 1 h produced substantial antitumor activity with little myelosuppression. We designed a phase II trial to study the efficacy and toxicity of 10 mg/m2 PLD on Days 1, 8 and 15, plus 70 mg/m2 paclitaxel weekly in patients with untreated metastatic breast cancer and a high risk of cardiotoxicity. The study included 35 patients, with 31 (88.5%) evaluable for efficacy and 35 (100%) for toxicity. A total of 28 patients (80%) had two or more sites of disease. Overall, 4 complete and 16 partial responses were noted with an overall response rate of 64.5%, with 6 cases of stable and 5 cases of progressive disease. Toxicity was found to be manageable in that the only grade 3–4 side effects recorded were palmar-plantar erythrodysesthesia, 8.5%; mucositis, 2.8%; leucopenia, 12.5%; anemia, 2.8% and AST/ALT, 2.8%. No cardiotoxicity was observed. In conclusion, weekly PLD plus paclitaxel appears to be a well-tolerated and effective approach for metastatic breast cancer patients with a high risk of cardiotoxicity. PMID:22966374

  20. Hypersensitivity reaction studies of a polyethoxylated castor oil-free, liposome-based alternative paclitaxel formulation.

    PubMed

    Wang, Hongbo; Cheng, Guang; Du, Yuan; Ye, Liang; Chen, Wenzhong; Zhang, Leiming; Wang, Tian; Tian, Jingwei; Fu, Fenghua

    2013-03-01

    The commercial drug paclitaxel (Taxol) may introduce hypersensitivity reactions associated with the polyethoxylated castor oil-ethanol solvent. To overcome these problems, we developed a polyethoxylated castor oil-free, liposome-based alternative paclitaxel formulation, known as Lipusu. In this study, we performed in vitro and in vivo experiments to compare the safety profiles of Lipusu and Taxol, with special regard to hypersensitivity reactions. First, Swiss mice were used to determine the lethal dosages, and then to evaluate hypersensitivity reactions, followed by histopathological examination and enzyme-linked immunosorbent assays (ELISAs) of serum SC5b-9 and lung histamine. Additionally, healthy human serum was used to analyze in vitro complement activation. Finally, an MTT assay was used to determine the in vitro anti-proliferation activity. Our data clearly showed that Lipusu displayed a much higher safety margin and did not induce hypersensitivity or hypersensitivity-related lung lesions, which may be associated with the fact that Lipusu did not activate complement or increase histamine release in vivo. Moreover, Lipusu did not promote complement activation in healthy human serum in vitro, and demonstrated anti-proliferative activity against human cancer cells, similar to that of Taxol. Therefore, the improved formulation of paclitaxel, which exhibited a much better safety profile and comparable cytotoxic activity to Taxol, may bring a number of benefits to cancer patients.

  1. Positive-charged solid lipid nanoparticles as paclitaxel drug delivery system in glioblastoma treatment.

    PubMed

    Chirio, Daniela; Gallarate, Marina; Peira, Elena; Battaglia, Luigi; Muntoni, Elisabetta; Riganti, Chiara; Biasibetti, Elena; Capucchio, Maria Teresa; Valazza, Alberto; Panciani, Pierpaolo; Lanotte, Michele; Annovazzi, Laura; Caldera, Valentina; Mellai, Marta; Filice, Gaetano; Corona, Silvia; Schiffer, Davide

    2014-11-01

    Paclitaxel loaded solid lipid nanoparticles (SLN) of behenic acid were prepared with the coacervation technique. Generally, spherical shaped SLN with mean diameters in the range 300–600 nm were obtained. The introduction of charged molecules, such as stearylamine and glycol chitosan into the formulation allowed to obtain positive SLN with Zeta potential in the 8-20 mV range and encapsulation efficiency in the 25–90% range.Blood–brain barrier (BBB) permeability, tested in vitro through hCMEC/D3 cells monolayer, showed a significantly increase in the permeation of Coumarin-6, used as model drug, when vehicled in SLN. Positive-charged SLN do not seem to enhance permeation although stearylamine-positive SLN resulted the best permeable formulation after 24 h.Cytotoxicity studies on NO3 glioblastoma cell line demonstrated the maintenance of cytotoxic activity of all paclitaxel-loaded SLN that was always unmodified or greater compared with free drug. No difference in cytotoxicity was noted between neutral and charged SLN.Co-culture experiments with hCMEC/D3 and different glioblastoma cells evidenced that, when delivered in SLN, paclitaxel increased its cytotoxicity towards glioblastoma cells.

  2. Biomodulation of capecitabine by paclitaxel and carboplatin in advanced solid tumors and adenocarcinoma of unknown primary.

    PubMed

    Mikhail, Sameh; Lustberg, Maryam B; Ruppert, Amy S; Mortazavi, Amir; Monk, Paul; Kleiber, Barbara; Villalona-Calero, Miguel; Bekaii-Saab, Tanios

    2015-11-01

    Paclitaxel and carboplatin upregulate thymidine phosphorylase and thus may provide synergistic antitumor activity in combination with capecitabine (CTX). We, therefore, performed a phase I/II study of CTX. In the phase I study, patients with advanced solid tumors received carboplatin on day 1, paclitaxel on days 1, 8, 15 and capecitabine orally twice a day on days 8-21, every 4 weeks. Phase II patients with advanced adenocarcinoma of unknown primary (ACUP) were treated at the maximal tolerable dose. The phase I study enrolled 29 patients evaluable for dose limiting toxicity. The recommended phase II dose was capecitabine 750 mg/m(2) bid, paclitaxel 60 mg/m(2)/week and carboplatin AUC of 6. There were 9 confirmed responses, 5 partial responses and disease stabilization >3 months in 14 patients. The phase II study was prematurely terminated at 25 patients due to cessation of funding. The objective response rate was 32 % (95 % CI 0.15-0.54), the median progression-free survival 5.5 months (95 % CI 2.8-10.8 months) and the median overall survival 10.8 months (95 % CI 6.0-32.0 months). CTX demonstrated acceptable tolerability and antitumor activity. At the recommended dose level in patients with ACUP, this regimen showed encouraging preliminary activity.

  3. Efficacy of cisplatin, 5-fluorouracil, and paclitaxel regimen for carcinoma of the esophagus.

    PubMed

    Belani, C P; Luketich, J D; Landreaneau, R J; Kim, R; Ramanathan, R K; Day, R; Ferson, P F; Keenan, R J; Posner, M; Seeger, J; Lembersky, B

    1997-12-01

    Eighteen patients with esophageal carcinoma (16 adenocarcinoma, two squamous cell carcinoma) were treated with two cycles of induction chemotherapy consisting of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 175 mg/m2 (3-hour infusion), cisplatin 20 mg/m2/d x 4 days, and 5-fluorouracil 1 g/m2/d (continuous infusion x 4 days) separated by a 28-day interval before surgical resection. After resection, patients received two more cycles of the same regimen. A thorough staging evaluation was performed before patients were enrolled in the study. The salient chemotherapy toxicities included grade 3 nausea (two patients), grade 3 vomiting (two patients), grades 3 and 4 diarrhea (one patient each), and grades 3 and 4 neutropenia (two and 10 patients, respectively). No deaths occurred due to toxicity. Surgical resection was attempted in all 18 patients (100%) after two cycles of induction chemotherapy. Esophageal resection was successfully completed in 17 patients. Liver metastases were noted at laparotomy in the one patient who subsequently did not undergo esophageal resection. Surgical complications were minor, and no postoperative deaths occurred. Fifteen patients received two additional cycles of the paclitaxel/5-fluorouracil/cisplatin regimen postoperatively, two received only one cycle, and one refused further therapy. Of 15 patients alive, 14 show no evidence of disease. The 1-year actuarial survival rate of this group of patients is 82%. In conclusion, the paclitaxel/5-fluorouracil/cisplatin combination is well tolerated and is an active regimen in esophageal carcinoma. PMID:9427275

  4. Combination of Rotational Atherothrombectomy and Paclitaxel-Coated Angioplasty for Femoropopliteal Occlusion

    PubMed Central

    Scheer, F; Lüdtke, CW; Kamusella, P; Wiggermann, P; Vieweg, H; Schlöricke, E; Lichtenberg, M; Andresen, R; Wissgott, C

    2014-01-01

    OBJECTIVE The rotational atherothrombectomy with Straub Rotarex® is a safe and efficient treatment of acute/subactute vascular occlusions. The purpose of this study was to evaluate the benefit of paclitaxel-coated angioplasty after rotational atherothrombectomy over an observation period of six months. MATERIALS AND METHODS Overall, 29 patients were treated with the Rotarex catheter in combination with paclitaxel-coated angioplasty. All patients had acute/subacute and chronic occlusions of the superficial femoral artery (SFA) and/or popliteal arteries. The ankle-brachial index (ABI) was detected before the intervention, after the procedure, and after six months. Also clinical examination and ultrasound scans were done in the observation period. RESULTS There were no technical failures. The ABI shows a significant increase from 0.52 ± 0.17 to 0.91 ± 0.25 in the follow-up. By ultrasound examination, there were found two (6.9%) restenoses during the follow-up. There was one dissection during the intervention (3.5%). CONCLUSION The rotational atherothrombectomy in combination with paclitaxel-coated angioplasty might be an effective and safe method with a promising low rate of restenosis at six months. PMID:25983558

  5. Development and evaluation of paclitaxel nanoparticles using a quality-by-design approach.

    PubMed

    Yerlikaya, Firat; Ozgen, Aysegul; Vural, Imran; Guven, Olgun; Karaagaoglu, Ergun; Khan, Mansoor A; Capan, Yilmaz

    2013-10-01

    The aims of this study were to develop and characterize paclitaxel nanoparticles, to identify and control critical sources of variability in the process, and to understand the impact of formulation and process parameters on the critical quality attributes (CQAs) using a quality-by-design (QbD) approach. For this, a risk assessment study was performed with various formulation and process parameters to determine their impact on CQAs of nanoparticles, which were determined to be average particle size, zeta potential, and encapsulation efficiency. Potential risk factors were identified using an Ishikawa diagram and screened by Plackett-Burman design and finally nanoparticles were optimized using Box-Behnken design. The optimized formulation was further characterized by Fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy, atomic force microscopy, and gas chromatography. It was observed that paclitaxel transformed from crystalline state to amorphous state while totally encapsulating into the nanoparticles. The nanoparticles were spherical, smooth, and homogenous with no dichloromethane residue. In vitro cytotoxicity test showed that the developed nanoparticles are more efficient than free paclitaxel in terms of antitumor activity (more than 25%). In conclusion, this study demonstrated that understanding formulation and process parameters with the philosophy of QbD is useful for the optimization of complex drug delivery systems.

  6. Quercetin ameliorates paclitaxel-induced neuropathic pain by stabilizing mast cells, and subsequently blocking PKCε-dependent activation of TRPV1

    PubMed Central

    Gao, Wei; Zan, Yan; Wang, Zai-jie Jim; Hu, Xiao-yu; Huang, Fang

    2016-01-01

    Aim: Severe painful sensory neuropathy often occurs during paclitaxel chemotherapy. Since paclitaxel can activate mast cell and basophils, whereas quercetin, a polyphenolic flavonoid contained in various plants, which can specifically inhibit histamine release as a mast cell stabilizer. In this study we explore whether quercetin could ameliorate paclitaxel-induced neuropathic pain and elucidated the underlying mechanisms. Methods: Quercetin inhibition on histamine release was validated in vitro by detecting histamine release from rat basophilic leukemia (RBL-2H3) cells stimulated with paclitaxel (10 μmol/L). In the in vivo experiments, rats and mice received quercetin (20, 40 mg·kg-1·d-1) for 40 and 12 d, respectively. Meanwhile, the animals were injected with paclitaxel (2 mg/kg, ip) four times on d 1, 3, 5 and 7. Heat hyperalgesia and mechanical allodynia were evaluated at the different time points. The animals were euthanized and spinal cords and dorsal root ganglions were harvested for analyzing PKCε and TRPV1 expression levels. The plasma histamine levels were assessed in rats on d 31. Results: Pretreatment with quercetin (3, 10, 30 μmol/L) dose-dependently inhibited excessive histamine release from paclitaxel-stimulated RBL-2H3 cells in vitro, and quercetin administration significantly suppressed the high plasma histamine levels in paclitaxel-treated rats. Quercetin administration dose-dependently raised the thresholds for heat hyperalgesia and mechanical allodynia in paclitaxel-treated rats and mice. Furthermore, quercetin administration dose-dependently suppressed the increased expression levels of PKCε and TRPV1 in the spinal cords and DRGs of paclitaxel-treated rats and mice. Moreover, quercetin administration may inhibited the translocation of PKCε from the cytoplasm to the membrane in the spinal cord and DRG of paclitaxel-treated rats. Conclusion: Our results reveal the underlying mechanisms of paclitaxel-induced peripheral neuropathy and

  7. Paclitaxel resistance is associated with switch from apoptotic to autophagic cell death in MCF-7 breast cancer cells

    PubMed Central

    Ajabnoor, G M A; Crook, T; Coley, H M

    2012-01-01

    Taxanes remain first line chemotherapy in management of metastatic breast cancer and have a key role in epithelial ovarian cancer, with increasingly common use of weekly paclitaxel dosing regimens. However, their clinical utility is limited by the development of chemoresistance. To address this, we modelled in vitro paclitaxel resistance in MCF-7 cells. We show that at clinically relevant drug doses, emerging paclitaxel resistance is associated with profound changes in cell death responses and a switch from apoptosis to autophagy as the principal mechanism of drug-induced cytotoxicity. This was characterised by a complete absence of caspase-mediated apoptotic cell death (using the pan-caspase-inhibitor Z-VAD) in paclitaxel-resistant MCF-7TaxR cells, compared with parent MCF-7 or MDA-MB-231 cell lines on paclitaxel challenge, downregulation of caspase-7, caspase-9 and BCl2-interacting mediator of cell death (BIM) expression. Silencing with small interfering RNA to BIM in MCF-7 parental cells was sufficient to confer paclitaxel resistance, inferring the significance in downregulation of this protein in contributing to the resistant phenotype of the MCF-7TaxR cell line. Conversely, there was an increased autophagic response in the MCF-7TaxR cell line with reduced phospho-mTOR and relative resistance to the mTOR inhibitors rapamycin and RAD001. In conclusion, we show for the first time that paclitaxel resistance is associated with profound changes in cell death response with deletion of multiple apoptotic factors balanced by upregulation of the autophagic pathway and collateral sensitivity to platinum. PMID:22278287

  8. Antiangiogenic Therapy with Human Apolipoprotein(a) Kringle V and Paclitaxel in a Human Ovarian Cancer Mouse Model12

    PubMed Central

    Yu, Hyun-Kyung; Lee, Ho-Jeong; Yun, Seok-Joong; Lee, Sun-Joo; Langley, Robert R.; Yoon, Yeup; Yi, Lee S.H.; Bae, Duk-Soo; Kim, Jang-Seong; Kim, Sun Jin

    2014-01-01

    INTRODUCTION: The present study compared the effect of combination therapy using human apolipoprotein(a) kringle V (rhLK8) to conventional chemotherapy with paclitaxel for human ovarian carcinoma producing high or low levels of vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: Human ovarian carcinoma cells producing high (SKOV3ip1) or low (HeyA8) levels of VEGF were implanted into the peritoneal cavity of female nude mice. Seven days later, mice were randomized into four groups: control (vehicle), paclitaxel [5 mg/kg, weekly intraperitoneal (i.p.) injection], rhLK8 (50 mg/kg, daily i.p. injection), or the combination of paclitaxel and rhLK8. Mice were treated for 4 weeks and examined by necropsy. RESULTS: In mice implanted with SKOV3ip1 cells, rhLK8 treatment had no significant effect on tumor incidence or the volume of ascites but induced a significant decrease in tumor weight compared with control mice. Paclitaxel significantly reduced tumor weight and ascites volume, and combination treatment with paclitaxel and rhLK8 had an additive therapeutic effect. Similarly, in HeyA8 mice, the effect of combination treatment on tumor weight and tumor incidence was statistically significantly greater than that of paclitaxel or rhLK8 alone. Immunohistochemical analysis showed a significant decrease in microvessel density and a marked increase of apoptosis in tumor and tumor-associated endothelial cells in response to combination treatment with paclitaxel and rhLK8. CONCLUSION: Collectively, these results suggest that antiangiogenic therapy with rhLK8 in combination with taxane-based conventional chemotherapy could be effective for the treatment of ovarian carcinomas, regardless of VEGF status. PMID:25180060

  9. Fentanyl Enhances Hepatotoxicity of Paclitaxel via Inhibition of CYP3A4 and ABCB1 Transport Activity in Mice.

    PubMed

    Xie, Jing-Dun; Huang, Yang; Chen, Dong-Tai; Pan, Jia-Hao; Bi, Bing-Tian; Feng, Kun-Yao; Huang, Wan; Zeng, Wei-An

    2015-01-01

    Fentanyl, a potent opioid analgesic that is used to treat cancer pain, is commonly administered with paclitaxel in advanced tumors. However, the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanism of action is not well studied. The purpose of this study was to investigate the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanisms of action. Pharmacokinetic parameters of paclitaxel were tested using reversed phase high-performance liquid chromatography (RP-HPLC). Aspartate transaminase (AST), alanine aminotransferase (ALT), and mouse liver histopathology were examined. Moreover, the cytotoxicity of anti-carcinogens was examined using 1-(4, 5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), and the intracellular accumulation of doxorubicin and rhodamine 123 was detected by flow cytometry. Furthermore, the expression of ABCB1 and the activity of ABCB1 ATPase and CYP3A4 were also examined. In this study, the co-administration of fentanyl and paclitaxel prolonged the half-life (t1/2) of paclitaxel from 1.455 hours to 2.344 hours and decreased the clearance (CL) from 10.997 ml/h to 7.014 ml/h in mice. Fentanyl significantly increased the levels of ALT in mice to 88.2 U/L, which is more than 2-fold higher than the level detected in the control group, and it increased the histological damage in mouse livers. Furthermore, fentanyl enhanced the cytotoxicity of anti-carcinogens that are ABCB1 substrates and increased the accumulation of doxorubicin and rhodamine 123. Additionally, fentanyl stimulated ABCB1 ATPase activity and inhibited CYP3A4 activity in the liver microsomes of mice. Our study indicates that the obvious hepatotoxicity during this co-administration was due to the inhibition of CYP3A4 activity and ABCB1 transport activity. These findings suggested that the accumulation-induced hepatotoxicity of paclitaxel when it is combined with fentanyl should be avoided.

  10. Co-loaded paclitaxel/rapamycin liposomes: Development, characterization and in vitro and in vivo evaluation for breast cancer therapy

    PubMed Central

    Eloy, Josimar O.; Petrilli, Raquel; Topan, José Fernando; Antonio, Heriton Marcelo Ribeiro; Barcellos, Juliana Palma Abriata; Chesca, Deise L.; Serafini, Luciano Neder; Tiezzi, Daniel G.; Lee, Robert J.; Marchetti, Juliana Maldonado

    2016-01-01

    Paclitaxel and rapamycin have been reported to act synergistically to treat breast cancer. Albeit paclitaxel is available for breast cancer treatment, the most commonly used formulation in the clinic presents side effects, limiting its use. Furthermore, both drugs present pharmacokinetics drawbacks limiting their in vivo efficacy and clinic combination. As an alternative, drug delivery systems, particularly liposomes, emerge as an option for drug combination, able to simultaneously deliver co-loaded drugs with improved therapeutic index. Therefore, the purpose of this study is to develop and characterize a co-loaded paclitaxel and rapamycin liposome and evaluate it for breast cancer efficacy both in vitro and in vivo. Results showed that a SPC/Chol/DSPE-PEG (2000) liposome was able to co-encapsulate paclitaxel and rapamycin with suitable encapsulation efficiency values, nanometric particle size, low polydispersity and neutral zeta potential. Taken together, FTIR and thermal analysis evidenced drug conversion to the more bioavailable molecular and amorphous forms, respectively, for paclitaxel and rapamycin. The pegylated liposome exhibited excellent colloidal stability and was able to retain drugs encapsulated, which were released in a slow and sustained fashion. Liposomes were more cytotoxic to 4T1 breast cancer cell line than the free drugs and drugs acted synergistically, particularly when co-loaded. Finally, in vivo therapeutic evaluation carried out in 4T1-tumor-bearing mice confirmed the in vitro results. The co-loaded paclitaxel/rapamycin pegylated liposome better controlled tumor growth compared to the solution. Therefore, we expect that the formulation developed herein might be a contribution for future studies focusing on the clinical combination of paclitaxel and rapamycin. PMID:26836480

  11. Next generation deep sequencing identified a novel lncRNA n375709 associated with paclitaxel resistance in nasopharyngeal carcinoma

    PubMed Central

    Ren, Shuling; Li, Guo; Liu, Chao; Cai, Tao; Su, Zongwu; Wei, Ming; She, Li; Tian, Yongquan; Qiu, Yuanzheng; Zhang, Xin; Liu, Yong; Wang, Yunyun

    2016-01-01

    Paclitaxel chemoresistance restricts the therapeutic efficacy and prognosis of patients with nasopharyngeal carcinoma (NPC). Accumulating evidence suggests that aberrant expression of long non-coding RNAs (lncRNAs) contributes to cancer progression. Therefore, we aimed to identify lncRNAs associated with paclitaxel resistance in NPC. First, paclitaxel-resistant CNE-2 cells (CNE-2-Pr) were successfully established and confirmed to be 33.26±8.70 times more resistant than parental CNE-2 cells. Then, differential expression profile of lncRNAs associated with NPC paclitaxel resistance, which contained a total of 2,670 known lncRNAs and 4,820 novel lncRNAs, was constructed via next generation sequencing technology. Our qRT-PCR confirmed that 7 of the top 8 lncRNAs were expressed with the same trend as the prediction, including 4 known lncRNAs (n375709, n377806, n369241 and n335785) and 3 novel lncRNAs (Unigene6646, Unigene6644 and Unigene1654). Our group initially focused on lncRNA n375709, which was the most significantly overexpressed lncRNA of the known lncRNAs. CCK-8 assays demonstrated that further inhibition of lncRNA n375709 increased the paclitaxel sensitivity in NPC 5-8F and 6-10B cells. In conclusion, the present study provided an overview of the expression profiles of lncRNAs correlated with paclitaxel resistance. lncRNA n375709 was identified to be involved in the regulation of NPC paclitaxel resistance. PMID:27498905

  12. Co-loaded paclitaxel/rapamycin liposomes: Development, characterization and in vitro and in vivo evaluation for breast cancer therapy.

    PubMed

    Eloy, Josimar O; Petrilli, Raquel; Topan, José Fernando; Antonio, Heriton Marcelo Ribeiro; Barcellos, Juliana Palma Abriata; Chesca, Deise L; Serafini, Luciano Neder; Tiezzi, Daniel G; Lee, Robert J; Marchetti, Juliana Maldonado

    2016-05-01

    Paclitaxel and rapamycin have been reported to act synergistically to treat breast cancer. Albeit paclitaxel is available for breast cancer treatment, the most commonly used formulation in the clinic presents side effects, limiting its use. Furthermore, both drugs present pharmacokinetics drawbacks limiting their in vivo efficacy and clinic combination. As an alternative, drug delivery systems, particularly liposomes, emerge as an option for drug combination, able to simultaneously deliver co-loaded drugs with improved therapeutic index. Therefore, the purpose of this study is to develop and characterize a co-loaded paclitaxel and rapamycin liposome and evaluate it for breast cancer efficacy both in vitro and in vivo. Results showed that a SPC/Chol/DSPE-PEG (2000) liposome was able to co-encapsulate paclitaxel and rapamycin with suitable encapsulation efficiency values, nanometric particle size, low polydispersity and neutral zeta potential. Taken together, FTIR and thermal analysis evidenced drug conversion to the more bioavailable molecular and amorphous forms, respectively, for paclitaxel and rapamycin. The pegylated liposome exhibited excellent colloidal stability and was able to retain drugs encapsulated, which were released in a slow and sustained fashion. Liposomes were more cytotoxic to 4T1 breast cancer cell line than the free drugs and drugs acted synergistically, particularly when co-loaded. Finally, in vivo therapeutic evaluation carried out in 4T1-tumor-bearing mice confirmed the in vitro results. The co-loaded paclitaxel/rapamycin pegylated liposome better controlled tumor growth compared to the solution. Therefore, we expect that the formulation developed herein might be a contribution for future studies focusing on the clinical combination of paclitaxel and rapamycin. PMID:26836480

  13. Low-Dose Paclitaxel Reduces S100A4 Nuclear Import to Inhibit Invasion and Hematogenous Metastasis of Cholangiocarcinoma.

    PubMed

    Cadamuro, Massimiliano; Spagnuolo, Gaia; Sambado, Luisa; Indraccolo, Stefano; Nardo, Giorgia; Rosato, Antonio; Brivio, Simone; Caslini, Chiara; Stecca, Tommaso; Massani, Marco; Bassi, Nicolò; Novelli, Eugenio; Spirli, Carlo; Fabris, Luca; Strazzabosco, Mario

    2016-08-15

    Nuclear expression of the calcium-binding protein S100A4 is a biomarker of increased invasiveness in cholangiocarcinoma, a primary liver cancer with scarce treatment opportunities and dismal prognosis. In this study, we provide evidence that targeting S100A4 nuclear import by low-dose paclitaxel, a microtubule-stabilizing agent, inhibits cholangiocarcinoma invasiveness and metastatic spread. Administration of low-dose paclitaxel to established (EGI-1) and primary (CCA-TV3) cholangiocarcinoma cell lines expressing nuclear S100A4 triggered a marked reduction in nuclear expression of S100A4 without modifying its cytoplasmic levels, an effect associated with a significant decrease in cell migration and invasiveness. While low-dose paclitaxel did not affect cellular proliferation, apoptosis, or cytoskeletal integrity, it significantly reduced SUMOylation of S100A4, a critical posttranslational modification that directs its trafficking to the nucleus. This effect of low-dose paclitaxel was reproduced by ginkolic acid, a specific SUMOylation inhibitor. Downregulation of nuclear S100A4 by low-dose paclitaxel was associated with a strong reduction in RhoA and Cdc42 GTPase activity, MT1-MMP expression, and MMP-9 secretion. In an SCID mouse xenograft model, low-dose metronomic paclitaxel treatment decreased lung dissemination of EGI-1 cells without significantly affecting their local tumor growth. In the tumor mass, nuclear S100A4 expression by cholangiocarcinoma cells was significantly reduced, whereas rates of proliferation and apoptosis were unchanged. Overall, our findings highlight nuclear S100A4 as a candidate therapeutic target in cholangiocarcinoma and establish a mechanistic rationale for the use of low-dose paclitaxel in blocking metastatic progression of cholangiocarcinoma. Cancer Res; 76(16); 4775-84. ©2016 AACR. PMID:27328733

  14. Leaf-age effects on temperature responses of photosynthesis and respiration of an alpine oak, Quercus aquifolioides, in southwestern China.

    PubMed

    Zhou, Haoran; Xu, Ming; Pan, Hongli; Yu, Xiubo

    2015-11-01

    Temperature responses and sensitivity of photosynthesis (A(n_)T) and respiration for leaves at different ages are crucial to modeling ecosystem carbon (C) cycles and productivity of evergreen forests. Understanding the mechanisms and processes of temperature sensitivity may further shed lights on temperature acclimation of photosynthesis and respiration with leaf aging. The current study examined temperature responses of photosynthesis and respiration of young leaves (YLs) (fully expanded in current growth season) and old leaves (OLs) (fully expanded in last growth season) of Quercus aquifolioides Rehder and E.H. Wilson in an alpine oak forest, southwestern China. Temperature responses of dark respiration (R(dark)), net assimilation (A(n)), maximal velocity of carboxylation (V(cmax)) and maximum rate of electron transport (J(max)) were significantly different between the two leaf ages. Those differences implied different temperature response parameters should be used for leaves of different ages in modeling vegetation productivity and ecosystem C cycles in Q. aquifolioides forests and other evergreen forests. We found that RuBP carboxylation determined the downward shift of A(n_)T in OLs, while RuBP regeneration and the balance between Rubisco carboxylation and RuBP regeneration made little contribution. Sensitivity of stomatal conductance to vapor pressure deficit changed in OLs and compensated part of the downward shift. We also found that OLs of Q. aquifolioides had lower An due to lower stomatal conductance, higher stomatal conductance limitation and deactivation of the biochemical processes. In addition, the balance between R(dark) and A(n) changed between OLs and YLs, which was represented by a higher R(dark)/A(n) ratio for OLs.

  15. Leaf-age effects on temperature responses of photosynthesis and respiration of an alpine oak, Quercus aquifolioides, in southwestern China.

    PubMed

    Zhou, Haoran; Xu, Ming; Pan, Hongli; Yu, Xiubo

    2015-11-01

    Temperature responses and sensitivity of photosynthesis (A(n_)T) and respiration for leaves at different ages are crucial to modeling ecosystem carbon (C) cycles and productivity of evergreen forests. Understanding the mechanisms and processes of temperature sensitivity may further shed lights on temperature acclimation of photosynthesis and respiration with leaf aging. The current study examined temperature responses of photosynthesis and respiration of young leaves (YLs) (fully expanded in current growth season) and old leaves (OLs) (fully expanded in last growth season) of Quercus aquifolioides Rehder and E.H. Wilson in an alpine oak forest, southwestern China. Temperature responses of dark respiration (R(dark)), net assimilation (A(n)), maximal velocity of carboxylation (V(cmax)) and maximum rate of electron transport (J(max)) were significantly different between the two leaf ages. Those differences implied different temperature response parameters should be used for leaves of different ages in modeling vegetation productivity and ecosystem C cycles in Q. aquifolioides forests and other evergreen forests. We found that RuBP carboxylation determined the downward shift of A(n_)T in OLs, while RuBP regeneration and the balance between Rubisco carboxylation and RuBP regeneration made little contribution. Sensitivity of stomatal conductance to vapor pressure deficit changed in OLs and compensated part of the downward shift. We also found that OLs of Q. aquifolioides had lower An due to lower stomatal conductance, higher stomatal conductance limitation and deactivation of the biochemical processes. In addition, the balance between R(dark) and A(n) changed between OLs and YLs, which was represented by a higher R(dark)/A(n) ratio for OLs. PMID:26452765

  16. Temperature response of litter and soil organic matter decomposition is determined by chemical composition of organic material.

    PubMed

    Erhagen, Björn; Öquist, Mats; Sparrman, Tobias; Haei, Mahsa; Ilstedt, Ulrik; Hedenström, Mattias; Schleucher, Jürgen; Nilsson, Mats B

    2013-12-01

    The global soil carbon pool is approximately three times larger than the contemporary atmospheric pool, therefore even minor changes to its integrity may have major implications for atmospheric CO2 concentrations. While theory predicts that the chemical composition of organic matter should constitute a master control on the temperature response of its decomposition, this relationship has not yet been fully demonstrated. We used laboratory incubations of forest soil organic matter (SOM) and fresh litter material together with NMR spectroscopy to make this connection between organic chemical composition and temperature sensitivity of decomposition. Temperature response of decomposition in both fresh litter and SOM was directly related to the chemical composition of the constituent organic matter, explaining 90% and 70% of the variance in Q10 in litter and SOM, respectively. The Q10 of litter decreased with increasing proportions of aromatic and O-aromatic compounds, and increased with increased contents of alkyl- and O-alkyl carbons. In contrast, in SOM, decomposition was affected only by carbonyl compounds. To reveal why a certain group of organic chemical compounds affected the temperature sensitivity of organic matter decomposition in litter and SOM, a more detailed characterization of the (13) C aromatic region using Heteronuclear Single Quantum Coherence (HSQC) was conducted. The results revealed considerable differences in the aromatic region between litter and SOM. This suggests that the correlation between chemical composition of organic matter and the temperature response of decomposition differed between litter and SOM. The temperature response of soil decomposition processes can thus be described by the chemical composition of its constituent organic matter, this paves the way for improved ecosystem modeling of biosphere feedbacks under a changing climate.

  17. Dynamics of a DNA Gel

    NASA Astrophysics Data System (ADS)

    Adhikari, Ramesh; Bhattacharya, Aniket; Dogariu, Aristide

    We study in silico the properties of a gel consisting of DNA strands (modeled as semi-flexible chains) and linkers of varying flexibility, length, and topology. These linkers are envisioned and modeled as active components with additional attributes so as to mimic properties of a synthetic DNA gel containing motor proteins. We use Brownian dynamics to directly obtain frequency dependent complex shear moduli of the gel. We further carry out force spectroscopy on these computer generated gels and study the relaxation properties as a function of the important parameters of the model, e.g., densities and relative ratios of the DNAs and the linkers, the average life time of a link, etc. Our studies are relevant for designing synthetic bio-materials for both materials and medical applications.

  18. The effects of CO2 and nutrient fertilisation on the growth and temperature response of the mangrove Avicennia germinans.

    PubMed

    Reef, Ruth; Slot, Martijn; Motro, Uzi; Motro, Michal; Motro, Yoav; Adame, Maria F; Garcia, Milton; Aranda, Jorge; Lovelock, Catherine E; Winter, Klaus

    2016-08-01

    In order to understand plant responses to both the widespread phenomenon of increased nutrient inputs to coastal zones and the concurrent rise in atmospheric CO2 concentrations, CO2-nutrient interactions need to be considered. In addition to its potential stimulating effect on photosynthesis and growth, elevated CO2 affects the temperature response of photosynthesis. The scarcity of experiments testing how elevated CO2 affects the temperature response of tropical trees hinders our ability to model future primary productivity. In a glasshouse study, we examined the effects of elevated CO2 (800 ppm) and nutrient availability on seedlings of the widespread mangrove Avicennia germinans. We assessed photosynthetic performance, the temperature response of photosynthesis, seedling growth and biomass allocation. We found large synergistic gains in both growth (42 %) and photosynthesis (115 %) when seedlings grown under elevated CO2 were supplied with elevated nutrient concentrations relative to their ambient growing conditions. Growth was significantly enhanced under elevated CO2 only under high-nutrient conditions, mainly in above-ground tissues. Under low-nutrient conditions and elevated CO2, root volume was more than double that of seedlings grown under ambient CO2 levels. Elevated CO2 significantly increased the temperature optimum for photosynthesis by ca. 4 °C. Rising CO2 concentrations are likely to have a significant positive effect on the growth rate of A. germinans over the next century, especially in areas where nutrient availability is high.

  19. The effects of CO2 and nutrient fertilisation on the growth and temperature response of the mangrove Avicennia germinans.

    PubMed

    Reef, Ruth; Slot, Martijn; Motro, Uzi; Motro, Michal; Motro, Yoav; Adame, Maria F; Garcia, Milton; Aranda, Jorge; Lovelock, Catherine E; Winter, Klaus

    2016-08-01

    In order to understand plant responses to both the widespread phenomenon of increased nutrient inputs to coastal zones and the concurrent rise in atmospheric CO2 concentrations, CO2-nutrient interactions need to be considered. In addition to its potential stimulating effect on photosynthesis and growth, elevated CO2 affects the temperature response of photosynthesis. The scarcity of experiments testing how elevated CO2 affects the temperature response of tropical trees hinders our ability to model future primary productivity. In a glasshouse study, we examined the effects of elevated CO2 (800 ppm) and nutrient availability on seedlings of the widespread mangrove Avicennia germinans. We assessed photosynthetic performance, the temperature response of photosynthesis, seedling growth and biomass allocation. We found large synergistic gains in both growth (42 %) and photosynthesis (115 %) when seedlings grown under elevated CO2 were supplied with elevated nutrient concentrations relative to their ambient growing conditions. Growth was significantly enhanced under elevated CO2 only under high-nutrient conditions, mainly in above-ground tissues. Under low-nutrient conditions and elevated CO2, root volume was more than double that of seedlings grown under ambient CO2 levels. Elevated CO2 significantly increased the temperature optimum for photosynthesis by ca. 4 °C. Rising CO2 concentrations are likely to have a significant positive effect on the growth rate of A. germinans over the next century, especially in areas where nutrient availability is high. PMID:27259536

  20. A method for achieving monotonic frequency-temperature response for langasite surface-acoustic-wave high-temperature sensor

    NASA Astrophysics Data System (ADS)

    Shaoming, Bao; Yabing, Ke; Yanqing, Zheng; Lina, Cheng; Honglang, Li

    2016-02-01

    To achieve the monotonic frequency-temperature response for a high-temperature langasite (LGS) surface-acoustic-wave (SAW) sensor in a wide temperature range, a method utilizing two substrate cuts with different propagation angles on the same substrate plane was proposed. In this method, the theory of effective permittivity is adopted to calculate the temperature coefficients of frequency (TCF), electromechanical coupling coefficients (k2), and power flow angle (PFA) for different propagation angles on the same substrate plane, and then the two substrate cuts were chosen to have large k2 and small PFA, as well as the difference in their TCFs (ΔTCF) to always have the same sign of their values. The Z-cut LGS substrate plane was taken as an example, and the two suitable substrate cuts with propagation angles of 74 and 80° were chosen to derive a monotonic frequency-temperature response for LGS SAW sensors at -50 to 540 °C. Experiments on a LGS SAW sensor using the above two substrate cuts were designed, and its measured frequency-temperature response at -50 to 540 °C agreed well with the theory, demonstrating the high accuracy of the proposed method.

  1. Multiple phases of protien gels

    NASA Astrophysics Data System (ADS)

    Annaka, Masahiko; Tanaka, Toyoichi

    1994-03-01

    A multiple phase transition was observed in gels made by covalently cross-linking proteins in either native or denatured state. The enzymatic activity of the gels prepared from native α-chymotrypsin was determined for each of the multiple phases. The reversibility of the swelling degrees and the enzymatic reaction rates upon phase transition suggests that the protein is at a free energy minimum and thus in a phase.

  2. Topical Review: Polymer gel dosimetry

    PubMed Central

    Baldock, C; De Deene, Y; Doran, S; Ibbott, G; Jirasek, A; Lepage, M; McAuley, K B; Oldham, M; Schreiner, L J

    2010-01-01

    Polymer gel dosimeters are fabricated from radiation sensitive chemicals which, upon irradiation, polymerize as a function of the absorbed radiation dose. These gel dosimeters, with the capacity to uniquely record the radiation dose distribution in three-dimensions (3D), have specific advantages when compared to one-dimensional dosimeters, such as ion chambers, and two-dimensional dosimeters, such as film. These advantages are particularly significant in dosimetry situations where steep dose gradients exist such as in intensity-modulated radiation therapy (IMRT) and stereotactic radiosurgery. Polymer gel dosimeters also have specific advantages for brachytherapy dosimetry. Potential dosimetry applications include those for low-energy x-rays, high-linear energy transfer (LET) and proton therapy, radionuclide and boron capture neutron therapy dosimetries. These 3D dosimeters are radiologically soft-tissue equivalent with properties that may be modified depending on the application. The 3D radiation dose distribution in polymer gel dosimeters may be imaged using magnetic resonance imaging (MRI), optical-computerized tomography (optical-CT), x-ray CT or ultrasound. The fundamental science underpinning polymer gel dosimetry is reviewed along with the various evaluation techniques. Clinical dosimetry applications of polymer gel dosimetry are also presented. PMID:20150687

  3. Phase II study of preoperative paclitaxel/cisplatin with radiotherapy in locally advanced esophageal cancer

    SciTech Connect

    Kim, Dong W.; Blanke, Charles D.; Wu, Huiyun; Shyr, Yu; Berlin, Jordan; Beauchamp, R. Daniel; Chakravarthy, Bapsi . E-mail: bapsi.chak@vanderbilt.edu

    2007-02-01

    Purpose: Preoperative paclitaxel-based chemoradiotherapy may improve the response rates and survival in patients with localized esophageal cancer. We evaluated paclitaxel-based induction chemoradiotherapy in patients with localized esophageal cancer to determine its feasibility, clinical response, pathologic response, and overall survival. Methods and Materials: Between 1995 and 1998, 50 patients were enrolled in this study. At study entry, patients were categorized as either resectable or unresectable according to evaluation by an experienced thoracic surgeon. All patients were treated with paclitaxel 175 mg/m{sup 2} and cisplatin 75 mg/m{sup 2} on Day 1, 29 with radiotherapy to 3,000 cGy in 15 fractions. Resectable patients underwent esophagectomy 4 weeks later. Postoperatively, patients received two cycles of paclitaxel 175 mg/m{sup 2} on Day 1 and 5-fluorouracil 350 mg/m{sup 2} and leucovorin 300 mg on Days 1-3, given every 28 days. Patients who were deemed unsuitable for resection from the outset continued radiotherapy to a total dose of 6,000 cGy. Results: Of the 50 patients, all began neoadjuvant chemoradiotherapy, 40 patients underwent surgery, and 25 patients completed postoperative chemotherapy. A pathologic complete response was seen in 7 patients (17.5%). Patients with a pathologic response had a median survival of 32.4 months vs. 14.4 months for nonresponders (p <0.001). Patients with a clinical response had a median survival of 25.2 months compared with 15.6 months for nonresponders (p = 0.002). At a median follow up of 19.8 months (range 2.4-100.8), the median survival was 20.4 months and the 3-year overall survival rate was 23.2%. Conclusion: Although preoperative cisplatin/paclitaxel with 3,000 cGy was tolerable, this multimodality regimen did not appear to be superior to standard cisplatin/5-fluorouracil-containing regimens and its use is not recommended.

  4. Breast cancer cells evade paclitaxel-induced cell death by developing resistance to dasatinib

    PubMed Central

    Jeong, Yun-Ji; Kang, Jong Soon; Lee, Su In; So, Dong Min; Yun, Jieun; Baek, Ji Young; Kim, Sang Kyum; Lee, Kiho; Park, Song-Kyu

    2016-01-01

    Triple negative breast cancer (TNBC), which does not express the progesterone, estrogen, or HER2/neu receptor, is aggressive and difficult to treat. Paclitaxel, a tubulin stabilizing agent, is one of the most frequently prescribed anticancer agents for breast cancers, including TNBC. Residual disease that occurs due to resistance or partial resistance of cancer cells in a tumor against anticancer agents is the most important issue in oncology. In the present study, when MDA-MB-231 cells, a TNBC cell line, were treated with 30 µM paclitaxel, a slightly higher concentration than its GI50 value, for 6 days, a small number of cells with different morphologies survived. Among the surviving cells, small round cells were isolated, cloned, and named MDA-MB-231-JYJ cells. MDA-MB-231-JYJ cells were observed to be highly proliferative and tumorigenic. In addition, signal transduction molecules involved in proliferation, survival, malignancy, or stemness of cancer cells, such as c-Src, c-Met, Notch 1, c-Myc, Sox2, Oct3/4, Nanog, and E-cadherin were highly expressed or activated. While further study is required, MDA-MB-231-JYJ cells appear to have some of the characteristics of cancer precursor cells. Although MDA-MB-231-JYJ cells were isolated from the cells that survived in the continuous presence of paclitaxel, they were not resistant to paclitaxel but developed resistance to dasatinib, a Bcr-Abl and Src kinase family inhibitor. The activated state of Src and Notch 1, and the expression levels of c-Myc and cyclins in MDA-MB-231-JYJ cells were less affected than MDA-MB-231 cells by the treatment of dasatinib, which may explain the resistance of MDA-MB-231-JYJ cells to dasatinib. These results suggest that cancer cells that become resistant to dasatinib during the process of paclitaxel therapy in patients may appear, and caution is required in the design of clinical trials using these two agents. PMID:27602155

  5. Different in vitro metabolism of paclitaxel and docetaxel in humans, rats, pigs, and minipigs.

    PubMed

    Vaclavikova, Radka; Soucek, Pavel; Svobodova, Lenka; Anzenbacher, Pavel; Simek, Petr; Guengerich, F Peter; Gut, Ivan

    2004-06-01

    We investigated cytochrome P450 (P450)-catalyzed metabolism of the important cancer drugs paclitaxel and docetaxel in rat, pig, minipig, and human liver microsomes and cDNA-expressed P450 enzymes. In rat microsomes, paclitaxel was metabolized mainly to C3'-hydroxypaclitaxel (C3'-OHP) and to a lesser extent to C2-hydroxypaclitaxel (C2-OHP), di-hydroxypaclitaxel (di-OHP), and another unknown monohydroxylated paclitaxel. In pig and minipig microsomes, this unknown hydroxypaclitaxel was the main metabolite, whereas C3'-OHP was a minor product. In minipigs, C2-OHP was the next minor product. In human liver microsomes, 6 alpha-hydroxypaclitaxel (6 alpha-OHP) was the main metabolite, followed by C3'-OHP and C2-OHP. Among different cDNA-expressed human P450 enzymes (CYP1A2, 1B1, 2A6, 2C9, 2E1, and 3A4), only CYP3A4 enzyme formed C3'-OHP and C2-OHP. Docetaxel was metabolized in pig, minipig, rat, and human liver microsomes mainly to hydroxydocetaxel (OHDTX), whereas CYP3A-induced rat microsomes produced primarily diastereomeric hydroxyoxazolidinones. Human liver microsomes from 10 different individuals formed OHDTX at different rates correlated with CYP3A4 content. Troleandomycin as a selective inhibitor of CYP3A inhibited the formation of C3'-OHP, C2-OHP, and di-OHP, as well as the unknown OHP produced in rat, minipig, and pig microsomes. In human liver microsomes, troleandomycin inhibited C3'-OHP and C2-OHP formation, and a suitable inhibitor of human CYP2C8, fisetin, strongly inhibited the formation of 6 alpha-OHP, known to be catalyzed by human CYP2C8. In conclusion, the metabolism of docetaxel is the same in all four species, but metabolism of paclitaxel is different, and 6 alpha-OHP remains a uniquely human metabolite. Pigs and minipigs compared with each other formed the same metabolites of paclitaxel.

  6. Analgesic Effect of Intra-Articular Injection of Temperature-Responsive Hydrogel Containing Bupivacaine on Osteoarthritic Pain in Rats

    PubMed Central

    Kim, Taemin; Seol, Dong Rim; Hahm, Suk-Chan; Ko, Cheolwoong; Kim, Eun-Hye; Chun, Keyoungjin; Kim, Junesun; Lim, Tae-Hong

    2015-01-01

    The present study examined the analgesic effects of slow-releasing bupivacaine from hydrogel on chronic arthritic pain in rats. Osteoarthritis (OA) was induced by monosodium iodoacetate (MIA) injection into the right knee joint. Hydrogel (HG: 20, 30, and 50 μL) and temperature-sensitive hydrogel containing bupivacaine (T-gel: 20, 30, and 50 μL) were injected intra-articularly 14 days after MIA injection. Behavioral tests were conducted. The rats showed a significant decrease in weight load and paw withdrawal threshold (PWT). Intra-articular 0.5% bupivacaine (10 and 20 μL) significantly reversed MIA-induced decreased PWT, with no effect on weight load. In normal rats, hydrogel did not produce significant changes in PWT but at 30 and 50 μL slightly decreased weight bearing; T-gel did not cause any changes in both the weight load and PWT. In OA rats, T-gel at 20 μL had a significant analgesic effect for 2 days, even though T-gel at 50 μL further reduced the weight load, demonstrating that intra-articular T-gel (20 μL) has long-lasting analgesic effects in OA rats. Thus, T-gel designed to deliver analgesics into the joint cavity could be an effective therapeutic tool in the clinical setting. PMID:26881207

  7. Initial Testing (Stage 1) of the Tubulin Binding Agent Nanoparticle Albumin-Bound (nab) Paclitaxel (Abraxane®) by the Pediatric Preclinical Testing Program (PPTP)

    PubMed Central

    Houghton, Peter J.; Kurmasheva, Raushan T.; Kolb, E. Anders; Gorlick, Richard; Maris, John M.; Wu, Jianrong; Tong, Zeen; Arnold, Michael A.; Chatterjee, Moumita; Williams, Terence M.; Smith, Malcolm A.

    2015-01-01

    Background Nanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane®) is FDA approved for the treatment of several adult cancers. Antimitotic agents are essential components for curative therapy of pediatric solid tumors, although taxanes have shown limited activity. Because of the novel formulation, nab-paclitaxel was evaluated against a limited series of Pediatric Preclinical Testing Program (PPTP) solid tumors. Procedures Nab-paclitaxel was tested against a limited subset of PPTP solid tumor xenograft models at a dose of 50 mg/kg using a q4dx3 schedule intravenously. Results Nab-paclitaxel was well tolerated in vivo, producing maximum weight loss of approximately 10% with recovery to baseline weight in the week following the third dose. All 20 xenograft models tested were considered evaluable for efficacy. Nab-paclitaxel induced statistically significant differences in event-free survival (EFS) distribution compared to control in 19 of 20 (95%) of the solid tumors. Objective responses were observed in 12 of 20 (60%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in 5 of 8 Ewing sarcoma models and 6 of 8 rhabdomyosarcomas. There were no objective regressions in either neuroblastoma (n=2) or osteosarcoma (n=2) xenograft panels. At the dose tested, systemic exposures of nab-paclitaxel in mice were somewhat greater than those tolerated in humans. Conclusions The high level of activity observed against the rhabdomyosarcoma and Ewing sarcoma PPTP preclinical models makes nab-paclitaxel an interesting agent to consider for pediatric evaluation. PMID:25809532

  8. Autophagy inhibition re-sensitizes pulse stimulation-selected paclitaxel-resistant triple negative breast cancer cells to chemotherapy-induced apoptosis

    PubMed Central

    Wen, Jian; Yeo, Syn; Wang, Chenran; Chen, Song; Sun, Shaogang; Haas, Michael A.; Tu, Wei; Jin, Feng

    2016-01-01

    Chemotherapy is the mainstay of systemic treatment for triple negative breast cancer (TNBC); however, the development of drug resistance limits its effectiveness. Therefore, we investigated the underlying mechanism for drug resistance and potential approaches to overcome it for a more effective treatment for TNBCs. Using a pulse-stimulated selection strategy to mimic chemotherapy administration in the clinic, we developed a new paclitaxel-resistant MDA-MB-231 cell line and analyzed these cells for changes in autophagy activity, and the role and mechanisms of the increased autophagy in promoting drug resistance were determined. We found that the pulse-stimulated selection strategy with paclitaxel resulted in MDA-MB-231 variant cells with enhanced resistance to paclitaxel. These resistant cells were found to have enhanced basal autophagy activity, which confers a cytoprotective function under paclitaxel treatment stress. Inhibition of autophagy enhanced paclitaxel-induced cell death in these paclitaxel-resistant cells. We further revealed that up-regulated autophagy in resistant cells enhanced the clearance of damaged mitochondria. Last, we showed that the paclitaxel-resistant cancer cells acquired cross resistance to epirubicin and cisplatin. Together, these results suggest that combining autophagy inhibition with chemotherapy may be an effective strategy to improve treatment outcome in paclitaxel-resistant TNBC patients. PMID:25638397

  9. NMR mechanisms in gel dosimetry

    NASA Astrophysics Data System (ADS)

    Schreiner, L. J.

    2009-05-01

    Nuclear magnetic resonance was critical to the development of gel dosimetry, as it established the potential for three dimensional dosimetry with chemical dosimeter systems through magnetic resonance imaging [1]. In the last two decades MRI has served as the gold standard for imaging, while NMR relaxometry has played an important role in the development and understanding of the behaviour of new gel dosimetry systems. Therefore, an appreciation of the relaxation mechanisms determining the NMR behaviour of irradiated gel dosimeters is important for a full comprehension of a considerable component of the literature on gel dosimetry. A number of excellent papers have presented this important theory, this brief review will highlight some of the salient points made previously [1-5]. The spin relaxation of gel dosimeters (which determines the dose dependence in most conventional MR imaging) is determined principally by the protons on water molecules in the system. These water protons exist in different environments, or groups (see Figure 1): on bulk water, on water hydrating the chemical species that are being modified under irradiation, and on water hydrating the gel matrix used to spatially stabilize the dosimeter (e.g., gelatin, agarose, etc). The spin relaxation depends on the inherent relaxation rate of each spin group, that is, on the relaxation rate which would be observed for the specific group if it were isolated. Also, the different water environments are not isolated from each other, and the observed relaxation rate also depends on the rate of exchange of magnetization between the groups, and on the fraction of protons in each group. In fact, the water exchanges quickly between the environments, so that relaxation is in what is usually termed the fast exchange regime. In the limit of fast exchange, the relaxation of the water protons is well characterized by a single exponential and hence by a single apparent relaxation rate. In irradiated gel dosimeters this

  10. Pharmaceutical development of an oral tablet formulation containing a spray dried amorphous solid dispersion of docetaxel or paclitaxel.

    PubMed

    Sawicki, Emilia; Beijnen, Jos H; Schellens, Jan H M; Nuijen, Bastiaan

    2016-09-25

    Previously, it was shown in Phase I clinical trials that solubility-limited oral absorption of docetaxel and paclitaxel can be drastically improved with a freeze dried solid dispersion (fdSD). These formulations, however, are unfavorable for further clinical research because of limitations in amorphicity of SD and scalability of the production process. To resolve this, a spray drying method for an SD (spSD) containing docetaxel or paclitaxel and subsequently drug products were developed. Highest saturation solubility (Smax), precipitation onset time (Tprecip), amorphicity, purity, residual solvents, yield/efficiency and powder flow of spSDs were studied. Drug products were monitored for purity/content and dissolution during 24 months at +15-25°C. Docetaxel spSD Smax was equal to that of fdSD but Tprecip was 3 times longer. Paclitaxel spSD Smax was 30% increased but Tprecip was equal to fdSD. spSDs were fully amorphous, >99% pure, <5% residual solvents, mean batch yield was 100g and 84%. spSDs had poor powder flow characteristics, which could not be resolved by changing settings, but by using 75% lactose as diluent. The drug product was a tablet with docetaxel or paclitaxel spSD and was stable for at least 24 months. Spray drying is feasible for the production of SD of docetaxel or paclitaxel for upcoming clinical trials.

  11. Modulation of MDR1 and MRP3 Gene Expression in Lung Cancer Cells after Paclitaxel and Carboplatin Exposure

    PubMed Central

    Melguizo, Consolación; Prados, Jose; Luque, Raquel; Ortiz, Raúl; Caba, Octavio; Álvarez, Pablo J.; Gonzalez, Beatriz; Aranega, Antonia

    2012-01-01

    Carboplatin-paclitaxel is a reference regimen in the treatment of locally advanced or disseminated non-small cell lung cancer (NSCLC). This paper discusses the multidrug resistance developed with this drug combination, which is one of the major obstacles to successful treatment. In order to understand and overcome the drug resistance pattern of NSCLC after carboplatin plus paclitaxel exposure, levels of mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance-associated protein 3 (MRP3) were investigated in primary NSCLC cell lines (A-549 and A-427) and a metastasis-derived NSCLC cell line (NODO). Our results showed that exposure of the three NSCLC lines to plasma concentrations of paclitaxel (5 μM) produced an increase in MDR1 expression, while MRP3 showed no alteration in expression. By contrast, the same cells exposed to carboplatin plasma concentrations (30 μM) showed overexpression of MRP3. In these cells, MDR1 showed no expression changes. Interestingly, the combination of both paclitaxel and carboplatin caused increased expression of the MDR1 drug resistance gene rather than the individual treatments. These results suggest that carboplatin and paclitaxel may induce drug resistance mediated by MDR1 and MRP3, which may be enhanced by the simultaneous use of both drugs. PMID:23443122

  12. Pluronic-poly (acrylic acid)-cysteine/Pluronic L121 mixed micelles improve the oral bioavailability of paclitaxel.

    PubMed

    Zhao, Yanli; Li, Yanli; Ge, Jianjun; Li, Na; Li, Ling-Bing

    2014-11-01

    The aim of the study is to synthesize a thiolated Pluronic copolymer, Pluronic-poly (acrylic acid)-cysteine copolymer, to construct a mixed micelle system with the Pluronic-poly (acrylic acid)-cysteine copolymer and Pluronic L121 (PL121) and to evaluate the potential of these mixed micelles as an oral drug delivery system for paclitaxel. Compared with Pluronic-poly (acrylic acid)-cysteine micelles, drug-loading capacity of Pluronic-poly (acrylic acid)-cysteine/PL121 mixed micelles was increased from 0.4 to 2.87%. In vitro release test indicated that Pluronic-poly (acrylic acid)-cysteine/PL121 mixed micelles exhibited a pH sensitivity. The permeability of drug-loaded micelles in the intestinal tract was studied with an in situ perfusion method in rats. The presence of verapamil and Pluronic both improved the intestinal permeability of paclitaxel, which further certified the inhibition effect of thiolated Pluronic on P-gp. In pharmacokinetic study, the area under the plasma concentration-time curve (AUC0→∞) of paclitaxel-loaded mixed micelles was four times greater than that of the paclitaxel solution (p < 0.05). In general, Pluronic-poly (acrylic acid)-cysteine/PL121 micelles were proven to be a potential oral drug delivery system for paclitaxel.

  13. Direct comparison of two albumin-based paclitaxel-loaded nanoparticle formulations: is the crosslinked version more advantageous?

    PubMed

    Li, Chunlei; Li, Yanhui; Gao, Yuqing; Wei, Na; Zhao, Xi; Wang, Caixia; Li, Yongfeng; Xiu, Xian; Cui, Jingxia

    2014-07-01

    Nanoparticles using albumin as particle matrix have entered the mainstream of drug delivery. It was reported that non-crosslinked albumin nanoparticles were unstable in circulation and could deliver drugs into tumor through gp60/SPARC pathway; in contrast, the delivery of drugs with stable nanoparticles was dependent on enhanced permeability and retention effect. Thus, it is questionable which kind of nanoparticles was more advantageous. Two versions of albumin-bound paclitaxel nanoparticles were prepared. In vitro, the non-crosslinked particles could rapidly disintegrate and the crosslinked was stable. The pharmacokinetics of both formulations was different especially at early time and the non-crosslinked particles were cleared rapidly. After non-crosslinked particle treatment paclitaxel had a tendency to accumulate into heart and kidney and following therapy with the crosslinked particles, paclitaxel was liable to be delivered into lung, spleen and liver. The delivery efficiency of paclitaxel into tumor following the non-crosslinked particle treatment was greater than that of the crosslinked (p<0.05), thus resulting in a considerably improved antineoplastic activity. Moreover, the non-crosslinked formulation was only slightly more toxic. It was concluded that the non-crosslinked formulation was more advantageous for the delivery of paclitaxel and our conclusion might be generalized to other lipophilic drugs delivered with albumin nanoparticles.

  14. Multidrug resistance reversal by co-delivery of tariquidar (XR9576) and paclitaxel using long-circulating liposomes

    PubMed Central

    Patel, Niravkumar R.; Rathi, Alok; Mongayt, Dmitriy; Torchilin, Vladimir P.

    2011-01-01

    One of the major obstacles to the success of cancer chemotherapy is the multidrug resistance (MDR) often resulting due to the overexpression of drug efflux transporter pumps such as P-glycoprotein (P-gp). Highly efficacious third generation P-gp inhibitors, like tariquidar, have shown promising results in overcoming the MDR. However, P-gp is also expressed in normal tissues like blood brain barrier, gastrointestinal track, liver, spleen and kidney. To maximize the efficacy of P-gp inhibitor and reduce the systemic toxicity, it is important to limit the exposure of P-gp inhibitors and the anticancer drugs to normal tissues and increase their co-localization with tumor cells. In this study, we have investigated the co-delivery of the P-gp inhibitor, tariquidar, and cytotoxic drug, paclitaxel, into tumor cells to reverse the MDR using long-circulating liposomes. Tariquidar- and paclitaxel-loaded long-circulating liposomes showed significant resensitization of the resistant variant for paclitaxel, which could be correlated with an increased accumulation of paclitaxel in tumor cells. These results suggest that the co-delivery of the P-gp inhibitor, tariquidar, and the cytotoxicity inducer, paclitaxel, looks like a promising approach to overcome the MDR. PMID:21703341

  15. A novel paclitaxel-loaded poly(epsilon-caprolactone)/Poloxamer 188 blend nanoparticle overcoming multidrug resistance for cancer treatment.

    PubMed

    Zhang, Yangqing; Tang, Lina; Sun, Leilei; Bao, Junbo; Song, Cunxian; Huang, Laiqiang; Liu, Kexin; Tian, Yan; Tian, Ge; Li, Zhen; Sun, Hongfan; Mei, Lin

    2010-06-01

    Multidrug resistance (MDR) of tumor cells is a major obstacle to the success of cancer chemotherapy. Poloxamers have been used in cancer therapy to overcome MDR. The objective of this research is to test the feasibility of paclitaxel-loaded poly(epsilon-caprolactone)/Poloxamer 188 (PCL/Poloxamer 188) nanoparticles to overcome MDR in a paclitaxel-resistant human breast cancer cell line. Paclitaxel-loaded nanoparticles were prepared by a water-acetone solvent displacement method using commercial PCL and self-synthesized PCL/Poloxamer 188 compound, respectively. PCL/Poloxamer 188 nanoparticles were found to be of spherical shape and tended to have a rough and porous surface. The nanoparticles had an average size of around 220nm, with a narrow size distribution. The in vitro drug release profile of both nanoparticle formulations showed a clear biphasic release pattern. There was an increased level of uptake of PCL/Poloxamer 188 nanoparticles (PPNP) in the paclitaxel-resistant human breast cancer cell line MCF-7/TAX, in comparison with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxol in the MCF-7/TAX cell culture, but the differences were not significant. However, the PCL/Poloxamer 188 nanoparticles achieved a significantly higher level of cytotoxicity than both of PCL nanoparticle formulation and Taxol(R), indicating that paclitaxel-loaded PCL/Poloxamer 188 nanoparticles could overcome MDR in human breast cancer cells and therefore could have considerable therapeutic potential for breast cancer. PMID:19969111

  16. Preparation, characterization, and antitumor activity of paclitaxel-loaded folic acid modified and TAT peptide conjugated PEGylated polymeric liposomes.

    PubMed

    Niu, Ruifang; Zhao, Peiqi; Wang, Hanjie; Yu, Man; Cao, Shuzhen; Zhang, Fei; Chang, Jin

    2011-06-01

    Targeting therapy is a promising strategy for enhancing the therapeutic potential of chemotherapeutic agents. In this study, we report the construction of a multifunctional drug delivery system, termed folic acid modified and TAT peptide conjugated PEGylated polymeric liposomes (FA-TATp-PLs), which is originally derived from octadecyl-quaternized lysine modified chitosan and cholesterol. Our data revealed that FA-TATp-PLs have a particle size of about 60 nm with a zeta potential of about 30 mV, a low burst release effect within the first day, a sustained release for the next 14 days in vitro as well as an instant cellular uptake by folate receptor-overexpressing KB human nasopharyngeal carcinoma cells. In vitro cytotoxicity of paclitaxel-loaded FA-TATp-PLs in KB cells was superior to that of Taxol(®). Furthermore, a comparable antitumor efficacy of paclitaxel-loaded FA-TATp-PLs and Taxol(®) was observed at the same doses in murine models bearing nasopharyngeal carcinoma. These results demonstrate that the paclitaxel formulation not only exhibits a higher antitumor activity but also significantly reduces the toxicity and improves the bioavailability as compared to that of free paclitaxel for the treatment of nasopharyngeal carcinoma. Taken together, our findings indicate that paclitaxel-loaded FA-TATp-PLs are a promising nano-sized drug formulation for future cancer therapy. PMID:20677917

  17. Cancer cell sensitization and improved treatment efficacy by combined sodium butyrate and paclitaxel formulations is cancer-type specific.

    PubMed

    Rivkin, Ilia; Cohen, Keren; Bod, Tal; Argov, Mirit; Margalit, Rimona

    2014-01-30

    We queried whether cancer treatment by combinations of paclitaxel and butyrate - free or formulated in drug delivery systems - can improve therapeutic responses compared to each drug alone. Combination treatments were conducted with HT-29 and HeLa cells, as representatives of differentiation-induced and cell-death-induced cancer lines, respectively. Pre-treatment of the HT-29 cells with butyrate (at doses inducing differentiation), followed by butyrate+paclitaxel generated changes in cell cycle profile, increased the level of dead cells beyond that of each drug alone, and allowed reduction in paclitaxel doses. A similar combination treatment of HeLa cells was detrimental, indicating that whether the combination is beneficial or not is cancer-type specific. We hypothesize that while butyrate-treated HT-29 cells became sensitive to paclitaxel-induced Fas-mediated apoptosis, butyrate-adapted HeLa cells became apoptosis-resistant. We next tested the same drug combination on HT-29 cells, but each drug in a specific tumor-targeted carrier. The combination of drug carriers outperformed an equidose combination of the free drugs, showing potential to achieve high therapeutic responses (even in drug-resistant cells) at significantly lower and detergent-free paclitaxel doses, which should allow for reduction in adverse effects and risks of toxicity.

  18. Pharmaceutical development of an oral tablet formulation containing a spray dried amorphous solid dispersion of docetaxel or paclitaxel.

    PubMed

    Sawicki, Emilia; Beijnen, Jos H; Schellens, Jan H M; Nuijen, Bastiaan

    2016-09-25

    Previously, it was shown in Phase I clinical trials that solubility-limited oral absorption of docetaxel and paclitaxel can be drastically improved with a freeze dried solid dispersion (fdSD). These formulations, however, are unfavorable for further clinical research because of limitations in amorphicity of SD and scalability of the production process. To resolve this, a spray drying method for an SD (spSD) containing docetaxel or paclitaxel and subsequently drug products were developed. Highest saturation solubility (Smax), precipitation onset time (Tprecip), amorphicity, purity, residual solvents, yield/efficiency and powder flow of spSDs were studied. Drug products were monitored for purity/content and dissolution during 24 months at +15-25°C. Docetaxel spSD Smax was equal to that of fdSD but Tprecip was 3 times longer. Paclitaxel spSD Smax was 30% increased but Tprecip was equal to fdSD. spSDs were fully amorphous, >99% pure, <5% residual solvents, mean batch yield was 100g and 84%. spSDs had poor powder flow characteristics, which could not be resolved by changing settings, but by using 75% lactose as diluent. The drug product was a tablet with docetaxel or paclitaxel spSD and was stable for at least 24 months. Spray drying is feasible for the production of SD of docetaxel or paclitaxel for upcoming clinical trials. PMID:27480397

  19. Rheological behavior of Slide Ring Gels.

    NASA Astrophysics Data System (ADS)

    Sharma, Vivek; Park, Jong Seung; Park, Jung O.; Srinivasarao, Mohan

    2006-03-01

    Slide ring gels were synthesized by chemically crosslinking, sparsely populated α-cyclodextrin (α-CD) present on the polyrotaxanes consisting of α-CD and polyethylene glycol (PEG). [1] Unlike physically or chemically crosslinked gels, slide ring gels are topological gels where crosslinks can slide along the chain. [2] We investigate the rheological behavior of these gels swollen in water and compare their viscoelastic properties to those of physical and chemical gels. We also study the equilibrium swelling behavior of these gels. [1] Okumura and Ito, Adv. Mater. 2001, 13, 485 [2] C. Zhao et al, J. Phys. Cond. Mat. 2005, 17, S2841

  20. Thixotropic gel for vadose zone remediation

    DOEpatents

    Riha, Brian D.

    2012-07-03

    A thixotropic gel suitable for use in subsurface bioremediation is provided along with a process of using the gel. The thixotropic gel provides a non-migrating injectable substrate that can provide below ground barrier properties. In addition, the gel components provide for a favorable environment in which certain contaminants are preferentially sequestered in the gel and subsequently remediated by either indigenous or introduced microorganisms.

  1. Thixotropic gel for vadose zone remediation

    DOEpatents

    Riha, Brian D.; Looney, Brian B.

    2015-10-27

    A thixotropic gel suitable for use in subsurface bioremediation is provided along with a process of using the gel. The thixotropic gel provides a non-migrating injectable substrate that can provide below ground barrier properties. In addition, the gel components provide for a favorable environment in which certain contaminants are preferentially sequestered in the gel and subsequently remediated by either indigenous or introduced microorganisms.

  2. Thixotropic gel for vadose zone remediation

    DOEpatents

    Rhia, Brian D.

    2011-03-01

    A thixotropic gel suitable for use in subsurface bioremediation is provided along with a process of using the gel. The thixotropic gel provides a non-migrating injectable substrate that can provide below ground barrier properties. In addition, the gel components provide for a favorable environment in which certain contaminants are preferentially sequestered in the gel and subsequently remediated by either indigenous or introduced microorganisms.

  3. Presynaptic N-Methyl-d-aspartate (NMDA) Receptor Activity Is Increased Through Protein Kinase C in Paclitaxel-induced Neuropathic Pain.

    PubMed

    Xie, Jing-Dun; Chen, Shao-Rui; Chen, Hong; Zeng, Wei-An; Pan, Hui-Lin

    2016-09-01

    Painful peripheral neuropathy is a severe adverse effect of chemotherapeutic drugs such as paclitaxel (Taxol). The glutamate N-methyl-d-aspartate receptors (NMDARs) are critically involved in the synaptic plasticity associated with neuropathic pain. However, paclitaxel treatment does not alter the postsynaptic NMDAR activity of spinal dorsal horn neurons. In this study, we determined whether paclitaxel affects presynaptic NMDAR activity by recording excitatory postsynaptic currents (EPSCs) of dorsal horn neurons in spinal cord slices. In paclitaxel-treated rats, the baseline frequency of miniature EPSCs (mEPSCs) was significantly increased; the NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5) completely normalized this frequency. Also, AP5 significantly reduced the amplitude of monosynaptic EPSCs evoked by dorsal root stimulation and reversed the reduction in the paired-pulse ratio of evoked EPSCs in paclitaxel-treated rats. Blocking GluN2A-containing, but not GluN2B-containing, NMDARs largely decreased the frequency of mEPSCs and the amplitude of evoked EPSCs of dorsal horn neurons in paclitaxel-treated rats. Furthermore, inhibition of protein kinase C fully reversed the increased frequency of mEPSCs and the amplitude of evoked EPSCs in paclitaxel-treated rats. Paclitaxel treatment significantly increased the protein level of GluN2A and phosphorylated GluN1 in the dorsal root ganglion. In addition, intrathecal injection of AP5 or systemic administration of memantine profoundly attenuated pain hypersensitivity induced by paclitaxel. Our findings indicate that paclitaxel treatment induces tonic activation of presynaptic NMDARs in the spinal cord through protein kinase C to potentiate nociceptive input from primary afferent nerves. Targeting presynaptic NMDARs at the spinal cord level may be an effective strategy for treating chemotherapy-induced neuropathic pain. PMID:27458019

  4. Capillary fracture of soft gels

    NASA Astrophysics Data System (ADS)

    Bostwick, Joshua B.; Daniels, Karen E.

    2013-10-01

    A liquid droplet resting on a soft gel substrate can deform that substrate to the point of material failure, whereby fractures develop on the gel surface that propagate outwards from the contact line in a starburst pattern. In this paper, we characterize (i) the initiation process, in which the number of arms in the starburst is controlled by the ratio of the surface tension contrast to the gel's elastic modulus, and (ii) the propagation dynamics showing that once fractures are initiated they propagate with a universal power law L∝t3/4. We develop a model for crack initiation by treating the gel as a linear elastic solid and computing the deformations within the substrate from the liquid-solid wetting forces. The elastic solution shows that both the location and the magnitude of the wetting forces are critical in providing a quantitative prediction for the number of fractures and, hence, an interpretation of the initiation of capillary fractures. This solution also reveals that the depth of the gel is an important factor in the fracture process, as it can help mitigate large surface tractions; this finding is confirmed with experiments. We then develop a model for crack propagation by considering the transport of an inviscid fluid into the fracture tip of an incompressible material and find that a simple energy-conservation argument can explain the observed material-independent power law. We compare predictions for both linear elastic and neo-Hookean solids, finding that the latter better explains the observed exponent.

  5. Ferrocenyl Paclitaxel and Docetaxel Derivatives: Impact of an Organometallic Moiety on the Mode of Action of Taxanes.

    PubMed

    Wieczorek, Anna; Błauż, Andrzej; Żal, Aleksandra; Arabshahi, Homayon John; Reynisson, Jóhannes; Hartinger, Christian G; Rychlik, Błażej; Plażuk, Damian

    2016-08-01

    A series of ferrocenyl analogues and derivatives of paclitaxel and docetaxel were synthesised and assayed for their antiproliferative/cytotoxic effects, impact on the cell cycle distribution and ability to induce tubulin polymerisation. The replacement of the 3'-N-benzoyl group of paclitaxel with a ferrocenoyl moiety, in particular, led to formation of an analogue that was at least one order of magnitude more potent in terms of antiproliferative activity than the parent compound (IC50 values of 0.11 versus 1.11 μm, respectively), but still preserved the classical taxane mode of action, that is, microtubule stabilisation leading to mitotic arrest. Molecular docking studies revealed an unexpected binding pocket in the tubulin structure for the ferrocenoyl group introduced in the paclitaxel backbone.

  6. Nab-paclitaxel and trastuzumab combination: a promising approach for neoadjuvant treatment in HER2-positive breast cancer

    PubMed Central

    Ricciardi, Giuseppina Rosaria Rita; Franchina, Tindara; Russo, Alessandro; Schifano, Silvia; Ferraro, Giuseppa; Adamo, Vincenzo

    2016-01-01

    Neoadjuvant therapy is a well-established approach for the treatment of locally advanced or inflammatory breast cancer (BC) and has been increasingly used in recent years not only as a management strategy but also as a research tool. Recently, nanoparticle albumin-bound paclitaxel (nab-paclitaxel)/trastuzumab combinations have been associated with promising activity in different clinical settings. In the present case, we report a complete pathological response after neoadjuvant treatment with the trastuzumab/nab-paclitaxel combination in a locally advanced human epidermal growth factor receptor 2 (HER2)-positive BC patient, with a good toxicity profile. This combination may represent a valid therapeutic option in the neoadjuvant therapy for HER2-positive locally advanced BC. PMID:27499629

  7. Guanylate-Binding Protein-1 protects ovarian cancer cell lines but not breast cancer cell lines from killing by paclitaxel.

    PubMed

    Tipton, Aaron R; Nyabuto, Geoffrey O; Trendel, Jill A; Mazur, Travis M; Wilson, John P; Wadi, Suzan; Justinger, Jacob S; Moore, Garret L; Nguyen, Peter T; Vestal, Deborah J

    2016-09-30

    Forced expression of the cytokine-induced large GTPase, human Guanylate-Binding Protein-1 (hGBP-1), in ovarian cancer cell lines increases resistance to paclitaxel. Elevated hGBP-1 RNA in ovarian tumors correlates with shorter recurrence-free survival. In contract, hGBP-1 is part of a gene signature predicting improved prognosis in all subtypes of breast cancers. hGBP-1 does not confer paclitaxel resistance on MCF-7 and TMX2-28 breast cancer cells. Expression of the isotype of the hGBP-1-interacting protein, PIM1, which may contribute to paclitaxel resistance when associated with hGBP-1, is different in breast and ovarian cancer cell lines. Breast cancer cell lines express the 44 kDa isoform of PIM-1, and ovarian cancer cell lines express the 33 kDa isoform. PMID:27590579

  8. Paclitaxel as Neoadjuvant Therapy for High Grade Angiosarcoma of the Spleen: a Brief Report and Literature Review

    PubMed Central

    Vakkalanka, Bhanu; Milhem, Mohammed

    2010-01-01

    Introduction: Splenic angiosarcoma is a rare tumor with only a few cases reported in the literature. Surgical resection offers the best chance of cure for this aggressive neoplasm but is often precluded by infiltration of the tumor to surrounding critical structures. We report a case of a locally advanced angiosarcoma rendered operable by treatment with Paclitaxel monotherapy. Case presentation: A 69 year old female presented with a high grade splenic angiosarcoma, considered inoperable due to the extent of local spread. She received three cycles of single agent Paclitaxel and underwent a successful resection of the tumor. Conclusion: Chemotherapy options for splenic angiosarcoma are not well studied. Paclitaxel as monotherapy is a useful therapeutic option in down staging tumors, facilitating surgical resection and merits further study in clinical trials. PMID:20981134

  9. Structural determinants of miR156a precursor processing in temperature-responsive flowering in Arabidopsis

    PubMed Central

    Kim, Wanhui; Kim, Hee-Eun; Jun, A Rim; Jung, Myeong Gyo; Jin, Suhyun; Lee, Joon-Hwa; Ahn, Ji Hoon

    2016-01-01

    MicroRNAs originate from primary transcripts (pri-miRNAs) containing hairpin structures. Plant pri-miRNAs have highly variable structures and little is known about the information encoded in their secondary structures. Arabidopsis miR156 is an ambient temperature-responsive miRNA and plays an important role in regulating flowering time. To identify the structural determinants for miR156 processing, we analyzed the effects of mutations introduced in the upper stem of pri-miR156a on its temperature-dependent processing and flowering time. The levels of pri-miR156a and mature miR156 were opposite at different temperatures. Mutations in the upper stem, especially the region closer to the miR156a/miR156a* duplex, reduced miR156 processing at 23 °C and 16 °C and caused a less severe phenotype compared with the un-mutated construct. Mutation in the second stem near the first cleavage site of pri-miR156a affected miR156 processing at 23 °C, but not at 16 °C. This was also seen in pri-miR172a, another ambient temperature-responsive miRNA. Replacement of the upper stem of pri-miR156a with that of pri-miR172a severely affected miR156 processing and flowering time. These results suggested that the upper stem of pri-miR156a is important for miR156 processing at different temperatures. In particular, the second stem adjacent to the first cleavage site plays a role in the regulation of ambient temperature-responsive flowering. PMID:27335452

  10. Sol-gel derived sorbents

    DOEpatents

    Sigman, Michael E.; Dindal, Amy B.

    2003-11-11

    Described is a method for producing copolymerized sol-gel derived sorbent particles for the production of copolymerized sol-gel derived sorbent material. The method for producing copolymerized sol-gel derived sorbent particles comprises adding a basic solution to an aqueous metal alkoxide mixture for a pH.ltoreq.8 to hydrolyze the metal alkoxides. Then, allowing the mixture to react at room temperature for a precalculated period of time for the mixture to undergo an increased in viscosity to obtain a desired pore size and surface area. The copolymerized mixture is then added to an immiscible, nonpolar solvent that has been heated to a sufficient temperature wherein the copolymerized mixture forms a solid upon the addition. The solid is recovered from the mixture, and is ready for use in an active sampling trap or activated for use in a passive sampling trap.

  11. Fundamentals of Polymer Gel Dosimeters

    NASA Astrophysics Data System (ADS)

    McAuley, Kim B.

    2006-12-01

    The recent literature on polymer gel dosimetry contains application papers and basic experimental studies involving polymethacrylic-acid-based and polyacrylamide-based gel dosimeters. The basic studies assess the relative merits of these two most commonly used dosimeters, and explore the effects of tetrakis hydroxymethyl phosphonium chloride (THPC) antioxidant on dosimeter performance. Polymer gel dosimeters that contain THPC or other oxygen scavengers are called normoxic dosimeters, because they can be prepared under normal atmospheric conditions, rather than in a glove box that excludes oxygen. In this review, an effort is made to explain some of the underlying chemical phenomena that affect dosimeter performance using THPC, and that lead to differences in behaviour between dosimeters made using the two types of monomer systems. Progress on the development of new more effective and less toxic dosimeters is also reported.

  12. Copolymers For Capillary Gel Electrophoresis

    DOEpatents

    Liu, Changsheng; Li, Qingbo

    2005-08-09

    This invention relates to an electrophoresis separation medium having a gel matrix of at least one random, linear copolymer comprising a primary comonomer and at least one secondary comonomer, wherein the comonomers are randomly distributed along the copolymer chain. The primary comonomer is an acrylamide or an acrylamide derivative that provides the primary physical, chemical, and sieving properties of the gel matrix. The at least one secondary comonomer imparts an inherent physical, chemical, or sieving property to the copolymer chain. The primary and secondary comonomers are present in a ratio sufficient to induce desired properties that optimize electrophoresis performance. The invention also relates to a method of separating a mixture of biological molecules using this gel matrix, a method of preparing the novel electrophoresis separation medium, and a capillary tube filled with the electrophoresis separation medium.

  13. Etodolac, a cyclooxygenase-2 inhibitor, attenuates paclitaxel-induced peripheral neuropathy in a mouse model of mechanical allodynia.

    PubMed

    Ito, Sunao; Tajima, Koyuki; Nogawa, Masaki; Inoue, Naoki; Kyoi, Takashi; Takahashi, Yosuke; Sasagawa, Takahiro; Nakamura, Akio; Kotera, Takashi; Ueda, Makoto; Yamashita, Yasuhiro; Banno, Kouji

    2012-07-01

    The effect of the cyclooxygenase-2 (COX-2) inhibitor etodolac on the mechanical allodynia induced by paclitaxel was investigated in mice and compared with the effects of the nonselective COX inhibitors indomethacin and diclofenac, the selective COX-2 inhibitor celecoxib, the calcium channel α(2)δ subunit inhibitor pregabalin, the sodium channel blocker mexiletine, and the serotonin-norepinephrine reuptake inhibitor duloxetine. The decrease in the paw-withdrawal threshold induced by paclitaxel was reversed by oral administration of etodolac at 10 mg/kg but was not affected by indomethacin, diclofenac, or celecoxib. The antiallodynic effect of etodolac gradually increased during repeated administration, and after 2 weeks the paw-withdrawal threshold at the preadministration point was significantly increased. Pregabalin, duloxetine, and mexiletine also showed an antiallodynic effect in this model. Whereas pregabalin had a preadministration effect similar to that of etodolac during repeated administration, mexiletine or duloxetine had no such effect. There was almost no difference in the distribution of etodolac and diclofenac in nervous tissue, indicating that COX inhibition is unlikely to be involved in the antiallodynic effect of etodolac. Etodolac did not show a neuroprotective effect against morphological transformations such as the axonal degeneration induced by paclitaxel. Instead, etodolac probably acts at the level of functional changes accompanying paclitaxel treatment, such as alterations in the activation state of components of the pain transmission pathway. Our findings suggest that etodolac attenuates paclitaxel-induced peripheral neuropathy by a COX-independent pathway and that it might be useful for the treatment of paclitaxel-induced peripheral neuropathy. PMID:22460833

  14. DUSP1 induces paclitaxel resistance through the regulation of p-glycoprotein expression in human ovarian cancer cells.

    PubMed

    Kang, Yu-Seon; Seok, Hyun-Jeong; Jeong, Eun-Jeong; Kim, Yuna; Yun, Seok-Joong; Min, Jeong-Ki; Kim, Sun Jin; Kim, Jang-Seong

    2016-09-01

    The heterogeneity and genetic instability of ovarian cancer cells often lead to the development of drug resistance, closely related with the increased cancer-related mortality. In this study, we investigated the role of dual-specificity phosphatase 1 (DUSP1) in the development of the resistance in human ovarian cancer cells against paclitaxel. Overexpression of DUSP1 in HeyA8 human ovarian cancer cells (HeyA8-DUSP1) up-regulated the expression of the drug efflux pump, p-glycoprotein. Consequently, HeyA8-DUSP1 cells are highly resistant to paclitaxel, with the resistance comparable to that of a multi-drug resistance cell line (HeyA8-MDR). Moreover, over expression of DUSP1 significantly increased the activation of p38 MAPK, leaving the activation of ERK1/2 and JNK1/2 unaffected. Pharmacological suppression of p38 MAPK activity prevents the up-regulation of p-glycoprotein expression and the consequent resistance against paclitaxel in HeyA8-DUSP1 cells. By contrast, HeyA8-MDR cells expressed a significantly higher level of DUSP1, but treatment with small interference RNA against DUSP1 significantly suppressed the expression of p-glycoprotein and the resistance against paclitaxel in HeyA8-MDR cells. Ectopic expression of MKK3, an upstream activator of p38 MAPK, significantly up-regulated the expression of p-glycoprotein and increased the consequent resistance against paclitaxel in HeyA8 cells. Collectively, these data indicated that DUSP1 may induce the resistance against paclitaxel through the p38 MAPK-mediated overexpression of p-glycoprotein in human ovarian cancer cells.

  15. Synergistic suppression of microtubule dynamics by discodermolide and paclitaxel in non-small cell lung carcinoma cells.

    PubMed

    Honore, Stéphane; Kamath, Kathy; Braguer, Diane; Horwitz, Susan Band; Wilson, Leslie; Briand, Claudette; Jordan, Mary Ann

    2004-07-15

    Discodermolide is a new microtubule-targeted antimitotic drug in Phase I clinical trials that, like paclitaxel, stabilizes microtubule dynamics and enhances microtubule polymer mass in vitro and in cells. Despite their apparently similar binding sites on microtubules, discodermolide acts synergistically with paclitaxel to inhibit proliferation of A549 human lung cancer cells (L. Martello et al., Clin. Cancer Res., 6: 1978-1987, 2000). To understand their synergy, we examined the effects of the two drugs singly and in combination in A549 cells and found that, surprisingly, their antiproliferative synergy is related to their ability to synergistically inhibit microtubule dynamic instability and mitosis. The combination of discodermolide and paclitaxel at their antiproliferative IC(50)s (7 nm for discodermolide and 2 nm for paclitaxel) altered all of the parameters of dynamic instability synergistically except the time-based rescue frequency. For example, together the drugs inhibited overall microtubule dynamicity by 71%, but each drug individually inhibited dynamicity by only 24%, giving a combination index (CI) of 0.23. Discodermolide and paclitaxel also synergistically blocked cell cycle progression at G(2)-M (41, 9.6, and 16% for both drugs together, for discodermolide alone, and for paclitaxel alone, respectively; CI = 0.59), and they synergistically enhanced apoptosis (CI = 0.85). Microtubules are unique receptors for drugs. The results suggest that ligands that bind to large numbers of binding sites on an individual microtubule can interact in a poorly understood manner to synergistically suppress microtubule dynamic instability and inhibit both mitosis and cell proliferation, with important consequences for combination clinical therapy with microtubule-targeted drugs.

  16. DUSP1 induces paclitaxel resistance through the regulation of p-glycoprotein expression in human ovarian cancer cells.

    PubMed

    Kang, Yu-Seon; Seok, Hyun-Jeong; Jeong, Eun-Jeong; Kim, Yuna; Yun, Seok-Joong; Min, Jeong-Ki; Kim, Sun Jin; Kim, Jang-Seong

    2016-09-01

    The heterogeneity and genetic instability of ovarian cancer cells often lead to the development of drug resistance, closely related with the increased cancer-related mortality. In this study, we investigated the role of dual-specificity phosphatase 1 (DUSP1) in the development of the resistance in human ovarian cancer cells against paclitaxel. Overexpression of DUSP1 in HeyA8 human ovarian cancer cells (HeyA8-DUSP1) up-regulated the expression of the drug efflux pump, p-glycoprotein. Consequently, HeyA8-DUSP1 cells are highly resistant to paclitaxel, with the resistance comparable to that of a multi-drug resistance cell line (HeyA8-MDR). Moreover, over expression of DUSP1 significantly increased the activation of p38 MAPK, leaving the activation of ERK1/2 and JNK1/2 unaffected. Pharmacological suppression of p38 MAPK activity prevents the up-regulation of p-glycoprotein expression and the consequent resistance against paclitaxel in HeyA8-DUSP1 cells. By contrast, HeyA8-MDR cells expressed a significantly higher level of DUSP1, but treatment with small interference RNA against DUSP1 significantly suppressed the expression of p-glycoprotein and the resistance against paclitaxel in HeyA8-MDR cells. Ectopic expression of MKK3, an upstream activator of p38 MAPK, significantly up-regulated the expression of p-glycoprotein and increased the consequent resistance against paclitaxel in HeyA8 cells. Collectively, these data indicated that DUSP1 may induce the resistance against paclitaxel through the p38 MAPK-mediated overexpression of p-glycoprotein in human ovarian cancer cells. PMID:27422607

  17. Far-Red Light-Activatable Prodrug of Paclitaxel for the Combined Effects of Photodynamic Therapy and Site-Specific Paclitaxel Chemotherapy.

    PubMed

    Thapa, Pritam; Li, Mengjie; Bio, Moses; Rajaputra, Pallavi; Nkepang, Gregory; Sun, Yajing; Woo, Sukyung; You, Youngjae

    2016-04-14

    Paclitaxel (PTX) is one of the most useful chemotherapeutic agents approved for several cancers, including ovarian, breast, pancreatic, and nonsmall cell lung cancer. However, it causes systemic side effects when administered parenterally. Photodynamic therapy (PDT) is a new strategy for treating local cancers using light and photosensitizer. Unfortunately, PDT is often followed by recurrence due to incomplete ablation of tumors. To overcome these problems, we prepared the far-red light-activatable prodrug of PTX by conjugating photosensitizer via singlet oxygen-cleavable aminoacrylate linker. Tubulin polymerization enhancement and cytotoxicity of prodrugs were dramatically reduced. However, once illuminated with far-red light, the prodrug effectively killed SKOV-3 ovarian cancer cells through the combined effects of PDT and locally released PTX. Ours is the first PTX prodrug that can be activated by singlet oxygen using tissue penetrable and clinically useful far-red light, which kills the cancer cells through the combined effects of PDT and site-specific PTX chemotherapy.

  18. Paclitaxel with mitoxantrone with or without 5-fluorouracil and high-dose leucovorin in the treatment of metastatic breast cancer.

    PubMed

    Greco, F A; Hainsworth, J D

    1997-10-01

    Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a highly active single agent in the treatment of breast cancer. However, its optimal incorporation into combination regimens awaits definition. We added paclitaxel, administered by 1-hour infusion, to a previously described combination regimen that included mitoxantrone, 5-fluorouracil, and high-dose leucovorin. Forty-six patients with metastatic breast cancer received the following regimen as first- or second-line treatment: paclitaxel 135 mg/m2 by 1-hour intravenous infusion on day 1; mitoxantrone 10 mg/m2 by intravenous bolus on day 1; 5-fluorouracil 350 mg/m2 by intravenous bolus on days 1, 2, and 3; and leucovorin 300 mg intravenous over 30 to 60 minutes, immediately preceding 5-fluorouracil on days 1, 2, and 3. Courses were administered at 3-week intervals for a total of eight courses in responding patients. Of 45 assessable patients, 23 (51%) had major responses. Previous chemotherapy, and in particular previous treatment with doxorubicin, did not affect response rate. The median response duration was 7.5 months. Myelosuppression was moderately severe, with 76% of courses resulting in grade 3 or 4 leukopenia. There were four treatment-related deaths, two sepsis, one congestive heart failure, and one sepsis and congestive heart failure, the last two after a large cumulative anthracycline dose. This combination regimen was active as first- or second-line therapy for metastatic breast cancer, although how its activity compares with that of other combination regimens or with paclitaxel alone is unclear. Myelosuppression was more severe than had been anticipated based on previous results with the mitoxantrone/5-fluorouracil/high-dose leucovorin regimen or with single-agent paclitaxel administered at this dose and schedule. The infrequent development of cardiotoxicity in these patients suggests that the paclitaxel/mitoxantrone combination may not share the problems previously reported with

  19. Disruption of HepG2 cell adhesion by gold nanoparticle and Paclitaxel disclosed by in situ QCM measurement.

    PubMed

    Wei, Xiao-Lan; Mo, Zhi-Hong; Li, Biao; Wei, Jin-Min

    2007-09-01

    Cell adhesion is a crucial issue for cytotoxicity or anticancer effectiveness for tumor cells. However, how both nanoparticles and drugs affect cell adhesion has not yet been defined. Herein, we report for the first time that gold nanoparticles and Paclitaxel can disrupt adhesion, as well as enhance apoptosis of HepG2 cell individually and synergistically, as observed by in situ measurement using quartz crystal microbalance (QCM). It was also found by MTT assay that gold nanoparticles of low cellular cytotoxicity enhance the antiproliferation and apoptosis of HepG2 cell induced by Paclitaxel. Those findings would be of great potential for biomedical application of nanoparticles.

  20. Encapsulation of paclitaxel into a bio-nanocomposite. A study combining inelastic neutron scattering to thermal analysis and infrared spectroscopy

    NASA Astrophysics Data System (ADS)

    Martins, Murillo L.; Orecchini, Andrea; Aguilera, Luis; Eckert, Juergen; Embs, Jan; Matic, Aleksander; Saeki, Margarida J.; Bordallo, Heloisa N.

    2015-01-01

    The anticancer drug paclitaxel was encapsulated into a bio-nanocomposite formed by magnetic nanoparticles, chitosan and apatite. The aim of this drug carrier is to provide a new perspective against breast cancer. The dynamics of the pure and encapsulated drug were investigated in order to verify possible molecular changes caused by the encapsulation, as well as to follow which interactions may occur between paclitaxel and the composite. Fourier transformed infrared spectroscopy, thermal analysis, inelastic and quasi-elastic neutron scattering experiments were performed. These very preliminary results suggest the successful encapsulation of the drug.

  1. The effect of multivalent cations and Tau on paclitaxel-stabilized microtubule assembly, disassembly, and structure.

    PubMed

    Safinya, Cyrus R; Chung, Peter J; Song, Chaeyeon; Li, Youli; Ewert, Kai K; Choi, Myung Chul

    2016-06-01

    In this review we describe recent studies directed at understanding the formation of novel nanoscale assemblies in biological materials systems. In particular, we focus on the effects of multivalent cations, and separately, of microtubule-associated protein (MAP) Tau, on microtubule (MT) ordering (bundling), MT disassembly, and MT structure. Counter-ion directed bundling of paclitaxel-stabilized MTs is a model electrostatic system, which parallels efforts to understand MT bundling by intrinsically disordered proteins (typically biological polyampholytes) expressed in neurons. We describe studies, which reveal an unexpected transition from tightly spaced MT bundles to loose bundles consisting of strings of MTs as the valence of the cationic counter-ion decreases from Z=3 to Z=2. This transition is not predicted by any current theories of polyelectrolytes. Notably, studies of a larger series of divalent counter-ions reveal strong ion specific effects. Divalent counter-ions may either bundle or depolymerize paclitaxel-stabilized MTs. The ion concentration required for depolymerization decreases with increasing atomic number. In a more biologically related system we review synchrotron small angle x-ray scattering (SAXS) studies on the effect of the Tau on the structure of paclitaxel-stabilized MTs. The electrostatic binding of MAP Tau isoforms leads to an increase in the average radius of microtubules with increasing Tau coverage (i.e. a re-distribution of protofilament numbers in MTs). Finally, inspired by MTs as model nanotubes, we briefly describe other more robust lipid-based cylindrical nanostructures, which may have technological applications, for example, in drug encapsulation and delivery. PMID:26684364

  2. Chemotherapy-Related Amenorrhea after Adjuvant Paclitaxel-Trastuzumab (APT Trial)

    PubMed Central

    Ruddy, Kathryn J.; Guo, Hao; Barry, William; Dang, Chau T.; Yardley, Denise A.; Moy, Beverly; Marcom, P. Kelly; Albain, Kathy S.; Rugo, Hope S.; Ellis, Matthew J.; Shapira, Iuliana; Wolff, Antonio C.; Carey, Lisa A.; Overmoyer, Beth A.; Hudis, Clifford; Krop, Ian E.; Burstein, Harold J.; Winer, Eric P.; Partridge, Ann H.; Tolaney, Sara M.

    2016-01-01

    Purpose Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. Learning how frequently paclitaxel and trastuzumab cause amenorrhea is important. Most other adjuvant breast cancer therapies induce CRA in approximately 50% of all premenopausal recipients [1]. Methods 410 patients enrolled on the APT Trial, a single-arm phase 2 adjuvant study of 12 weeks of paclitaxel and trastuzumab followed by nine months of trastuzumab monotherapy. Eligible patients had ≤3cm node-negative HER2+ breast cancers. Premenopausal enrollees were asked to complete menstrual surveys every 3-12 months for 72 months. Women who responded to at least one survey at least 15 months after chemotherapy initiation (and who did not undergo hysterectomy and/or bilateral oophorectomy or receive ovarian suppressing medications prior to 15 months) were included in this analysis. A participant was defined as having amenorrhea in follow-up if her self-reported last menstrual period at last follow-up was greater than 12 months prior to the survey. Results Among the 64 women in the evaluable population (median age at study entry 44 years, range 27-52 years), the median time between chemotherapy initiation and last menstrual survey was 51 months (range 16-79). 18 of 64 women (28%, 95% CI 18-41%) were amenorrheic at that time point. Conclusions Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel and trastuzumab for early stage breast cancer appear lower than those seen historically with standard alkylator-based breast cancer regimens. Future studies are needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms. PMID:25981899

  3. The effect of multivalent cations and Tau on paclitaxel-stabilized microtubule assembly, disassembly, and structure.

    PubMed

    Safinya, Cyrus R; Chung, Peter J; Song, Chaeyeon; Li, Youli; Ewert, Kai K; Choi, Myung Chul

    2016-06-01

    In this review we describe recent studies directed at understanding the formation of novel nanoscale assemblies in biological materials systems. In particular, we focus on the effects of multivalent cations, and separately, of microtubule-associated protein (MAP) Tau, on microtubule (MT) ordering (bundling), MT disassembly, and MT structure. Counter-ion directed bundling of paclitaxel-stabilized MTs is a model electrostatic system, which parallels efforts to understand MT bundling by intrinsically disordered proteins (typically biological polyampholytes) expressed in neurons. We describe studies, which reveal an unexpected transition from tightly spaced MT bundles to loose bundles consisting of strings of MTs as the valence of the cationic counter-ion decreases from Z=3 to Z=2. This transition is not predicted by any current theories of polyelectrolytes. Notably, studies of a larger series of divalent counter-ions reveal strong ion specific effects. Divalent counter-ions may either bundle or depolymerize paclitaxel-stabilized MTs. The ion concentration required for depolymerization decreases with increasing atomic number. In a more biologically related system we review synchrotron small angle x-ray scattering (SAXS) studies on the effect of the Tau on the structure of paclitaxel-stabilized MTs. The electrostatic binding of MAP Tau isoforms leads to an increase in the average radius of microtubules with increasing Tau coverage (i.e. a re-distribution of protofilament numbers in MTs). Finally, inspired by MTs as model nanotubes, we briefly describe other more robust lipid-based cylindrical nanostructures, which may have technological applications, for example, in drug encapsulation and delivery.

  4. Novel targets for paclitaxel nano formulations: Hopes and hypes in triple negative breast cancer.

    PubMed

    Bakrania, Anita K; Variya, Bhavesh C; Patel, Snehal S

    2016-09-01

    Triple negative breast cancer is defined as one of the utmost prevailing breast cancers worldwide, possessing an inadequate prognosis and treatment option limited to chemotherapy and radiotherapy, creating a challenge for researchers as far as developing a specific targeted therapy is concerned. The past research era has shown several promising outcomes for TNBC such as nano-formulations of the chemotherapeutic agents already used for the management of the malignant tumor. Taking a glance at paclitaxel nano formulations, it has been proven beneficial in several researches in the past decade; nevertheless its solubility is often a challenge to scientists in achieving success. We have henceforth discussed the basic heterogeneity of triple negative breast cancer along with the current management options as well as a brief outlook on pros and cons of paclitaxel, known as the most widely used chemotherapeutic agent for the treatment of the disease. We further analyzed the need of nanotechnology pertaining to the problems encountered with the current paclitaxel formulations available discussing the strategic progress in various nano-formulations till date taking into account the basic research strategies required in terms of solubility, permeability, physicochemical properties, active and passive targeting. A thorough review in recent advances in active targeting for TNBC was carried out whereby the various ligands which are at present finding its way into TNBC research such as hyaluronic acid, folic acid, transferrin, etc. were discussed. These ligands have specific receptor affinity to TNBC tumor cells hence can be beneficial for novel drug targeting approaches. Conversely, there are currently several novel strategies in the research pipeline whose targeting ligands have not yet been studied. Therefore, we reviewed upon the numerous novel receptor targets along with the respective nano-formulation aspects which have not yet been fully researched upon and could be

  5. A self-assembling nanoparticle for paclitaxel delivery in ovarian cancer

    PubMed Central

    Xiao, Kai; Luo, Juntao; Fowler, Wiley; Li, Yuanpei; Lee, Joyce; Wang, Li; Lam, Kit S.

    2009-01-01

    Paclitaxel (PTX) is one of the most effective chemotherapeutic drugs for the treatment of a variety of cancers. However, it is associated with serious side effects caused by PTX itself and the Cremophor EL emulsifier. In the present study, we report the development of a well-defined amphiphilic linear–dendritic copolymer (named as telodendrimer) composed of polyethylene glycol (PEG), cholic acid (CA, a facial amphiphilic molecule) and lysine, which can form drug-loaded core/shell micelles when mixed with hydrophobic drug, such as PTX, under aqueous condition. We have used PEG5k-CA8, a representive telodendrimer, to prepare paclitaxel-loaded nanoparticles (PTX-PEG5k-CA8 NPs) with high loading capacity (7.3 mg PTX/mL) and a size of 20–60 nm. This novel nanoformulation of PTX was found to exhibit similar in vitro cytotoxic activity against ovarian cancer cells as the free drug (Taxol®) or paclitaxel/ human serum albumin nanoaggregate (Abraxane®). The maximum tolerated doses (MTDs) of PTX-PEG5k-CA8 NPs after single dose and five consective daily doses in mice were approximately 75 and 45 mg PTX/kg, respectively, which were 2.5-fold higher than those of Taxol®. In both subcutaneous and orthotopic intraperitoneal murine models of ovarian cancer, PTX-PEG5k-CA8 NPs achieved superior toxicity profiles and antitumor effects compared to Taxol® and Abraxane® at equivalent PTX doses, which were attributed to their preferential tumor accumulation, and deep penetration into tumor tissue, as confirmed by near infrared fluorescence (NIRF) imaging. PMID:19660809

  6. Phase II Study of Carboplatin and Paclitaxel in Advanced Thymoma and Thymic Carcinoma

    PubMed Central

    Lemma, Girum L.; Lee, Ju-Whei; Aisner, Seena C.; Langer, Corey J.; Tester, William J.; Johnson, David H.; Loehrer, Patrick J.

    2011-01-01

    Purpose The purpose of this study was to evaluate the impact of carboplatin and paclitaxel in patients with advanced previously untreated thymoma and thymic carcinoma. Patients and Methods We conducted a prospective multicenter study in patients with unresectable thymoma (n = 21) or thymic carcinoma (n = 23). Patients were treated with carboplatin (area under the curve, 6) plus paclitaxel (225 mg/m2) every 3 weeks for a maximum of six cycles. The primary end point of this trial was to evaluate the objective response rate. Results From February 2001 through January 2008, 46 patients were enrolled. Thirteen patients had grade 4 or greater toxicity, mostly neutropenia. Using RECIST (Response Evaluation Criteria in Solid Tumors) 1.0 criteria, three complete responses (CRs) and six partial responses (PRs; objective response rate [ORR], 42.9%; 90% CI, 24.5% to 62.8%) were observed in the thymoma cohort; 10 patients had stable disease. For patients with thymic carcinoma, no CRs and five PRs (ORR, 21.7%; 90% CI, 9.0% to 40.4%) were observed; 12 patients had stable disease. Progression-free survival (PFS) was 16.7 (95% CI, 7.2 to 19.8) and 5.0 (95% CI, 3.0 to 8.3) months for thymoma and thymic carcinoma cohorts, respectively. To date, only seven patients (33.3%) with thymoma have died, compared with 16 patients (69.6%) with thymic carcinoma. Median survival time was 20.0 months (95% CI, 5.0 to 43.6 months) for patients with thymic carcinoma, but it has not been reached for patients with thymoma. Conclusion Carboplatin plus paclitaxel has moderate clinical activity for patients with thymic malignancies, but this seems less than expected with anthracycline-based therapy. Patients with thymic carcinoma have poorer PFS and overall survival than patients with thymoma. PMID:21502559

  7. Synthesis and characterization of polymeric nanospheres loaded with the anticancer drug paclitaxel and magnetic particles

    NASA Astrophysics Data System (ADS)

    Závišová, Vlasta; Koneracká, Martina; Múčková, Marta; Kopčanský, Peter; Tomašovičová, Natália; Lancz, Gábor; Timko, Milan; Pätoprstá, Božena; Bartoš, Peter; Fabián, Martin

    2009-05-01

    We describe the preparation (by nanoprecipitation) and characterization of nanospheres (NPs) for magnetic drug targeting made of a magnetic fluid with poly(ethylene glycol), poly( D, L-lactic- co-glycolic acid) (PLGA), and the anticancer drug paclitaxel (Taxol ®). Infrared spectroscopy confirmed the incorporation of the drug in the PLGA NPs, which were also characterized in terms of morphology, size (typical diameter 200-250 nm) and colloidal stability in aqueous solutions of NaCl. Drug release and in vivo toxicity experiments of the prepared samples were performed. Their stability, magnetic properties (superparamagnetism), and lethal dose were found to be acceptable for the proposed application in cancer therapy.

  8. The Temperature Response and Aggressiveness of Peyronellaea pinodes Isolates Originating from Wild and Domesticated Pisum sp. in Israel.

    PubMed

    Golani, M; Abbo, S; Sherman, A; Frenkel, O; Shtienberg, D

    2016-08-01

    Domesticated pea fields are grown in relatively close proximity to wild pea species in Israel. Despite the major role attributed to ascochyta blight in causing yield losses in domesticated pea, very limited information is available on the pathogens prevailing in natural ecosystems. The objectives of this study were (i) to identify the species causing ascochyta blight symptoms on leaves, stems, and petioles of domesticated pea and wild Pisum plants in Israel, and (ii) to quantify the temperature response(s) and aggressiveness of such pathogens originating from Pisum plants growing in sympatric and allopatric contexts. Eighteen fungal isolates were examined and identified; three of them were sampled from Pisum sativum, 11 from Pisum fulvum, and four from Pisum elatius. All isolates were identified as Peyronellaea pinodes. Spore germination and mycelial growth took place over a wide range of temperatures, the lower and upper cardinal temperatures being 2 to 9 and 33 to 38°C, respectively; the optimal temperatures ranged from 22 to 26°C. At an optimal temperature, disease severity was significantly higher for plants maintained under moist conditions for 24 h postinoculation than for those exposed to humidity for 5 or 10 h. Analyses of the data revealed that temperature responses, spore germination rates, and aggressiveness of isolates sampled from domesticated pea plants did not differ from those of isolates sampled from adjacent or distant wild populations. Host specificity was not observed. These observations suggest that Israel may be inhabited by a single metapopulation of P. pinodes. PMID:27050578

  9. Dual pH and temperature responsive hydrogels based on β-cyclodextrin derivatives for atorvastatin delivery.

    PubMed

    Yang, Kaiwen; Wan, Sicheng; Chen, Binbin; Gao, Wenxia; Chen, Jiuxi; Liu, Miaochang; He, Bin; Wu, Huayue

    2016-01-20

    2-Methylacrylic acid modified β-cyclodextrin was copolymerized with 2-methylacrylic acid and N,N'-methylene diacrylamide to fabricate dual pH and temperature responsive hydrogels for the controlled release of atorvastatin. The swelling behaviors, pH and temperature responsive atorvastatin release profiles of the hydrogels were investigated. The results indicated that the hydrogel prepared in DMSO exhibited the best swelling rate, which was 51 for 10 min and 252 for 16 h when immersed in medium of buffer solution with pH=8.06. The media with low (pH ≤ 3.84) and high (pH ≥ 10.34) pH values would reduce the swelling rate of hydrogels. The swelling of the hydrogel was increased with increasing temperature from 30 °C to 45 °C. Atorvastatin was loaded in the hydrogel for drug release investigation. The cumulative release rate of atorvastatin was as high as 90.5% in pH=8.06 buffer solution. The solubility of atorvastatin was improved from 0.13 to 1.2mg/mL in the hydrogel. PMID:26572359

  10. An imaging-guided platform for synergistic photodynamic/photothermal/chemo-therapy with pH/temperature-responsive drug release.

    PubMed

    Lv, Ruichan; Yang, Piaoping; He, Fei; Gai, Shili; Yang, Guixin; Dai, Yunlu; Hou, Zhiyao; Lin, Jun

    2015-09-01

    To integrate biological imaging and multimodal therapies into one platform for enhanced anti-cancer efficacy, we have designed a novel core/shell structured nano-theranostic by conjugating photosensitive Au25(SR)18 - (SR refers to thiolate) clusters, pH/temperature-responsive polymer P(NIPAm-MAA), and anti-cancer drug (doxorubicin, DOX) onto the surface of mesoporous silica coated core-shell up-conversion nanoparticles (UCNPs). It is found that the photodynamic therapy (PDT) derived from the generated reactive oxygen species and the photothermal therapy (PTT) arising from the photothermal effect can be simultaneously triggered by a single 980 nm near infrared (NIR) light. Furthermore, the thermal effect can also stimulate the pH/temperature sensitive polymer in the cancer sites, thus realizing the targeted and controllable DOX release. The combined PDT, PTT and pH/temperature responsive chemo-therapy can markedly improve the therapeutic efficacy, which has been confirmed by both in intro and in vivo assays. Moreover, the doped rare earths endow the platform with dual-modal up-conversion luminescent (UCL) and computer tomography (CT) imaging properties, thus achieving the target of imaging-guided synergistic therapy under by a single NIR light. PMID:26093792

  11. The Temperature Response and Aggressiveness of Peyronellaea pinodes Isolates Originating from Wild and Domesticated Pisum sp. in Israel.

    PubMed

    Golani, M; Abbo, S; Sherman, A; Frenkel, O; Shtienberg, D

    2016-08-01

    Domesticated pea fields are grown in relatively close proximity to wild pea species in Israel. Despite the major role attributed to ascochyta blight in causing yield losses in domesticated pea, very limited information is available on the pathogens prevailing in natural ecosystems. The objectives of this study were (i) to identify the species causing ascochyta blight symptoms on leaves, stems, and petioles of domesticated pea and wild Pisum plants in Israel, and (ii) to quantify the temperature response(s) and aggressiveness of such pathogens originating from Pisum plants growing in sympatric and allopatric contexts. Eighteen fungal isolates were examined and identified; three of them were sampled from Pisum sativum, 11 from Pisum fulvum, and four from Pisum elatius. All isolates were identified as Peyronellaea pinodes. Spore germination and mycelial growth took place over a wide range of temperatures, the lower and upper cardinal temperatures being 2 to 9 and 33 to 38°C, respectively; the optimal temperatures ranged from 22 to 26°C. At an optimal temperature, disease severity was significantly higher for plants maintained under moist conditions for 24 h postinoculation than for those exposed to humidity for 5 or 10 h. Analyses of the data revealed that temperature responses, spore germination rates, and aggressiveness of isolates sampled from domesticated pea plants did not differ from those of isolates sampled from adjacent or distant wild populations. Host specificity was not observed. These observations suggest that Israel may be inhabited by a single metapopulation of P. pinodes.

  12. Temperature-responsive smart nanoreactors: poly(N-isopropylacrylamide)-coated Au@mesoporous-SiO2 hollow nanospheres.

    PubMed

    Chen, Zhe; Cui, Zhi-Min; Cao, Chang-Yan; He, Wei-Dong; Jiang, Lei; Song, Wei-Guo

    2012-09-18

    A nanoreactor with temperature-responsive poly(N-isopopylacrylamide) (PNIPAM) coated on the external pore mouth of mesoporous silica hollow spheres and Au nanoparticles at the internal pore mouth were fabricated. Such spatial separation allows both Au nanoparticles and PNIPAM to function without interfering with each other. Transmission electron microscopy (TEM), thermogravimetric analysis (TGA), Fourier transform infrared (FTIR) spectra, and temperature-dependent optical transmittance curves demonstrate successful grafting of PNIPAM. This nanoreactor shows repeated on/off catalytic activity switched by temperature control. It shows excellent catalytic activity toward 4-nitrophenol (4-NP) reduction at 30 °C [below lower critical solution temperature (LCST) of PNIPAM] with a turnover frequency (TOF) of 14.8 h(-1). However, when the temperature was 50 °C (above LCST), the TOF dropped to 2.4 h(-1). Kinetic studies indicated that diffusion into the mesopores of the catalyst was the key factor, and the temperature-responsive behavior of PNIPAM was able to control this diffusion.

  13. Effects of Two Short-Term, Intermittent Hypoxic Training Protocols on the Finger Temperature Response to Local Cold Stress.

    PubMed

    Keramidas, Michail E; Kounalakis, Stylianos N; Eiken, Ola; Mekjavic, Igor B

    2015-09-01

    The study examined the effects of two short-term, intermittent hypoxic training protocols, namely exercising in hypoxia and living in normoxia (LL-TH; n=8), and exercising in normoxia preceded by a series of brief intermittent hypoxic exposures at rest (IHE+NOR; n=8), on the finger temperature response during a sea-level local cold test. In addition, a normoxic group was assigned as a control group (NOR; n=8). All groups trained on a cycle-ergometer 1 h/day, 5 days/week for 4 weeks at 50% of peak power output. Pre, post, and 11 days after the last training session, subjects immersed their right hand for 30 min in 8°C water. In the NOR group, the average finger temperature was higher in the post (+2.1°C) and 11-day after (+2.6°C) tests than in the pre-test (p≤0.001). Conversely, the fingers were significantly colder immediately after both hypoxic protocols (LL-TH: -1.1°C, IHE+NOR: -1.8°C; p=0.01). The temperature responses returned to the pre-training level 11 days after the hypoxic interventions. Ergo, present findings suggest that short-term intermittent hypoxic training impairs sea-level local cold tolerance; yet, the hypoxic-induced adverse responses seem to be reversible within a period of 11 days.

  14. Gluing gels: A nanoparticle solution

    NASA Astrophysics Data System (ADS)

    Appel, Eric A.; Scherman, Oren A.

    2014-03-01

    Synthetic polymer gels with certain surface chemistries can be glued together by a simple and inexpensive method that uses commercially available silica nanoparticles. Biological tissues can also be joined by this nanotechnological route, eliminating the need for sutures, additional adhesives or chemical reactions.

  15. Physicochemical behaviour of chitin gels.

    PubMed

    Vachoud, L; Zydowicz, N; Domard, A

    2000-06-30

    Syneresis of chitin gels formed in the course of N-acetylation of chitosan in hydroalcoholic media has been studied. A critical cross-linking density related to a critical acetylation degree for which the gel undergoes weak syneresis and swells in water was shown (degree of acetylation (DA) 88%). Above this value, the weight loss during syneresis increases with DA. Conversely, syneresis decreases on increasing the polymer concentration, but disappears at a macroscopic level for a polymer concentration close to the critical concentration of entanglement in the initial solution. An increase in temperature favours the formation of hydrophobic interactions and new inter- and intramolecular hydrogen bondings. Due to the weak polyelectrolyte character of chitin, the weight of the gel depends on the pH and ionic strength of the media. Swelling-deswelling experiments show that the swelling of the gel is not fully reversible in relation with the formation of new cross-links during the depletion of the network. Our results reveals that the balance between segment-segment and segment-solvent interactions as well as the molecular mobility play the major role.

  16. Nonlinear elasticity of alginate gels

    NASA Astrophysics Data System (ADS)

    Hashemnejad, Seyed Meysam; Kundu, Santanu

    Alginate is a naturally occurring anionic polysaccharide extracted from brown algae. Because of biocompatibility, low toxicity, and simple gelation process, alginate gels are used in biomedical and food applications. Here, we report the rheological behavior of ionically crosslinked alginate gels, which are obtained by in situ gelation of alginates with calcium salts, in between two parallel plates of a rheometer. Strain stiffening behavior was captured using large amplitude oscillatory shear (LAOS) experiments. In addition, negative normal stress was observed for these gels, which has not been reported earlier for any polysaccharide networks. The magnitude of negative normal stress increases with applied strain and can exceed that of the shear stress at large strain. Rheological results fitted with a constitutive model that considers both stretching and bending of chains indicate that nonlinearity is likely related to the stretching of the chains between the crosslink junctions. The results provide an improved understanding of the deformation mechanism of ionically crosslinked alginate gel and the results will be important in developing synthetic extracellular matrix (ECM) from these materials.

  17. Paclitaxel-induced hyperalgesia modulates negative affective component of pain and NR1 receptor expression in the frontal cortex in rats.

    PubMed

    Noda, Kazuko; Akita, Hisanao; Ogata, Masanori; Saji, Makoto

    2014-03-01

    Paclitaxel, one of the chemotherapeutic agents clinically used to treat several types of cancer, produces side effects such as peripheral neuropathy, sensory abnormalities, and hyperalgesia. Since hyperalgesia remains after cessation of paclitaxel therapy and becomes chronic, we hypothesize that alteration in memory and the cognitive process of pain underlies hyperalgesia. To test this hypothesis, we examined whether drug-induced hyperalgesia alters the affective component of pain and the NMDA-NR1 and mGluR1 receptors as a mediator for signal transmission and memory of pain. Mechanical sensitivity was measured by von Frey filament test after intraperitoneal injection of paclitaxel in rats. Paclitaxel-induced hyperalgesia was confirmed over almost the entire 14-day period of observation after the treatment. The effect of paclitaxel-induced hyperalgesia on the affective component of pain was assessed using pain-induced place aversion. The formalin-induced conditioned place aversion was completely abolished in the paclitaxel-treated rats. Immunoblot analysis of NR1 and mGluR1 protein levels in various brain regions was performed after paclitaxel treatment. Treatment reduced only the NR1 expression within the frontal cortex. These results suggest that the hypofunction of memory processes with the reduced NMDA receptors in the frontal cortex might be involved in the expression of abnormal emotional behaviors accompanied by hyperalgesia.

  18. Development of innovative paclitaxel-loaded small PLGA nanoparticles: study of their antiproliferative activity and their molecular interactions on prostatic cancer cells.

    PubMed

    Le Broc-Ryckewaert, D; Carpentier, R; Lipka, E; Daher, S; Vaccher, C; Betbeder, D; Furman, C

    2013-10-01

    Taxanes, including paclitaxel, are anti-cancer drugs approved for the treatment of prostate cancer but which have limited clinical application due to their hydrophobicity, their low therapeutic index and the emergence of chemoresistance. These side effects may be avoided through the use of new drug delivery systems such as nanoparticles, and paclitaxel-loaded PLGA nanoparticles up to 200 nm in size have shown encouraging results. As it is known that size affects the tissular penetration and distribution of tumors via the enhanced permeability and retention effect, so nanoparticles smaller than 100 nm are potentially interesting vehicles for improving paclitaxel delivery and efficacy. In this work, new paclitaxel-loaded small PLGA nanoparticles, between 49 nm and 95 nm in size and with positive or negative surface charges, were prepared without detergent. They were stable in the presence of serum, and HPLC showed that high paclitaxel loading and stability were achieved. Intracellular uptake of these nanoparticles was studied in PC3 cells by flow cytometry. Confocal studies confirmed a high tubulin destructuration at very low dose with these nanoparticles. This study suggests that both positively and negatively charged paclitaxel-loaded small PLGA nanoparticles deliver this drug into PC3 cells, and that this nanoparticle mode of delivery highly improves paclitaxel efficiency by up to two log-increase. These results also highlight the importance of small nanoparticles for drug delivery in cancer applications and are extremely promising for in vivo studies.

  19. Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial

    PubMed Central

    Pugliese, Mariateresa; Gallo, Marco; Brignardello, Enrico; Milla, Paola; Orlandi, Fabio; Limone, Paolo Piero; Arvat, Emanuela; Boccuzzi, Giuseppe; Piovesan, Alessandro

    2016-01-01

    Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11. PMID:27766105

  20. Capillary fracture of soft gels.

    PubMed

    Bostwick, Joshua B; Daniels, Karen E

    2013-10-01

    A liquid droplet resting on a soft gel substrate can deform that substrate to the point of material failure, whereby fractures develop on the gel surface that propagate outwards from the contact line in a starburst pattern. In this paper, we characterize (i) the initiation process, in which the number of arms in the starburst is controlled by the ratio of the surface tension contrast to the gel's elastic modulus, and (ii) the propagation dynamics showing that once fractures are initiated they propagate with a universal power law L[proportional]t(3/4). We develop a model for crack initiation by treating the gel as a linear elastic solid and computing the deformations within the substrate from the liquid-solid wetting forces. The elastic solution shows that both the location and the magnitude of the wetting forces are critical in providing a quantitative prediction for the number of fractures and, hence, an interpretation of the initiation of capillary fractures. This solution also reveals that the depth of the gel is an important factor in the fracture process, as it can help mitigate large surface tractions; this finding is confirmed with experiments. We then develop a model for crack propagation by considering the transport of an inviscid fluid into the fracture tip of an incompressible material and find that a simple energy-conservation argument can explain the observed material-independent power law. We compare predictions for both linear elastic and neo-Hookean solids, finding that the latter better explains the observed exponent.

  1. Capillary fracture of soft gels.

    PubMed

    Bostwick, Joshua B; Daniels, Karen E

    2013-10-01

    A liquid droplet resting on a soft gel substrate can deform that substrate to the point of material failure, whereby fractures develop on the gel surface that propagate outwards from the contact line in a starburst pattern. In this paper, we characterize (i) the initiation process, in which the number of arms in the starburst is controlled by the ratio of the surface tension contrast to the gel's elastic modulus, and (ii) the propagation dynamics showing that once fractures are initiated they propagate with a universal power law L[proportional]t(3/4). We develop a model for crack initiation by treating the gel as a linear elastic solid and computing the deformations within the substrate from the liquid-solid wetting forces. The elastic solution shows that both the location and the magnitude of the wetting forces are critical in providing a quantitative prediction for the number of fractures and, hence, an interpretation of the initiation of capillary fractures. This solution also reveals that the depth of the gel is an important factor in the fracture process, as it can help mitigate large surface tractions; this finding is confirmed with experiments. We then develop a model for crack propagation by considering the transport of an inviscid fluid into the fracture tip of an incompressible material and find that a simple energy-conservation argument can explain the observed material-independent power law. We compare predictions for both linear elastic and neo-Hookean solids, finding that the latter better explains the observed exponent. PMID:24229192

  2. Prospective evaluation of concurrent paclitaxel and radiation therapy after adjuvant doxorubicin and cyclophosphamide chemotherapy for Stage II or III breast cancer

    SciTech Connect

    Burstein, Harold J. . E-mail: hburstein@partners.org; Bellon, Jennifer R.; Galper, Sharon; Lu, H.-M.; Kuter, Irene; Wong, Julia; Gelman, Rebecca; Bunnell, Craig A.; Parker, Leroy M.; Garber, Judy E.; Winer, Eric P.; Harris, Jay R.; Powell, Simon N.

    2006-02-01

    Purpose: To evaluate the safety and feasibility of concurrent radiation therapy and paclitaxel-based adjuvant chemotherapy, given either weekly or every 3 weeks, after adjuvant doxorubicin and cyclophosphamide (AC). Methods and Materials: After definitive breast surgery and AC chemotherapy, 40 patients with operable Stage II or III breast cancer received protocol-based treatment with concurrent paclitaxel and radiation therapy. Paclitaxel was evaluated on 2 schedules, with treatment given either weekly x 12 weeks (60 mg/m{sup 2}), or every 3 weeks x 4 cycles (135-175 mg/m{sup 2}). Radiation fields and schedules were determined by the patient's surgery and pathology. The tolerability of concurrent therapy was evaluated in cohorts of 8 patients as a phase I study. Results: Weekly paclitaxel treatment at 60 mg/m{sup 2} per week with concurrent radiation led to dose-limiting toxicity in 4 of 16 patients (25%), including 3 who developed pneumonitis (either Grade 2 [1 patient] or Grade 3 [2 patients]) requiring steroids. Efforts to eliminate this toxicity in combination with weekly paclitaxel through treatment scheduling and CT-based radiotherapy simulation were not successful. By contrast, dose-limiting toxicity was not encountered among patients receiving concurrent radiation with paclitaxel given every 3 weeks at 135-175 mg/m{sup 2}. However, Grade 2 radiation pneumonitis not requiring steroid therapy was seen in 2 of 24 patients (8%) treated in such a fashion. Excessive radiation dermatitis was not observed with either paclitaxel schedule. Conclusions: Concurrent treatment with weekly paclitaxel and radiation therapy is not feasible after adjuvant AC chemotherapy for early-stage breast cancer. Concurrent treatment using a less frequent paclitaxel dosing schedule may be possible, but caution is warranted in light of the apparent possibility of pulmonary injury.

  3. Balancing activity and tolerability of neoadjuvant paclitaxel- and docetaxel-based chemotherapy for HER2-positive early stage breast cancer: sensitivity analysis of randomized trials.

    PubMed

    Carbognin, Luisa; Sperduti, Isabella; Nortilli, Rolando; Brunelli, Matteo; Vicentini, Cecilia; Pellini, Francesca; Pollini, Giovanni Paolo; Giannarelli, Diana; Tortora, Giampaolo; Bria, Emilio

    2015-03-01

    Paclitaxel and docetaxel represent the most adopted taxanes in the neoadjuvant treatment of HER2-positive breast cancer. Questions still remain with regard to their difference in terms of activity and tolerability. Events for pathological complete response (pCR), severe and febrile neutropenia (FN), and severe neurotoxicity were pooled by adopting a fixed- and random-effect model. A sensitivity analysis to test for the interaction between paclitaxel and docetaxel was accomplished. Absolute differences with 95% confidence intervals (CIs) and the number of patients needed to treat/harm (NNT/NNH) were calculated to derive the Likelihood of being Helped or Harmed (LHH). Data from 15 trials (3601 patients) were included. Paclitaxel significantly increases pCR rate by 6.8% in comparison with docetaxel (43.4%, 95% CI 41.1-45.7% versus 36.6%, 95% CI 34.3-39.0%, p=0.0001), regardless of the chemotherapy backbone, with an absolute difference of 9% and 9.2% for anthracycline-based or free-regimens. Paclitaxel significantly improves pCR versus docetaxel with a single HER2-inhibition by 6.7% (p=0.0012), with no difference if combined with a dual HER2-inhibition. Severe neutropenia and FN are significantly lower with paclitaxel, with an absolute difference of 32.4% (p<0.0001) and 2.5% (p=0.0059), respectively. Conversely, severe neurotoxicity is slightly higher with paclitaxel (3%, p=0.0001). The LHH ratio calculated for pCR and severe neutropenia is 2.0 and 0.7 for paclitaxel and docetaxel. Although the activity of neoadjuvant paclitaxel and docetaxel HER2-positive breast cancer is considered similar, the slight advantage in pCR, the significantly lower neutropenia and FN, do favor paclitaxel (in the weekly fashion) over docetaxel, despite the slightly worst neurotoxicity.

  4. Study of Fricke gel dosimeter response for different gel quality

    NASA Astrophysics Data System (ADS)

    Cavinato, C. C.; Campos, L. L.

    2010-11-01

    The Fricke xylenol gel (FXG) dosimeter has been studied for application in radiotherapy because it is capable of to measure the spatial distribution of radiation doses. The dosimetry is based on the oxidation of ferrous (Fe2+) to ferric (Fe3+) ions radiation induced, related to the radiation dose. The gel material usually employed is the 300 Bloom gelatin, which is imported and very expensive in Brazil. Aiming to analyze the viability of to use a locally produced and low cost gel material, in this work the spectrophotometric responses of FXG solutions prepared using 270 Bloom gelatin commercially available and 300 Bloom gelatin imported were compared. The absorption spectra of solutions prepared with 5% by weight 270 and 300 Bloom gelatins non-irradiated and irradiated with 60Co gamma radiation in the dose range between 0.5 and 100 Gy were analysed, the dose-response curves were evaluated and the useful dose range was established. The obtained results indicate that the FXG solution prepared with 270 Bloom gelatin presents good performance, similar to that presented by the FXG solution prepared with 300 Bloom gelatin and its use can be recommended owing to the low cost and the availability in local market.

  5. A Paclitaxel-Loaded Recombinant Polypeptide Nanoparticle Outperforms Abraxane in Multiple Murine Cancer Models

    PubMed Central

    Bhattacharyya, Jayanta; Bellucci, Joseph J.; Weitzhandler, Isaac; McDaniel, Jonathan R.; Spasojevic, Ivan; Li, Xinghai; Lin, Chao-Chieh; Chi, Jen-Tsan Ashley; Chilkoti, Ashutosh

    2015-01-01

    Packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumor specific uptake and therapeutic potential. To this end, here we conjugated paclitaxel (PTX) to recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into ~60-nm diameter near-monodisperse nanoparticles that increased the systemic exposure of PTX by 7-fold compared to free drug and 2-fold compared to the FDA approved taxane nanoformulation (Abraxane®). The tumor uptake of the CP-PTX nanoparticle was 5-fold greater than free drug and 2-fold greater than Abraxane. In a murine cancer model of human triple negative breast cancer and prostate cancer, CP-PTX induced near complete tumor regression after a single dose in both tumor models, whereas at the same dose, no mice treated with Abraxane survived for more than 80 days (breast) and 60 days (prostate) respectively. These results show that a molecularly engineered nanoparticle with precisely engineered design features outperforms Abraxane, the current gold standard for paclitaxel delivery. PMID:26239362

  6. Reducing Both Pgp Overexpression and Drug Efflux with Anti-Cancer Gold-Paclitaxel Nanoconjugates.

    PubMed

    Li, Fei; Zhou, Xiaofei; Zhou, Hongyu; Jia, Jianbo; Li, Liwen; Zhai, Shumei; Yan, Bing

    2016-01-01

    Repeated administrations of anti-cancer drugs to patients often induce drug resistance. P-glycoprotein (Pgp) facilitates an efficient drug efflux, preventing cellular accumulation of drugs and causing multi-drug resistance (MDR). In this study, we developed a gold-paclitaxel nanoconjugate system to overcome MDR. Gold nanoparticles (GNPs) were conjugated with β-cyclodextrin enclosing paclitaxel (PTX) molecules and PEG molecules. GNP conjugates were effectively endocytosed by both drug-sensitive human lung cancer H460 cells and Pgp-overexpressed drug-resistant H460PTX cells. Compared with PTX, PGNPs did not induce the Pgp overexpression in drug-sensitive H460 cells after long-term treatment and also avoided being pumped out of cells by overexpressed Pgp molecules in H460PTX with a 17-fold lower EC50 compared to PTX. Fluorescent microscopy and flow cytometry further confirmed that fluorescent labeled PGNPs (f-PGNPs) maintained a high cellular PTX level in both H460 and H460PTX cells. These results demonstrated that nano-drug conjugates were able to avoid the development of drug resistance in sensitive cells and evade Pgp-mediated drug resistance and to maintain a high cytotoxicity in drug-resistant cancer cells. These findings exemplify a powerful nanotechnological approach to the long-lasting issue of chemotherapy-induced drug resistance. PMID:27467397

  7. Design and optimization of novel paclitaxel-loaded folate-conjugated amphiphilic cyclodextrin nanoparticles.

    PubMed

    Erdoğar, Nazlı; Esendağlı, Güneş; Nielsen, Thorbjorn T; Şen, Murat; Öner, Levent; Bilensoy, Erem

    2016-07-25

    As nanomedicines are gaining momentum in the therapy of cancer, new biomaterials emerge as alternative platforms for the delivery of anticancer drugs with bioavailability problems. In this study, two novel amphiphilic cyclodextrins (FCD-1 and FCD-2) conjugated with folate group to enable active targeting to folate positive breast tumors were introduced. The objective of this study was to develop and characterize new folated-CD nanoparticles via 3(2) factorial design for optimal final parameters. Full physicochemical characterization studies were performed. Blank and paclitaxel loaded FCD-1 and FCD-2 nanoparticles remained within the range of 70-275nm and 125-185nm, respectively. Zeta potential values were neutral and -20mV for FCD-1 and FCD-2 nanoparticles, respectively. Drug release studies showed initial burst release followed by a longer sustained release. Blank nanoparticles had no cytotoxicity against L929 cells. T-47D and ZR-75-1 human breast cancer cells with different levels of folate receptor expression were used to assess anti-cancer efficacy. Through targeting the folate receptor, these nanoparticles were efficiently engulfed by the breast cancer cells. Additionally, breast cancer cells became more sensitive to cytotoxic and/or cytostatic effects of PCX delivered by FCD-1 and FCD-2. In conclusion, these novel folate-conjugated cyclodextrin nanoparticles can therefore be considered as promising alternative systems for safe and effective delivery of paclitaxel with a folate-dependent mechanism. PMID:27282534

  8. Pegylated polyelectrolyte nanoparticles containing paclitaxel as a promising candidate for drug carriers for passive targeting.

    PubMed

    Szczepanowicz, Krzysztof; Bzowska, Monika; Kruk, Tomasz; Karabasz, Alicja; Bereta, Joanna; Warszynski, Piotr

    2016-07-01

    Targeted drug delivery systems are of special importance in cancer therapies, since serious side effects resulting from unspecific accumulation of highly toxic chemotherapeutics in healthy tissues can restrict effectiveness of the therapy. In this work we present the method of preparing biocompatible, polyelectrolyte nanoparticles containing the anticancer drug that may serve as a vehicle for passive tumor targeting. The nanoparticles were prepared via direct encapsulation of emulsion droplets in a polyelectrolyte multilayer shell. The oil cores that contained paclitaxel were stabilized by docusate sodium salt/poly-l-lysine surface complex (AOT/PLL) and were encapsulated in shells formed by the LbL adsorption of biocompatible polyelectrolytes, poly-L-glutamic acid (PGA) and PLL up to 5 or 6 layers. The surface of the nanoparticles was pegylated through the adsorption of the pegylated polyelectrolyte (PGA-g-PEG) as the outer layer to prolong the persistence of the nanocarriers in the circulation. The synthesized nanoparticles were stable in cell culture medium containing serum and their average size was 100nm, which makes them promising candidates for passive targeted drug delivery. This notion was further confirmed by the results of studying the biological effects of nanoformulations on two tumor cell lines: mouse colon carcinoma cell line CT26-CEA and the mouse mammary carcinoma cell line 4T1. The empty polyelectrolyte nanoparticles did not affect the viability of the tested cells, whereas encapsulated paclitaxel retained its strong cytotoxic/cytostatic activity. PMID:27037784

  9. Molecular dynamics of paclitaxel encapsulated by salicylic acid-grafted chitosan oligosaccharide aggregates.

    PubMed

    Wang, Xiao-Ying; Zhang, Ling; Wei, Xiao-Hong; Wang, Qi

    2013-02-01

    Chitosan oligosaccharide (COS) derivatives have attracted significant interest in drug delivery systems because of their well-known low toxicity, excellent biocompatibility, and biodegradability. Paclitaxel-loaded nanoparticles based on salicylic acid-grafted chitosan oligosaccharide (COS/SA) were synthesized and characterized. Then, in order to understand the mechanism of the actions of the paclitaxel (PTX) encapsulated by COS/SA, all-atom molecular dynamics simulations were performed to analyze the aggregation of COS/SA molecules. The van der Waals and hydrophobic interactions are the major driving forces for the drug encapsulation process. Electrostatic and hydrogen-bonding interactions also play helpful roles in the COS/SA aggregation. Analyses of the radial distribution function and solvent accessible surface area indicate that the COS/SA nanoparticles are highly hydrosoluble and that the nanoparticles can significantly enhance the aqueous solubility of a hydrophobic drug. Different drug loading systems are also investigated in this work, and the best theoretical drug loading is found to be 10% (w/w). The present work provides insights into the mechanism of the atomic structures of drug-loaded polymeric nanoparticles and presents new perspective for the design of drug delivery systems with desirable properties.

  10. MCAK and Paclitaxel Have Differential Effects on Spindle Microtubule Organization and Dynamics

    PubMed Central

    Rizk, Rania S.; Bohannon, Kevin P.; Wetzel, Laura A.; Powers, James; Shaw, Sidney L.

    2009-01-01

    Within the mitotic spindle, there are multiple populations of microtubules with different turnover dynamics, but how these different dynamics are maintained is not fully understood. MCAK is a member of the kinesin-13 family of microtubule-destabilizing enzymes that is required for proper establishment and maintenance of the spindle. Using quantitative immunofluorescence and fluorescence recovery after photobleaching, we compared the differences in spindle organization caused by global suppression of microtubule dynamics, by treating cells with low levels of paclitaxel, versus specific perturbation of spindle microtubule subsets by MCAK inhibition. Paclitaxel treatment caused a disruption in spindle microtubule organization marked by a significant increase in microtubules near the poles and a reduction in K-fiber fluorescence intensity. This was correlated with a faster t1/2 of both spindle and K-fiber microtubules. In contrast, MCAK inhibition caused a dramatic reorganization of spindle microtubules with a significant increase in astral microtubules and reduction in K-fiber fluorescence intensity, which correlated with a slower t1/2 of K-fibers but no change in the t1/2 of spindle microtubules. Our data support the model that MCAK perturbs spindle organization by acting preferentially on a subset of microtubules, and they support the overall hypothesis that microtubule dynamics is differentially regulated in the spindle. PMID:19158381

  11. Novel thermo-sensitive core-shell nanoparticles for targeted paclitaxel delivery

    NASA Astrophysics Data System (ADS)

    Li, Yuanpei; Pan, Shirong; Zhang, Wei; Du, Zhuo

    2009-02-01

    Novel thermo-sensitive nanoparticles self-assembled from poly(N,N-diethylacrylamide- co-acrylamide)-block-poly(γ-benzyl L-glutamate) were designed for targeted drug delivery in localized hyperthermia. The lower critical solution temperature (LCST) of nanoparticles was adjusted to a level between physiological body temperature (37 °C) and that used in local hyperthermia (about 43 °C). The temperature-dependent performances of the core-shell nanoparticles were systemically studied by nuclear magnetic resonance (NMR), circular dichroism (CD), fluorescence spectroscopy, dynamic light scattering (DLS), and atom force microscopy (AFM). The mean diameter of the nanoparticles increased slightly from 110 to 129 nm when paclitaxel (PTX), a poorly water-soluble anti-tumor drug, was encapsulated. A stability study in bovine serum albumin (BSA) solution indicated that the PTX loaded nanoparticles may have a long circulation time under physiological environments as the LCST was above physiological body temperature and the shell remained hydrophilic at 37 °C. The PTX release profiles showed thermo-sensitive controlled behavior. The proliferation inhibiting activity of PTX loaded nanoparticles was evaluated against Hela cells in vitro, compared with Taxol (a formulation of paclitaxel dissolved in Cremophor EL and ethanol). The cytotoxicity of PTX loaded nanoparticles increased obviously when hyperthermia was performed. The nanoparticles synthesized here could be an ideal candidate for thermal triggered anti-tumor PTX delivery system.

  12. Facile preparation of paclitaxel loaded silk fibroin nanoparticles for enhanced antitumor efficacy by locoregional drug delivery.

    PubMed

    Wu, Puyuan; Liu, Qin; Li, Rutian; Wang, Jing; Zhen, Xu; Yue, Guofeng; Wang, Huiyu; Cui, Fangbo; Wu, Fenglei; Yang, Mi; Qian, Xiaoping; Yu, Lixia; Jiang, Xiqun; Liu, Baorui

    2013-12-11

    Non-toxic, safe materials and preparation methods are among the most important factors when designing nanoparticles (NPs) for future clinical application. Here we report a novel and facile method encapsulating anticancer drug paclitaxel (PTX) into silk fibroin (SF), a biocompatible and biodegradable natural polymer, without adding any toxic organic solvents, surfactants or other toxic agents. The paclitaxel loaded silk fibroin nanoparticles (PTX-SF-NPs) with a diameter of 130 nm were formed in an aqueous solution at room temperature by self-assembling of SF protein, which demonstrated mainly silk I conformation in the NPs. In cellular uptake experiments, coumarin-6 loaded SF NPs were taken up efficiently by two human gastric cancer cell lines BGC-823 and SGC-7901. In vitro cytotoxicity studies demonstrated that PTX kept its pharmacological activity when incorporating into PTX-SF-NPs, while SF showed no cytotoxicity to cells. The in vivo antitumor effects of PTX-SF-NPs were evaluated on gastric cancer nude mice exnograft model. We found that locoregional delivery of PTX-SF-NPs demonstrated superior antitumor efficacy by delaying tumor growth and reducing tumor weights compared with systemic administration. Furthermore, the organs of mice in NP treated groups didn't show obvious toxicity, indicating the in vivo safety of SF NPs. These results suggest that SF NPs are promising drug delivery carriers, and locoregional delivery of SF NPs could be a potential future clinical cancer treatment regimen.

  13. Hydrophobically modified inulin as an amphiphilic carbohydrate polymer for micellar delivery of paclitaxel for intravenous route.

    PubMed

    Muley, Pratik; Kumar, Sunny; El Kourati, Fadoua; Kesharwani, Siddharth S; Tummala, Hemachand

    2016-03-16

    Micellization offers several advantages for the delivery of water insoluble drugs including a nanoparticulate 'core-shell' delivery system for drug targeting. Recently, hydrophobically modified polysaccharides (HMPs) are gaining recognition as micelle forming polymers to encapsulate hydrophobic drugs. In this manuscript, for the first time, we have evaluated the self-assembling properties of a lauryl carbamate derivative of the poly-fructose natural polymer inulin (Inutec SP1(®) (INT)) to form paclitaxel (PTX) loaded micelles. INT self-assembled into well-defined micellar structures in aqueous environment with a low critical micellar concentration of 27.8 μg/ml. INT micelles exhibited excellent hemocompatibility and low toxicity to cultured cells. PTX loaded INT micelles exhibited a mean size of 256.37 ± 10.45 nm with excellent drug encapsulation efficiency (95.66 ± 2.25%) and loading (8.69 ± 0.22%). PTX loaded micelles also displayed sustained release of PTX and enhanced anti-cancer efficacy in-vitro in mouse melanoma cells (B16F10) compared to Taxol formulation with Cremophor EL as solvent. In addition, PTX loaded INT micelles exhibited comparable in-vivo antitumor activity in B16F10 allograft mouse model at half the dose of Taxol. In conclusion, INT offers safe, inexpensive and natural alternative to widely used PEG-modified polymers for the formulation of micellar delivery systems for paclitaxel.

  14. Endocytosis of fluorescent cyclodextrins by intestinal Caco-2 cells and its role in paclitaxel drug delivery.

    PubMed

    Réti-Nagy, Katalin; Malanga, Milo; Fenyvesi, Éva; Szente, Lajos; Vámosi, György; Váradi, Judit; Bácskay, Ildikó; Fehér, Pálma; Ujhelyi, Zoltán; Róka, Eszter; Vecsernyés, Miklós; Balogh, György; Vasvári, Gábor; Fenyvesi, Ferenc

    2015-12-30

    Cyclodextrins are widely used excipients in pharmaceutical formulations. They are mainly utilized as solubilizers and absorption enhancers, but recent results revealed their effects on cell membranes and pharmacological barriers. In addition to the growing knowledge on their interaction with plasma membranes, it was confirmed that cyclodextrins are able to enter cells by endocytosis. The number of the tested cyclodextrins was limited, and the role of this mechanism in drug absorption and delivery is not known. Our aim was to examine the endocytosis of fluorescently labeled hydroxypropyl-β-cyclodextrin, random methyl-β-cyclodextrin and soluble β-cyclodextrin polymer, and the cellular uptake of the fluorescent paclitaxel derivative-random methyl-β-cyclodextrin complex. The studied cyclodextrin derivatives were able to enter Caco-2 intestinal cells and localized in vesicles in the cytoplasm, while their permeability was very limited through Caco-2 monolayers. We demonstrated for the first time that the fluorescent paclitaxel derivative and rhodamine-labeled random methyl-β-cyclodextrin were detected in the same intracellular vesicles after treating cells with their inclusion complex. These results indicate that the endocytosis of cyclodextrin complexes can contribute to drug absorption processes.

  15. Dasatinib (BMS-35482) has synergistic activity with paclitaxel and carboplatin in ovarian cancer cells

    PubMed Central

    Teoh, Deanna; Ayeni, Tina A.; Rubatt, Jennifer M.; Adams, David J.; Grace, Lisa; Starr, Mark D.; Barry, William T; Berchuck, Andrew; Murphy, Susan K.; Secord, Angeles Alvarez

    2010-01-01

    Purpose To explore the activity of dasatinib alone and in combination with paclitaxel and carboplatin in ovarian cancer cells and to determine if dasatinib activity can be predicted based on evaluation of the SRC pathway. Experimental Design Microarray analysis was performed for IGROV1, OVCAR3, A2780 and SKOV3 ovarian cancer cells and the status of the genomic SRC signature pathway was determined. Cells were treated with carboplatin, paclitaxel and dasatinib individually and in combination. Pre- and post-treatment phospho-SRC (pSRC) and SRC protein expression was determined. Dose-response curves were constructed, and drug interaction was assessed by the Combination Index (CI) method. Results SRC protein expression levels reflected the SRC pathway genomic signature in the cell lines with the lowest (SKOV3) and highest (IGROV1) pathway expression, but not in those with intermediate expression (OVCAR3, A2780). Dasatinib treatment caused loss of pSRC in all cell lines, with 50% growth inhibition for IGROV1 at 70nM, OVCAR3 at 34nM, A2780 at 4.1μM and SKOV3 at 530nM. Dasatinib combined with cytotoxics yielded a synergistic effect (CI=0.46 to 0.79) in all cell lines except SKOV3. Conclusion Dasatinib in combination with standard chemotherapeutic agents appears to interact in a synergistic manner in some ovarian cancer cell lines. Further research is needed to evaluate tumor cell characteristics which predict response to dasatinib. PMID:21208651

  16. Cytotoxic and anti-angiogenic paclitaxel solubilized and permeation-enhanced by natural product nanoparticles

    PubMed Central

    Liu, Zhijun; Zhang, Fang; Koh, Gar Yee; Dong, Xin; Hollingsworth, Javoris; Zhang, Jian; Russo, Paul S.; Yang, Peiying; Stout, Rhett W.

    2014-01-01

    Paclitaxel (PTX) is one of the most potent intravenous chemotherapeutic agents to date, yet an oral formulation has been problematic due to its low solubility and permeability. Using the recently discovered solubilizing properties of rubusoside (RUB), we investigated this unique PTX-RUB formulation. Paclitaxel was solubilized by RUB in water to levels of 1.6 to 6.3 mg/mL at 10 to 40% weight/volume. These, nanomicellar, PTX-RUB complexes were dried to a powder which was subsequently reconstituted in physiologic solutions. After 2.5 hrs in gastric fluid 85 to 99% of PTX-RUB remained soluble, while 79 to 96% remained soluble in intestinal fluid. The solubilization of PTX was mechanized by the formation of water-soluble spherical nanomicelles between PTX and RUB with an average diameter of 6.6 nm. Compared with Taxol®, PTX-RUB nanoparticles were nearly four times more permeable in Caco-2 cell monocultures. In a side-by-side comparison with DMSO-solubilized PTX, PTX-RUB maintained the same level of cytotoxicity against three human cancer cell lines with IC50 values ranging from 4 nM to 20 nM. Additionally, tubular formation and migration of HUVECs were inhibited at levels as low as 5 nM. These chemical and biological properties demonstrated by the PTX-RUB nanoparticles may improve oral bioavailability and enable further pharmacokinetic, toxicologic, and efficacy investigations. PMID:25243454

  17. Reducing Both Pgp Overexpression and Drug Efflux with Anti-Cancer Gold-Paclitaxel Nanoconjugates

    PubMed Central

    Li, Fei; Zhou, Xiaofei; Zhou, Hongyu; Jia, Jianbo; Li, Liwen; Zhai, Shumei; Yan, Bing

    2016-01-01

    Repeated administrations of anti-cancer drugs to patients often induce drug resistance. P-glycoprotein (Pgp) facilitates an efficient drug efflux, preventing cellular accumulation of drugs and causing multi-drug resistance (MDR). In this study, we developed a gold-paclitaxel nanoconjugate system to overcome MDR. Gold nanoparticles (GNPs) were conjugated with β-cyclodextrin enclosing paclitaxel (PTX) molecules and PEG molecules. GNP conjugates were effectively endocytosed by both drug-sensitive human lung cancer H460 cells and Pgp-overexpressed drug-resistant H460PTX cells. Compared with PTX, PGNPs did not induce the Pgp overexpression in drug-sensitive H460 cells after long-term treatment and also avoided being pumped out of cells by overexpressed Pgp molecules in H460PTX with a 17-fold lower EC50 compared to PTX. Fluorescent microscopy and flow cytometry further confirmed that fluorescent labeled PGNPs (f-PGNPs) maintained a high cellular PTX level in both H460 and H460PTX cells. These results demonstrated that nano-drug conjugates were able to avoid the development of drug resistance in sensitive cells and evade Pgp-mediated drug resistance and to maintain a high cytotoxicity in drug-resistant cancer cells. These findings exemplify a powerful nanotechnological approach to the long-lasting issue of chemotherapy-induced drug resistance. PMID:27467397

  18. Ultrasound triggered image-guided drug delivery to inhibit vascular reconstruction via paclitaxel-loaded microbubbles.

    PubMed

    Zhu, Xu; Guo, Jun; He, Cancan; Geng, Huaxiao; Yu, Gengsheng; Li, Jinqing; Zheng, Hairong; Ji, Xiaojuan; Yan, Fei

    2016-01-01

    Paclitaxel (PTX) has been recognized as a promising drug for intervention of vascular reconstructions. However, it is still difficult to achieve local drug delivery in a spatio-temporally controllable manner under real-time image guidance. Here, we introduce an ultrasound (US) triggered image-guided drug delivery approach to inhibit vascular reconstruction via paclitaxel (PTX)-loaded microbubbles (PLM) in a rabbit iliac balloon injury model. PLM was prepared through encapsulating PTX in the shell of lipid microbubbles via film hydration and mechanical vibration technique. Our results showed PLM could effectively deliver PTX when exposed to US irradiation and result in significantly lower viability of vascular smooth muscle cells. Ultrasonographic examinations revealed the US signals from PLM in the iliac artery were greatly increased after intravenous administration of PLM, making it possible to identify the restenosis regions of iliac artery. The in vivo anti-restenosis experiments with PLM and US greatly inhibited neointimal hyperplasia at the injured site, showing an increased lumen area and reduced the ratio of intima area and the media area (I/M ratio). No obvious functional damages to liver and kidney were observed for those animals. Our study provided a promising approach to realize US triggered image-guided PTX delivery for therapeutic applications against iliac restenosis.

  19. Ultrasound triggered image-guided drug delivery to inhibit vascular reconstruction via paclitaxel-loaded microbubbles

    PubMed Central

    Zhu, Xu; Guo, Jun; He, Cancan; Geng, Huaxiao; Yu, Gengsheng; Li, Jinqing; Zheng, Hairong; Ji, Xiaojuan; Yan, Fei

    2016-01-01

    Paclitaxel (PTX) has been recognized as a promising drug for intervention of vascular reconstructions. However, it is still difficult to achieve local drug delivery in a spatio-temporally controllable manner under real-time image guidance. Here, we introduce an ultrasound (US) triggered image-guided drug delivery approach to inhibit vascular reconstruction via paclitaxel (PTX)-loaded microbubbles (PLM) in a rabbit iliac balloon injury model. PLM was prepared through encapsulating PTX in the shell of lipid microbubbles via film hydration and mechanical vibration technique. Our results showed PLM could effectively deliver PTX when exposed to US irradiation and result in significantly lower viability of vascular smooth muscle cells. Ultrasonographic examinations revealed the US signals from PLM in the iliac artery were greatly increased after intravenous administration of PLM, making it possible to identify the restenosis regions of iliac artery. The in vivo anti-restenosis experiments with PLM and US greatly inhibited neointimal hyperplasia at the injured site, showing an increased lumen area and reduced the ratio of intima area and the media area (I/M ratio). No obvious functional damages to liver and kidney were observed for those animals. Our study provided a promising approach to realize US triggered image-guided PTX delivery for therapeutic applications against iliac restenosis. PMID:26899550

  20. Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin–paclitaxel doublet chemotherapy

    PubMed Central

    Roulstone, V; Twigger, K; Zaidi, S; Pencavel, T; Kyula, JN; White, C; McLaughlin, M; Seth, R; Karapanagiotou, EM; Mansfield, D; Coffey, M; Nuovo, G; Vile, RG; Pandha, HS; Melcher, AA; Harrington, KJ

    2016-01-01

    Oncolytic reovirus is currently under active investigation in a range of tumour types. Early phase studies have shown that this agent has modest monotherapy efficacy and its future development is likely to focus on combination regimens with cytotoxic chemotherapy. Indeed, phase I/II clinical trials have confirmed that reovirus can be safely combined with cytotoxic drugs, including a platin—taxane doublet regimen, which is currently being tested in a phase III clinical trial in patients with relapsed/metastatic head and neck cancer. Therefore, we have tested this triple (reovirus, cisplatin, paclitaxel) combination therapy in a panel of four head and neck cancer cell lines. Using the combination index (CI) method, the triple therapy demonstrated synergistic cytotoxicity in vitro in both malignant and non-malignant cell lines. In head and neck cancer cell lines, this was associated with enhanced caspase 3 and 7 cleavage, but no increase in viral replication. In vitro analyses confirmed colocalisation of markers of reovirus infection and caspase 3. Triple therapy was significantly more effective than reovirus or cisplatin—paclitaxel in athymic nude mice. These data suggest that the combination of reovirus plus platin—taxane doublet chemotherapy has significant activity in head and neck cancer and underpin the current phase III study in this indication. PMID:22895509

  1. Cysteine modified and bile salt based micelles: preparation and application as an oral delivery system for paclitaxel.

    PubMed

    Xu, Wei; Fan, Xiaohui; Zhao, Yanli; Li, Lingbing

    2015-04-01

    The aim of the present study is to construct a cysteine modified polyion complex micelles made of Pluronic F127-chitosan (PF127-CS), Pluronic F127-cysteine (PF127-cysteine) and sodium cholate (NaC) and to evaluate the potential of the micelles as an oral drug delivery system for paclitaxel. Systematic studies on physicochemical properties including size distribution, zeta-potential and morphology were conducted to validate the formation of micelle structure. Compared with Pluronic micelles, drug-loading capacity of PF127-CS/PF127-cysteine/NaC micelles was increased from 3.35% to 12.77%. Both the critical micelle concentration and the stability test confirmed that the PF127-CS/PF127-cysteine/NaC micelles were more stable in aqueous solution than sodium cholate micelles. Pharmacokinetic study demonstrated that when oral administration the area under the plasma concentration-time curve (AUC0-∞) and the absolute bioavailability of paclitaxel-loaded micelles were five times greater than that of the paclitaxel solution. In general, PF127-CS/PF127-cysteine/NaC micelles were proven to be a potential oral drug delivery system for paclitaxel.

  2. Bisphosphonates Inhibit Stellate Cell Activity and Enhance Antitumor Effects of Nanoparticle Albumin Bound-Paclitaxel in Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Gonzalez-Villasana, Vianey; Rodriguez-Aguayo, Cristian; Arumugam, Thiruvengadam; Cruz-Monserrate, Zobeida; Fuentes-Mattei, Enrique; Deng, Defeng; Hwang, Rosa F.; Wang, Huamin; Ivan, Cristina; Garza, Raul Joshua; Cohen, Evan; Gao, Hui; Armaiz-Pena, Guillermo N.; Monroig-Bosque, Paloma del C.; Philip, Bincy; Rashed, Mohammed H.; Aslan, Burcu; Erdogan, Mumin Alper; Gutierrez-Puente, Yolanda; Ozpolat, Bulent; Reuben, James M.; Sood, Anil K.; Logsdon, Craig; Lopez-Berestein, Gabriel

    2014-01-01

    Pancreatic stellate cells (PSCs) have been recognized as the principal cells responsible for the production of fibrosis in PDAC. Recently PSCs have been noted to share characteristics with cells of monocyte-macrophage lineage (MML cells). Thus, we tested whether PSCs could be targeted with the nitrogen-containing bisphosphonates (NBPs) [pamidronate (Pam) or zoledronic acid (ZA)], which are potent MML cell inhibitors. In addition, we tested NBPs treatment combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to enhance antitumor activity. In vitro we observed that PSCs possess α-naphthyl butyrate esterase (ANBE) enzyme activity, a specific marker of MML cells. Moreover NBPs inhibited PSCs proliferation, activation, release of macrophage chemoattractant protein-1 (MCP-1) and type I collagen expression. NBPs also induced PSC apoptosis and cell cycle arrest in the G1 phase. In vivo, NBPs inactivated PSCs; reduced fibrosis; inhibited tumor volume, tumor weight, peritoneal dissemination, angiogenesis, and cell proliferation; and increased apoptosis in an orthotopic murine model of PDAC. These in vivo antitumor effects were enhanced when NBPs were combined with nab-paclitaxel but not gemcitabine (Gem). Our study suggests that targeting PSCs and tumor cells with NBPs in combination with nab-paclitaxel may be a novel therapeutic approach to PDAC. PMID:25193509

  3. Metabolomics Analysis of Hormone-Responsive and Triple-Negative Breast Cancer Cell Responses to Paclitaxel Identify Key Metabolic Differences.

    PubMed

    Stewart, Delisha A; Winnike, Jason H; McRitchie, Susan L; Clark, Robert F; Pathmasiri, Wimal W; Sumner, Susan J

    2016-09-01

    To date, no targeted therapies are available to treat triple negative breast cancer (TNBC), while other breast cancer subtypes are responsive to current therapeutic treatment. Metabolomics was conducted to reveal differences in two hormone receptor-negative TNBC cell lines and two hormone receptor-positive Luminal A cell lines. Studies were conducted in the presence and absence of paclitaxel (Taxol). TNBC cell lines had higher levels of amino acids, branched-chain amino acids, nucleotides, and nucleotide sugars and lower levels of proliferation-related metabolites like choline compared with Luminal A cell lines. In the presence of paclitaxel, each cell line showed unique metabolic responses, with some similarities by type. For example, in the Luminal A cell lines, levels of lactate and creatine decreased while certain choline metabolites and myo-inositol increased with paclitaxel. In the TNBC cell lines levels of glutamine, glutamate, and glutathione increased, whereas lysine, proline, and valine decreased in the presence of drug. Profiling secreted inflammatory cytokines in the conditioned media demonstrated a greater response to paclitaxel in the hormone-positive Luminal cells compared with a secretion profile that suggested greater drug resistance in the TNBC cells. The most significant differences distinguishing the cell types based on pathway enrichment analyses were related to amino acid, lipid and carbohydrate metabolism pathways, whereas several biological pathways were differentiated between the cell lines following treatment. PMID:27447733

  4. Top-down and Bottom-up Approaches in Production of Aqueous Nanocolloids of Low Soluble Drug Paclitaxel

    PubMed Central

    Pattekari, P.; Zheng, Z.; Zhang, X.; Levchenko, T.; Torchilin, V.

    2015-01-01

    Nano-encapsulation of poorly soluble anticancer drug was developed with sonication assisted layer-by-layer polyelectrolyte coating (SLbL). We changed the strategy of LbL-encapsulation from making microcapsules with many layers in the walls for encasing highly soluble materials to using very thin polycation / polyanion coating on low soluble nanoparticles to provide their good colloidal stability. SLbL encapsulation of paclitaxel resulted in stable 100-200 nm diameter colloids with high electrical surface ξ-potential (of -45 mV) and drug content in the nanoparticles of 90 wt %. In the top-down approach, nanocolloids were prepared by rupturing powder of paclitaxel using ultrasonication and simultaneous sequential adsorption of oppositely charged biocompatible polyelectrolytes. In the bottom-up approach paclitaxel was dissolved in organic solvent (ethanol or acetone), and drug nucleation was initiated by gradual worsening the solution with the addition of aqueous polyelectrolyte assisted by ultrasonication. Paclitaxel release rates from such nanocapsules were controlled by assembling multilayer shells with variable thicknesses and are in the range of 10-20 hours. PMID:21442095

  5. Paclitaxel-loaded ethosomes®: potential treatment of squamous cell carcinoma, a malignant transformation of actinic keratoses.

    PubMed

    Paolino, Donatella; Celia, Christian; Trapasso, Elena; Cilurzo, Felisa; Fresta, Massimo

    2012-05-01

    Topical application of anticancer drugs for the treatment of malignancies represents a new challenge in dermatology, potentially being an alternative therapeutic approach for the efficacious treatment of non-melanoma skin cancer, that is, actinic keratoses, and malignant lesions of the skin caused by ultraviolet radiation. Anti-proliferative and antimitotic drugs, including many of the taxanes, are currently under investigation for the treatment of cutaneous malignant transformation of actinic keratoses, particularly the squamous cell carcinoma. Paclitaxel-loaded ethosomes® are proposed as topical drug delivery systems for the treatment of this pathology due to their suitable physicochemical characteristics and enhanced skin penetration ability for deep dermal delivery. Our in vitro data show that the skin application of paclitaxel-loaded ethosomes® improved the permeation of paclitaxel in a stratum corneum-epidermis membrane model and increased its anti-proliferative activity in a squamous cell carcinoma model as compared to the free drug. The results obtained encouraged the use of the paclitaxel-loaded ethosomes® as the formulation for the potential treatment of squamous cell carcinoma, a malignant transformation of actinic keratoses.

  6. Paclitaxel-loaded nanoparticles of star-shaped cholic acid-core PLA-TPGS copolymer for breast cancer treatment.

    PubMed

    Tang, Xiaolong; Cai, Shuyu; Zhang, Rongbo; Liu, Peng; Chen, Hongbo; Zheng, Yi; Sun, Leilei

    2013-01-01

    A system of novel nanoparticles of star-shaped cholic acid-core polylactide-d-α-tocopheryl polyethylene glycol 1000 succinate (CA-PLA-TPGS) block copolymer was developed for paclitaxel delivery for breast cancer treatment, which demonstrated superior in vitro and in vivo performance in comparison with paclitaxel-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles and linear PLA-TPGS nanoparticles. The paclitaxel- or couramin 6-loaded nanoparticles were fabricated by a modified nanoprecipitation method and then characterized in terms of size, surface charge, surface morphology, drug encapsulation efficiency, and in vitro drug release. The CA-PLA-TPGS nanoparticles were found to be spherical in shape with an average size of around 120 nm. The nanoparticles were found to be stable, showing no change in the particle size and surface charge during 90-day storage of the aqueous solution. The release profiles of the paclitaxel-loaded nanoparticles exhibited typically biphasic release patterns. The results also showed that the CA-PLA-TPGS nanoparticles have higher antitumor efficacy than the PLA-TPGS nanoparticles and PLGA nanoparticles in vitro and in vivo. In conclusion, such nanoparticles of star-shaped cholic acid-core PLA-TPGS block copolymer could be considered as a potentially promising and effective strategy for breast cancer treatment.

  7. Top-down and bottom-up approaches in production of aqueous nanocolloids of low solubility drug paclitaxel.

    PubMed

    Pattekari, P; Zheng, Z; Zhang, X; Levchenko, T; Torchilin, V; Lvov, Y

    2011-05-21

    Nano-encapsulation of a poorly soluble anticancer drug was demonstrated with a sonication assisted layer-by-layer polyelectrolyte coating (SLbL). We changed the strategy of LbL-encapsulation from making microcapsules with many layers in the walls for encasing highly soluble materials to using a very thin polycation/polyanion coating on low solubility nanoparticles to provide them with good colloidal stability. SLbL encapsulation of paclitaxel resulted in stable 100-200 nm diameter colloids with a high electrical surface ξ-potential (of -45 mV) and drug content in the nanoparticles of 90 wt%. In the top-down approach, nanocolloids were prepared by rupturing a powder of paclitaxel using ultrasonication and simultaneous sequential adsorption of oppositely charged biocompatible polyelectrolytes. In the bottom-up approach paclitaxel was dissolved in organic solvent (ethanol or acetone), and drug nucleation was initiated by the addition of aqueous polyelectrolyte assisted by ultrasonication. Paclitaxel release rates from such nanocapsules were controlled by assembling multilayer shells with variable thicknesses and were in the range of 10-20 h.

  8. Paclitaxel-loaded ethosomes®: potential treatment of squamous cell carcinoma, a malignant transformation of actinic keratoses.

    PubMed

    Paolino, Donatella; Celia, Christian; Trapasso, Elena; Cilurzo, Felisa; Fresta, Massimo

    2012-05-01

    Topical application of anticancer drugs for the treatment of malignancies represents a new challenge in dermatology, potentially being an alternative therapeutic approach for the efficacious treatment of non-melanoma skin cancer, that is, actinic keratoses, and malignant lesions of the skin caused by ultraviolet radiation. Anti-proliferative and antimitotic drugs, including many of the taxanes, are currently under investigation for the treatment of cutaneous malignant transformation of actinic keratoses, particularly the squamous cell carcinoma. Paclitaxel-loaded ethosomes® are proposed as topical drug delivery systems for the treatment of this pathology due to their suitable physicochemical characteristics and enhanced skin penetration ability for deep dermal delivery. Our in vitro data show that the skin application of paclitaxel-loaded ethosomes® improved the permeation of paclitaxel in a stratum corneum-epidermis membrane model and increased its anti-proliferative activity in a squamous cell carcinoma model as compared to the free drug. The results obtained encouraged the use of the paclitaxel-loaded ethosomes® as the formulation for the potential treatment of squamous cell carcinoma, a malignant transformation of actinic keratoses. PMID:22414731

  9. Paclitaxel-loaded nanoparticles of star-shaped cholic acid-core PLA-TPGS copolymer for breast cancer treatment

    PubMed Central

    2013-01-01

    A system of novel nanoparticles of star-shaped cholic acid-core polylactide-d-α-tocopheryl polyethylene glycol 1000 succinate (CA-PLA-TPGS) block copolymer was developed for paclitaxel delivery for breast cancer treatment, which demonstrated superior in vitro and in vivo performance in comparison with paclitaxel-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles and linear PLA-TPGS nanoparticles. The paclitaxel- or couramin 6-loaded nanoparticles were fabricated by a modified nanoprecipitation method and then characterized in terms of size, surface charge, surface morphology, drug encapsulation efficiency, and in vitro drug release. The CA-PLA-TPGS nanoparticles were found to be spherical in shape with an average size of around 120 nm. The nanoparticles were found to be stable, showing no change in the particle size and surface charge during 90-day storage of the aqueous solution. The release profiles of the paclitaxel-loaded nanoparticles exhibited typically biphasic release patterns. The results also showed that the CA-PLA-TPGS nanoparticles have higher antitumor efficacy than the PLA-TPGS nanoparticles and PLGA nanoparticles in vitro and in vivo. In conclusion, such nanoparticles of star-shaped cholic acid-core PLA-TPGS block copolymer could be considered as a potentially promising and effective strategy for breast cancer treatment. PMID:24134303

  10. Well-defined, size-tunable, multi-functional micelles for efficient paclitaxel delivery for cancer treatment

    PubMed Central

    Luo, Juntao; Xiao, Kai; Li, Yuanpei; Lee, Joyce S.; Shi, Lifang; Tan, Yih-Horng; Xing, Li; Cheng, R. Holland; Liu, Gang-Yu; Lam, Kit S.

    2010-01-01

    We have developed a well-defined and biocompatible amphiphilic telodendrimer system (PEG-b-dendritic oligo-cholic acid) which can self-assemble into multifunctional micelles in aqueous solution for efficient delivery of hydrophobic drugs such as paclitaxel. In this telodendrimer system, cholic acid is essential for the formation of stable micelles with high drug loading capacity, owing to its facial amphiphilicity. A series of telodendrimers with variable length of PEG chain and number of cholic acid in the dendritic blocks were synthesized. The structure and molecular weight of each of these telodendrimers were characterized, and their critical micellization concentration (CMC), drug-loading properties, particle sizes and cytotoxicity were examined and evaluated for further optimization for anticancer drug delivery. The sizes of the micelles, with and without paclitaxel loading, could be tuned from 11.5 to 21 nm and from 15 to 141 nm, respectively. Optical imaging studies in xenograft models demonstrated preferential uptakes of the smaller paclitaxel-loaded micelles (17–60 nm) by the tumor, and the larger micelles (150 nm) by the liver and lung. The toxicity and anti-tumor efficacy profiles of these paclitaxel-loaded micelles in xenograft models were found to be superior to those of Taxol® and Abraxane®. PMID:20536174

  11. Fentanyl Enhances Hepatotoxicity of Paclitaxel via Inhibition of CYP3A4 and ABCB1 Transport Activity in Mice

    PubMed Central

    Pan, Jia-Hao; Bi, Bing-Tian; Feng, Kun-Yao; Huang, Wan; Zeng, Wei-An

    2015-01-01

    Fentanyl, a potent opioid analgesic that is used to treat cancer pain, is commonly administered with paclitaxel in advanced tumors. However, the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanism of action is not well studied. The purpose of this study was to investigate the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanisms of action. Pharmacokinetic parameters of paclitaxel were tested using reversed phase high-performance liquid chromatography (RP-HPLC). Aspartate transaminase (AST), alanine aminotransferase (ALT), and mouse liver histopathology were examined. Moreover, the cytotoxicity of anti-carcinogens was examined using 1-(4, 5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), and the intracellular accumulation of doxorubicin and rhodamine 123 was detected by flow cytometry. Furthermore, the expression of ABCB1 and the activity of ABCB1 ATPase and CYP3A4 were also examined. In this study, the co-administration of fentanyl and paclitaxel prolonged the half-life (t1/2) of paclitaxel from 1.455 hours to 2.344 hours and decreased the clearance (CL) from 10.997 ml/h to 7.014 ml/h in mice. Fentanyl significantly increased the levels of ALT in mice to 88.2 U/L, which is more than 2-fold higher than the level detected in the control group, and it increased the histological damage in mouse livers. Furthermore, fentanyl enhanced the cytotoxicity of anti-carcinogens that are ABCB1 substrates and increased the accumulation of doxorubicin and rhodamine 123. Additionally, fentanyl stimulated ABCB1 ATPase activity and inhibited CYP3A4 activity in the liver microsomes of mice. Our study indicates that the obvious hepatotoxicity during this co-administration was due to the inhibition of CYP3A4 activity and ABCB1 transport activity. These findings suggested that the accumulation-induced hepatotoxicity of paclitaxel when it is combined with fentanyl should be avoided. PMID:26633878

  12. Paclitaxel-loaded polymeric microparticles: quantitative relationships between in vitro drug release rate and in vivo pharmacodynamics.

    PubMed

    Tsai, Max; Lu, Ze; Wientjes, M Guillaume; Au, Jessie L-S

    2013-12-28

    Intraperitoneal therapy (IP) has demonstrated survival advantages in patients with peritoneal cancers, but has not become a widely practiced standard-of-care in part due to local toxicity and sub-optimal drug delivery. Paclitaxel-loaded, polymeric microparticles were developed to overcome these limitations. The present study evaluated the effects of microparticle properties on paclitaxel release (extent and rate) and in vivo pharmacodynamics. In vitro paclitaxel release from microparticles with varying physical characteristics (i.e., particle size, copolymer viscosity and composition) was evaluated. A method was developed to simulate the dosing rate and cumulative dose released in the peritoneal cavity based on the in vitro release data. The relationship between the simulated drug delivery and treatment outcomes of seven microparticle compositions was studied in mice bearing IP human pancreatic tumors, and compared to that of the intravenous Cremophor micellar paclitaxel solution used off-label in previous IP studies. Paclitaxel release from polymeric microparticles in vitro was multi-phasic; release was greater and more rapid from microparticles with lower polymer viscosities and smaller diameters (e.g., viscosity of 0.17 vs. 0.67 dl/g and diameter of 5-6 vs. 50-60 μm). The simulated drug release in the peritoneal cavity linearly correlated with treatment efficacy in mice (r(2)>0.8, p<0.001). The smaller microparticles, which distribute more evenly in the peritoneal cavity compared to the large microparticles, showed greater dose efficiency. For single treatment, the microparticles demonstrated up to 2-times longer survival extension and 4-times higher dose efficiency, relative to the paclitaxel/Cremophor micellar solution. Upon repeated dosing, the paclitaxel/Cremophor micellar solution showed cumulative toxicity whereas the microparticle that yielded 2-times longer survival did not display cumulative toxicity. The efficacy of IP therapy depended on both

  13. 21 CFR 520.1452 - Moxidectin gel.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Moxidectin gel. 520.1452 Section 520.1452 Food and..., FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1452 Moxidectin gel. (a) Specifications. Each milliliter of gel contains 20 milligrams (2 percent) moxidectin. (b) Sponsor. See No....

  14. Spring-loaded polymeric gel actuators

    DOEpatents

    Shahinpoor, Mohsen

    1995-01-01

    Spring-loaded electrically controllable polymeric gel actuators are disclosed. The polymeric gels can be polyvinyl alcohol, polyacrylic acid, or polyacrylamide, and are contained in an electrolytic solvent bath such as water plus acetone. The action of the gel is mechanically biased, allowing the expansive and contractile forces to be optimized for specific applications.

  15. Spring-loaded polymeric gel actuators

    DOEpatents

    Shahinpoor, M.

    1995-02-14

    Spring-loaded electrically controllable polymeric gel actuators are disclosed. The polymeric gels can be polyvinyl alcohol, polyacrylic acid, or polyacrylamide, and are contained in an electrolytic solvent bath such as water plus acetone. The action of the gel is mechanically biased, allowing the expansive and contractile forces to be optimized for specific applications. 5 figs.

  16. Estimation of blood perfusion using phase shift in temperature response to sinusoidal heating at the skin surface.

    PubMed

    Liu, J; Xu, L X

    1999-09-01

    A closed form analytical solution of the Pennes' bio-heat equation was obtained for temperature distributions in the skin tissue subject to the sinusoidal heat flux. Phase shifts in the surface temperature response were revealed to be related to local blood perfusion rate and heating frequency. The influence of the thermal contact resistance on the perfusion estimation was investigated. It has been proved that this influence is relatively small because of the phase shift based estimation and can be effectively eliminated by application of highly conductive grease. This analysis provides the theoretical foundation for a new noninvasive modality of blood perfusion estimation based on the surface temperature measurement which can have significant applications in future clinical practices.

  17. Self-Extinguishing Lithium Ion Batteries Based on Internally Embedded Fire-Extinguishing Microcapsules with Temperature-Responsiveness.

    PubMed

    Yim, Taeeun; Park, Min-Sik; Woo, Sang-Gil; Kwon, Hyuk-Kwon; Yoo, Jung-Keun; Jung, Yeon Sik; Kim, Ki Jae; Yu, Ji-Sang; Kim, Young-Jun

    2015-08-12

    User safety is one of the most critical issues for the successful implementation of lithium ion batteries (LIBs) in electric vehicles and their further expansion in large-scale energy storage systems. Herein, we propose a novel approach to realize self-extinguishing capability of LIBs for effective safety improvement by integrating temperature-responsive microcapsules containing a fire-extinguishing agent. The microcapsules are designed to release an extinguisher agent upon increased internal temperature of an LIB, resulting in rapid heat absorption through an in situ endothermic reaction and suppression of further temperature rise and undesirable thermal runaway. In a standard nail penetration test, the temperature rise is reduced by 74% without compromising electrochemical performances. It is anticipated that on the strengths of excellent scalability, simplicity, and cost-effectiveness, this novel strategy can be extensively applied to various high energy-density devices to ensure human safety. PMID:26177284

  18. Guiding Empirical and Theoretical Explorations of Organic Matter Decay By Synthesizing Temperature Responses of Enzyme Kinetics, Microbes, and Isotope Fluxes

    NASA Astrophysics Data System (ADS)

    Billings, S. A.; Ballantyne, F.; Lehmeier, C.; Min, K.

    2014-12-01

    Soil organic matter (SOM) transformation rates generally increase with temperature, but whether this is realized depends on soil-specific features. To develop predictive models applicable to all soils, we must understand two key, ubiquitous features of SOM transformation: the temperature sensitivity of myriad enzyme-substrate combinations and temperature responses of microbial physiology and metabolism, in isolation from soil-specific conditions. Predicting temperature responses of production of CO2 vs. biomass is also difficult due to soil-specific features: we cannot know the identity of active microbes nor the substrates they employ. We highlight how recent empirical advances describing SOM decay can help develop theoretical tools relevant across diverse spatial and temporal scales. At a molecular level, temperature effects on purified enzyme kinetics reveal distinct temperature sensitivities of decay of diverse SOM substrates. Such data help quantify the influence of microbial adaptations and edaphic conditions on decay, have permitted computation of the relative availability of carbon (C) and nitrogen (N) liberated upon decay, and can be used with recent theoretical advances to predict changes in mass specific respiration rates as microbes maintain biomass C:N with changing temperature. Enhancing system complexity, we can subject microbes to temperature changes while controlling growth rate and without altering substrate availability or identity of the active population, permitting calculation of variables typically inferred in soils: microbial C use efficiency (CUE) and isotopic discrimination during C transformations. Quantified declines in CUE with rising temperature are critical for constraining model CUE estimates, and known changes in δ13C of respired CO2 with temperature is useful for interpreting δ13C-CO2 at diverse scales. We suggest empirical studies important for advancing knowledge of how microbes respond to temperature, and ideas for theoretical

  19. Construction of a smart temperature-responsive GPx mimic based on the self-assembly of supra-amphiphiles.

    PubMed

    Zou, Huixin; Sun, Hongcheng; Wang, Liang; Zhao, Linlu; Li, Jiaxi; Dong, Zeyuan; Luo, Quan; Xu, Jiayun; Liu, Junqiu

    2016-01-28

    Glutathione peroxidase (GPx) is a major defense against hydroperoxides as a kind of seleno-enzyme that protects cells from oxidative damage. A supramolecular vesicle with controllable GPx activity and morphology has been successfully constructed by the self-assembly of supra-amphiphiles formed by host-guest recognition between cyclodextrin and adamantane derivatives. By introducing thermosensitive poly(N-isopropylacrylamide) (PNIPAM) scaffolds and the catalytic moiety selenium into adamantane and cyclodextrin, respectively, the complex of catalysis-functionalized cyclodextrin with thermosensitivity-functionalized adamantane directed the formation of a supramolecular vesicle which acted as a GPx mimic at 37 °C. The self-assembled nanoenzyme exhibited an obvious temperature responsive characteristic and high GPx-like catalytic activity promoting the reduction of hydrogen peroxide (H2O2) with glutathione (GSH) as the reducing substrate at 37 °C. However, the vesicle disassembled when the temperature decreased to 25 °C due to the transition of PNIPAM between the coil and the globule. Interestingly, the catalytic activity changed along with the transformation of morphologies. The vesicle structure self-assembled at 37 °C provided the favorable microenvironment for the enzymatic reaction, hence we successfully developed a temperature-responsive nanoenzyme model. Moreover, the catalytic activity of the thermosensitive GPx mimic exhibited excellent reversibility and typical saturation kinetics behaviour similar to a natural enzyme catalyst. It is assumed that the proposed GPx model not only has remarkable advantages such as easy functionalization and facile preparation but also provided a new way to develop intelligent responsive materials. PMID:26616916

  20. The E3 ubiquitin ligase HOS1 regulates low ambient temperature-responsive flowering in Arabidopsis thaliana.

    PubMed

    Lee, Jeong Hwan; Kim, Jae Joon; Kim, Soo Hyun; Cho, Hyun Jung; Kim, Joonki; Ahn, Ji Hoon

    2012-10-01

    Ubiquitin-dependent proteolysis regulates multiple aspects of plant growth and development, but little is known about its role in ambient temperature-responsive flowering. In addition to being regulated by daylength, the onset of flowering in many plants can also be delayed by low ambient temperatures. Here, we show that HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES 1 (HOS1), which encodes an E3 ubiquitin ligase, controls flowering time in response to ambient temperatures (16 and 23°C) and intermittent cold. hos1 mutants flowered early, and were insensitive to ambient temperature, but responded normally to vernalization and gibberellic acid. Genetic analyses suggested that this ambient temperature-insensitive flowering was independent of FLOWERING LOCUS C (FLC). Also, FLOWERING LOCUS T (FT) and TWIN SISTER OF FT (TSF) expression was up-regulated in hos1 mutants at both temperatures. The ft tsf mutation almost completely suppressed the early flowering of hos1 mutants at different temperatures, suggesting that FT and TSF are downstream of HOS1 in the ambient temperature response. A lesion in CONSTANS (CO) did not affect the ambient temperature-insensitive flowering phenotype of hos1-3 mutants. In silico analysis showed that FVE was spatiotemporally co-expressed with HOS1. A HOS1-green fluorescent protein (GFP) fusion co-localized with FVE-GFP in the nucleus at both 16 and 23°C. HOS1 physically interacted with FVE and FLK in yeast two-hybrid and co-immunoprecipitation assays. Moreover, hos1 mutants were insensitive to intermittent cold. Collectively, our results suggest that HOS1 acts as a common regulator in the signaling pathways that control flowering time in response to low ambient temperature.