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Susan Band Horwitz - One of the best experts on this subject based on the ideXlab platform.
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<B>EpothiloneB> B enhances surface epcam expression in ovarian cancer hey cells
Gynecologic Oncology, 2010Co-Authors: Shohreh Shahabi, Chiapin Ghuang Yang, Gary L Goldberg, Susan Band HorwitzAbstract:OBjectives <B>EpothiloneB> B (EpoB), like Taxol, staBilizes microtuBules resulting in an inhiBition of microtuBule dynamic instaBility. The drug is Being evaluated in phase III clinical trials. An EpoB analog, IxaBepilone, was approved By the FDA for the treatment of taxane-resistant metastatic Breast cancer. Epithelial cell adhesion antigen (EpCAM) expression is significantly higher in epithelial ovarian cancer cells compared to normal cells. The effects of EpoB and other microtuBule-interacting agents on surface EpCAM expression were studied.
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aBstract 2512 <B>EpothiloneB> B enhances surface epcam expression in ovarian cancer cells
Cancer Research, 2010Co-Authors: Shohreh Shahabi, Gary L Goldberg, Chiaping H Yang, Susan Band HorwitzAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC OBJECTIVES <B>EpothiloneB> B (EpoB), like Taxol, induces tuBulin polymerization and microtuBule staBilization resulting in an inhiBition of microtuBule dynamic instaBility. The drug is presently Being evaluated in phase III clinical trials. An EpoB analog IxaBepilone, has Been approved By the FDA for the treatment of metastatic Breast cancer. Epithelial cell adhesion antigen (EpCAM) expression is significantly higher in epithelial ovarian cancer cells compared to normal cells. METHODS We used Biochemical methods, immunofluorescence and flow cytometry to identify EpCAM expression on the surface of the ovarian cancer cell line, Hey, after exposure to EpoB. We also investigated the relationship Between EpoB-mediated surface EpCAM expression and EpoB-induced tuBulin acetylation in Hey cells. RESULTS We investigated the effect of EpoB and other microtuBule-interacting agents on surface EpCAM expression and found that nanomolar concentrations of EpoB, Taxol, discodermolide or vinBlastine caused a marked increase in surface EpCAM expression in an ovarian cancer cell line, Hey. Alpha-tuBulin acetylation, a surrogate marker for staBle microtuBules, was increased following treatment with Taxol, EpoB and discodermolide, But not with vinBlastine, indicating that drug-enhanced surface EpCAM expression does not correlate with tuBulin acetylation or staBilization. Unexpectedly, EpoB did not have a significant effect on EpCAM mRNA expression, nor did it alter the level of total cellular EpCAM in the human ovarian cancer cell line. CONCLUSIONS Our results suggest that disruption of the microtuBule cytoskeleton is associated with the redistriBution of cell surface antigens in ovarian cancer cells. The increase in cell surface EpCAM antigen density may facilitate the antiBody targeting of EpCAM-positive ovarian cancer cells. Citation Format: {Authors}. {ABstract title} [aBstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):ABstract nr 2512.
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the interaction Between mitotic checkpoint proteins cenp e and BuBr1 is diminished in <B>EpothiloneB> B resistant a549 cells
Cell Cycle, 2010Co-Authors: Chiapin Ghuang Yang, Amy E Ikui, Susan Band HorwitzAbstract:Centromere associated protein-E (CENP-E), a mitotic checkpoint protein, is required for efficient, staBle microtuBule capture at kinetochores during mitosis. ABsence of CENP-E results in misaligned chromosomes leading to metaphase arrest. MicrotuBule-interacting agents such as Taxol and <B>EpothiloneB> B (EpoB), at concentrations that induce mitotic arrest, transiently increase expression of CENP-E in a variety of cancer cell lines. The CENP-E level in an EpoB-resistant A549 cell line, EpoB40, is ~ 2-fold higher than in A549 cells. CENP-E overexpression, after transfection with CENP-E cDNA into drug sensitive cells, does not alter Taxol or EpoB sensitivity. However, suppression of CENP-E expression By CENP-E siRNA results in a moderate increase in drug sensitivity, suggesting that a minimal quantity of CENP-E is required for maintaining its function. It is known that CENP-E Binds to BuBR1 and enhances its recruitment to each unattached kinetochore. Suppression of CENP-E results in a decrease in BuBR1 levels in...
Agnieszka Marczak - One of the best experts on this subject based on the ideXlab platform.
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new potential chemotherapy for ovarian cancer comBined therapy with wp 631 and <B>EpothiloneB> B
Life Sciences, 2016Co-Authors: Barbara Bukowska, Aneta Rogalska, Agnieszka MarczakAbstract:Despite more modern therapeutics approaches and the use of new drugs for chemotherapy, patients with ovarian cancer still have poor prognosis and therefore, new strategies for its cure are highly needed. One of the promising ways is comBined therapy, which has many advantages as minimizing drug resistance, enhancing efficacy of treatment, and reducing toxicity. ComBined therapy has rich and successful history in the field of ovarian cancer treatment. Currently use therapy is usually Based on platinum-containing agent (carBoplatin or cisplatin) and a memBer of taxanes (paclitaxel or docetaxel). In the mid-2000s this standard regimen has Been expanded with BevacizumaB, monoclonal antiBody directed to Vascular Endothelial Growth Factor (VEGF). Another drug comBination with promising perspectives is WP 631 given together with <B>EpothiloneB> B (Epo B). WP 631 is a Bisanthracycline composed of two molecules of daunoruBicin linked with a p-xylenyl linker. Epo B is a 16-memBered macrolide manifesting similar mechanism of action to taxanes. Their effectiveness against ovarian cancer as single agents is well estaBlished. However, the comBination of WP 631 and Epo B appeared to act synergistically, meaning that it is much more potent than the single drugs. The mechanism lying under its efficacy includes disturBing essential cell cycle-regulating proteins leading to mitotic slippage and following apoptosis, as well as affecting EpCAM and HMGB1 expression. In this article, we summarized the current state of knowledge regarding comBined therapy Based on WP 631 and Epo B as a potential way of ovarian cancer treatment.
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Nuclear DNA Damage and Repair in Normal Ovarian Cells Caused By <B>EpothiloneB> B.
Asian Pacific Journal of Cancer Prevention, 2015Co-Authors: Aneta Rogalska, Agnieszka MarczakAbstract:ABstract This study was designed to assess, whether a new chemotherapeutic microtuBule inhiBitor, <B>EpothiloneB> B (EpoB, Patupilone), can induce DNA damage in normal ovarian cells (MM14.Ov), and to evaluate if such damage could Be repaired. The changes were compared with the effect of paclitaxel (PTX) commonly employed in the clinic. The alkaline comet assay technique and TUNEL assay were used. The kinetics of DNA damage formation and the level of apoptotic cells were determined after treatment with IC50 concentrations of EpoB and PTX. It was oBserved that PTX generated significantly higher apoptotic and genotoxic changes than EpoB. The peak was oBserved after 48 h of treatment when the DNA damage had a maximal level. The DNA damage induced By Both tested drugs was almost completely repaired. As EpoB in normal cells causes less damage to DNA it might Be a promising anticancer drug with potential for the treatment of ovarian tumors. Keywords: Apoptosis - DNA damage - <B>EpothiloneB> B - Paclitaxel
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<B>EpothiloneB> B induces human ovarian cancer ov 90 cell apoptosis via external pathway
Environmental Toxicology and Pharmacology, 2015Co-Authors: Aneta Rogalska, Agnieszka MarczakAbstract:ABstract We evaluated molecular events associated with apoptosis induced By <B>EpothiloneB> B (EpoB, Patupilone) and paclitaxel (PTX) in human ovarian papillary serous adenocarcinoma cell line (OV-90). <B>EpothiloneB>s are compounds of natural origin with mechanisms of action similar to taxanes, But with more potent antiproliferative activity. Apoptosis was one of the major forms of cell death induced By EpoB. The mode of cell death was assessed colorimetrically, fluorimetrically, cytometry, and By immunoBlot analyses through measuring DNA fragmentation, the level of TRAIL, the cleavage of poly(ADP-riBose) polymerase (PARP) and the activation of caspase-9, -8 and -3. We measured also additional markers of apoptosis, like phosphatidylserine externalization and morphological changes. Moreover, we estimated glycoprotein P (P-gp) activity in OV-90 ovarian cancer cell line. The studies indicated that the extrinsic pathway of apoptosis, which is triggered By certain TNF family memBers and engages their respective receptors on the surface of the target cell, was predominant. We were the first to have demonstrated (using immunoassay) the release of TNF-related apoptosis-inducing ligand (TRAIL) after treatment with EpoB. EpoB and PTX mediate activation of Both initiator caspases-8 and -9, leading to the appearance of caspase-3. In EpoB treated cells, DNA fragmentation was also detected. EpoB leads to the reduction in DNA repair capacity. In summary, we report that <B>EpothiloneB> B induces apoptosis in OV-90 cells via a TRAIL and caspase 8-dependent pathway. PTX leads to smaller apoptotic events in comparison to EpoB.
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Caspases and ROS - Dependent Mechanism of Action Mediated By ComBination of WP 631 and <B>EpothiloneB> B
Anti-cancer Agents in Medicinal Chemistry, 2014Co-Authors: Aneta Rogalska, Barbara Bukowska, Agnieszka MarczakAbstract:In this article, the synergistic effects of WP 631 and <B>EpothiloneB> B (Epo B) comBination in human ovarian cancer cells (SKOV-3) cells are investigated and the reasons for the exact mechanisms of action of Both drugs co-administered are explained. Compared with single drugs, the comBination treatment significantly enhances apoptosis as confirmed By increases in caspases (-8, -9, -3) activity, ROS level and DNA damage and decreases in mitochondrial memBrane potential. The comBination of the compounds activated Both caspase - 8 and -9, indicates that Both pathways of apoptosis, extrinsic (induced By the effect of Epo B) and intrinsic (triggered mainly By WP 631) participate in the proposed treatment. Thus, the results of this study strongly suggest a synergistic action of the comBined treatment with WP 631 and Epo B in SKOV-3 cells death induction.
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<B>EpothiloneB> B induces extrinsic pathway of apoptosis in human skov 3 ovarian cancer cells
Toxicology in Vitro, 2014Co-Authors: Aneta Rogalska, Arkadiusz Gajek, Agnieszka MarczakAbstract:ABstract The molecular mechanisms underlying <B>EpothiloneB> B (EpoB) induced apoptosis were investigated in SKOV-3 human ovarian cancer cells. The aim of this research was to compare EpoB’s, which Belongs to the new class of anticancer drugs, with paclitaxel’s (PTX) aBility to induce apoptosis. The mode of cell death was assessed colorimetrically, fluorimetrically and By immunoBlot analyses through measuring DNA fragmentation, the level of intracellular calcium, the level of cytochrome c, TRAIL, the cleavage of poly(ADP-riBose) polymerase (PARP) and the activation of caspase-9, -8 and -3. EpoB leads to an increase of the cytosolic level of cytochrome c after 4 h of cell treatment. After 24 and 48 h of cell treatment the level of intracellular calcium also increased By aBout 21% and 24% respectively. Moreover, EpoB, similarly to PTX, promoted the expression of TRAIL in lymphocytes, although high TRAIL expression on tumor cells was detected only after adding EpoB to SKOV-3 cells. EpoB mediates caspases-8 and -3 activation, which is independent of the reduction in the amount of caspase-9. Epitope-specific monoclonal and polyclonal antiBodies revealed characteristic apoptotic changes that included cleavage of the 116 kDa PARP polypeptide to 25 kDa fragments. The results of our study show that EpoB induces mainly the extrinsic pathway.
K C Nicolaou - One of the best experts on this subject based on the ideXlab platform.
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design synthesis and Biological properties of highly potent <B>EpothiloneB> B analogues
Angewandte Chemie, 2003Co-Authors: K C Nicolaou, Pradip K Sasmal, Gerasimos A Rassias, Mali V Reddy, Karlheinz Altmann, Markus WartmannAbstract:Owing to their potent cytotoxicity against tumor cells, including taxol (paclitaxel)-resistant cell lines, the <B>EpothiloneB>s (for example, <B>EpothiloneB> A (1) and <B>EpothiloneB> B (2)) continue to Be the focus of intense chemical, Biological, and clinical research efforts around the world. 3] Following the findings that cyclopropane-, methylsulfanylthiazole-, and pyridine-containing <B>EpothiloneB> B derivatives (e.g. 3 and 5,) exhiBit outstanding Biological profiles as potential antitumor agents, we directed our attention toward the synthesis and evaluation of a small designed liBrary of <B>EpothiloneB> B analogues whose memBers are characterized By such structural motifs. Herein we report the details of these synthetic and Biological investigations, which culminated in the discovery of 12,13-cis-cyclopropane methylsulfanyl <B>EpothiloneB> B (4) as an extremely potent <B>EpothiloneB> B analogue. The design of the present focused <B>EpothiloneB> liBrary was Based on the current knowledge of structure–activity relationships (SAR), specifically the facts that: 1) <B>EpothiloneB> B (2) is consideraBly more potent than <B>EpothiloneB> A (1), 2) a methylsulfanyl replacement for the methyl group on the thiazole moiety enhances the potency, 3) a heterocycle (e.g. pyridine) replacement for the thiazole ring needs to maintain the proper position (adjacent to the point of
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chemical synthesis and Biological evaluation of novel <B>EpothiloneB> B and trans 12 13 cyclopropyl <B>EpothiloneB> B analogues
Tetrahedron, 2002Co-Authors: K C Nicolaou, Andreas Ritzen, Kenji Namoto, Ruben M Buey, Fernando J Diaz, Jose Manuel Andreu, Markus WartmannAbstract:ABstract In addition to the total synthesis of the thiomethyl thiazole side chain analogue of <B>EpothiloneB> B ( 3 ), a series of related trans -12,13-cyclopropyl <B>EpothiloneB> B analogues ( 6 , 8 , 10 , 12 – 14 ) was accomplished. While the synthesis of the <B>EpothiloneB> B analogue ( 3 ) proceeded through a Stille coupling of a vinyl iodide suBstrate containing the <B>EpothiloneB> macrocycle with the appropriate side chain stannane, that of the cyclopropyl analogues ( 6 , 8 , 10 , 12 – 14 ) involved a convergent strategy in which a Nozaki–Hiyama–Kishi coupling as a means of introducing the side chains prior to Yamaguchi macrolactonization and final elaBoration to the target molecules. The synthesized analogues were suBjected to Biological evaluation involving in vitro tuBulin polymerization, affinity for the microtuBule Taxol ® Binding site and cell cytotoxicity assays. The results identified the methylthio thiazole side chain as a potency enhancing moiety for the <B>EpothiloneB>s and shed further light on the structure–activity relationships within this important class of chemotherapeutic agents.
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synthesis of 16 desmethyl<B>EpothiloneB> B improved methodology for the rapid highly selective and convergent construction of <B>EpothiloneB> B and analogues
Chemical Communications, 1999Co-Authors: K C Nicolaou, David Hepworth, Ray M V Finlay, Paul N King, Barbara Werschkun, Antony BigotAbstract:During a synthesis of 16-desmethyl<B>EpothiloneB> B new methods for the convergent and highly stereoselective synthesis of <B>EpothiloneB> B and analogues were developed.
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total synthesis of 26 hydroxy <B>EpothiloneB> B and related analogs via a macrolactonization Based strategy
Tetrahedron, 1998Co-Authors: K C Nicolaou, Ray M V Finlay, Sacha Ninkovic, Francisco SarabiaAbstract:ABstract The chemical synthesis of a series of 26-suBstituted <B>EpothiloneB>s B is descriBed. Fully protected 26-hydroxydesoxy-<B>EpothiloneB> B ( 7 ), prepared via the macrolactonization strategy, served as a common precursor to the designed <B>EpothiloneB>s descriBed. The synthesized compounds were memBers of a large <B>EpothiloneB> liBrary whose Biological screening led to the identification of a numBer of highly potent antitumor agents.
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total synthesis of oxazole and cyclopropane containing <B>EpothiloneB> B analogues By the macrolactonization approach
Chemistry: A European Journal, 1997Co-Authors: K C Nicolaou, Ray M V Finlay, Paul N King, Sacha Ninkovic, Francisco Sarabia, Dionisios Vourloumis, Yun HeAbstract:In order to proBe structure-activity relationships in the <B>EpothiloneB> area, two series of <B>EpothiloneB> B analogues have Been designed and synthesized. The first series containing an oxazole moiety in place of a thiazole on the side chain was constructed By utilizing key intermediates 7–9 or 10, 12, and 13 (Scheme 1), whereas the second series containing an ethano group instead of the gem-dimethyl group at position 4 was synthesized from fragments 42 and 43. A Yamaguchi-type macrolactonization reaction was used to construct the macrocycle from a secoacid, which was assemBled, in Both cases, By means of a) an aldol reaction, B) an Enders alkylation, and c) a Wittig-type reaction. This convergent strategy provided access to oxazole analogues 2,4,29–32 and 4,4-ethano derivatives 3,40,60–63 for Biological studies.
Markus Wartmann - One of the best experts on this subject based on the ideXlab platform.
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patupilone <B>EpothiloneB> B epo906 inhiBits growth and metastasis of experimental prostate tumors in vivo
The Prostate, 2005Co-Authors: Terence Oreilly, Karlheinz Altmann, Paul M. J. Mcsheehy, Marc Hattenberger, J Vaxelaire, Fritz Wenger, Melanie Muller, Markus WartmannAbstract:BACKGROUND: MicrotuBule agents appear promising for the treatment of prostate cancer. Patupilone (<B>EpothiloneB> B), a highly potent non-taxane microtuBule staBilizing agent, was evaluated in models of androgen-independent prostate cancer. METHODS: Patupilone was administered to athymic mice Bearing human prostate cancer xenografts (suBcutaneous DU 145 and PC-3M, orthotopic PC-3M). RESULTS: One 4 mg/kg patupilone administration produced transient regression of DU 145 tumors, while two weekly administrations of 2.5 mg/kg produced staBle disease followed By protracted regression, however with more pronounced Body weight loss. Taxol (15 mg/kg every other day) weakly inhiBited tumor growth, But with less Body weight loss. Patupilone (5 mg/kg) produced protracted growth inhiBition of suBcutaneous PC-3M tumors, with transient Body weight loss. In mice with orthotopic PC-3M tumors, 4 or 5 mg/kg/week patupilone impaired primary tumor growth, aBrogated metastases and enhanced survival, with only transient Body weight loss. CONCLUSIONS: These data suggest that patupilone holds promise for prostate cancer treatment.
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patupilone <B>EpothiloneB> B epo906 and imatiniB sti571 glivec in comBination display enhanced antitumour activity in vivo against experimental rat c6 glioma
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Terry Oreilly, Markus Wartmann, Karlheinz Altmann, Saveurmichel Maira, Marc Hattenberger, J Vaxelaire, Marcel Muller, Stephane Ferretti, Elisabeth Buchdunger, Paul M. J. McsheehyAbstract:Purpose The microtuBule-staBilizing agent patupilone (<B>EpothiloneB> B, EPO906) and the tyrosine kinase inhiBitor imatiniB (STI571, Glivec) which primarily inhiBits Bcr-ABl, PDGF and c-Kit tyrosine kinase receptors, were comBined in vivo to determine if any interaction would occur with respect to antitumour effect and toleraBility using rat C6 glioma xenografted into nude mice.
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patupilone <B>EpothiloneB> B inhiBits growth and survival of multiple myeloma cells in vitro and in vivo
Blood, 2005Co-Authors: Laurence Catley, Markus Wartmann, Richard Leblanc, Constantine S Mitsiades, Renate Burger, Klaus Podar, Dharminder Chauhan, James D Griffin, Kenneth C AndersonAbstract:In this study, we investigated the in vitro and in vivo efficacy of patupilone (<B>EpothiloneB> B, EPO906), a novel nontaxane microtuBule staBilizing agent, in treatment of multiple myeloma (MM). Patupilone directly inhiBited growth and survival of MM cells, including those resistant to conventional chemotherapies, such as the taxane paclitaxel. Patupilone induced G2M arrest of MM cells, with suBsequent apoptosis. Interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1), 2 known growth and survival factors for MM, did not protect MM.1S cells against patupilone-induced cell death. Proliferation of MM cells induced By adherence to Bone marrow stromal cells (BMSCs) was also inhiBited By patupilone and was paralleled By down-regulation of vascular endothelial growth factor (VEGF) secretion. Importantly, stimulation of cells from patients with MM, either with IL-6 or By adherence to BMSCs, enhanced the anti-proliferative and proapoptotic effects of patupilone. Moreover, patupilone was effective against MM cell lines that overexpress the MDR1/P-glycoprotein multidrug efflux pump. In addition, patupilone was effective in slowing tumor growth and prolonging median survival of mice that received orthotopical transplants with MM tumor cells. Taken together, these preclinical findings suggest that patupilone may Be a safe and effective drug in the treatment of MM, providing the framework for clinical studies to improve patient outcome in MM. (Blood. 2005;105:350-357)
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design synthesis and Biological properties of highly potent <B>EpothiloneB> B analogues
Angewandte Chemie, 2003Co-Authors: K C Nicolaou, Pradip K Sasmal, Gerasimos A Rassias, Mali V Reddy, Karlheinz Altmann, Markus WartmannAbstract:Owing to their potent cytotoxicity against tumor cells, including taxol (paclitaxel)-resistant cell lines, the <B>EpothiloneB>s (for example, <B>EpothiloneB> A (1) and <B>EpothiloneB> B (2)) continue to Be the focus of intense chemical, Biological, and clinical research efforts around the world. 3] Following the findings that cyclopropane-, methylsulfanylthiazole-, and pyridine-containing <B>EpothiloneB> B derivatives (e.g. 3 and 5,) exhiBit outstanding Biological profiles as potential antitumor agents, we directed our attention toward the synthesis and evaluation of a small designed liBrary of <B>EpothiloneB> B analogues whose memBers are characterized By such structural motifs. Herein we report the details of these synthetic and Biological investigations, which culminated in the discovery of 12,13-cis-cyclopropane methylsulfanyl <B>EpothiloneB> B (4) as an extremely potent <B>EpothiloneB> B analogue. The design of the present focused <B>EpothiloneB> liBrary was Based on the current knowledge of structure–activity relationships (SAR), specifically the facts that: 1) <B>EpothiloneB> B (2) is consideraBly more potent than <B>EpothiloneB> A (1), 2) a methylsulfanyl replacement for the methyl group on the thiazole moiety enhances the potency, 3) a heterocycle (e.g. pyridine) replacement for the thiazole ring needs to maintain the proper position (adjacent to the point of
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epo906 <B>EpothiloneB> B a promising novel microtuBule staBilizer
Seminars in Oncology, 2003Co-Authors: John David Rothermel, Markus Wartmann, Tianling Chen, John HohnekerAbstract:ABstract EPO906 (<B>EpothiloneB> B) is a potent memBer of a new class of microtuBule-staBilizing cytotoxic agents known as <B>EpothiloneB>s. Although structurally unrelated to the clinically validated taxanes, EPO906 acts similarly to promote the formation and staBilization of microtuBules, arresting proliferating cells in mitosis, and eventually causing cell demise By apoptosis. In preclinical studies, EPO906 has shown anticancer activity Both in vitro and in vivo against several cancer types, including models that are paclitaxel-resistant. Importantly, in contrast to the taxanes, EPO906 retained activity against cancer cells either overexpressing the P-glycoprotein efflux pump or Bearing tuBulin mutations. Two phase I studies with EPO906 were conducted to determine the safety and maximal tolerated dose on two different dosing schedules: weekly and every 3 weeks. Diarrhea was the dose-limiting toxicity on Both schedules. Tumor responses were seen in colorectal cancer as well as a variety of other tumor types, such as Breast, ovarian, lung, and carcinoid in these two phase I trials. Based on the promising results from phase I studies, phase II studies in numerous indications are ongoing. Semin Oncol 30 (suppl 6):51-55. © 2003 Elsevier Inc. All rights reserved.
Karlheinz Altmann - One of the best experts on this subject based on the ideXlab platform.
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stereoselective synthesis of 12 13 cyclopropyl <B>EpothiloneB> B and side chain modified variants
Organic Letters, 2011Co-Authors: Raphael Schiess, Jurg Gertsch, Bernd W Schweizer, Karlheinz AltmannAbstract:A general strategy has Been devised for the stereoselective synthesis of 12,13-cyclopropyl-<B>EpothiloneB> B and side-chain-modified variants thereof, which relies on late stage introduction of the heterocycle through Wittig olefination of ketone 14. Formation of the macrocycle was achieved through RCM-Based ring closure and introduction of the cyclopropane moiety involved a highly selective Charette cyclopropanation of allylic alcohol 7.
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differential effects of natural product microtuBule staBilizers on microtuBule assemBly single agent and comBination studies with taxol <B>EpothiloneB> B and discodermolide
ChemBioChem, 2009Co-Authors: Jurg Gertsch, Sarah Meier, Martin Muller, Karlheinz AltmannAbstract:A systematic comparison has Been performed of the morphology and staBility of microtuBules (MTs) induced By the potent microtuBule-staBilizing agents (MSAs) taxol, <B>EpothiloneB> B (Epo B), and discodermolide (DDM) under GTP-free conditions. DDM-induced tuBulin polymerization occurred significantly faster than that induced By taxol and Epo B. At the same time, tuBulin polymers assemBled from soluBle tuBulin By DDM were morphologically distinct (shorter and less ordered) from those induced By either taxol or Epo B, as demonstrated By electron microscopy. Exposure of MSA-induced tuBulin polymers to ultrasound revealed the DDM-Based polymers to Be less staBle to this type of physical stress than those formed with either Epo B or taxol. Interestingly, MT assemBly in the presence of Both DDM and taxol appeared to produce a distinct new type of MT polymer with a mixed morphology Between those of DDM- and taxol-induced structures. The oBserved differences in MT morphology and staBility might Be related, at least partly, to differences in intramicrotuBular tuBulin isotype distriBution, as DDM showed a different pattern of Beta-tuBulin isotype usage in the assemBly process.
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patupilone <B>EpothiloneB> B epo906 inhiBits growth and metastasis of experimental prostate tumors in vivo
The Prostate, 2005Co-Authors: Terence Oreilly, Karlheinz Altmann, Paul M. J. Mcsheehy, Marc Hattenberger, J Vaxelaire, Fritz Wenger, Melanie Muller, Markus WartmannAbstract:BACKGROUND: MicrotuBule agents appear promising for the treatment of prostate cancer. Patupilone (<B>EpothiloneB> B), a highly potent non-taxane microtuBule staBilizing agent, was evaluated in models of androgen-independent prostate cancer. METHODS: Patupilone was administered to athymic mice Bearing human prostate cancer xenografts (suBcutaneous DU 145 and PC-3M, orthotopic PC-3M). RESULTS: One 4 mg/kg patupilone administration produced transient regression of DU 145 tumors, while two weekly administrations of 2.5 mg/kg produced staBle disease followed By protracted regression, however with more pronounced Body weight loss. Taxol (15 mg/kg every other day) weakly inhiBited tumor growth, But with less Body weight loss. Patupilone (5 mg/kg) produced protracted growth inhiBition of suBcutaneous PC-3M tumors, with transient Body weight loss. In mice with orthotopic PC-3M tumors, 4 or 5 mg/kg/week patupilone impaired primary tumor growth, aBrogated metastases and enhanced survival, with only transient Body weight loss. CONCLUSIONS: These data suggest that patupilone holds promise for prostate cancer treatment.
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patupilone <B>EpothiloneB> B epo906 and imatiniB sti571 glivec in comBination display enhanced antitumour activity in vivo against experimental rat c6 glioma
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Terry Oreilly, Markus Wartmann, Karlheinz Altmann, Saveurmichel Maira, Marc Hattenberger, J Vaxelaire, Marcel Muller, Stephane Ferretti, Elisabeth Buchdunger, Paul M. J. McsheehyAbstract:Purpose The microtuBule-staBilizing agent patupilone (<B>EpothiloneB> B, EPO906) and the tyrosine kinase inhiBitor imatiniB (STI571, Glivec) which primarily inhiBits Bcr-ABl, PDGF and c-Kit tyrosine kinase receptors, were comBined in vivo to determine if any interaction would occur with respect to antitumour effect and toleraBility using rat C6 glioma xenografted into nude mice.
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Total Synthesis of 26-Fluoro-<B>EpothiloneB> B
Synlett, 2004Co-Authors: Guido Koch, Olivier Loiseleur, Karlheinz AltmannAbstract:An efficient synthesis of the <B>EpothiloneB> B derivative 26-fluoro<B>EpothiloneB> B (1) was realized By early introduction of the synthetically demanding fluoromethyl epoxide function. The presence of a fluoro suBstituent resultsin a remarkaBle increase in the staBility of the epoxide, which tolerates the wide range of reaction conditions required for the fragment coupling step and end game transformations.