epothilones

Summary

Summary: A group of 16-member MACROLIDES which stabilize MICROTUBULES in a manner similar to PACLITAXEL. They were originally found in the myxobacterium Sorangium cellulosum, now renamed to Polyangium (MYXOCOCCALES).

Top Publications

  1. Thomas E, Gomez H, Li R, Chung H, Fein L, Chan V, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007;25:5210-7 pubmed
    ..Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes. ..
  2. Gong G, Sun X, Liu X, Hu W, Cao W, Liu H, et al. Mutation and a high-throughput screening method for improving the production of Epothilones of Sorangium. J Ind Microbiol Biotechnol. 2007;34:615-23 pubmed
    The epothilones are highly promising prospective anticancer agents that are produced by the myxobacterium Sorangium cellulosum. We mutated the epothilone producing S. cellulosum strain So0157-2 to improve the production of epothilones...
  3. Mozzetti S, Iantomasi R, De Maria I, Prislei S, Mariani M, Camperchioli A, et al. Molecular mechanisms of patupilone resistance. Cancer Res. 2008;68:10197-204 pubmed publisher
    ..Furthermore, patupilone represents a promising first-line option for the treatment of high-risk ovarian cancer patients, who exhibit high TUBB3 levels and poor response to standard paclitaxel-platin chemotherapy. ..
  4. Cortes J, Baselga J. Targeting the microtubules in breast cancer beyond taxanes: the epothilones. Oncologist. 2007;12:271-80 pubmed
    ..The natural epothilones and their analogs are a novel class of microtubule-stabilizing agents that bind tubulin and result in apoptotic ..
  5. Perez E. Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Mol Cancer Ther. 2009;8:2086-95 pubmed publisher
    ..Microtubule inhibitors (MTI) such as taxanes, vinca alkaloids, and epothilones stabilize or destabilize microtubules, thereby suppressing microtubule dynamics required for proper mitotic ..
  6. Moulder S, Li H, Wang M, Gradishar W, Perez E, Sparano J, et al. A phase II trial of trastuzumab plus weekly ixabepilone and carboplatin in patients with HER2-positive metastatic breast cancer: an Eastern Cooperative Oncology Group Trial. Breast Cancer Res Treat. 2010;119:663-71 pubmed publisher
    ..Weekly ixabepilone and carboplatin plus trastuzumab have an acceptable toxicity profile, but are not likely to be associated with an RR of 75% in HER2+ MBC. Efficacy appears comparable to paclitaxel, carboplatin, and trastuzumab. ..
  7. Denduluri N, Low J, Lee J, Berman A, Walshe J, Vatas U, et al. Phase II trial of ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previously untreated with taxanes. J Clin Oncol. 2007;25:3421-7 pubmed
    ..Women with metastatic breast cancer previously untreated with taxanes have a meaningful durable response to single-agent ixabepilone therapy. Minimal hematologic toxicity and no grade 3 sensory neuropathy were noted. ..
  8. Burris H. Preclinical investigations with epothilones in breast cancer models. Semin Oncol. 2008;35:S15-21; quiz S39 pubmed publisher
    The epothilones constitute a novel class of microtubule inhibitors that act like the taxanes by hyperstabilizing tubulin polymerization, thus disrupting functioning of the mitotic spindle...
  9. Park S, Park J, Jung W, Han A, Ban Y, Kim E, et al. Heterologous production of epothilones B and D in Streptomyces venezuelae. Appl Microbiol Biotechnol. 2008;81:109-17 pubmed publisher
    b>Epothilones, produced from the myxobacterium Sorangium cellulosum, are potential anticancer agents that stabilize microtubules in a similar manner to paclitaxel...

More Information

Publications62

  1. Lee F, Smykla R, Johnston K, Menard K, McGlinchey K, Peterson R, et al. Preclinical efficacy spectrum and pharmacokinetics of ixabepilone. Cancer Chemother Pharmacol. 2009;63:201-12 pubmed publisher
    ..This is accompanied by favorable pharmacokinetics. Ixabepilone has reduced susceptibility to resistance due to P-gp overexpression, tubulin mutations, and alterations in beta-tubulin isotype expression. ..
  2. Dreicer R, Li S, Manola J, Haas N, Roth B, Wilding G. Phase 2 trial of epothilone B analog BMS-247550 (ixabepilone) in advanced carcinoma of the urothelium (E3800): a trial of the Eastern Cooperative Oncology Group. Cancer. 2007;110:759-63 pubmed
    ..Responses in visceral, nodal, and soft tissues sites were observed. Granulocytopenia without fever, fatigue, and sensory neuropathy was common. ..
  3. Jacobs S, Fox E, Krailo M, Hartley G, Navid F, Wexler L, et al. Phase II trial of ixabepilone administered daily for five days in children and young adults with refractory solid tumors: a report from the children's oncology group. Clin Cancer Res. 2010;16:750-4 pubmed publisher
    ..Ixabepilone at 8 mg/m(2)/dose daily for 5 days was tolerable in children and adolescents, but did not show evidence of clinical activity in the childhood solid tumors studied. ..
  4. Yardley D. Activity of ixabepilone in patients with metastatic breast cancer with primary resistance to taxanes. Clin Breast Cancer. 2008;8:487-92 pubmed publisher
    ..The epothilones are a novel class of antineoplastic agents, developed to overcome tumor-resistance mechanisms...
  5. Vahdat L. Clinical studies with epothilones for the treatment of metastatic breast cancer. Semin Oncol. 2008;35:S22-30; quiz S40 pubmed publisher
    ..b>Epothilones, which also stabilize microtubules but by a different mechanism, are in clinical development primarily to ..
  6. Ajani J, Safran H, Bokemeyer C, Shah M, Lenz H, Van Cutsem E, et al. A multi-center phase II study of BMS-247550 (Ixabepilone) by two schedules in patients with metastatic gastric adenocarcinoma previously treated with a taxane. Invest New Drugs. 2006;24:441-6 pubmed
    Ixabepilone is one of the epothilones, a new class of cytotoxics, that function as microtubule-stabilizing agents...
  7. Denduluri N, Lee J, Walshe J, Berman A, Vatas U, Chow C, et al. Phase II trial of ixabepilone, an epothilone B analog, given daily for three days every three weeks, in metastatic breast cancer. Invest New Drugs. 2007;25:63-7 pubmed
    ..Although ixabepilone was well-tolerated, the dose of 8-10 mg/m(2) daily for 3 days is not an effective therapy in metastatic breast cancer previously exposed to taxanes. ..
  8. Bijman M, van Nieuw Amerongen G, Laurens N, van Hinsbergh V, Boven E. Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton. Mol Cancer Ther. 2006;5:2348-57 pubmed
    ..In conclusion, HNTCs of microtubule-targeting agents efficiently reduce endothelial cell motility by interference with microtubule dynamics preventing the activation of Rac1/Cdc42 and disorganizing the actin cytoskeleton. ..
  9. Lee J, Swain S. Development of novel chemotherapeutic agents to evade the mechanisms of multidrug resistance (MDR). Semin Oncol. 2005;32:S22-6 pubmed
    ..b>Epothilones are among the most advanced of the new agents in clinical development...
  10. Pivot X, Dufresne A, Villanueva C. Efficacy and safety of ixabepilone, a novel epothilone analogue. Clin Breast Cancer. 2007;7:543-9 pubmed
    The epothilones and their analogues are a new class of anticancer agents derived from the fermentation of myxobacterium Sorangium cellulosum...
  11. Stupp R, Tosoni A, Bromberg J, Hau P, Campone M, Gijtenbeek J, et al. Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group. Ann Oncol. 2011;22:2144-9 pubmed publisher
    ..No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration. ..
  12. Cigler T, Vahdat L. Integrating epothilones into the treatment of patients with metastatic breast cancer: clinical perspectives on incorporating recent data in the practice setting. Clin Breast Cancer. 2008;8 Suppl 4:S166-70 pubmed publisher
    ..Ultimately, however, inevitable intrinsic or acquired resistance to chemotherapy limits treatment options. The epothilones, a novel class of microtubule-stabilizing agents that have incomplete cross-resistance with taxanes and are ..
  13. Fornier M. Ixabepilone, first in a new class of antineoplastic agents: the natural epothilones and their analogues. Clin Breast Cancer. 2007;7:757-63 pubmed
    ..The epothilones and their analogues are a novel class of antimicrotubule agents that has demonstrated antitumor activity in the ..
  14. Kadra G, Finetti P, Toiron Y, Viens P, Birnbaum D, Borg J, et al. Gene expression profiling of breast tumor cell lines to predict for therapeutic response to microtubule-stabilizing agents. Breast Cancer Res Treat. 2012;132:1035-47 pubmed publisher
    ..Genomic predictors for Tax- and Ixa-sensitivity can be derived from BTCL and may be helpful for better selecting cytotoxic treatment in BC patients. ..
  15. Forster M, Kaye S, Oza A, Sklenar I, Johri A, Cheung W, et al. A phase Ib and pharmacokinetic trial of patupilone combined with carboplatin in patients with advanced cancer. Clin Cancer Res. 2007;13:4178-84 pubmed
    ..The optimal dose for this regimen is currently being further refined in phase II trials. ..
  16. Hussain M, Tangen C, Lara P, Vaishampayan U, Petrylak D, Colevas A, et al. Ixabepilone (epothilone B analogue BMS-247550) is active in chemotherapy-naive patients with hormone-refractory prostate cancer: a Southwest Oncology Group trial S0111. J Clin Oncol. 2005;23:8724-9 pubmed
    The epothilones are a new class of tubulin-polymerizing agents with activity in taxane-sensitive and resistant tumor models. We evaluated ixabepilone (BMS-247550) in patients with metastatic hormone-refractory prostate cancer (HRPC)...
  17. Rubin E, Rothermel J, Tesfaye F, Chen T, Hubert M, Ho Y, et al. Phase I dose-finding study of weekly single-agent patupilone in patients with advanced solid tumors. J Clin Oncol. 2005;23:9120-9 pubmed
    ..In contrast with murine studies, patupilone has a relatively prolonged terminal half-life in humans. The partial responses in patients previously treated with taxanes is consistent with promising preclinical results. ..
  18. Brunden K, Zhang B, Carroll J, Yao Y, Potuzak J, Hogan A, et al. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J Neurosci. 2010;30:13861-6 pubmed publisher
    ..These results suggest that certain brain-penetrant MT-stabilizing agents might provide a viable therapeutic strategy for the treatment of AD and FTDs...
  19. Michaud L. The epothilones: how pharmacology relates to clinical utility. Ann Pharmacother. 2009;43:1294-309 pubmed publisher
    To review the pharmacologic properties of a novel class of chemotherapeutic agents, the epothilones, and to summarize findings from recent clinical trials investigating the various epothilones in cancer therapy...
  20. Morrow P, Divers S, Provencher L, Luoh S, Petrella T, Giurescu M, et al. Phase II study evaluating the efficacy and safety of sagopilone (ZK-EPO) in patients with metastatic breast cancer that has progressed following chemotherapy. Breast Cancer Res Treat. 2010;123:837-42 pubmed publisher
    ..5%) and fatigue (44.6%). There were no deaths related to the study drug. Sagopilone was moderately tolerated in both treatment arms and showed limited activity in heavily pre-treated patients with MBC. ..
  21. Donovan D, Vahdat L. Epothilones: clinical update and future directions. Oncology (Williston Park). 2008;22:408-16; discussion 416, 421, 424 passim pubmed
    b>Epothilones are cytotoxic compounds that function in a similar fashion to paclitaxel and show promise for the treatment of a variety of cancers by inducing microtubule bundling and apoptotic cell death...
  22. Sakaushi S, Nishida K, Fukada T, Senda Murata K, Oka S, Sugimoto K. Differential responses of mitotic spindle pole formation to microtubule-stabilizing agents epothilones A and B at low concentrations. Cell Cycle. 2008;7:477-83 pubmed
    ..In the present study, we examined whether the microtubule-stabilizing agents epothilones A and B, which are structurally similar, affect the centrosome/spindle pole architecture...
  23. Rustin G, Reed N, Jayson G, Ledermann J, Adams M, Perren T, et al. A phase II trial evaluating two schedules of sagopilone (ZK-EPO), a novel epothilone, in patients with platinum-resistant ovarian cancer. Ann Oncol. 2011;22:2411-6 pubmed publisher
    ..No acute allergic infusion reactions were observed. Sagopilone is effective, with balanced tolerability, in patients with recurrent platinum-resistant ovarian cancer. ..
  24. Dizon D, Blessing J, McMeekin D, Sharma S, Disilvestro P, Alvarez R. Phase II trial of ixabepilone as second-line treatment in advanced endometrial cancer: gynecologic oncology group trial 129-P. J Clin Oncol. 2009;27:3104-8 pubmed publisher
    ..CONCLUSION In a cohort of women with advanced or recurrent endometrial cancer who were previously treated with paclitaxel, ixabepilone showed modest activity of limited duration as a second-line agent. ..
  25. Tang L, Chung L, Carney J, Starks C, Licari P, Katz L. Generation of new epothilones by genetic engineering of a polyketide synthase in Myxococcus xanthus. J Antibiot (Tokyo). 2005;58:178-84 pubmed
    b>Epothilones, potent cytotoxic agents and potential anticancer drugs, are complex polyketides produced by a modular polyketide synthase (PKS)...
  26. Vahdat L. Ixabepilone: a novel antineoplastic agent with low susceptibility to multiple tumor resistance mechanisms. Oncologist. 2008;13:214-21 pubmed publisher
    ..One new drug class of great interest in this respect is the epothilones and their analogues, which are microtubule inhibitors with low susceptibility to several mechanisms of drug ..
  27. O Reilly T, McSheehy P, Wenger F, Hattenberger M, Muller M, Vaxelaire J, et al. Patupilone (epothilone B, EPO906) inhibits growth and metastasis of experimental prostate tumors in vivo. Prostate. 2005;65:231-40 pubmed
    ..These data suggest that patupilone holds promise for prostate cancer treatment. ..
  28. Magnani M, Ortuso F, Soro S, Alcaro S, Tramontano A, Botta M. The betaI/betaIII-tubulin isoforms and their complexes with antimitotic agents. Docking and molecular dynamics studies. FEBS J. 2006;273:3301-10 pubmed
    ..Our analysis provides structural insights about the recognition mode and the stabilization mechanism of these antimitotic agents and provides useful suggestions for the design of more potent and selective antimitotic agents. ..
  29. Harrison M, Swanton C. Epothilones and new analogues of the microtubule modulators in taxane-resistant disease. Expert Opin Investig Drugs. 2008;17:523-46 pubmed
    ..Preliminary clinical trial data do suggest modest activity of epothilones in truly taxane-resistant patient cohorts, indicating the potential niche for these agents in a molecularly ..
  30. Ferretti S, Allegrini P, O Reilly T, Schnell C, Stumm M, Wartmann M, et al. Patupilone induced vascular disruption in orthotopic rodent tumor models detected by magnetic resonance imaging and interstitial fluid pressure. Clin Cancer Res. 2005;11:7773-84 pubmed
    ..Changes in IFP preceded and correlated with tumor response, suggesting that IFP may be a surrogate biomarker for patupilone efficacy. ..
  31. Vansteenkiste J, Lara P, Le Chevalier T, Breton J, Bonomi P, Sandler A, et al. Phase II clinical trial of the epothilone B analog, ixabepilone, in patients with non small-cell lung cancer whose tumors have failed first-line platinum-based chemotherapy. J Clin Oncol. 2007;25:3448-55 pubmed
    Ixabepilone is the first in a new class of antineoplastic agents, the epothilones and their analogs...
  32. Fojo T, Menefee M. Mechanisms of multidrug resistance: the potential role of microtubule-stabilizing agents. Ann Oncol. 2007;18 Suppl 5:v3-8 pubmed
    ..polymerization, such as the vinca alkaloids and those that stabilize microtubules, such as the taxanes and epothilones. The taxanes paclitaxel (Taxol) and docetaxel (Taxotere) were the first antimicrotubule agents approved for use ..
  33. Hortobagyi G, Gomez H, Li R, Chung H, Fein L, Chan V, et al. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat. 2010;122:409-18 pubmed publisher
    ..The observed differences in survival favored the combination arm. A clinical benefit was also seen in patients in the KPS 70-80 subgroup. ..
  34. Rosenberg J, Weinberg V, Kelly W, Michaelson D, Hussain M, Wilding G, et al. Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients : randomized phase 2 study of ixabepilone or mitoxantrone and prednisone. Cancer. 2007;110:556-63 pubmed
    ..Ixabepilone and MP had modest activity as second-line chemotherapy for docetaxel-refractory HRPC. The median survival for the entire cohort treated in this study was 9.8 months. ..
  35. Baselga J, Zambetti M, Llombart Cussac A, Manikhas G, Kubista E, Steger G, et al. Phase II genomics study of ixabepilone as neoadjuvant treatment for breast cancer. J Clin Oncol. 2009;27:526-34 pubmed publisher
    ..indicate an inverse relation between ER expression levels and ixabepilone sensitivity. Neoadjuvant ixabepilone demonstrated promising activity and a manageable safety profile in patients with invasive breast tumors. ..
  36. Fumoleau P, Coudert B, Isambert N, Ferrant E. Novel tubulin-targeting agents: anticancer activity and pharmacologic profile of epothilones and related analogues. Ann Oncol. 2007;18 Suppl 5:v9-15 pubmed
    b>Epothilones are 16-member ring macrolides with antimicrotubule activity that share a similar mechanism of action to the taxanes but have demonstrated potent antiproliferative activity in several different multidrug-resistant and ..
  37. Mutka S, Carney J, Liu Y, Kennedy J. Heterologous production of epothilone C and D in Escherichia coli. Biochemistry. 2006;45:1321-30 pubmed
    The epothilones are a family of polyketide natural products that show a high potential as anticancer drugs...
  38. Posadas E, Undevia S, Manchen E, Wade J, Colevas A, Karrison T, et al. A phase II study of ixabepilone (BMS-247550) in metastatic renal-cell carcinoma. Cancer Biol Ther. 2007;6:490-3 pubmed
    ..Ixabepilone administered at a dose of 40 mg/m2 every 21 days should not be advanced for further study in metastatic RCC. Given previous results, however, other dosing schedules may be worthy of further investigation. ..
  39. Rivera E, Gomez H. Chemotherapy resistance in metastatic breast cancer: the evolving role of ixabepilone. Breast Cancer Res. 2010;12 Suppl 2:S2 pubmed publisher
    ..The present article reviews treatment options in taxane-resistant metastatic breast cancer and the role of ixabepilone in this setting. ..
  40. De Geest K, Blessing J, Morris R, Yamada S, Monk B, Zweizig S, et al. Phase II clinical trial of ixabepilone in patients with recurrent or persistent platinum- and taxane-resistant ovarian or primary peritoneal cancer: a gynecologic oncology group study. J Clin Oncol. 2010;28:149-53 pubmed publisher
  41. Peterson J, Tucker C, Favours E, Cheshire P, Creech J, Billups C, et al. In vivo evaluation of ixabepilone (BMS247550), a novel epothilone B derivative, against pediatric cancer models. Clin Cancer Res. 2005;11:6950-8 pubmed
    ..Importantly, the present results showed a clear distinction in sensitivity of pediatric solid tumors to this epothilone derivative compared with paclitaxel. ..
  42. Toppmeyer D, Goodin S. Ixabepilone, a new treatment option for metastatic breast cancer. Am J Clin Oncol. 2010;33:516-21 pubmed publisher
    ..Further clinical studies are evaluating the combination of ixabepilone with targeted agents such as trastuzumab or bevacizumab to further define the role of this novel agent in the treatment of MBC. ..
  43. Mani S, McDaid H, Grossman A, Muggia F, Goel S, Griffin T, et al. Peripheral blood mononuclear and tumor cell pharmacodynamics of the novel epothilone B analogue, ixabepilone. Ann Oncol. 2007;18:190-5 pubmed
    ..Therefore, this technically straightforward assay should be considered as a complement to the clinical development of novel microtubule-binding agents. ..
  44. Ogura H, Nishida C, Hoch U, Perera R, Dawson J, Ortiz de Montellano P. EpoK, a cytochrome P450 involved in biosynthesis of the anticancer agents epothilones A and B. Substrate-mediated rescue of a P450 enzyme. Biochemistry. 2004;43:14712-21 pubmed
    The epothilones are a new class of highly promising anticancer agents with a mode of action akin to that of paclitaxel but with distinct advantages over that drug...
  45. Hoffmann J, Fichtner I, Lemm M, Lienau P, Hess Stumpp H, Rotgeri A, et al. Sagopilone crosses the blood-brain barrier in vivo to inhibit brain tumor growth and metastases. Neuro Oncol. 2009;11:158-66 pubmed publisher
    ..Sagopilone is currently being investigated in a broad phase II clinical trial program, including patients with glioblastoma, NSCLC, breast cancer, and melanoma. ..
  46. Chou T, Zhang X, Zhong Z, Li Y, Feng L, Eng S, et al. Therapeutic effect against human xenograft tumors in nude mice by the third generation microtubule stabilizing epothilones. Proc Natl Acad Sci U S A. 2008;105:13157-62 pubmed publisher
    The epothilones represent a promising class of natural product-based antitumor drug candidates...
  47. Lee F, Borzilleri R, Fairchild C, Kamath A, Smykla R, Kramer R, et al. Preclinical discovery of ixabepilone, a highly active antineoplastic agent. Cancer Chemother Pharmacol. 2008;63:157-66 pubmed publisher
    The epothilones and their analogs constitute a novel class of antineoplastic agents, produced by the myxobacterium Sorangium cellulosum...
  48. Chuang E, Wiener N, Christos P, Kessler R, Cobham M, Donovan D, et al. Phase I trial of ixabepilone plus pegylated liposomal doxorubicin in patients with adenocarcinoma of breast or ovary. Ann Oncol. 2010;21:2075-80 pubmed publisher
    ..This combination demonstrated efficacy in patients with breast and ovarian cancer and merits further evaluation in these settings. ..
  49. Lee J, Swain S. Peripheral neuropathy induced by microtubule-stabilizing agents. J Clin Oncol. 2006;24:1633-42 pubmed
    Microtubule-stabilizing agents (MTSAs), including the taxanes and epothilones, are effective chemotherapeutic agents for the treatment of many cancers...
  50. Buzdar A. Clinical experience with epothilones in patients with breast cancer. Clin Breast Cancer. 2008;8 Suppl 2:S71-8 pubmed
    ..cancer with lower susceptibility to resistance mechanisms than current agents has led to the discovery of the epothilones and their analogues...
  51. Reichenbach H, Hofle G. Discovery and development of the epothilones : a novel class of antineoplastic drugs. Drugs R D. 2008;9:1-10 pubmed
    The epothilones are a novel class of antineoplastic agents possessing antitubulin activity. The compounds were originally identified as secondary metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum...
  52. Feyen F, Cachoux F, Gertsch J, Wartmann M, Altmann K. Epothilones as lead structures for the synthesis-based discovery of new chemotypes for microtubule stabilization. Acc Chem Res. 2008;41:21-31 pubmed
    b>Epothilones are macrocyclic bacterial natural products with potent microtubule-stabilizing and antiproliferative activity...
  53. Oehler C, Von Bueren A, Furmanova P, Broggini Tenzer A, Orlowski K, Rutkowski S, et al. The microtubule stabilizer patupilone (epothilone B) is a potent radiosensitizer in medulloblastoma cells. Neuro Oncol. 2011;13:1000-10 pubmed publisher