Structure–Activity Relationship of the Epothilones and the First In Vivo Comparison with Paclitaxel

Su, Dai‐Shi; Balog, Aaron; Meng, Dongfang; Bertinato, Peter; Zheng, Yongxiang; Chou, Ting‐Chao; He, Liangmei; Horwitz, Susan Band

doi:10.1002/anie.199720931

Cited by 126 publications

(111 citation statements)

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“…Of these 5 patients, 2 developed Grade 4 neutropenia. The ANC nadirs of the other 3 patients were 1006/mm 3 , 2412/mm 3 , and 2001/mm 3 . The ranges and medians of the nadirs of the ANC, platelet count, and hemoglobin level during cycle 1 are listed in Table 3.…”

Section: Dose Escalationmentioning

confidence: 89%

“…In vitro, ixabepilone is cytotoxic at low nanomolar concentrations, more potent than the taxanes at inducing microtubule polymerization, and it is synergistic with a number of other anticancer agents. 2,3,5 In vivo, ixabepilone is orally bioavailable and the antitumor activity observed after oral administration is comparable to that observed after parenteral administration. Ixabepilone is more active against in vivo tumor models when administered in divided doses.…”

mentioning

confidence: 98%

“…[1][2][3][4][5][6] The epothilones are obtained from the fermentation broth of the cellulose-degrading myxobacterium, Sorangium cellulosum. 7 These natural products are polyketide-derived, 16-membered ring macrolides.…”

mentioning

confidence: 99%

“…Ixabepilone is more active against in vivo tumor models when administered in divided doses. 2,3,5 Furthermore, ixabepilone has a broad spectrum of activity in vitro and in vivo against cancer models that are naturally insensitive to the taxanes or have developed resistance to the taxanes, 2,3,5 suggesting that it may offer improved clinical efficacy in taxane-insensitive and taxane-sensitive cancers. Preliminary data from Phase I and II trials indicate potential activity of ixabepilone in breast, cervical, pancreatic, prostate, and renal cell carcinomas.…”

mentioning

confidence: 99%

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A Phase I clinical trial of ixabepilone (BMS‐247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days

Zhuang

Agrawal

Edgerly

et al. 2005

Cancer

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BACKGROUNDThe epothilones are a novel class of microtubule‐stabilizing agents. Ixabepilone (BMS‐247550; NSC 710428) is a semisynthetic analog of the natural product epothilone B. The authors conducted a Phase I study by administering ixabepilone to patients as a 1‐hour intravenous infusion daily for 3 consecutive days every 21 days.METHODSTwenty‐six patients were enrolled and received ixabepilone at a starting dose of 8 or 10 mg/m2 per day for 3 consecutive days.RESULTSOne hundred and nineteen cycles were administered to 26 patients. The maximum‐tolerated dose was 8 mg/m2 per day of ixabepilone administered as a 1‐hour intravenous infusion daily for 3 consecutive days every 21 days. The dose‐limiting toxicity (DLT) was neutropenia. Other nonhematologic Grade 3 toxicities included fatigue (3 cycles), hyponatremia (1 cycle), anorexia (1 cycle), ileus (1 cycle), stomatitis (1 cycle), and emesis (1 cycle). Prolonged disease stabilization was observed in patients with mesothelioma, ovarian carcinoma, and renal cell carcinoma.CONCLUSIONSThe recommended Phase II dose of ixabepilone on the daily schedule for 3 days was 8–10 mg/m2 per day. Neutropenia was the DLT. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting. Cancer 2005. Published 2005 by the American Cancer Society.

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Section: Dose Escalationmentioning

confidence: 89%

mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A Phase I clinical trial of ixabepilone (BMS‐247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days

Zhuang

Agrawal

Edgerly

et al. 2005

Cancer

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“…More recently discovered compounds with a taxol-like mechanism of action include the discodermolides (4,5), eleutherobins (6), laulimalides (7), and epothilones (8)(9)(10)(11)(12)(13)(14). Despite their supposed common binding site on tubulin assemblies (15)(16)(17)(18), their chemical structures and͞or pharmacological profiles are drastically different.…”

mentioning

confidence: 99%

The synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: Curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice

Chou

O’Connor

Tong

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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108

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We have evaluated two synthetic epothilone analogues lacking the 12,13-epoxide functionality, 12,13-desoxyepothilone B (dEpoB), and 12,13-desoxyepothilone F (dEpoF). The concentrations required for 50% growth inhibition (IC50) for a variety of anticancer agents were measured in CCRF-CEM͞VBL1000 cells (2,048-fold resistance to vinblastine). By using dEpoB, dEpoF, aza-EpoB, and paclitaxel, 8 yr). This continued exposure led to the development of 2.1-, 4,848-, and 2,553-fold resistance to each drug, respectively. The therapeutic effect of dEpoB and paclitaxel was also compared in vivo in a mouse model by using various tumor xenografts. dEpoB is much more effective in reducing tumor sizes in all MDR tumors tested. Analysis of dEpoF, an analog possessing greater aqueous solubility than dEpoB, showed curative effects similar to dEpoB against K562, CCRF-CEM, and MX-1 xenografts. These results indicate that dEpoB and dEpoF are efficacious antitumor agents with both a broad chemotherapeutic spectrum and wide safety margins.

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Chemie und Biologie der Epothilone

1998

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Nur wenige Monate nach Veröffentlichung der absoluten Konfiguration von Epothilon A (siehe rechts, R=H) und B (R=Me) wurden bereits die ersten Totalsynthesen dieser Naturstoffe beschrieben. Sie zogen schon zuvor wegen ihrer starken cytostatischen Eigenschaften viel Aufmerksamkeit auf sich, wobei ihr Wirkungsmechanismus dem von Taxol ähnelt. Neben der Beschreibung der wichtigsten Totalsynthesen und biologischen Eigenschaften der natürlichen Epothilone A–E bietet der Aufatz von Nicolaou et al. auch eine systematische Übersicht über zahlreiche Epothilon‐Analoga, die in den Regionen A–D modifiziert wurden, um Erkenntnisse über Struktur‐Aktivitäts‐Beziehungen zu erhalten.

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Structure–Activity Relationship of the Epothilones and the First In Vivo Comparison with Paclitaxel

Cited by 126 publications

References 28 publications

A Phase I clinical trial of ixabepilone (BMS‐247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days

A Phase I clinical trial of ixabepilone (BMS‐247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days

The synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: Curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice

Chemie und Biologie der Epothilone

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