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The Oncologist, Vol. 13, No. 3, 214-221, March 2008; doi:10.1634/theoncologist.2007-0167
© 2008 AlphaMed Press

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Breast Cancer

Ixabepilone: A Novel Antineoplastic Agent with Low Susceptibility to Multiple Tumor Resistance Mechanisms

Linda Vahdat

Weill Cornell Breast Center, Weill Cornell Medical College, New York, New York, USA

Key Words. Epothilones • Ixabepilone • Taxanes • Drug resistance • Solid tumors

Correspondence: Linda Vahdat, M.D., Breast Cancer Research Program, Weill Medical College of Cornell University, 425 E. 61st, 8th Floor, New York, New York 10065, USA. Telephone: 212-821-0644; Fax: 212-821-0758; e-mail: ltv2001{at}med.cornell.edu

Received September 18, 2007; accepted for publication January 29, 2008.

Disclosure: L.V. has acted as a consultant to Bristol-Myers Squibb Oncology within the last 2 years. No other potential conflicts of interest were reported by the author, planners, reviewers, or staff managers of this article.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 Clinical Activity of Ixabepilone
 Ixabepilone: In Vitro Activity...
 Ixabepilone: Preclinical...
 Mode of Action of...
 Future Developments
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Evaluate the clinical significance of the lower susceptibility of epothilones to key mechanisms of drug resistance.
  2. Explain the key mechanisms of drug resistance to which epothilones display lower susceptibility.
  3. Describe the mechanism of action of ixabepilone.
  4. Describe how ixabepilone promotes tumor cell death through apoptosis.
  5. Identify six types of solid tumors in which ixabepilone has demonstrated single-agent activity.
  6. Discuss the preclinical and clinical activity of ixabepilone in chemotherapy-resistant tumors.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Clinical Activity of Ixabepilone
 Ixabepilone: In Vitro Activity...
 Ixabepilone: Preclinical...
 Mode of Action of...
 Future Developments
 Conclusions
 References
 
Tumor resistance to chemotherapeutic agents ultimately leads to treatment failure in the majority of cancer patients. The identification of new agents that are less susceptible to mechanisms of tumor resistance could, therefore, bring significant clinical benefits to patients with advanced cancer. 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 resistance.

Ixabepilone is an analogue of natural epothilone B with activity against a wide range of tumor types, including drug-resistant tumors. This is consistent with the preclinical activity of ixabepilone against human cancer cell lines resistant to taxanes and other agents. Taxane resistance in these cells may be acquired or primary and results from several mechanisms, such as overexpression of multidrug-resistance proteins and the βIII-tubulin isoform.

Ixabepilone has demonstrated efficacy as monotherapy or in combination with capecitabine in anthracycline- and taxane-pretreated/resistant metastatic breast cancer (MBC), and has recently been approved for use in resistant/refractory MBC. Other epothilones, such as patupilone, KOS-1584, and ZK-EPO, are also being evaluated in drug-resistant cancers. Ixabepilone represents a new treatment option for MBC patients with cancers resistant to available chemotherapeutic agents.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Clinical Activity of Ixabepilone
 Ixabepilone: In Vitro Activity...
 Ixabepilone: Preclinical...
 Mode of Action of...
 Future Developments
 Conclusions
 References
 
Resistance to chemotherapeutics remains one of the most significant stumbling blocks to achieving long-term remissions in cancer therapy. While the currently available chemotherapy agents certainly induce clinical responses, cancers ultimately progress in the vast majority of cases after a period of ongoing response [1]. Multidrug resistance (MDR) to a particular agent is defined as resistance not only to other agents of the same drug class, but also to agents from structurally unrelated classes. This is often a result of overexpression of efflux pump proteins such as P-glycoprotein (P-gp; encoded by MDR1) and multidrug resistance–associated protein (MRP) [1]. These efflux pumps limit the effectiveness of agents such as anthracyclines and taxanes by transporting them out of their site of action within tumor cells. Tumor resistance can be primary or acquired. In the case of primary resistance, there is high physiologic expression of MDR proteins in the tissue from which the tumor arises, as is seen in renal or hepatic tissues [2]. In other cases, resistance is acquired, resulting from de novo MDR protein overexpression following treatment with MDR-inducing agents. Although attempts have been made to overcome MDR through treatment with reversal agents, to date these have been largely unsuccessful (for a review, see Nobili et al. [3]).

In general, mechanisms of resistance to microtubule inhibitors (MTIs) are somewhat different from those of other drug classes in that alterations in the molecular target, tubulin, also can result in acquired resistance. For example, expression of the βIII-tubulin isoform has been associated with poor response to taxanes in non-small cell lung carcinoma (NSCLC) [4], ovarian cancer [5], gastric cancer [6], and prostate cancer [7]. Furthermore, mutations in β-tubulin can also prevent taxanes from binding to their target [8], and hence from stabilizing microtubules (the mechanism of action of this class of agent). Therefore, one avenue of antineoplastic drug development has focused on identifying compounds that are less susceptible to these common drug-resistance mechanisms; such agents may represent a clinically significant addition to the armamentarium of treatment options that could be used to treat drug-resistant cancer and ultimately extend survival.

One new class of agents that is of interest in this regard is the epothilones and their analogues. These are 16-member macrolides produced by the myxobacterium Sorangium cellulosum [9, 10]. Epothilones A and B, in particular, have high in vitro antitumor activity through their ability to disrupt microtubule dynamics, leading to cell-cycle arrest and apoptosis [11]. Although they share a common therapeutic target with other MTIs, the epothilones have a distinct mode of binding to tubulin that may reduce cross-resistance. Significantly, epothilones display lower susceptibility to several key mechanisms of drug resistance, such as elevated expression of MDR, overexpression of βIII-tubulin, and β-tubulin mutations [12–14], making them interesting candidates for evaluation in the clinic, especially in diseases where anthracyclines and taxanes are heavily used.

Since the initial identification of natural epothilones as antineoplastic agents, chemical modification has allowed the generation of synthetic and semisynthetic analogues with superior metabolic and pharmacokinetic properties in the clinical setting. Ixabepilone (BMS-247550, aza-epothilone B), a semisynthetic analogue of epothilone B, has a lactone–lactam modification that minimizes susceptibility to esterase degradation [15]. Ixabepilone has been shown to have clinical activity against multiple tumor types, including those resistant to common chemotherapeutic agents, and is effective in metastatic breast cancer (MBC) as monotherapy or in combination with capecitabine. This review briefly summarizes these clinical data and focuses on the preclinical characteristics of ixabepilone that allow it to overcome both primary and acquired tumor resistance.


   CLINICAL ACTIVITY OF IXABEPILONE
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Activity of Ixabepilone
Ixabepilone: In Vitro Activity...
 Ixabepilone: Preclinical...
 Mode of Action of...
 Future Developments
 Conclusions
 References
 
Ixabepilone has demonstrated single-agent activity against a wide variety of solid tumors, including breast cancer (early- and late-stage disease) [16, 17], NSCLC [18], pancreatic cancer [19], renal cell cancer (RCC) [20], prostate cancer [21], and lymphoma [22]. The majority of these studies involved tumors that were heavily pretreated. The largest phase II trial with ixabepilone monotherapy was conducted in anthracycline-, taxane-, and capecitabine-resistant MBC patients [23]. In this population, ixabepilone (administered at a dose of 40 mg/m2 as a 3-hour i.v. infusion every 3 weeks) produced an overall response rate (ORR) of 12% and a median progression-free survival (PFS) time of 3.1 months [23]. Ixabepilone also showed activity in another phase II trial in taxane-resistant MBC patients, with a response rate of 12% [24]. A phase II trial evaluated ixabepilone (administered at a dose of 32 mg/m2 as a 3-hour i.v. infusion every 3 weeks or at a dose of 6 mg/m2 as a 1-hour i.v. infusion for five consecutive days every 3 weeks) in NSCLC patients who had failed a first-line platinum-based chemotherapy regimen [18]. ORRs of 14.3% (32 mg/m2 dose) and 11.6% (6 mg/m2 daily x 5 dose) were reported [18].

Two additional phase II trials have evaluated the activity of ixabepilone in patients with metastatic prostate cancer. Ixabepilone monotherapy produced prostate-specific antigen (PSA) declines of >50% in 17% of patients with hormone- and taxane-refractory prostate cancer, with a median survival time of 10.4 months [25]. A second trial evaluated the activity of ixabepilone as a single agent or in combination with estramustine phosphate in chemotherapy-naïve prostate cancer patients progressing after castration. PSA declines of >50% were observed in 48% of patients treated with ixabepilone monotherapy and 68% of patients treated with the combination regimen [26]. ORRs were 32% for ixabepilone monotherapy and 48% for the combination of ixabepilone plus estramustine [26]. Efficacy results from ixabepilone trials in resistant/pretreated cancers are summarized in Table 1. Clinical trials comparing the efficacy and safety of ixabepilone with those of taxanes are in progress in MBC patients. Nonetheless, in taxane-sensitive tumors, the activity of ixabepilone appears to be comparable with that of other chemotherapeutic agents [27].


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  		Table 1. Clinical efficacy of ixabepilone against a range of resistant/pretreated tumors

 
Ongoing or planned phase I/II studies in a range of tumors are investigating whether ixabepilone can also be safely combined with a variety of agents, including liposomal doxorubicin, bevacizumab, cetuximab, and epirubicin (see http://www.ClinicalTrials.gov). A phase II study in advanced breast cancer demonstrated activity and an acceptable safety profile for ixabepilone combined with capecitabine in taxane- and anthracycline-pretreated MBC patients [28]. A large, randomized, phase III trial comparing ixabepilone plus capecitabine with capecitabine monotherapy demonstrated greater efficacy for the combination with a significantly longer median PFS time (5.8 months versus 4.2 months; p < .001) and higher response rate (35% versus 14%; p < .001) [27].

In addition to these studies in tumors with acquired resistance to chemotherapy, ixabepilone has also been shown to have activity in the treatment of cancers that are typically considered chemotherapy resistant. For example, ixabepilone has activity in RCC [20], suggesting that this agent may represent a treatment option even for this highly refractory disease [29] that is known to be one of the tumors with the highest levels of endogenous MDR [2]. Ixabepilone also demonstrated marked activity against advanced pancreatic cancer in a phase II study, resulting in a 6-month survival rate (the primary endpoint) of 60% [19]. This disease currently has a very poor prognosis, even following treatment with gemcitabine, the current standard of care [30].

The main toxicities typically associated with ixabepilone treatment (administered at a dose of 40 mg/m2 every 3 weeks) are neutropenia, sensory neuropathy, fatigue, arthralgias, myalgias, and stomatitis. These adverse effects are often manageable with dose modifications/supportive therapy, and the sensory neuropathy has been reversible in most cases once treatment is modified or stopped. Various phase II studies conducted with alternative dosing of ixabepilone (administered at a dose of 6 mg/m2 as a 1-hour i.v. infusion on days 1–5 every 3 weeks) have reported a lower rate of grade 3 or 4 sensory neuropathy. These include taxane-pretreated MBC (n = 37; rate, 3%), taxane-naïve MBC (n = 22; rate, 0%), and platinum-pretreated/refractory NSCLC (n = 69; rate, 6%) [16, 18, 31].

Overall survival for MBC patients has improved over the past 5 years with the introduction of multiple, new active agents [32]. However, drug-resistant disease is an increasing clinical challenge, and ixabepilone (or other members of this novel drug class) may prove to be of value in this context, based on the clinical experience to date [17, 23, 24]. The remainder of this review focuses on the characteristics of ixabepilone at a preclinical level, which may, at least in part, explain the activity observed in the clinical setting.


   IXABEPILONE: IN VITRO ACTIVITY IN DRUG-RESISTANT CELL LINES
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Activity of Ixabepilone
 Ixabepilone: In Vitro Activity...
Ixabepilone: Preclinical...
 Mode of Action of...
 Future Developments
 Conclusions
 References
 
Ixabepilone is highly active in vitro, with cytotoxicity demonstrated against a panel of 21 cell lines derived from breast, lung, prostate, colon, and ovarian cancers, as well as leukemias [15]. Fifty percent inhibitory concentration values of ixabepilone in these cell lines are low, in the range of 1.4–34.5 nM. Importantly, in vitro activity is retained in cell lines selected for resistance to paclitaxel, including the HCT116/VM46 colon and A2780Tax ovarian cancer lines, which are resistant to paclitaxel as a result of overexpression of MDR proteins [33] and a mutation in β-tubulin [34], respectively. Clonogenic cell-killing experiments further demonstrate that, while paclitaxel and ixabepilone display similar cell-killing activity against paclitaxel-sensitive cell lines, ixabepilone is substantially more cytotoxic than paclitaxel against lines defined as paclitaxel resistant [15] (Table 2). Moreover, in these paclitaxel-resistant cell lines, ixabepilone almost completely retains the antineoplastic activity it has against paclitaxel-sensitive cell lines (Table 2).


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  		Table 2. Preclinical activity of ixabepilone versus paclitaxel against pretreated/resistant human tumor models [15]

 

   IXABEPILONE: PRECLINICAL ACTIVITY IN VIVO
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Activity of Ixabepilone
 Ixabepilone: In Vitro Activity...
 Ixabepilone: Preclinical...
Mode of Action of...
 Future Developments
 Conclusions
 References
 
The observed in vitro activity of ixabepilone against resistant tumor cell lines is recapitulated in vivo using xenograft models with tumors derived from the cell lines described above and from other drug-resistant cell lines (Table 2) [15]. These include xenografts displaying acquired resistance to paclitaxel through a range of mechanisms: MDR-mediated drug efflux, β-tubulin mutation, and overexpression of the βIII-tubulin isoform. For example, activity is seen in the HCT116/VM46 xenograft model (described above) and in Pat-7, which was established directly from an ovarian tumor biopsy immediately following the development of paclitaxel resistance and expresses high levels of MDR and MRP1 [15]. The in vivo activity of ixabepilone in these models is consistent with the low susceptibility of this agent to cell membrane transporters such as P-gp and MRP1 [12]. Importantly, ixabepilone does not appear to induce expression of the MDR or MRP1 genes, a characteristic that could potentially prevent the development of cross-resistance with other agents [12]. In vivo activity of ixabepilone is also seen in the A2780Tax ovarian cancer xenograft model, indicating that ixabepilone is unaffected by the specific point mutation in β-tubulin that confers resistance to paclitaxel in these cells. Ixabepilone also displays in vivo activity in the Pat-21 breast cancer xenograft model, which is derived from a biopsy of a tumor that was clinically resistant to paclitaxel because of overexpression of βIII-tubulin and downregulation of the βII isoform [14]. Preclinical experiments have demonstrated that, unlike paclitaxel, ixabepilone can bind multiple isoforms of β-tubulin, including the βIII isoform [14]. These results are consistent with the recent demonstration, through computational methods, that epothilone A displays no preference for either the βI- or βIII-tubulin isoform [35].

Importantly, in addition to the xenograft models described above, ixabepilone is also active in vivo against a pancreatic tumor xenograft displaying intrinsic insensitivity to paclitaxel [15]. This tumor xenograft, Pat-26, was derived from a liver metastasis in a pancreatic cancer patient who had never received chemotherapy, suggesting that ixabepilone may also provide clinical benefit to patients with cancers considered intrinsically resistant to the currently available agents. In all cases described above, the antitumor activity of ixabepilone (as measured by log-cell kill) was 3.0 to 5.3-fold greater than that of paclitaxel.

In summary, these findings, together with the in vitro findings described above, demonstrate that ixabepilone has high activity against a wide range of tumor types in the preclinical setting. Moreover, ixabepilone has lower susceptibility to several key mechanisms of tumor resistance. It is these two characteristics of ixabepilone that collectively underlie the clinical activity of this agent across tumor types, including heavily pretreated and drug-resistant tumors.


   MODE OF ACTION OF IXABEPILONE
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Activity of Ixabepilone
 Ixabepilone: In Vitro Activity...
 Ixabepilone: Preclinical...
 Mode of Action of...
Future Developments
 Conclusions
 References
 
Like the natural epothilones A and B, ixabepilone promotes tumor cell death by stabilizing microtubules and inducing apoptosis [36], and is a highly active MTI [15]. Significantly, ixabepilone induces apoptosis through multiple pathways that appear to be selective to this class of agents, including enhancement of caspase-2 activity [37] and p53-mediated activation of the death effector Bax via induction of PUMA (p53 upregulated modulator of apoptosis) expression [38]. In contrast, taxanes mediate apoptosis primarily via caspase 9 activation [36]. These differences in mode of action may, at least in part, underlie the activity of ixabepilone against multiple tumor types that are resistant and/or refractory to taxanes.


   FUTURE DEVELOPMENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Activity of Ixabepilone
 Ixabepilone: In Vitro Activity...
 Ixabepilone: Preclinical...
 Mode of Action of...
 Future Developments
Conclusions
 References
 
The promising phase II clinical results with ixabepilone have led to two large phase III trials evaluating ixabepilone in combination with capecitabine versus capecitabine alone. The first study in patients with anthracycline- and taxane-pretreated MBC (NCT00080301) has been completed and demonstrated superior efficacy for the combination of ixabepilone plus capecitabine, with a significantly longer median PFS time and higher response rate [24]. Based on its activity, ixabepilone was approved by the U.S. Food and Drug Administration in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to an anthracycline and a taxane. In addition, in view of data obtained in phase II trials, ixabepilone was approved as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

A second phase III study in patients with anthracycline-pretreated, taxane-resistant MBC (NCT00082433) has completed recruitment of patients [39]. That study will examine overall survival in the taxane-resistant patient population.

Once an agent has demonstrated efficacy in the metastatic setting, it is of great interest to evaluate the same agent in earlier stages of disease, where maximum benefit can be obtained. Various studies have shown that, in the neoadjuvant setting, MDR expression may represent one of the main determinants of resistance to chemotherapy in breast cancer patients [40, 41]. Thus, early disease may provide an opportunity to assess the activity of ixabepilone in MDR-related resistant breast cancer. Ixabepilone, therefore, has also been evaluated as a single agent in the neoadjuvant setting for breast cancer [42]. A pathologic complete response in the breast (pCRB) was observed in 18% of patients after four cycles of therapy [42]. In addition, 32% of patients were able to undergo breast-conserving surgery [42]. The 18% pCRB rate reported after four cycles of ixabepilone compared favorably with the pCRB rates in studies of single-agent taxanes administered for four cycles of neoadjuvant therapy [42].

Other epothilones are also undergoing clinical evaluation, and have been shown to have activity in the drug-resistant setting. Of these, patupilone (EPO-906, natural epothilone B) is furthest along in development. Patupilone has demonstrated preclinical in vitro and in vivo activity against a range of tumor lines [13, 43, 44], including those overexpressing MDR proteins [11, 13, 43]. It will now be of interest to see whether this agent also retains activity against paclitaxel-resistant cell lines overexpressing βIII-tubulin or bearing β-tubulin mutations, as observed for ixabepilone. Phase II studies have demonstrated the activity of patupilone against drug-resistant disease, including RCC and relapsed/refractory ovarian cancer [45, 46], and phase III studies are in progress. Epothilone D (desoxyepothilone B; KOS-862) also has demonstrated preclinical activity against a number of MDR xenografts, including the doxorubicin-resistant breast cancer line MCF7 (see Goodin et al. [47]). Clinically, phase II efficacy of epothilone D has been shown in anthracycline- and taxane-pretreated MBC patients [48, 49]. The fully synthetic epothilone B analogue ZK-EPO also has demonstrated in vivo preclinical activity against resistant tumor cell lines, including breast, colorectal, ovarian, lung, and pancreatic cancer, glioma, and melanoma models [50, 51]. Preliminary clinical results show that ZK-EPO has some activity in taxane-pretreated or resistant breast cancer [52] and uterine cancer [53]. In a phase II trial in patients with platinum-resistant ovarian cancer that evaluated two dosing schedules of ZK-EPO, an ORR of 19% was reported [54]. Finally, the epothilone D analogue KOS-1584 (dehydelone) has been shown to have preclinical activity against a range of tumor types, including paclitaxel-resistant lymphoblastic leukemia and NSCLC [55]. Dehydelone is at a very early stage of clinical development, but preliminary data from a phase I trial suggest that this agent led to minor responses or disease stabilization in some patients with various tumors [56, 57].


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Activity of Ixabepilone
 Ixabepilone: In Vitro Activity...
 Ixabepilone: Preclinical...
 Mode of Action of...
 Future Developments
 Conclusions
References
 
Because of the high incidence of tumor resistance to available chemotherapeutic agents, there is a pressing need for new antineoplastics with efficacy in patients with drug-resistant disease. The epothilones and their analogues are a class of highly active MTIs that have low susceptibility to several mechanisms of tumor resistance. The epothilone B analogue ixabepilone has been approved as monotherapy or in combination with capecitabine for the treatment of resistant/refractory MBC and has been shown to have promising clinical activity against various other tumor types. The unique mode of binding of ixabepilone to its therapeutic target, its activation of selective apoptotic pathways, and its low susceptibility to multiple mechanisms of tumor resistance are important properties that underlie the clinical activity of this agent. The outcomes of clinical studies with other agents in this class and further clinical development of ixabepilone, including its use in earlier stages of breast cancer, are eagerly awaited.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Clinical Activity of Ixabepilone
 Ixabepilone: In Vitro Activity...
 Ixabepilone: Preclinical...
 Mode of Action of...
 Future Developments
 Conclusions
 References
 

  1. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol 2005;205:275–292.[CrossRef][Medline]
  2. Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins: Role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 2005;204:216–237.[CrossRef][Medline]
  3. Nobili S, Landini I, Giglioni B et al. Pharmacological strategies for overcoming multidrug resistance. Curr Drug Targets 2006;7:861–879.[CrossRef][Medline]
  4. Seve P, Mackey J, Isaac S et al. Class III beta-tubulin expression in tumor cells predicts response and outcome in patients with non-small cell lung cancer receiving paclitaxel. Mol Cancer Ther 2005;4:2001–2007.[Abstract/Free Full Text]
  5. Mozzetti S, Ferlini C, Concolino P et al. Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients. Clin Cancer Res 2005;11:298–305.[Abstract/Free Full Text]
  6. Urano N, Fujiwara Y, Doki Y et al. Clinical significance of class III beta-tubulin expression and its predictive value for resistance to docetaxel-based chemotherapy in gastric cancer. Int J Oncol 2006;28:375–381.[Medline]
  7. Ranganathan S, Benetatos CA, Colarusso PJ et al. Altered beta-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells. Br J Cancer 1998;77:562–566.[Medline]
  8. Monzo M, Rosell R, Sanchez JJ et al. Paclitaxel resistance in non-small-cell lung cancer associated with beta-tubulin gene mutations. J Clin Oncol 1999;17:1786–1793.[Abstract/Free Full Text]
  9. Höfle G, Bedorf N. Epothilone, deren herstellungsverfahren sowie sie enthaltende mittel. Available at http://v3.espacenet.com/results?DB=EPODOC&sf=a&PN=DE4138042&CY=ep&PGS=10&ST=advanced&LG=en. Accessed August 9, 2007.
  10. Gerth K, Bedorf N, Hofle G et al. Epothilones A and B: Antifungal and cytotoxic compounds from Sorangium cellulosum (Myxobacteria). Production, physico-chemical and biological properties. J Antibiot (Tokyo) 1996;49:560–563.[Medline]
  11. Bollag DM, McQueney PA, Zhu J et al. Epothilones, a new class of microtubule-stabilizing agents with a Taxol-like mechanism of action. Cancer Res 1995;55:2325–2333.[Abstract/Free Full Text]
  12. Wartmann M, Altmann KH. The biology and medicinal chemistry of epothilones. Curr Med Chem Anticancer Agents 2002;2:123–148.[CrossRef][Medline]
  13. Kowalski RJ, Giannakakou P, Hamel E. Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol®). J Biol Chem 1997;272:2534–2541.[Abstract/Free Full Text]
  14. Jordan MA, Miller H, Ray A et al. The Pat-21 breast cancer model derived from a patient with primary Taxol® resistance recapitulates the phenotype of its origin, has altered β-tubulin expression and is sensitive to ixabepilone. Proc Am Assoc Cancer Res 2006;47:LB-280a.
  15. Lee FY, Borzilleri R, Fairchild CR et al. BMS-247550: A novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 2001;7:1429–1437.[Abstract/Free Full Text]
  16. Low JA, Wedam SB, Lee JJ et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol 2005;23:2726–2734.[Abstract/Free Full Text]
  17. Roché H, Yelle L, Cognetti F et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy. J Clin Oncol 2007;25:3415–3420.[Abstract/Free Full Text]
  18. Vansteenkiste J, Lara PN Jr, Le Chevalier T 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;25:3448–3455.[Abstract/Free Full Text]
  19. Whitehead RP, McCoy S, Rivkin SE et al. A phase II trial of epothilone B analogue BMS-247550 (NSC #710428) ixabepilone, in patients with advanced pancreas cancer: A Southwest Oncology Group study. Invest New Drugs 2006;24:515–520.[CrossRef][Medline]
  20. Fojo AT, Menefee ME, Poruchynsky M et al. A translational study of ixabepilone (BMS-247550) in renal cell cancer (RCC): Assessment of its activity and demonstration of target engagement in tumor cells. J Clin Oncol 2005;23:388S.
  21. Hussain M, Tangen CM, Lara PN Jr 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;23:8724–8729.[Abstract/Free Full Text]
  22. O'Connor O, Straus D, Moskowitz C et al. Targeting the microtubule apparatus in indolent and mantle cell lymphoma with the novel epothilone analog BMS 247550 induces major and durable remissions in very drug resistant disease. J Clin Oncol 2005;23:577s.
  23. Perez EA, Lerzo G, Pivot X et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 2007;25:3407–3414.[Abstract/Free Full Text]
  24. Thomas E, Tabernero J, Fornier M et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol 2007;25:3399–3406.[Abstract/Free Full Text]
  25. Rosenberg JE, Weinberg VK, Kelly WK 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;110:556–563.[CrossRef][Medline]
  26. Galsky MD, Small EJ, Oh WK et al. Multi-institutional randomized phase II trial of the epothilone B analog ixabepilone (BMS-247550) with or without estramustine phosphate in patients with progressive castrate metastatic prostate cancer. J Clin Oncol 2005;23:1439–1446.[Abstract/Free Full Text]
  27. Thomas ES, Gomez HL, Li RK et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 2007;25:5210–5217.[Abstract/Free Full Text]
  28. Bunnell CA, Klimovsky J, Thomas E. Final efficacy results of a phase I/II trial of ixabepilone in combination with capecitabine in patients with metastatic breast cancer (MBC) previously treated with a taxane and an anthracycline. J Clin Oncol 2006;24;(18) (suppl):10511a.
  29. National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology. Kidney Cancer. Version 3.2007. Accessed December 19, 2007.
  30. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Pancreatic Adenocarcinoma. Version 1.2007. Accessed August 9, 2007.
  31. Denduluri N, Low JA, Lee JJ 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;25:3421–3427.[Abstract/Free Full Text]
  32. Gennari A, Conte P, Rosso R et al. Survival of metastatic breast carcinoma patients over a 20-year period: A retrospective analysis based on individual patient data from six consecutive studies. Cancer 2005;104:1742–1750.[CrossRef][Medline]
  33. Long BH, Wang L, Lorico A et al. Mechanisms of resistance to etoposide and teniposide in acquired resistant human colon and lung carcinoma cell lines. Cancer Res 1991;51:5275–5283.[Abstract/Free Full Text]
  34. Giannakakou P, Sackett DL, Kang YK et al. Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. J Biol Chem 1997;272:17118–17125.[Abstract/Free Full Text]
  35. Magnani M, Ortuso F, Soro S et al. The betaI/betaIII-tubulin isoforms and their complexes with antimitotic agents. Docking and molecular dynamics studies. FEBS J 2006;273:3301–3310.[CrossRef][Medline]
  36. Bode CJ, Gupta ML Jr, Reiff EA et al. Epothilone and paclitaxel: Unexpected differences in promoting the assembly and stabilization of yeast microtubules. Biochemistry 2002;41:3870–3874.[CrossRef][Medline]
  37. Rojas-Espaillet LA, Uyar D, Grabowski D et al. Apoptotic pathways induced by ixabepilone in paclitaxel-refractory ovarian carcinoma cells. Proc Am Assoc Cancer Res 2005;46:5318a.
  38. Yamaguchi H, Chen J, Bhalla K et al. Regulation of Bax activation and apoptotic response to microtubule-damaging agents by p53 transcription-dependent and -independent pathways. J Biol Chem 2004;279:39431–39437.[Abstract/Free Full Text]
  39. ClinicalTrials.gov. Epothilone (Ixabepilone) Plus Capecitabine Versus Capecitabine Alone in Patients With Advanced Breast Cancer. Available at http://clinicaltrials.gov/show/NCT00082433. Accessed August 9, 2007.
  40. Chevillard S, Pouillart P, Beldjord C et al. Sequential assessment of multidrug resistance phenotype and measurement of S-phase fraction as predictive markers of breast cancer response to neoadjuvant chemotherapy. Cancer 1996;77:292–300.[CrossRef][Medline]
  41. Wang CS, LaRue H, Fortin A et al. mdr1 mRNA expression by RT-PCR in patients with primary breast cancer submitted to neoadjuvant therapy. Breast Cancer Res Treat 1997;45:63–74.[CrossRef][Medline]
  42. Baselga J, Gianni L, Llombart A et al. Predicting response to ixabepilone: Genomics study in patients receiving single agent ixabepilone as neoadjuvant treatment for breast cancer (BC). Breast Cancer Res Treat 2005;94:S31.
  43. Altmann KH, Wartmann M, O'Reilly T. Epothilones and related structures – a new class of microtubule inhibitors with potent in vivo antitumor activity. Biochim Biophys Acta 2000;1470:M79–M91.[Medline]
  44. O'Reilly T, McSheehy PM, Wenger F et al. Patupilone (epothilone B, EPO906) inhibits growth and metastasis of experimental prostate tumors in vivo. Prostate 2005;65:231–240.[CrossRef][Medline]
  45. Smit W, Sufliarsky J, Spanik S et al. Phase I/II dose-escalation trial of patupilone every 3 weeks in patients with relapsed/refractory ovarian cancer. J Clin Oncol 2005;23:5056a.
  46. Thompson J, Swerdloff J, Escudier B et al. Phase II trial evaluating the safety and efficacy of EPO906 in patients with advanced renal cancer. Proc Am Soc Clin Oncol 2003;22:405.
  47. Goodin S, Kane MP, Rubin EH. Epothilones: Mechanism of action and biologic activity. J Clin Oncol 2004;22:2015–2025.[Abstract/Free Full Text]
  48. Buzdar A, Silverman P, Kaufman PA et al. A phase II study of KOS-862 (epothilone D) in anthracycline- and taxane-pretreated metastatic breast cancer: Updated results. Breast Cancer Res Treat 2005;94:1087a.
  49. Overmoyer B, Waintraub S, Kaufman P et al. Phase II trial of KOS-862 (epothilone D) in anthracycline and taxane pretreated metastatic breast cancer. J Clin Oncol 2005;23:778a.
  50. Hoffman J, Winsel S, Hammer S et al. Comparative antiproliferative activities and cellular distribution of the third-generation epothilone ZK-EPO and taxanes. Eur J Cancer Suppl 2006;4:190.
  51. Klar U, Buchmann B, Schwede W et al. Total synthesis and antitumor activity of ZK-EPO: The first fully synthetic epothilone in clinical development. Angew Chem Int Ed Engl 2006;45:7942–7948.[CrossRef]
  52. Schmid P, Kiewe P, Kuehnhardt D et al. A phase I study of the novel, third generation epothilone ZK-EPO in patients with advanced solid tumors. J Clin Oncol 2005;23:2051a.
  53. Arnold D, Voigt W, Kiewe P et al. Weekly administration of ZK-EPO, a novel third-generation epothilone, in patients with refractory solid tumors: Results of a phase I trial. Ann Oncol 2006;17:ix136–ix143.[Free Full Text]
  54. Rustin GJ, Reed NS, Jayson G et al. Phase II trial of the novel epothilone ZK-EPO in patients with platinum resistant ovarian cancer. J Clin Oncol 2007;25:5527a.
  55. Chou T-C, Zhang X, Dong H et al. Therapeutic evaluation of the second-generation epothilone, dehydelone, as a microtubule-stabilization antitumor agent in xenograft models. Proc Am Assoc Cancer Res 2006;47:116.
  56. Villalona-Calero M, Goel S, Schaaf L et al. First-in-human phase I trial of a novel epothilone, KOS-1584. J Clin Oncol 2006;24:2003a.
  57. Burris H, Stopeck A, Thomas E et al. Phase I trial of a novel epothilone, KOS-1584, using a weekly dosing schedule. Eur J Cancer Suppl 2006;4:638a.



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