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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 2/2009

Open Access 01-01-2009 | Original Article

Preclinical efficacy spectrum and pharmacokinetics of ixabepilone

Authors: Francis Y. F. Lee, Richard Smykla, Kathy Johnston, Krista Menard, Kelly McGlinchey, Russell W. Peterson, Amy Wiebesiek, Gregory Vite, Craig R. Fairchild, Robert Kramer

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2009

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Abstract

Purpose

Ixabepilone, a semisynthetic analog of natural epothilone B, was developed for use in cancer treatment. This study extends previous findings regarding the efficacy of ixabepilone and its low susceptibility to tumor resistance mechanisms and describes the pharmacokinetics of this new antineoplastic agent.

Methods

The cytotoxicity of ixabepilone was assessed in vitro in breast, lung, and colon tumor cell lines and in vivo in human xenografts in mice. Antitumor activities of ixabepilone and taxanes were compared in multidrug-resistant models in vivo. Differential drug uptake of ixabepilone and paclitaxel was assessed in a P-glycoprotein (P-gp)-resistant colon cancer model in vitro. The pharmacokinetic profile of ixabepilone was established in mice and humans.

Results

Ixabepilone demonstrated potent cytotoxicity in a broad range of human cancer cell lines in vitro and in a wide range of xenografts in vivo. Ixabepilone was ~3-fold more potent than docetaxel in the paclitaxel-resistant Pat-21 xenograft model (resistant due to overexpression of βIII-tubulin and a lack of βII-tubulin). Ixabepilone activity against P-gp-overexpressing breast and colon cancer was confirmed in in vivo models. Cellular uptake of ixabepilone, but not paclitaxel, was established in a P-gp-overexpressing model. The pharmacokinetics of ixabepilone was characterized by rapid tissue distribution and extensive tissue binding.

Conclusions

Cytotoxicity studies against a range of tumor types in vitro and in vivo demonstrate that ixabepilone has potent and broad-spectrum antineoplastic activity. This is accompanied by favorable pharmacokinetics. Ixabepilone has reduced susceptibility to resistance due to P-gp overexpression, tubulin mutations, and alterations in β-tubulin isotype expression.
Literature
1.
2.
Moscow JMC, Cowan KH (2003) Drug resistance and its clinical circumvention. In: Kufe D, Pollock R, Weischselbaum R, Bast R, Gansler T, Holland J, Frei E (eds) Cancer medicine. BC Decker, Hamilton
3.
Endicott JA, Ling V (1989) The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem 58:137–171PubMedCrossRef
4.
Gottesman MM, Pastan I (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 62:385–427PubMedCrossRef
5.
Lee FYF, Borzilleri R, Fairchild CR, Kim S-H, Long BH, Raventoz-Suarez C, Vite GD, Rose WC, Kramer RA (2001) BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor activity. Clin Cancer Res 7:1429–1437PubMed
6.
Jordan M, Miller H, Ni L, Castenada S, Inigo I, Kan D, Lewin A, Ryseck R, Kramer R, Wilson L, Lee FY (2006) The Pat-21 breast cancer model derived from a patient with primary Taxol® resistance recapitulates the phenotype of its origin, has altered beta-tubulin expression and is sensitive to ixabepilone. In: Proc Am assoc cancer res 97th annual meeting, LB-280
7.
Altaha R, Fojo T, Reed E, Abraham J (2003) Epothilones: a novel class of non-taxane microtubule-stabilizing agents. Curr Pharm Des 8:1707–1712CrossRef
8.
Bollag DM, McQueney PA, Zhu J, Hensens O, Koupal L, Liesch J, Goetz M, Lazarides E, Woods CM (1995) Epothilones, a new class of microtubule-stabilizing agents with a Taxol-like mechanism of action. Cancer Res 55:2325–2333PubMed
9.
Bode CJ, Gupta ML, Reiff EA, Suprenant KA, Georg GI, Himes RH (2002) Epothilone and paclitaxel: unexpected differences in promoting the assembly and stabilization of yeast microtubules. Biochemistry 41:3870–3874PubMedCrossRef
10.
Chou T-C, Zhang X-G, Bolag A, Su D-S, Meng D, Salvin K, Bertino J, Danishefsky SJ (1998) Desoxyepothilone B: an efficacious microtubule-targeted antitumor agent with a promising in vivo profile relative to epothilone B. Proc Natl Acad Sci USA 95:9642–9647PubMedCrossRef
11.
Lee F, Borzilerri R, fairchild C, Kamath A, Smykla R, Kramer R, Vite G (2008) Preclinical discovery of ixabepilone, a highly active antineoplastic agent. Cancer Chemother Pharmacol (in press)
12.
Awada A, Burris D, de Valeriola D (2001) Phase I clinical and pharmacology study of the epothilone B analog BMS-247550 given weekly in patients with advanced solid tumors. Clin Cancer Res 7:3801S
13.
Loruzzo P, Wozniak A, Flaherty L, Shields A, Wright J, Lebwhol D (2001) Phase I clinical trial of BMS-247550 (aka Epothilone B Analog; NSC710428) in adult patients with advanced solid tumors. Proc Am Soc Clin Oncol 20 (abstr. #2125)
14.
Spriggs D, Soignet S, Bienvenu B, Letrent S, Lebwohl D, Jones S, Burris HI (2001) Phase I first-in-man study of the epothilone B analog BMS-247550 in patients with advanced cancer. Proc Am Soc Clin Oncol 20 (abstr. 428)
15.
Hao D, Hammond LA, deBono JS, Tolcher AW, Berg KE, Bass A, Mays TA, Smith LS, Drengler R, Rowinsky EK (2002) Continuous weekly administration of the epothilone-B derivative, BMS247,550 (NSC710428): a phase I and pharmacokinetic (PK) study. Proc Am Soc Clin Oncol 21 (abstr. #411)
16.
Ajani JA, Shah MA, Bokemeyer C, Lenz H-J, Burris HA, Cutsem EV, Usakewicz J, Peeters O, Voi M, Lebwohl D, Safran H (2002) Phase II study of the novel epothilone BMS-247550 in patients (pts) with metastatic gastric adenocarcinoma previously treated with a taxane. Proc Am Soc Clin Oncol 21 (abstr. 619)
17.
Baselga J, Gianni L, Llombart A, Manikhas G, Kubista E, Steger G (2005) Predicting response to ixabepilone: genomics study in patients receiving single agent ixabepilone as neoadjuvant treatment for breast cancer (BC). Breast Cancer Res Treat 94:S31 (abstr. 305)
18.
Fojo A, Menefee M, Poruchynsky M, Edgerly M, Mickley L, Li N, Tapia E, Merino M, Balis F, Bates S (2005) 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 23:388S (abstr 4541)
19.
Galsky MD, Small EJ, Oh WK, Chen I, Smith DC, Colevas AD, Martone L, Curley T, DeLaCruz A, Scher HI, Kelly WK (2005) 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 23:1439–1446PubMedCrossRef
20.
Hussain M, Tangen CM, Lara PN Jr, Vaishampayan UN, Petrylak DP, Colevas AD, Sakr WA, Crawford ED (2005) 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 23:8724–8729PubMedCrossRef
21.
O’Connor O, Straus D, Moskowitz C, Hamlin P, Portlock C, Gerecitano J, Neylon E, Colevas D, Zelenetz A (2005) 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 23:16S (abstr. 6569)
22.
Smith SM, Pro B, Besien Kv, Conner K, Karrison T, Wong S, Stiff P, Vokes E (2005) A phase II study of epothilone B analog BMS-247550 (NSC 710428) in patients with relapsed aggressive non-Hodgkin’s lymphomas. J Clin Oncol 23:16S (abstr. 6625)
23.
Conte P, Thomas E, Martin M, Klimovsky J, Tabernero J (2006) Phase II study of ixabepilone in patients (pts) with taxane-resistant metastatic breast cancer (MBC): final report. J Clin Oncol 24:18S (abstr. 10505)
24.
Whitehead RP, McCoy S, Rivkin SE, Gross HM, Conrad ME, Doolittle GC, Wolff RA, Goodwin JW, Dakhil SR, Abbruzzese JL (2006) 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 24:512–520
25.
Roche H, Yelle L, Cognetti F, Mauriac L, Bunnell C, Sparano J, Kerbrat P, Delord J-P, Vahdat L, Peck R, Lebwohl D, Ezzeddine R, Cure H (2007) 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 25:3415–3420PubMedCrossRef
26.
Thomas E, Tabernero J, Fornier M, Conte P, Fumoleau P, Lluch A, Vahdat LT, Bunnell CA, Burris HA, Viens P, Baselga J, Rivera E, Guarneri V, Poulart V, Klimovsky J, Lebwohl D, Martin M (2007) Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol 25:3399–3406PubMedCrossRef
27.
Vansteenkiste J, Lara PN Jr, Le Chevalier T, Breton J-L, Bonomi P, Sandler AB, Socinski MA, Delbaldo C, McHenry B, Lebwohl D, Peck R, Edelman M (2007) 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 25:3448–3455PubMedCrossRef
28.
Zhuang SH, Hung YE, Hung L, Robey RW, Sackett DL, Linehan WM, Bates SE, Fojo T, Poruchynsky MS (2007) Evidence for microtubule target engagement in tumors of patients receiving ixabepilone. Clin Cancer Res 13:7480–7486PubMedCrossRef
29.
Long BH, Wang L, Lorico A, Wang RRC, Brattain MG, Casazza AM (1991) Mechanisms of resistance to etoposide and teniposide in acquired resistant human colon and lung carcinoma cell lines. Cancer Res 51:5275–5284PubMed
30.
Riss TL, Moravec RA (1992) Comparison of MTT, XTT, and a novel tetrazolium compound MTS for in vitro proliferation and chemosensitivity assays. Mol Biol Cell 3(Suppl):184a
31.
Gehan EA (1965) A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52:203–223PubMed
32.
Lee F, Sciandra J, Siemann D (1989) A study of the mechanism of resistance to Adriamycin in vivo. Glutathione metabolism, P-glycoprotein expression and drug transport. Biochem Pharmacol 38:3697–3705PubMedCrossRef
33.
Mani S, McDaid H, Hamilton A, Hochster H, Cohen MB, Khabelle D, Griffin T, Lebwohl DE, Liebes L, Muggia F, Horwitz SB (2004) Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors. Clin Cancer Res 10:1289–1298PubMedCrossRef
34.
Gadgeel SM, Wozniak A, Boinpally RR, Wiegand R, Heilbrun LK, Jain V, Parchment R, Colevas D, Cohen MB, LoRusso PM (2005) Phase I clinical trial of BMS-247550, a derivative of epothilone B, using accelerated titration 2B design. Clin Cancer Res 11:6233–6239PubMedCrossRef
35.
Aghajanian C, Burris HA III, Jones S, Spriggs DR, Cohen MB, Peck R, Sabbatini P, Hensley ML, Greco FA, Dupont J, O’Connor OA (2007) Phase I study of the novel epothilone analog ixabepilone (BMS-247550) in patients with advanced solid tumors and lymphomas. J Clin Oncol 25:1082–1088PubMedCrossRef
36.
Chou T-C, O’Connor OA, Tong WP, Guan Y, Zhang Z-G, Stachel SJ, Lee C, Danishefsky SJ (2001) 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. PNAS 98:8113–8118PubMedCrossRef
37.
Lee FYF, Vite GD, Hofle G, Kim SH, Clark J, Fager K, Kennedy K, Smykla R, Wen M, Leavitt K, Johnston KA, Peterson RW, Kamath A, Franchini M, Schulze G, Fairchild C, Raghavan K, Long BH, Kramer R (2002) The discovery of BMS-310705: a water-soluble and chemically stable semi-synthetic epothilone possessing potent parenteral and oral antitumor activity against models of taxane-sensitive and -resistant human tumors in vivo. Proc Am Assoic Cancer Res 43:792–793
38.
Rubin EH, Rothermel J, Tesfaye F, Chen T, Hubert M, Ho Y-Y, Hsu C-H, Oza AM (2005) Phase I dose-finding study of weekly single-agent patupilone in patients with advanced solid tumors. J Clin Oncol 23:9120–9129PubMedCrossRef
39.
Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, Viens P, Cai C, Mullaney B, Peck R, Hortobagyi GN (2007) 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 25:3407–3414PubMedCrossRef
40.
Lee H, Xu L, Wu S, Paul B, Baselga J, Llombart A, Steger GG, Galbraith S, Clark E (2006) Predictive biomarker discovery and validation for the targeted chemotherapeutic ixabepilone. J Clin Oncol 24:18S (abstr. 3011)
41.
Thomas ES, Gomez HL, Li RK, Chung H-C, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roche HH (2007) Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 25:5210–5217PubMedCrossRef
Metadata
Title
Preclinical efficacy spectrum and pharmacokinetics of ixabepilone
Authors
Francis Y. F. Lee
Richard Smykla
Kathy Johnston
Krista Menard
Kelly McGlinchey
Russell W. Peterson
Amy Wiebesiek
Gregory Vite
Craig R. Fairchild
Robert Kramer
Publication date
01-01-2009
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 2/2009
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-008-0727-5

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