Skip to main content

Advertisement

SpringerLink
Log in

Pharmacokinetic profile of the microtubule stabilizer patupilone in tumor-bearing rodents and comparison of anti-cancer activity with other MTS in vitro and in vivo

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Introduction

Patupilone is a microtubule stabilizer (MTS) currently in clinical development. Here, we evaluate the anti-cancer activity in vitro and in vivo in comparison to paclitaxel and describe the pharmacokinetics (PK) of patupilone in tumor-bearing nude mice and rats.

Methods

The potency in vitro of patupilone and two other MTS, paclitaxel and ixabepilone, was determined using human colon carcinoma cell lines with low (HCT-116, HT-29, RKO) and high (HCT-15) P-glycoprotein expression (P-gp), as well as two multi-drug resistance (MDR) model cell pairs, MCF7/ADR and KB-8511 cells and their respective drug-sensitive parental counterparts. The PK of patupilone was investigated in nude mice bearing HCT-15 or HT-29 xenografts and in rats bearing s.c. pancreatic CA20498 tumors or A15 glioma tumors. Anti-cancer activity in vivo was compared to that of paclitaxel using three different human tumor colon models. The retention and efficacy of patupilone was compared in small and large HT-29 xenografts whose vascularity was determined by non-invasive magnetic resonance imaging.

Results

Patupilone was highly potent in vitro against four different colon carcinoma cell lines including those showing multi-drug-resistance. In contrast, paclitaxel and ixabepilone displayed significantly reduced activity with markedly increased resistance factors. In both rats and mice, a single i.v. bolus injection of patupilone (1.5–4 mg/kg) rapidly distributed from plasma to all tissues and was slowly eliminated from muscle, liver and small intestine, but showed longer retention in tumor and brain with no apparent elimination over 24 h. Patupilone showed significant activity against three human colon tumor models in vivo, unlike paclitaxel, which only had activity against low P-gp expressing tumors. In HT-29 tumors, patupilone activity and retention were independent of tumor size, blood volume and flow.

Conclusions

The high potency of patupilone, which is not affected by P-gp expression either in vitro or in vivo, and favorable PK, independent of tumor vascularity, suggest that it should show significant activity in colorectal cancer and in other indications where high P-gp expression may compromise taxane activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Hoefle G, Steinmetz H, Bedorf N, Schomberg D, Gerth K, Reichenbach H (1996) Epothilone A and B - novel 16-membered macrolides with cytotoxic activity: isolation, crystal structure, and conformation in solution. Angew Chem Int Ed Engl 35:1567–1569

    Article  CAS  Google Scholar 

  2. Buey RM, Diaz JF, Andreu JM et al (2004) Interaction of epothilone analogs with the paclitaxel binding site: relationship between binding affinity, microtubule stabilization, and cytotoxicity. Chem Biol 11:225–236

    Article  PubMed  CAS  Google Scholar 

  3. Reese M, Sanchez-Pedregal VM, Kubicek K et al (2007) Structural basis of the activity of the microtubule-stabilizing agent epothilone A studied by NMR spectroscopy in solution. Angew Chem Int Ed Engl 46:1864–1868

    Article  PubMed  CAS  Google Scholar 

  4. Bollag DM, McQueney PA, Zhu J et al (1995) Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res 55:2325–2333

    PubMed  CAS  Google Scholar 

  5. Broker LE, Huisman C, Span SW, Rodriguez JA, Kruyt FA, Giaccone G (2004) Cathepsin B mediates caspase-independent cell death induced by microtubule stabilizing agents in non-small cell lung cancer cells. Cancer Res 64:27–30

    Article  PubMed  Google Scholar 

  6. Ferretti S, Allegrini PR, O’Reilly et al (2005) Patupilone induced vascular disruption in orthotopic rodent tumor models detected by magnetic resonance imaging and interstitial fluid pressure. Clin Cancer Res 11:7773–7784

    Article  PubMed  CAS  Google Scholar 

  7. Wartmann M, Altmann K-H (2002) The Biology and Medicinal Chemistry of Epothilones. Curr Med Chem – Anti-Cancer Agents 2:123–148

    Article  CAS  Google Scholar 

  8. Tanabe KM, Millward M, Allen JD (2005) Interactions of patupilone (epothilone B) with multidrug transporter proteins. Proceedings of the 96th annual meeting AACR, Ananheim, CA; Apr 16–20, p. 809

  9. Giannakakou P, Sackett DL, Kang YK (1995) Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. J Biol Chem 272:17118–17125

    Article  Google Scholar 

  10. Thorpe PE (2004) Vascular targeting agents as cancer chemotherapeutics. Clin Cancer Res 10:415–427

    Article  PubMed  Google Scholar 

  11. Bocci G, Nicholaou KC, Kerbel RS (2002) Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective anti-angiogenic window for various drugs. Cancer Res 62:6938–6943

    PubMed  CAS  Google Scholar 

  12. Woltering EA, Lewis JM, Maxwell PJ et al (2003) Development of a novel in vitro human tissue-based angiogenesis assay to evaluate the effect of antiangiogenic drugs. Annals of Surgery 237:790–798

    Article  PubMed  Google Scholar 

  13. Goodin S, Kane MP, Rubin EH (2004) Epothilones: mechanism of action and biologic activity. J Clin Oncol 22:2015–2025

    Article  PubMed  CAS  Google Scholar 

  14. O’Neil BH, Goldberg RM (2005) Chemotherapy for advanced colorectal cancer: let’s not forget how we got here (until we really can). Semin Oncol 32:35–42

    Article  PubMed  CAS  Google Scholar 

  15. Melichar B, Casado Er, Tabernero J, et al. Patupilone in chemotherapy-pretreated patients with advanced colorectal cancer (CRC) receiving nutritional support and intensive diarrea management: a phase I multicenter trial. Ann Oncol 2006; 17 (Supplement 9), Abstract 31st ESMO congress

  16. Kretzschmar A, Kohne CH, Dorken B (1997) Docetaxel in treatment of other solid tumors. Med Klin (Munich) 92(Suppl 4):16–22

    Article  CAS  Google Scholar 

  17. Sharma N, Ramachandran S, Bowers M et al (2000) Multiple factors other than p53 influence colon cancer sensitivity to paclitaxel. Cancer Chemother Pharmacol 46:329–337

    Article  PubMed  CAS  Google Scholar 

  18. Goldstein LJ (1996) MDR1 gene expression in solid tumors. Eur J Cancer 32A:1039–1050

    Article  PubMed  CAS  Google Scholar 

  19. Schinkel AH, Jonker JW (2003) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Delivery Rev 55:3–29

    Article  CAS  Google Scholar 

  20. Blobe GC, Sachs CW, Khan WA, Fabbro D, Stabel S, Wetsel WC, Obeid LM, Fine RL, Hannun YA (1993) Selective regulation of protein kinase C (PKC) isoenzymes in multidrug-resistant MCF-7 cells. J Biol Chem 268:658–664

    PubMed  CAS  Google Scholar 

  21. Masters JR (2002) HeLa cells 50 years on: the good, the bad and the ugly. Nature Rev 2:315–319

    Article  CAS  Google Scholar 

  22. Akiyama S, Fojo A, Hanover JA, Pastan I, Gottesman MM (1985) Isolation and genetic characterization of human KB cell lines resistant to multiple drugs. Somatic Cell and Molecular Genetics 11:117–126

    Article  PubMed  CAS  Google Scholar 

  23. Wu L, Smythe AM, Stinson SF, Mullendore LA, Monks A, Scudiero DA, Paull KD, Koutsoukos AD, Rubinstein LV, Boyd MR et al (1992) Multidrug-resistant phenotype of disease oriented panels of human tumor cell lines used for anticancer drug screening. Cancer Res 52:3029–3034

    PubMed  CAS  Google Scholar 

  24. Meyer T, Regenass U, Fabbro D, Alteri E, Rösel J, Müller M, Caravatti G, Matter A (1989) A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo antitumor activity. Int J Cancer 43:851–856

    Article  PubMed  CAS  Google Scholar 

  25. Boulay A, Zumstein-Mecker S, Stephan C et al (2005) Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64:252–261

    Article  Google Scholar 

  26. O’Reilly T, McSheehy PM, Wenger F, Hattenberger M, Muller M, Vaxelaire J, Altmann KH, Wartmann M (2005) Patupilone (epothilone B, EPO906) inhibits growth and metastasis of experimental prostate tumors in vivo. Prostate 65:231–240

    Article  PubMed  CAS  Google Scholar 

  27. Blum W, Aichholz R, Ramstein P, Kühnol J, Brüggen J, O’Reilly T, Flörsheimer A (2001) In vivo metabolism of epothilone B in tumor-bearing nude mice: identification of three new epothilone B metabolites by capillary high-pressure liquid chromatography/mass spectrometry/tandem mass spectrometry. Rapid Commun Mass Spectrom 15(1):41–49

    Article  PubMed  CAS  Google Scholar 

  28. Traxler P, Allegrini PR, Brandt R et al (2004) AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res 64:4931–4941

    Article  PubMed  CAS  Google Scholar 

  29. Klar U, Buchmann B, Schwede W et al (2006) Total Synthesis and Antitumor Activity of ZK-EPO: The First Fully Synthetic Epothilone in Clinical Development. Angew Chem 45:7942–7948

    Article  CAS  Google Scholar 

  30. Khalifa MA, Abdoh AA, Mannel RS et al (1997) P-glycoprotein as a prognostic indicator in pre- and post-chemotherapy ovarian carcinoma. Int J Gyn Path 16:69–75

    Article  CAS  Google Scholar 

  31. Penson RT, Oliva E, Skates SJ et al (2004) Expression of multidrug resistance-1 protein inversely correlates with paclitaxel response and survival in ovarian cancer patients: a study in serial samples. Gyn Onc 93:98–106

    Article  CAS  Google Scholar 

  32. Hinoshita E, Uchiumi T, Taguchi K, Kinukawa N, Tsuneyoshi M, Maehara Y, Sugimachi K, Kuwano M (2000) Increased expression of an ATP-binding cassette superfamily transporter, multidrug resistance protein 2, in human colorectal carcinomas. Clin Cancer Res 6:2401–2407

    PubMed  CAS  Google Scholar 

  33. Kamath K, Wilson L, Cabral F, Jordan MA (2005) BetaIII-tubulin induces paclitaxel resistance in association with reduced effects on microtubule dynamic instability. J Biol Chem 280(13):12902–12907

    Article  PubMed  CAS  Google Scholar 

  34. Pellegrini F, Budman DR (2005) review: tubulin function, action of antitubulin drugs and new drug development. Cancer Invest 23:264–273

    Article  PubMed  CAS  Google Scholar 

  35. Morse DL, Gray H, Payne CM, Gillies RJ (2005) Docetaxel induces cell death through mitotic catastrophe in human breast cancer cells. Mol Cancer Ther 4(10):1495–1504

    Article  PubMed  CAS  Google Scholar 

  36. Eng C, Kindler HL, Nattam S et al (2004) A phase-II trial of the epothilone B analog, BMS-247550, in patients with previously treated advanced colorectal cancer. Ann Oncol 15:928–932

    Article  PubMed  CAS  Google Scholar 

  37. Saulnier M, Roman D, Mahl A et al (2003) Integrative toxicological and pharmacogenomic investigations of intestinal effects induced by epothilone B after single intraveneous administration in rats. Clin Cancer Res 9(16, part 2):A270

    Google Scholar 

  38. Siracka E, Pappova N, Pipa V, Durkovsky J (1979) Changes in blood flow of growing experimental tumor determined by the clearance of 133Xe. Neoplasma 26:173–177

    PubMed  CAS  Google Scholar 

  39. Sevick EM, Jain RK (1989) Geometric resistance to blood flow in solid tumors perfused ex vivo: effects of tumor size and perfusion pressure. Cancer Res 49:3506–3512

    PubMed  CAS  Google Scholar 

  40. McSheehy PMJ, Robinson SP, Ojugo ASE et al (1998) Carbogen breathing increases 5-fluorouracil uptake and cytotoxicity in hypoxic murine tumours: a magnetic resonance study in vivo. Cancer Res 58:1185–1194

    PubMed  CAS  Google Scholar 

  41. Casillas S, Dietz DW, Brand MI, Jones SC, Vladisavljevic A, Milsom JW (1997) Perfusion to colorectal cancer liver metastases is not uniform and depends on tumor location and feeding vessel. J Surg Res 67:179–185

    Article  PubMed  CAS  Google Scholar 

  42. Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987–989

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Mike Becquet, Mark Hattenberger, Melanie Muller, Samuel Kunz, Fabienne Schaeffer, Julian Vaxelaire, Robert Reuter and Jacqueline Loretan for their excellent technical support.

Author information

Authors and Affiliations

  1. Oncology Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, 4002, Switzerland

    Terence O’Reilly, Markus Wartmann, Joseph Brueggen, Andreas Floersheimer, Michel Maira & Paul M. J. McSheehy

  2. Global Imaging Group, Oncology Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, 4002, Switzerland

    Peter R. Allegrini

Authors
  1. Terence O’Reilly
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus Wartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joseph Brueggen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter R. Allegrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andreas Floersheimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michel Maira
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paul M. J. McSheehy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul M. J. McSheehy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

O’Reilly, T., Wartmann, M., Brueggen, J. et al. Pharmacokinetic profile of the microtubule stabilizer patupilone in tumor-bearing rodents and comparison of anti-cancer activity with other MTS in vitro and in vivo. Cancer Chemother Pharmacol 62, 1045–1054 (2008). https://doi.org/10.1007/s00280-008-0695-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-008-0695-9

Keywords

Search

Navigation