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Class III β-tubulin is a marker of paclitaxel resistance in carcinomas of unknown primary site

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Abstract

Purpose

In this study, we determine the prevalence and the prognostic value of the class III β-tubulin microtubule protein examined immunohistochemically, in tumors of 40 patients with carcinomas of unknown primary site treated with paclitaxel-based chemotherapy.

Methods

Immunohistochemical intensity of staining and percentage of cells were quantified. Clinical characteristics, response to chemotherapy, progression-free survival, and overall survival were assessed for relationships with the expression of class III β-tubulin.

Results

The response rate was 17.9% (seven partial responses among 39 valuable patients), while eleven patients had a stable disease (28.2%) and 21 patients progressed on therapy (53.8%). Patients with high class III β-tubulin expression were more resistant to taxane-based chemotherapy, defined as progression under treatment, while patient characteristics were not found to be correlated with response to chemotherapy. Patients whose tumors expressed high levels of class III β-tubulin isotype had shorter overall survival, while there was a trend for an association with progression free survival. Multivariate analysis showed that class III β-tubulin expression was independently correlated with progression free survival and overall survival.

Conclusions

These findings suggest that a high level of expression of class III β-tubulin in tumor cells is associated with resistance to paclitaxel and decreased survival in patients with carcinomas of unknown primary receiving paclitaxel-based chemotherapy.

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Abbreviations

CUP:

Carcinomas of unknown primary

OS:

Overall survival

PS:

Performance status

PFS:

Progression-free survival

References

  1. Banerjee A, Roach MC, Trcka P, Luduena RF (1990) Increased microtubule assembly in bovine brain tubulin lacking the type III isotype of beta-tubulin. J Biol Chem 265:1794–1799

    PubMed  CAS  Google Scholar 

  2. Blaszyk H, Hartmann A, Bjornsson J (2003) Cancer of unknown primary: clinicopathologic correlations. APMIS 111:1089–1094

    Article  PubMed  Google Scholar 

  3. Briasoulis E, Kalofonos H, Bafaloukos D, Samantas E, Fountzilas G, Xiros N, Skarlos D, Christodoulou C, Kosmidis P, Pavlidis N (2000) Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II hellenic cooperative oncology group study. J Clin Oncol 18:3101–3107

    PubMed  CAS  Google Scholar 

  4. Bugat R, Bataillard A, Lesimple T, Voigt JJ, Culine S, Lortholary A, Merrouche Y, Ganem G, Kaminsky MC, Negrier S, Perol M, Laforet C, Bedossa P, Bertrand G, Coindre JM, Fizazi K (2003) Summary of the standards, options and recommendations for the management of patients with carcinoma of unknown primary site (2002). Br J Cancer 89(Suppl1):S59–S66

    Article  PubMed  Google Scholar 

  5. Burkhart CA, Kavallaris M, Band Horwitz S (2001) The role of beta-tubulin isotypes in resistance to antimitotic drugs. Biochim Biophys Acta 1471:O1–O9

    PubMed  CAS  Google Scholar 

  6. Culine S, Kramar A, Saghatchian M, Bugat R, Lesimple T, Lortholary A, Merrouche Y, Laplanche A, Fizazi K (2002) Development and validation of a prognostic model to predict the length of survival in patients with carcinomas of an unknown primary site. J Clin Oncol 20:4679–4683

    Article  PubMed  Google Scholar 

  7. Derry WB, Wilson L, Khan IA, Luduena RF, Jordan MA (1997) Taxol differentially modulates the dynamics of microtubules assembled from unfractionated and purified beta-tubulin isotypes. Biochemistry 36:3554–3562

    Article  PubMed  CAS  Google Scholar 

  8. Dumontet C, Sikic BI (1999) Mechanisms of action of and resistance to antitubulin agents: microtubule dynamics, drug transport, and cell death. J Clin Oncol 17:1061–1070

    PubMed  CAS  Google Scholar 

  9. Ferrandina G, Zannoni GF, Martinelli E, Paglia A, Gallotta V, Mozzetti S, Scambia G, Ferlini C (2006) Class III beta-tubulin overexpression is a marker of poor clinical outcome in advanced ovarian cancer patients. Clin Cancer Res 12:2774–2779

    Article  PubMed  CAS  Google Scholar 

  10. Giannakakou P, Sackett DL, Kang YK, Zhan Z, Buters JT, Fojo T, Poruchynsky MS (1997) Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. J Biol Chem 272:17118–17125

    Article  PubMed  CAS  Google Scholar 

  11. Greco FA, Burris HA 3rd, Litchy S, Barton JH, Bradof JE, Richards P, Scullin DC Jr, Erland JB, Morrissey LH, Hainsworth JD (2002) Gemcitabine, carboplatin, and paclitaxel for patients with carcinoma of unknown primary site: a Minnie Pearl Cancer Research Network study. J Clin Oncol 20:1651–1656

    Article  PubMed  CAS  Google Scholar 

  12. Greco FA, Erland JB, Morrissey LH, Burris HA 3rd, Hermann RC, Steis R, Thompson D, Gray J, Hainsworth JD (2000) Carcinoma of unknown primary site: phase II trials with docetaxel plus cisplatin or carboplatin. Ann Oncol 11:211–215

    Article  PubMed  CAS  Google Scholar 

  13. Greco FA, Hainsworth JD (1999) The evolving role of paclitaxel for patients with carcinoma of unknown primary site. Semin Oncol 26:129–133

    PubMed  CAS  Google Scholar 

  14. Greco FA, Vaughn WK, Hainsworth JD (1986) Advanced poorly differentiated carcinoma of unknown primary site: recognition of a treatable syndrome. Ann Intern Med 104:547–553

    PubMed  CAS  Google Scholar 

  15. Hainsworth JD, Erland JB, Kalman LA, Schreeder MT, Greco FA (1997) Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide. J Clin Oncol 15:2385–2393

    PubMed  CAS  Google Scholar 

  16. Hainsworth JD, Greco FA (1993) Treatment of patients with cancer of an unknown primary site. N Engl J Med 329:257–263

    Article  PubMed  CAS  Google Scholar 

  17. Hari M, Yang H, Zeng C, Canizales M, Cabral F (2003) Expression of class III beta-tubulin reduces microtubule assembly and confers resistance to paclitaxel. Cell Motil Cytoskeleton 56:45–56

    Article  PubMed  CAS  Google Scholar 

  18. 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 280:12902–12907

    Article  PubMed  CAS  Google Scholar 

  19. Kavallaris M, Burkhart CA, Horwitz SB (1999) Antisense oligonucleotides to class III beta-tubulin sensitize drug-resistant cells to Taxol. Br J Cancer 80:1020–1025

    Article  PubMed  CAS  Google Scholar 

  20. Kavallaris M, Kuo DY, Burkhart CA, Regl DL, Norris MD, Haber M, Horwitz SB (1997) Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. J Clin Invest 100:1282–1293

    Article  PubMed  CAS  Google Scholar 

  21. Le Chevalier T, Cvitkovic E, Caille P, Harvey J, Contesso G, Spielmann M, Rouesse J (1988) Early metastatic cancer of unknown primary origin at presentation. A clinical study of 302 consecutive autopsied patients. Arch Intern Med 148:2035–2039

    Article  PubMed  CAS  Google Scholar 

  22. Lu Q, Luduena RF (1993) Removal of beta III isotype enhances taxol induced microtubule assembly. Cell Struct Funct 18:173–182

    Article  PubMed  CAS  Google Scholar 

  23. Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214

    Article  PubMed  CAS  Google Scholar 

  24. Mozzetti S, Ferlini C, Concolino P, Filippetti F, Raspaglio G, Prislei S, Gallo D, Martinelli E, Ranelletti FO, Ferrandina G, Scambia G (2005) Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients. Clin Cancer Res 11:298–305

    PubMed  CAS  Google Scholar 

  25. Paradiso A, Mangia A, Chiriatti A, Tommasi S, Zito A, Latorre A, Schittulli F, Lorusso V (2005) Biomarkers predictive for clinical efficacy of taxol-based chemotherapy in advanced breast cancer. Ann Oncol 16(Suppl4):iv14–iv19

    Article  PubMed  Google Scholar 

  26. Pavlidis N, Briasoulis E, Hainsworth J, Greco FA (2003) Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer 39:1990–2005

    Article  PubMed  CAS  Google Scholar 

  27. Ranganathan S, Benetatos CA, Colarusso PJ, Dexter DW, Hudes GR (1998) Altered beta-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells. Br J Cancer 77:562–566

    PubMed  CAS  Google Scholar 

  28. Rosell R, Scagliotti G, Danenberg KD, Lord RV, Bepler G, Novello S, Cooc J, Crino L, Sanchez JJ, Taron M, Boni C, De Marinis F, Tonato M, Marangolo M, Gozzelino F, Di Costanzo F, Rinaldi M, Salonga D, Stephens C (2003) Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer. Oncogene 22:3548–3553

    Article  PubMed  CAS  Google Scholar 

  29. Seve P, Isaac S, Tredan O, Souquet PJ, Pacheco Y, Perol M, Lafanechere L, Penet A, Peiller EL, Dumontet C (2005) Expression of class III {beta}-tubulin is predictive of patient outcome in patients with non-small cell lung cancer receiving vinorelbine-based chemotherapy. Clin Cancer Res 11:5481–5486

    Article  PubMed  CAS  Google Scholar 

  30. Seve P, Mackey J, Isaac S, Tredan O, Souquet PJ, Pacheco Y, Lai R, Volch A, Dumontet C (2005) Class III B-tubulin expression in tumor cells predicts response and outcome in patients with non-small cell lung cancer receiving paclitaxel. Mol Cancer Therap 4:7001–7006

    Google Scholar 

  31. Urano N, Fujiwara Y, Doki Y, Kim SJ, Miyoshi Y, Noguchi S, Miyata H, Takiguchi S, Yasuda T, Yano M, Monden M (2006) Clinical significance of class III beta-tubulin expression and its predictive value for resistance to docetaxel-based chemotherapy in gastric cancer. Int J Oncol 28:375–381

    PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Mary Burns for her administrative assistance. This work was supported by a grant from Hospices Civils de Lyon.

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Authors and Affiliations

  1. Department of Internal Medicine, Hôtel Dieu, 1 Place de l’Hôpital, Hospices Civils de Lyon, 69288, Lyon Cedex 02, France

    Pascal Sève

  2. Department of Oncology, University of Alberta, Edmonton, AB, Canada, T6G 1Z2

    Pascal Sève, Tony Reiman, John Hanson, Michael Sawyer & John R. Mackey

  3. Experimental Oncology, University of Alberta, Edmonton, AB, Canada, T6G 1Z2

    Pascal Sève, Tony Reiman, Cheryl Santos, Lorelei Johnson & Michael Sawyer

  4. Department of Pathology, University of Alberta, Edmonton, AB, Canada, T6G 1Z2

    Raymond Lai, Laith Dabbagh & John R. Mackey

  5. Laboratoire d’Immunologie des Hémopathies, Hôpital Edouard-Herriot, 5 Place d’Arsonval, 69437, Lyon Cedex 03, France

    Charles Dumontet

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  1. Pascal Sève
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  2. Tony Reiman
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Correspondence to Pascal Sève.

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Sève, P., Reiman, T., Lai, R. et al. Class III β-tubulin is a marker of paclitaxel resistance in carcinomas of unknown primary site. Cancer Chemother Pharmacol 60, 27–34 (2007). https://doi.org/10.1007/s00280-006-0343-1

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  • DOI: https://doi.org/10.1007/s00280-006-0343-1

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