Skip to main content

Advertisement

SpringerLink
Log in

Scheduling of paclitaxel and gefitinib to inhibit repopulation for optimal treatment of human cancer cells and xenografts that overexpress the epidermal growth factor receptor

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

Abstract

Purpose

In clinical studies, evaluating the combination of chemotherapy and the epidermal growth factor receptor (EGFR) inhibitor gefitinib, treatments were administered concurrently, despite it being counter-intuitive to give a cytostatic agent concurrent with cycle-active chemotherapy. One strategy to enhance efficacy might be to give the agents sequentially, thus allowing selective inhibition of repopulation of cancer cells between doses of chemotherapy. Here, we evaluate the hypothesis that sequential administration might allow inhibition of repopulation by gefitinib, with tumor cells re-entering cycle to allow sensitivity to subsequent chemotherapy.

Methods

Sequential and concurrent administration of paclitaxel and gefitinib were studied in vitro and in xenografts using EGFR over-expressing, EGFR-mutant, and EGFR wild-type human cancer cell lines. We evaluated cell cycle distribution and repopulation during treatment.

Results

The sequential use of gefitinib and paclitaxel to treat EGFR over-expressing A431 cells in vitro decreased repopulation compared to chemotherapy alone, and there was greater cell kill compared to concurrent treatment. In contrast, combined treatment led to greater growth delay than use of gefitinib alone for concurrent but not for sequential treatment of mice bearing A431 xenografts; concurrent treatment had greater effects to reduce functional vasculature in the tumors. Conversely, sequential treatment led to greater growth delay than concurrent treatment of EGFR-mutant HCC-827 xenografts that are sensitive to lower doses of gefitinib.

Conclusions

These studies highlight the importance of considering effects on the cell cycle, and on the solid tumor microenvironment, including tumor vasculature, when scheduling cytostatic and cytotoxic agents in combination.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Kim JJ, Tannock IF (2005) Repopulation of cancer cells during therapy: an important cause of treatment failure. Nat Rev Cancer 5:516–525

    Article  PubMed  CAS  Google Scholar 

  2. Rosenblum ML, Knebel KD, Vasquez DA, Wilson CB (1976) In vivo clonogenic tumour cell kinetics following 1,3-bis(2-chloroethyl)-1-nitrosourea brain tumour therapy. Cancer Res 36:3718–3725

    PubMed  CAS  Google Scholar 

  3. Stephens TC, Peacock JH (1977) Tumour volume response, initial cell kill and cellular repopulation in B16 melanoma treated with cyclophosphamide and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. Br J Cancer 36:313–321

    Article  PubMed  CAS  Google Scholar 

  4. Rosenblum ML, Gerosa MA, Dougherty DV, Wilson CB (1983) Improved treatment of a brain-tumour model. Part 1: advantages of single- over multiple-dose BCNU schedules. J Neurosurg 58:177–182

    Article  PubMed  CAS  Google Scholar 

  5. Durand RE, Vanderbyl SL (1989) Tumour resistance to therapy: a genetic or kinetic problem? Cancer Commun 1:277–283

    PubMed  CAS  Google Scholar 

  6. Durand RE (1990) Multicell spheroids as a model for cell kinetic studies. Cell Tissue Kinet 23:141–159

    PubMed  CAS  Google Scholar 

  7. Bourhis J, Wilson G, Wibault P, Janot F, Bosq J, Armand JP et al (1994) Rapid tumour cell proliferation after induction chemotherapy in oropharyngeal cancer. Laryngoscope 104:468–472

    Article  PubMed  CAS  Google Scholar 

  8. Milas L, Nakayama T, Hunter N, Jones S, Lin TM, Yamada S et al (1994) Dynamics of tumour cell clonogen repopulation in a murine sarcoma treated with cyclophosphamide. Radiother Oncol 30:247–253

    Article  PubMed  CAS  Google Scholar 

  9. Wu L, Tannock IF (2003) Repopulation in murine breast tumours during and after sequential treatments with cyclophosphamide and 5-fluorouracil. Cancer Res 63:2134–2138

    PubMed  CAS  Google Scholar 

  10. Rowinsky EK (2004) The ErbB family: targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med 55:433–457

    Article  PubMed  CAS  Google Scholar 

  11. El-Rayes BF, LoRusso PM (2004) Targeting the epidermal growth factor receptor. Br J Cancer 91:418–424

    Article  PubMed  CAS  Google Scholar 

  12. Harari PM (2004) Epidermal growth factor receptor inhibition strategies in oncology. Endocr Relat Cancer 11:689–708

    Article  PubMed  CAS  Google Scholar 

  13. Kris MG, Natale RB, Herbst RS, Lynch TJ, Prager D, Belani CP et al (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290:2149–2158

    Article  PubMed  CAS  Google Scholar 

  14. Perez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D et al (2004) Determinants of tumour response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 22:3238–3247

    Article  PubMed  CAS  Google Scholar 

  15. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S et al (2005) National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132

    Article  PubMed  CAS  Google Scholar 

  16. Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, TRIBUTE Investigator Group et al (2005) TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23:5892–5899

    Article  PubMed  CAS  Google Scholar 

  17. Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V et al (2004) Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. J Clin Oncol 22:777–784

    Article  PubMed  CAS  Google Scholar 

  18. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C et al (2004) Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 22:785–794

    Article  PubMed  CAS  Google Scholar 

  19. Rusnak DW, Alligood KJ, Mullin RJ, Spehar GM, Arenas-Elliott C, Martin AM et al (2007) Assessment of epidermal growth factor receptor (EGFR, ErbB1) and HER2 (ErbB2) protein expression levels and response to lapatinib (Tykerb®, GW572016) in an expanded panel of human normal and tumour cell lines. Cell Prolif 40:580–594

    Article  PubMed  CAS  Google Scholar 

  20. Amann J, Kalyankrishna S, Massion PP, Ohm JE, Girard L, Shigematsu H et al (2005) Aberrant epidermal growth factor receptor signalling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Res 65:226–235

    PubMed  CAS  Google Scholar 

  21. Fung AS, Jonkman J, Tannock IF (2012) Quantitative immunohistochemistry for evaluating the distribution of Ki67 and other biomarkers in tumor sections and use of the method to study repopulation in xenografts after treatment with paclitaxel. Neoplasia 14:324–334

    PubMed  CAS  Google Scholar 

  22. Primeau AJ, Rendon A, Hedley D, Lilge L, Tannock IF (2005) The distribution of the anticancer drug Doxorubicin in relation to blood vessels in solid tumours. Clin Cancer Res 11:8782–8788

    Article  PubMed  CAS  Google Scholar 

  23. Albain KS, Green SJ, Ravdin PM, Cobau CD, Levine EG, Ingle JN et al (2002) Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG 8814). Proc Am Soc Clin Oncol 21:37a

    Google Scholar 

  24. Morelli MP, Cascone T, Troiani T, De Vita F, Orditura M, Laus G et al (2005) Sequence-dependent antiproliferative effects of cytotoxic drugs and epidermal growth factor receptor inhibitors. Ann Oncol 16:iv61–iv68

    Article  PubMed  Google Scholar 

  25. Solit DB, She Y, Lobo J, Kris MG, Scher HI, Rosen N et al (2005) Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumours to paclitaxel. Clin Cancer Res 11:1983–1989

    Article  PubMed  CAS  Google Scholar 

  26. Davies AM, Ho C, Lara PN, Mack P, Gumerlock PH, Gandara DR (2006) Pharmacodynamic separation of epidermal growth factor receptor tyrosine kinase inhibitors and chemotherapy in non-small-cell lung cancer. Clin Lung Cancer 7:385–388

    Article  PubMed  CAS  Google Scholar 

  27. Kassouf W, Luongo T, Brown G, Adam L, Dinney CPN (2006) Schedule dependent efficacy of gefitinib and docetaxel for bladder cancer. J Urol 176:787–792

    Article  PubMed  CAS  Google Scholar 

  28. Verheul HMW, Qian DZ, Carducci MA, Pili R (2007) Sequence-dependent antitumour effects of differentiation agents in combination with cell cycle-dependent cytotoxic drugs. Cancer Chemother Pharmacol 60:329–339

    Article  PubMed  CAS  Google Scholar 

  29. Amin DN, Hida K, Bielenberg DR, Klagsbrun M (2006) Tumour endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res 66:2173–2180

    Article  PubMed  CAS  Google Scholar 

  30. Shaked Y, Henke E, Roodhart JM, Mancuso P, Langenberg MH, Colleoni M et al (2008) Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 14:263–273

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported by a grant from the Canadian Institutes of Health Research [# MOP 15388]. We thank Dr. Licun Wu for technical support with in vivo studies.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, 610 University Avenue, Toronto, ON, M5G 2M9, Canada

    Andrea S. Fung, Man Yu, Qian Jess Ye & Ian F. Tannock

Authors
  1. Andrea S. Fung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Man Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qian Jess Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ian F. Tannock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ian F. Tannock.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 225 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fung, A.S., Yu, M., Ye, Q.J. et al. Scheduling of paclitaxel and gefitinib to inhibit repopulation for optimal treatment of human cancer cells and xenografts that overexpress the epidermal growth factor receptor. Cancer Chemother Pharmacol 72, 585–595 (2013). https://doi.org/10.1007/s00280-013-2229-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-013-2229-3

Keywords

Search

Navigation