This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Solit, D. B. Articles by Sirotnak, F. M. Search for Related Content PubMed PubMed Citation Articles by Solit, D. B. Articles by Sirotnak, F. M.

Pulsatile Administration of the Epidermal Growth Factor Receptor Inhibitor Gefitinib Is Significantly More Effective than Continuous Dosing for Sensitizing Tumors to Paclitaxel

Departments of ¹ Medicine and ² Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: David B. Solit, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 646-422-4459; Fax: 253-423-3415; E-mail: solitd{at}mskcc.org.

Purpose: Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. Continuous inhibition of EGFR signaling is thought necessary for optimal inhibition of tumor cell proliferation. We hypothesized that continuous gefitinib may antagonize the effects of cytotoxics that inhibit tumor cells in other phases of the cell cycle. Furthermore, we hypothesized that intermittent dosing would allow for dose escalation and greater inhibition of EGFR-dependent antiapoptotic pathways.

Experimental Design: To test these assertions, we compared combinations of paclitaxel and gefitinib using either intermittent or continuous dosing schedules in mice.

Results: We found that when used in combination with paclitaxel, pulsatile gefitinib was significantly superior to continuous dosing. When gefitinib was administered for one or two consecutive days before paclitaxel, much higher doses could be given safely. Two days of gefitinib treatment before paclitaxel was most effective, causing significantly greater mean tumor regression and a higher percentage of complete responses than other schedules.

Conclusions: The results suggest that the dose and schedule of an EGFR inhibitor required to effectively inhibit proliferation may differ from that required to stimulate apoptosis or to induce other effects. The former may require continuous EGFR inhibition to maintain cell cycle arrest, whereas sensitization to apoptosis may be optimally induced by profound but temporary inhibition of survival pathways. Our data suggest that the effects of receptor inhibition vary as a function of dose and schedule and that continuous administration of tyrosine kinase inhibitors may not be the best schedule with which to combine such agents with taxanes.

Key Words: Gefitinib • Iressa • EGFR • Taxol • Synergy • xenografts

This article has been cited by other articles:

				S. Staal, M. J. O'Connell, and C. J. Allegra The Marriage of Growth Factor Inhibitors and Chemotherapy: Bliss or Bust? J. Clin. Oncol., April 1, 2009; 27(10): 1545 - 1548. [Full Text] [PDF]

				G. J. Riely, N. A. Rizvi, M. G. Kris, D. T. Milton, D. B. Solit, N. Rosen, E. Senturk, C. G. Azzoli, J. R. Brahmer, F. M. Sirotnak, et al. Randomized Phase II Study of Pulse Erlotinib Before or After Carboplatin and Paclitaxel in Current or Former Smokers With Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., January 10, 2009; 27(2): 264 - 270. [Abstract] [Full Text] [PDF]

				A. J. Gonzales, K. E. Hook, I. W. Althaus, P. A. Ellis, E. Trachet, A. M. Delaney, P. J. Harvey, T. A. Ellis, D. M. Amato, J. M. Nelson, et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor Mol. Cancer Ther., July 1, 2008; 7(7): 1880 - 1889. [Abstract] [Full Text] [PDF]

				A. Sawai, S. Chandarlapaty, H. Greulich, M. Gonen, Q. Ye, C. L. Arteaga, W. Sellers, N. Rosen, and D. B. Solit Inhibition of Hsp90 Down-regulates Mutant Epidermal Growth Factor Receptor (EGFR) Expression and Sensitizes EGFR Mutant Tumors to Paclitaxel Cancer Res., January 15, 2008; 68(2): 589 - 596. [Abstract] [Full Text] [PDF]

				J. Witham, M. R. Valenti, A. K. De-Haven-Brandon, S. Vidot, S. A. Eccles, S. B. Kaye, and A. Richardson The Bcl-2/Bcl-XL Family Inhibitor ABT-737 Sensitizes Ovarian Cancer Cells to Carboplatin Clin. Cancer Res., December 1, 2007; 13(23): 7191 - 7198. [Abstract] [Full Text] [PDF]

				M. V. Karamouzis, J. R. Grandis, and A. Argiris Therapies Directed Against Epidermal Growth Factor Receptor in Aerodigestive Carcinomas JAMA, July 4, 2007; 298(1): 70 - 82. [Abstract] [Full Text] [PDF]

				U. Gatzemeier, A. Pluzanska, A. Szczesna, E. Kaukel, J. Roubec, F. De Rosa, J. Milanowski, H. Karnicka-Mlodkowski, M. Pesek, P. Serwatowski, et al. Phase III Study of Erlotinib in Combination With Cisplatin and Gemcitabine in Advanced Non-Small-Cell Lung Cancer: The Tarceva Lung Cancer Investigation Trial J. Clin. Oncol., April 20, 2007; 25(12): 1545 - 1552. [Abstract] [Full Text] [PDF]

				M. Shrader, M. S. Pino, L. Lashinger, M. Bar-Eli, L. Adam, C. P.N. Dinney, and D. J. McConkey Gefitinib Reverses TRAIL Resistance in Human Bladder Cancer Cell Lines via Inhibition of AKT-Mediated X-Linked Inhibitor of Apoptosis Protein Expression Cancer Res., February 15, 2007; 67(4): 1430 - 1435. [Abstract] [Full Text] [PDF]

				B. A. Helfrich, D. Raben, M. Varella-Garcia, D. Gustafson, D. C. Chan, L. Bemis, C. Coldren, A. Baron, C. Zeng, W. A. Franklin, et al. Antitumor Activity of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Gefitinib (ZD1839, Iressa) in Non-Small Cell Lung Cancer Cell Lines Correlates with Gene Copy Number and EGFR Mutations but not EGFR Protein Levels Clin. Cancer Res., December 1, 2006; 12(23): 7117 - 7125. [Abstract] [Full Text] [PDF]

				D. H. Johnson Targeted therapies in combination with chemotherapy in non-small cell lung cancer. Clin. Cancer Res., July 15, 2006; 12(14): 4451s - 4457s. [Abstract] [Full Text] [PDF]

				B. J. Friedmann, M. Caplin, B. Savic, T. Shah, C. J. Lord, A. Ashworth, J. A. Hartley, and D. Hochhauser Interaction of the epidermal growth factor receptor and the DNA-dependent protein kinase pathway following gefitinib treatment. Mol. Cancer Ther., February 1, 2006; 5(2): 209 - 218. [Abstract] [Full Text] [PDF]

				G. K. Schwartz and M. A. Shah Targeting the Cell Cycle: A New Approach to Cancer Therapy J. Clin. Oncol., December 20, 2005; 23(36): 9408 - 9421. [Abstract] [Full Text] [PDF]

				H. I. Scher and C. L. Sawyers Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis J. Clin. Oncol., November 10, 2005; 23(32): 8253 - 8261. [Abstract] [Full Text] [PDF]

				D. R. Gandara and P. H. Gumerlock Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Plus Chemotherapy: Case Closed or Is the Jury Still Out? J. Clin. Oncol., September 1, 2005; 23(25): 5856 - 5858. [Full Text] [PDF]

				D. Gandara, S. Narayan, P. N. Lara Jr., Z. Goldberg, A. Davies, D. H.M. Lau, P. Mack, P. Gumerlock, and S. Vijayakumar Integration of Novel Therapeutics into Combined Modality Therapy of Locally Advanced Non-Small Cell Lung Cancer Clin. Cancer Res., July 1, 2005; 11(13): 5057s - 5062s. [Abstract] [Full Text] [PDF]