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 Sumitomo, M. Articles by Hayakawa, M. Search for Related Content PubMed PubMed Citation Articles by Sumitomo, M. Articles by Hayakawa, M.

ZD1839 Modulates Paclitaxel Response in Renal Cancer by Blocking Paclitaxel-Induced Activation of the Epidermal Growth Factor Receptor–Extracellular Signal-Regulated Kinase Pathway

Department of Urology, National Defense Medical College, Tokorozawa, Saitama, Japan

Purpose: We evaluated the antitumor activity of ZD1839, a selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, in combination with paclitaxel in human renal cell carcinomas (RCCs).

Experimental Design: Eight human RCC lines and the surgical specimens obtained from 10 RCC patients were used. The protein expression was detected by Western blotting, immunohistochemistry and/or flow cytometry. Apoptosis was evaluated by flow cytometry and fragmented DNA ELISA. SKRC-49 tumor xenografts in athymic nude mice were treated with ZD1839 and/or paclitaxel, and tumor volume was determined

Results: EGFR protein was expressed and phosphorylated in eight RCC lines and EGFR expression was markedly increased in RCC specimens compared with adjacent normal renal tissues. Treatment of SKRC-49 with 1 µM ZD1839 resulted in a marked decrease in the phosphorylation of EGFR but not of HER-2. Treatment of SKRC-49 with ZD1839 in combination with 5 nM paclitaxel resulted in a significant increase in apoptotic cell number compared with paclitaxel alone, whereas ZD1839 alone failed to induce apoptosis. Although administration of ZD1839 or paclitaxel resulted in a transient growth inhibition in SKRC-49 xenografts, significant tumor regrowth delay was observed when paclitaxel was combined with ZD1839. Paclitaxel phosphorylated extracellular signal-regulated kinase through EGFR activation predominantly in cancer cells. ZD1839 promoted paclitaxel-induced Bcl-2 down-regulation resulting in promoting apoptosis by blocking paclitaxel-induced activation of the EGFR—extracellular signal-regulated kinase antiapoptotic pathway independent of Akt activity in SKRC-49.

Conclusions: Our findings support the idea that the significant clinical benefit is obtained from ZD1839 in combination with paclitaxel for the treatment of RCC.

This article has been cited by other articles:

				M. A. Morgan, L. A. Parsels, L. E. Kollar, D. P. Normolle, J. Maybaum, and T. S. Lawrence The Combination of Epidermal Growth Factor Receptor Inhibitors with Gemcitabine and Radiation in Pancreatic Cancer Clin. Cancer Res., August 15, 2008; 14(16): 5142 - 5149. [Abstract] [Full Text] [PDF]

				P. Steiner, C. Joynes, R. Bassi, S. Wang, J. R. Tonra, Y. R. Hadari, and D. J. Hicklin Tumor Growth Inhibition with Cetuximab and Chemotherapy in Non-Small Cell Lung Cancer Xenografts Expressing Wild-type and Mutated Epidermal Growth Factor Receptor Clin. Cancer Res., March 1, 2007; 13(5): 1540 - 1551. [Abstract] [Full Text] [PDF]

				M. N. Younes, Y. W. Park, Y. D. Yazici, M. Gu, A. A. Santillan, X. Nong, S. Kim, S. A. Jasser, A. K. El-Naggar, and J. N. Myers Concomitant inhibition of epidermal growth factor and vascular endothelial growth factor receptor tyrosine kinases reduces growth and metastasis of human salivary adenoid cystic carcinoma in an orthotopic nude mouse model. Mol. Cancer Ther., November 1, 2006; 5(11): 2696 - 2705. [Abstract] [Full Text] [PDF]

				J. Jones, H. Otu, D. Spentzos, S. Kolia, M. Inan, W. D. Beecken, C. Fellbaum, X. Gu, M. Joseph, A. J. Pantuck, et al. Gene Signatures of Progression and Metastasis in Renal Cell Cancer Clin. Cancer Res., August 15, 2005; 11(16): 5730 - 5739. [Abstract] [Full Text] [PDF]