| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Clinical Trials |
Ottawa Regional Cancer Centre, Ottawa, Ontario, K1H 1C4 Canada [M. D., D. A. E. P., G. G., D. S., I. A. J. L.]; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5 Canada [M. D., D. A. E. P., I. A. J. L.]; Hamilton Regional Cancer Centre, Hamilton, Ontario, L8V 5C2 Canada [H. W. H., P. M.]; Lady Davis Institute of the Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, H3T 1E2 Canada [G. B., W. H. M.]; and National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, K7L 3N6 Canada [S. M., L. S.]
Purpose: Epidermal growth factor receptor (EGFR) appears to play an important role in the pathogenesis of colorectal cancer. We have performed a Phase I/II study of the EGFR tyrosine kinase inhibitor ZD1839 in metastatic colorectal cancer patients in which serial biopsies were taken pre- and posttreatment to assess biological activity.
Experimental Design: Paired biopsies were obtained from colorectal cancer patients before and after treatment. Proliferation and apoptosis were assessed using Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase-mediated nick end labeling assays, respectively. Immunohistochemistry for EGFR, activated EGFR, phosphorylated Akt, phosphorylated ERK, p27Kip1, and ß-catenin was also performed.
Results: Posttreatment samples showed a statistically significant reduction in the cancer cell proliferation index (mean proliferation index pretreatment 31%; posttreatment 21%; P = 0.047). The mean cancer cell apoptosis index also increased from 6 to 12% in posttreatment samples, although this difference did not achieve statistical significance. All pretreatment samples showed strong staining for EGFR. Loss of immunohistochemical staining for activated EGFR, phosphorylated Akt, and phosphorylated ERK in cancer cells was observed in some patients after treatment. p27Kip1 was absent in the cancer cells of most pretreatment biopsies; two patients showed a marked increase in staining for nuclear p27Kip1 after treatment with ZD1839. These two patients also showed large increases in apoptotic index.
Conclusions: ZD1839 inhibits EGFR signaling and proliferation in the cancer cells of patients with metastatic colorectal cancer. ZD1839 may also induce cancer cell apoptosis in a subset of colorectal cancer patients via up-regulation of p27Kip1.
This article has been cited by other articles:
|
|
 |
|
  M. Agulnik, E. W.E. Cohen, R. B. Cohen, E. X. Chen, E. E. Vokes, S. J. Hotte, E. Winquist, S. Laurie, D. N. Hayes, J. E. Dancey, et al. Phase II Study of Lapatinib in Recurrent or Metastatic Epidermal Growth Factor Receptor and/or erbB2 Expressing Adenoid Cystic Carcinoma and Non Adenoid Cystic Carcinoma Malignant Tumors of the Salivary Glands J. Clin. Oncol., September 1, 2007; 25(25): 3978 - 3984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Yamasaki, D. Zhang, C. Bartholomeusz, T. Sudo, G. N. Hortobagyi, K. Kurisu, and N. T. Ueno Sensitivity of breast cancer cells to erlotinib depends on cyclin-dependent kinase 2 activity Mol. Cancer Ther., August 1, 2007; 6(8): 2168 - 2177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Yamasaki, M. J. Johansen, D. Zhang, S. Krishnamurthy, E. Felix, C. Bartholomeusz, R. J. Aguilar, K. Kurisu, G. B. Mills, G. N. Hortobagyi, et al. Acquired Resistance to Erlotinib in A-431 Epidermoid Cancer Cells Requires Down-regulation of MMAC1/PTEN and Up-regulation of Phosphorylated Akt Cancer Res., June 15, 2007; 67(12): 5779 - 5788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I Chau, D Cunningham, T Hickish, A Massey, L Higgins, R Osborne, N Botwood, and A Swaisland Gefitinib and irinotecan in patients with fluoropyrimidine-refractory, irinotecan-naive advanced colorectal cancer: a phase I-II study Ann. Onc., April 1, 2007; 18(4): 730 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E Calvo, S. Malik, L. Siu, G. Baillargeon, J Irish, S. Chin, P Santabarbara, J. Kreisberg, E. Rowinsky, and M Hidalgo Assessment of erlotinib pharmacodynamics in tumors and skin of patients with head and neck cancer Ann. Onc., April 1, 2007; 18(4): 761 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Agulnik, A. M. Oza, G. R. Pond, and L. L. Siu Impact and Perceptions of Mandatory Tumor Biopsies for Correlative Studies in Clinical Trials of Novel Anticancer Agents J. Clin. Oncol., October 20, 2006; 24(30): 4801 - 4807. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Nicolle, A. Daher, P. Maille, M. Vermey, S. Loric, A. Bakkar, H. Wallerand, D. Vordos, F. Vacherot, S. G. D. de Medina, et al. Gefitinib Inhibits the Growth and Invasion of Urothelial Carcinoma Cell Lines in which Akt and MAPK Activation Is Dependent on Constitutive Epidermal Growth Factor Receptor Activation. Clin. Cancer Res., May 1, 2006; 12(9): 2937 - 2943. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Rothenberg, B. LaFleur, D. E. Levy, M. K. Washington, S. L. Morgan-Meadows, R. K. Ramanathan, J. D. Berlin, A. B. Benson III, and R. J. Coffey Randomized Phase II Trial of the Clinical and Biological Effects of Two Dose Levels of Gefitinib in Patients With Recurrent Colorectal Adenocarcinoma J. Clin. Oncol., December 20, 2005; 23(36): 9265 - 9274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Bates and T. Fojo Epidermal Growth Factor Receptor Inhibitors: A Moving Target? Clin. Cancer Res., October 15, 2005; 11(20): 7203 - 7205. [Full Text] [PDF]
|
|
|
|
|
|
S. Ogino, J. A. Meyerhardt, M. Cantor, M. Brahmandam, J. W. Clark, C. Namgyal, T. Kawasaki, K. Kinsella, A. L. Michelini, P. C. Enzinger, et al. Molecular Alterations in Tumors and Response to Combination Chemotherapy with Gefitinib for Advanced Colorectal Cancer Clin. Cancer Res., September 15, 2005; 11(18): 6650 - 6656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Davis, R. Takamori, C. P. Raut, H. Q. Xiong, R. S. Herbst, W. M. Stadler, J. V. Heymach, G. D. Demetri, A. Rashid, Y. Shen, et al. Pharmacodynamic Analysis of Target Inhibition and Endothelial Cell Death in Tumors Treated with the Vascular Endothelial Growth Factor Receptor Antagonists SU5416 or SU6668 Clin. Cancer Res., January 15, 2005; 11(2): 678 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J. Petty, K. H. Dragnev, V. A. Memoli, Y. Ma, N. B. Desai, A. Biddle, T. H. Davis, W. C. Nugent, N. Memoli, M. Hamilton, et al. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition Represses Cyclin D1 in Aerodigestive Tract Cancers Clin. Cancer Res., November 15, 2004; 10(22): 7547 - 7554. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Cell Growth & Differentiation |
