A pharmacodynamic study of the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in metastatic colorectal cancer patients.
OBJECTIVE
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.


METHODS
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, p27(Kip1), and beta-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. p27(Kip1) was absent in the cancer cells of most pretreatment biopsies; two patients showed a marked increase in staining for nuclear p27(Kip1) 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 p27(Kip1).
Daneshmand
Manijeh
M
Ottawa Regional Cancer Centre, Ottawa, Ontario, K1H 1C4 Canada.
Parolin
Doris A E
DA
Hirte
Holger W
HW
Major
Pierre
P
Goss
Glenwood
G
Stewart
David
D
Batist
Gerald
G
Miller
Wilson H
WH
Matthews
Sarah
S
Seymour
Lesley
L
Lorimer
Ian A J
IA
D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000493:pharmacokinetics*; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis; D051176:beta Catenin
D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; D011799:Quinazolines; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D000077156:Gefitinib