title: Optimization for the blockade of epidermal growth factor receptor signaling for therapy of human pancreatic carcinoma.
abstract: We determined the optimal administration schedule of a novel epidermal growth factor receptor (EGFR) protein tyrosine kinase inhibitor (PKI), PKI 166 (4-(R)-phenethylamino-6-(hydroxyl)phenyl-7H-pyrrolo[2.3-d]-pyrimidine), alone or in combination with gemcitabine (administered i.p.) for therapy of L3.6pl human pancreatic carcinoma growing in the pancreas of nude mice. Seven days after orthotopic implantation of L3.6pl cells, the mice received daily oral doses of PKI 166. PKI 166 therapy significantly inhibited phosphorylation of the EGFR without affecting EGFR expression. EGFR phosphorylation was restored 72 h after cessation of therapy. Seven days after orthotopic injection of L3.6pl cells, groups of mice received daily or thrice weekly oral doses of PKI 166 alone or in combination with gemcitabine. Treatment with PKI 166 (daily), PKI 166 (3 times/week), or gemcitabine alone produced a 72%, 69%, or 70% reduction in the volume of pancreatic tumors in mice, respectively. Daily oral PKI 166 or thrice weekly oral PKI 166 in combination with injected gemcitabine produced 97% and 95% decreases in volume of pancreatic cancers and significant inhibition of lymph node and liver metastasis. Daily oral PKI 166 produced a 20% decrease in body weight, whereas treatment 3 times/week did not. Decreased microvessel density, decreased proliferating cell nuclear antigen staining, and increased tumor cell and endothelial cell apoptosis correlated with therapeutic success. Collectively, our results demonstrate that three weekly oral administrations of an EGFR tyrosine kinase inhibitor in combination with gemcitabine are sufficient to significantly inhibit primary and metastatic human pancreatic carcinoma.
authors.affiliation: Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Solorzano
authors.forename: C H
authors.initials: CH
authors.lastname: Baker
authors.forename: R
authors.initials: R
authors.lastname: Tsan
authors.forename: P
authors.initials: P
authors.lastname: Traxler
authors.forename: P
authors.initials: P
authors.lastname: Cohen
authors.forename: E
authors.initials: E
authors.lastname: Buchdunger
authors.forename: J J
authors.initials: JJ
authors.lastname: Killion
authors.forename: I J
authors.initials: IJ
authors.lastname: Fidler
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D016228:Endothelial Growth Factors / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000032:analysis; D008222:Lymphokines / Q000032:analysis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011758:Pyrroles / Q000493:pharmacokinetics / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D011743:Pyrimidines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003841:Deoxycytidine; C410026:PKI 166; D012264:Ribonucleotide Reductases; D066246:ErbB Receptors; D000093542:Gemcitabine