Optimization for the blockade of epidermal growth factor receptor signaling for therapy of human pancreatic carcinoma

摘要: 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 L3.6pl human pancreatic carcinoma growing pancreas nude mice. Seven days after orthotopic implantation cells, mice received daily oral doses 166. significantly inhibited phosphorylation EGFR without affecting expression. was restored 72 h cessation therapy. injection groups thrice weekly gemcitabine. Treatment (daily), (3 times/week), produced 72%, 69%, 70% reduction volume tumors mice, respectively. Daily injected 97% and 95% decreases cancers significant inhibition lymph node liver metastasis. 20% decrease body weight, whereas treatment 3 times/week did not. Decreased microvessel density, decreased proliferating cell nuclear antigen staining, increased tumor endothelial apoptosis correlated therapeutic success. Collectively, our results demonstrate that three administrations an are sufficient to inhibit primary metastatic carcinoma.