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

We determined the optimal administration schedule of a novel epidermal grow th factor receptor (EGFR) protein tyrosine kinase inhibitor (PKI), PKI 166 (4-(R)-phenethylamino-6(hydroxyl)phenyl-7H-pyrrolo[2.3-d]-pyrimidine), alon e 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 phosphoryla tion of the EGFR without affecting EGFR expression. EGFR phosphorylation wa s restored 72 h after cessation of therapy. Seven days after orthotopic inj ection 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, respec tively. Daily oral PKI 166 or thrice weekly oral PKI 166 in combination wit h injected gemcitabine produced 97% and 95% decreases in volume of pancreat ic cancers and significant inhibition of lymph node and liver metastasis. D aily oral PKI 166 produced a 20% decrease in body weight, whereas treatment 3 times/week did not. Decreased microvessel density, decreased proliferati ng cell nuclear antigen staining, and increased tumor cell and endothelial cell apoptosis correlated with therapeutic success. Collectively, our resul ts demonstrate that three weekly oral administrations of an EGFR tyrosine k inase inhibitor in combination with gemcitabine are sufficient to significa ntly inhibit primary and metastatic human pancreatic carcinoma.