Pharmacodynamic studies with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839.

摘要: Abstract ZD1839 is an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks signal transduction pathways implicated in the proliferation and survival of cancer cells, other host-dependent processes promoting growth. Based on its promising preclinical antitumor activity favorable toxicity profile, ZD 1839 has recently entered clinical trials. A particular challenge development this exciting compound to explore biological (pharmacodynamic) against EGFR receptor-dependent serial biopsies. Such studies might be assistance predicting subset tumors will benefit from therapy. They also may prove whether complete blockade achieved vivo. This latest point particularly relevant because optimal dose (ie, a resulting inhibition) would preferred maximally tolerated being used with conventional nontargeted chemotherapeutic drugs. series have identified potentially useful surrogate markers (eg, phosphorylation downstream molecules such as mitogen-activated protein [MAPK], Akt, or p27) could marker efficacy. In various tumor types, head neck squamous carcinoma gastric breast adenocarcinoma, relationship between (such phosphorylated MAPK) been characterized, further supporting potential these for pharmacodynamic studies. Preliminary analysis skin biopsies patients participating phase I trials shown results substantial changes EGFR-dependent molecules, MAPK, p27, STAT3, others. encouraging results, assessing activated EGFR, selected II treated are currently planned ongoing.