Biomaterial Database

Pharmacodynamic studies with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839. 2001

J Albanell, and F Rojo, and J Baselga

Medical Oncology Service, Vall d'Hebron Hospital, Barcelona, Spain.

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

UI	MeSH Term	Description	Entries
D008024	Ligands	A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)	Ligand
D011799	Quinazolines	A group of aromatic heterocyclic compounds that contain a bicyclic structure with two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring.	Quinazoline
D002986	Clinical Trials as Topic	Works about pre-planned studies of the safety, efficacy, or optimum dosage schedule (if appropriate) of one or more diagnostic, therapeutic, or prophylactic drugs, devices, or techniques selected according to predetermined criteria of eligibility and observed for predefined evidence of favorable and unfavorable effects. This concept includes clinical trials conducted both in the U.S. and in other countries.	Clinical Trial as Topic
D004353	Drug Evaluation, Preclinical	Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications.	Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077156	Gefitinib	A selective tyrosine kinase inhibitor for the EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) that is used for the treatment of locally advanced or metastatic NON-SMALL CELL LUNG CANCER.	Iressa,N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-(3-(4-morpholinyl)propoxy)-4-quinazolinamide,ZD 1839,ZD1839
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000970	Antineoplastic Agents	Substances that inhibit or prevent the proliferation of NEOPLASMS.	Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D014407	Tumor Cells, Cultured	Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.	Cultured Tumor Cells,Neoplastic Cells, Cultured,Cultured Neoplastic Cells,Cell, Cultured Neoplastic,Cell, Cultured Tumor,Cells, Cultured Neoplastic,Cells, Cultured Tumor,Cultured Neoplastic Cell,Cultured Tumor Cell,Neoplastic Cell, Cultured,Tumor Cell, Cultured