[The mechanisms of the resistance to molecular targeting agents].
Increasing knowledge of the mechanism of the initiation and progression of various cancers is the catalyst for developing new anticancer therapeutics that target specific molecules expressed in cancer cells. STI571 (imatinib mesylate) is an example of the successful development of a rationally designed and targeted agent. Its target is the constitutively active tyrosine kinase, BCR-ABL in chronic myelogenous leukemia (CML). Clinical studies with STI571 in CML demonstrated that many patients with advanced stage disease respond initially but then relapse. Drug resistance is associated with the reactivation of BCR-ABL signal transduction. Another targeted protein-tyrosine kinase inhibitor that was approved for clinical use is ZD1839 (Iressa). ZD1839 is an orally active and selective inhibitor for epidermal growth factor receptor (EGFR) tyrosine kinase. HER2 is overexpressed in 25-30% of breast cancers and associated with shorter time to relapse and lower survival rate. Specific targeting of these cancers can be accomplished with Herceptin directed against the extracellular domain of the HER2 protein. However, even in the selected group of patients with high levels of HER2, the response to Herceptin is limited in magnitude and duration. The mechanisms of the resistance to these targeted agents were reviewed.
Akiyama
Shin-ichi
S
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics, Graduate School of Medical and Dental Sciences, Kagoshima University.
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001549:Benzamides; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D000077156:Gefitinib; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D009369:Neoplasms / Q000188:drug therapy*; D010879:Piperazines; D011743:Pyrimidines / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D011799:Quinazolines; D000068877:Imatinib Mesylate; D000068878:Trastuzumab; D000077156:Gefitinib