title: Tyrosine kinase inhibitors and multidrug resistance proteins: interactions and biological consequences.
abstract: Although multidrug resistance (MDR) proteins are known to play a role in drug resistance and modification pharmacodynamic characteristics of certain conventional chemotherapeutics, information about their interactions with tyrosine kinase inhibitors (TKIs) remains fragmentary and somewhat controversial. The chronic administration of TKIs in many clinical situations strongly suggests that any possible interactions with MDR transporters should be studied as a function of time. For example, short periods of exposure to TKIs could provide insights into the nature of the binding to MDR-related proteins, either as substrates or as inhibitors, whereas prolonged exposure to TKIs could provide insights into cellular responses to binding/inhibition of MDR-related proteins. In this report, we provide evidence that suggests that both Gefitinib and Vandetanib may act as transported substrates for Breast Cancer Resistance Protein (BCRP, ABCG2). Conversely, the interaction of Gefitinib and Vandetanib with P-glycoprotein (PgP, MDR1) appeared to be as inhibitors alone. Consistent with this, short periods of exposure (≤24 h) to either Gefitinib or Vandetanib increased the effectiveness of SN-38, the active metabolite of CPT-11. Conversely, prolonged exposure (5 days) decreased SN-38 effectiveness, and was associated with BCRP up-regulation and reduced cell accumulation in S-phase, possibly though reduced intracellular accumulation of SN-38. This report underlines the needs for more detailed characterisation new biologically targeted anticancer drugs, in particular analysing periods of both short and prolonged drug exposure reflecting potentially distinct situations in the clinic in order to optimise future development in combination with established chemotherapeutic approaches.
authors.affiliation: Clinical Experimental Oncology Laboratory, National Cancer Institute, Bari, Italy. a.azzariti@oncologico.bari.it
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
authors.forename: Letizia
authors.initials: L
authors.lastname: Porcelli
authors.forename: Grazia M
authors.initials: GM
authors.lastname: Simone
authors.forename: Anna E
authors.initials: AE
authors.lastname: Quatrale
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.forename: Massimo
authors.initials: M
authors.lastname: Zucchetti
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Jian Ming
authors.initials: JM
authors.lastname: Xu
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D004285:Dogs; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D000077156:Gefitinib; D006801:Humans; D000077146:Irinotecan; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism*; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077146:Irinotecan; D004317:Doxorubicin; D008942:Mitoxantrone; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib; D002166:Camptothecin; C452423:vandetanib