Tyrosine kinase inhibitors and multidrug resistance proteins: interactions and biological consequences
| Autor: | Angelo Paradiso, Amalia Azzariti, Massimo Zucchetti, Maurizio D'Incalci, G.M. Simone, Nicola Antonio Colabufo, Anna Elisa Quatrale, Letizia Porcelli, Roberto Perrone, Jianming Xu, Francesco Berardi |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Time Factors Abcg2 medicine.drug_class Antineoplastic Agents Drug resistance Pharmacology Irinotecan Toxicology Vandetanib Tyrosine-kinase inhibitor Cell Line Dogs Gefitinib Piperidines Cell Line Tumor medicine ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans Pharmacology (medical) ATP Binding Cassette Transporter Subfamily B Member 1 Protein Kinase Inhibitors P-glycoprotein biology Biological Transport Protein-Tyrosine Kinases Drug Resistance Multiple Neoplasm Proteins Multiple drug resistance Oncology Doxorubicin Drug Resistance Neoplasm Quinazolines biology.protein ATP-Binding Cassette Transporters Camptothecin Mitoxantrone Tyrosine kinase medicine.drug |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 65:335-346 |
| ISSN: | 1432-0843 0344-5704 |
| DOI: | 10.1007/s00280-009-1039-0 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink