TY - JOUR
T1 - Tyrosine kinase inhibitors and multidrug resistance proteins
T2 - Interactions and biological consequences
AU - Azzariti, Amalia
AU - Porcelli, Letizia
AU - Simone, Grazia M.
AU - Quatrale, Anna E.
AU - Colabufo, Nicola A.
AU - Berardi, Francesco
AU - Perrone, Roberto
AU - Zucchetti, Massimo
AU - D'Incalci, Maurizio
AU - Xu, Jian Ming
AU - Paradiso, Angelo
PY - 2010/1
Y1 - 2010/1
N2 - 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.
AB - 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.
KW - BCRP
KW - Gefitinib
KW - P-glycoprotein
KW - Resistance
KW - Vandetanib
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U2 - 10.1007/s00280-009-1039-0
DO - 10.1007/s00280-009-1039-0
M3 - Article
C2 - 19495754
AN - SCOPUS:71349086685
VL - 65
SP - 335
EP - 346
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 2
ER -