OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib.
Intrinsic sensitivity of newly diagnosed chronic myeloid leukemia (CML) patients to imatinib (IC50(imatinib)) correlates with molecular response. IC50(imatinib) is defined as the in vitro concentration of drug required to reduce phosphorylation of the adaptor protein Crkl by 50%. We now show that interpatient variability in IC50(imatinib) is mainly due to differences in the efficiency of imatinib intracellular uptake and retention (IUR). In 25 untreated CML patients, the IC50(imatinib) strongly correlated (R (2) = -0.484, P = .014 at 2 muM imatinib) with the IUR of [(14)C]imatinib. The addition of prazosin, a potent inhibitor of OCT-1 cellular transporter, reduced the IUR and eliminated interpatient variability. IC50 values for the more potent BCR-ABL inhibitor nilotinib (AMN107) did not correlate with IC50(imatinib) (R(2) =-0.0561, P > .05). There was also no correlation between IC50(nilotinib) and the IUR for [(14)C]nilotinib (R (2) = 0.457, P > .05). Prazosin had no effect on nilotinib IUR, suggesting that influx of nilotinib is not mediated by OCT-1. In conclusion, whereas OCT-1-mediated influx may be a key determinant of molecular response to imatinib, it is unlikely to impact on cellular uptake and patient response to nilotinib. Determining interpatient and interdrug differences in cellular uptake and retention could allow individual optimization of kinase inhibitor therapy.
White
Deborah L
DL
Division of Hematology, Institute of Medical and Veterinary Science (IMVS) & Hanson Institute, Adelaide, South Australia. deb.white@imvs.sa.gov.au
Saunders
Verity A
VA
Dang
Phuong
P
Engler
Jane
J
Zannettino
Andrew C W
AC
Cambareri
Antony C
AC
Quinn
Steven R
SR
Manley
Paul W
PW
Hughes
Timothy P
TP
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001549:Benzamides; D002247:Carbon Isotopes; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000378:metabolism; D050811:Octamer Transcription Factor-1 / Q000502:physiology*; D010766:Phosphorylation; D010879:Piperazines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001549:Benzamides; C082869:CRKL protein; D002247:Carbon Isotopes; D009687:Nuclear Proteins; D050811:Octamer Transcription Factor-1; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; C498826:nilotinib