Alpha1-acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571.
Despite the efficacy of STI571 (Glivec, Novartis, Basle, Switzerland) in treating chronic myeloid leukemia (CML), drug resistance has already been noted both in vitro and in vivo. As plasma proteins, including alpha-1-acid glycoprotein (AGP), may reduce drug efficacy through binding, AGP was investigated for its ability to interact with STI571. At all stages of CML, AGP plasma level was significantly higher than in normal controls (P <.05). The glycoprotein was purified from normal plasma and individual chronic myeloid leukemia (CML) patients' plasma by low-pressure chromatography. The influence of alpha1-acid glycoprotein (AGP), in the presence of STI571, on the proliferation of Philadelphia chromosome-positive (Ph+) cells was examined. Normal AGP, even at supraphysiological concentrations, did not block the effect of STI571 on K562-cell proliferation in vitro. Moreover, CML-derived AGP failed to block the effect of STI571 on Ph+ cells in vitro. Thus, these in vitro findings suggest that AGP will not abrogate the antileukemic activity of STI571.
Jørgensen
Heather G
HG
Academic Transfusion Medicine Unit, Department of Medicine, University of Glasgow, Glasgow Royal Infirmary, United Kingdom.
Elliott
Moira A
MA
Allan
Elaine K
EK
Carr
Christine E
CE
Holyoake
Tessa L
TL
Smith
Kevin D
KD
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D015153:Blotting, Western; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood* / Q000188:drug therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D009961:Orosomucoid / Q000032:analysis / Q000502:physiology*; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D009961:Orosomucoid; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl