TY - JOUR
T1 - Determination of α-1 acid glycoprotein in patients with Ph+ chronic myeloid leukemia during the first 13 weeks of therapy with STI571
AU - Le Coutre, Philipp
AU - Kreuzer, Karl Anton
AU - Na, Il Kang
AU - Lupberger, Joachim
AU - Holdhoff, Matthias
AU - Appelt, Christine
AU - Schwarz, Michaela
AU - Müller, Christian
AU - Gambacorti-Passerini, Carlo
AU - Platzbecker, Uwe
AU - Bonnet, Ragnhild
AU - Ehninger, Gerhard
AU - Schmidt, Christian A.
N1 - Funding Information:
Correspondence and reprint requests to: Philipp le Coutre, Abteilung für Hämatologie und Onkologie, Campus Virchow, Charité, Humboldt Universität, Augustenburger Platz 1, 13353 Berlin, Germany. Fax: 49.30.450.553.964. E-mail: lecoutrep@aol.com. 1This study was supported by grants from Novartis Pharmaceuticals, Deutsche Krebshilfe, and Jose Carreras Fonds. 2Abteilung für Hämatologie und Onkologie, Campus Virchow, Charité, Humboldt Universität Berlin, Germany. 3Institut für Laboratoriumsmedizin und Pathobiochemie, Campus Virchow, Charité, Humboldt Universität Berlin, Germany. 4Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy. 5Abteilung für Hämatologie und Onkologie, Universitätsklinikum Carl Gustav Carus Universität, Dresden, Germany.
PY - 2002
Y1 - 2002
N2 - The tyrosine kinase activity of the BCR/ABL fusion protein is required for the transformation in patients with chronic myeloid leukemia. The tyrosine kinase inhibitor STI571 inhibits the BCR/ABL and ABL kinase activity and consequently inhibits growth of BCR/ABL-positive cells. However, resistance to STI571 has been demonstrated in Ph+ cell lines and in CML patients and can be explained in some cases by point mutations within the ATP-binding pocket or amplification of the bcr/abl gene. In previous investigations using a nu/nu mouse model, the binding of STI571 to elevated levels of the plasmaprotein α-1 acid glycoprotein (AGP) was identified as an additional mechanism of resistance to this therapeutic approach. Here we provide data on the expression of AGP in CML patients under therapy with STI571. Patients received 400 or 600 mg STI571 daily and apart from clinical parameters we determined AGP and C-reactive protein (CRP) plasma levels as well as the quantitative expression of both BCR/ABL and AGP mRNA in peripheral blood cells. Our data suggest that despite elevated AGP levels in 52% of our patients, no upfront resistance against STI571 was present. In conclusion, we demonstrated that during the first 13 weeks of STI571 therapy (i) plasma AGP levels in CML patients correlate with white blood cell count and stage of disease; (ii) patients with elevated AGP responded less rapidly to STI571; (iii) elevated AGP and CRP levels normalized in patients during treatment with STI571, although mRNA levels of AGP remained stable; (iv) initially normal levels of AGP remained in the normal range during treatment with STI571, indicating that STI571 does not trigger AGP expression in humans; and (v) in relapsed patients, elevation of AGP levels is present prior to hematological progress.
AB - The tyrosine kinase activity of the BCR/ABL fusion protein is required for the transformation in patients with chronic myeloid leukemia. The tyrosine kinase inhibitor STI571 inhibits the BCR/ABL and ABL kinase activity and consequently inhibits growth of BCR/ABL-positive cells. However, resistance to STI571 has been demonstrated in Ph+ cell lines and in CML patients and can be explained in some cases by point mutations within the ATP-binding pocket or amplification of the bcr/abl gene. In previous investigations using a nu/nu mouse model, the binding of STI571 to elevated levels of the plasmaprotein α-1 acid glycoprotein (AGP) was identified as an additional mechanism of resistance to this therapeutic approach. Here we provide data on the expression of AGP in CML patients under therapy with STI571. Patients received 400 or 600 mg STI571 daily and apart from clinical parameters we determined AGP and C-reactive protein (CRP) plasma levels as well as the quantitative expression of both BCR/ABL and AGP mRNA in peripheral blood cells. Our data suggest that despite elevated AGP levels in 52% of our patients, no upfront resistance against STI571 was present. In conclusion, we demonstrated that during the first 13 weeks of STI571 therapy (i) plasma AGP levels in CML patients correlate with white blood cell count and stage of disease; (ii) patients with elevated AGP responded less rapidly to STI571; (iii) elevated AGP and CRP levels normalized in patients during treatment with STI571, although mRNA levels of AGP remained stable; (iv) initially normal levels of AGP remained in the normal range during treatment with STI571, indicating that STI571 does not trigger AGP expression in humans; and (v) in relapsed patients, elevation of AGP levels is present prior to hematological progress.
KW - Drug resistance
KW - Protein binding
KW - Relapse
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U2 - 10.1006/bcmd.2002.0493
DO - 10.1006/bcmd.2002.0493
M3 - Article
C2 - 11987244
AN - SCOPUS:18344396578
SN - 1079-9796
VL - 28
SP - 75
EP - 85
JO - Blood Cells, Molecules, and Diseases
JF - Blood Cells, Molecules, and Diseases
IS - 1
ER -