title: Determination of alpha-1 acid glycoprotein in patients with Ph+ chronic myeloid leukemia during the first 13 weeks of therapy with STI571.
abstract: 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 -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.
authors: Abteilung für Hämatologie und Onkologie, Campus Virchow, Charité, Humboldt Universität, Berlin, Germany. lecoutrep@aol.com
authors: Philipp
authors: P
authors: le Coutre
authors: Karl-Anton
authors: KA
authors: Kreuzer
authors: Il-Kang
authors: IK
authors: Na
authors: Joachim
authors: J
authors: Lupberger
authors: Matthias
authors: M
authors: Holdhoff
authors: Christine
authors: C
authors: Appelt
authors: Michaela
authors: M
authors: Schwarz
authors: Christian
authors: C
authors: Müller
authors: Carlo
authors: C
authors: Gambacorti-Passerini
authors: Uwe
authors: U
authors: Platzbecker
authors: Ragnhild
authors: R
authors: Bonnet
authors: Gerhard
authors: G
authors: Ehninger
authors: Christian A
authors: CA
authors: Schmidt
mesh_terms: D000368:Aged; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000097:blood; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009961:Orosomucoid / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011379:Prognosis; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000097:blood; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D014408:Biomarkers, Tumor; D009961:Orosomucoid; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate