Role of α1 acid glycoprotein in the in vivo resistance of human BCR-ABL + leukemic cells to the Abl inhibitor STI571

Carlo Gambacorti-Passerini, Rossella Barni, Philipp Le Coutre, Massimo Zucchetti, Gonçalo Cabrita, Loredana Cleris, Francesca Rossi, Elisabetta Gianazza, Josef Brueggen, Robert Cozens, Pietro Pioltelli, Enrico Pogliani, Gianmarco Corneo, Franca Formelli, Maurizio D'Incalci

Research output: Contribution to journalArticle

Abstract

Background: Chronic myeloid leukemia is caused by a chromosomal translocation that results in an oncogenic fusion protein, Bcr-Abl. Bcr-Abl is a tyrosine kinase whose activity is inhibited by the antineoplastic drug STI571. This drug can cure mice given an injection of human leukemic cells, but treatment ultimately fails in animals that have large tumors when treatment is initiated. We created a mouse model to explore the mechanism of resistance in vivo. Methods: Nude mice were injected with KU812 Bcr-Abl + human leukemic cells. After 1 day (no evident tumors), 8 days, or 15 days (tumors >1 g), mice were treated with STI571 (160 mg/kg every 8 hours). Cells recovered from relapsing animals were used for in vitro experiments. Statistical tests were two-sided. Results: Tumors regressed initially in all STI571-treated mice, but all mice treated 15 days after injection of tumor cells eventually relapsed. Relapsed animals did not respond to further STI571 treatment, and their Bcr-Abl kinase activity in vivo was not inhibited by STI571, despite high plasma concentrations of the drug. However, tumor cells from resistant animals were sensitive to STI571 in vitro, suggesting that a molecule in the plasma of relapsed animals may inactivate the drug. The plasma protein α1 acid glyco-protein (AGP) bound STI571 at physiologic concentrations in vitro and blocked the ability of STI571 to inhibit Bcr-Abl kinase activity in a dose-dependent manner. Plasma AGP concentrations were strongly associated with tumor load. Erythromycin competed with STI571 for AGP binding, When animals bearing large tumors were treated with STI571 alone or with a combination of STI571 and erythromycin, greater tumor reductions and better long-term tumor-free survival (10 of 12 versus one of 13 at day 180; P

Original languageEnglish
Pages (from-to)1641-1650
Number of pages10
JournalJournal of the National Cancer Institute
Volume92
Issue number20
Publication statusPublished - Oct 18 2000

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Glycoproteins
Acids
Neoplasms
Erythromycin
Imatinib Mesylate
Phosphotransferases
bcr-abl Fusion Proteins
Pharmaceutical Preparations
Genetic Translocation
Injections
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Tumor Burden
Protein Binding
Nude Mice
Antineoplastic Agents
Protein-Tyrosine Kinases
Blood Proteins
Proteins
Therapeutics
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Role of α1 acid glycoprotein in the in vivo resistance of human BCR-ABL + leukemic cells to the Abl inhibitor STI571. / Gambacorti-Passerini, Carlo; Barni, Rossella; Le Coutre, Philipp; Zucchetti, Massimo; Cabrita, Gonçalo; Cleris, Loredana; Rossi, Francesca; Gianazza, Elisabetta; Brueggen, Josef; Cozens, Robert; Pioltelli, Pietro; Pogliani, Enrico; Corneo, Gianmarco; Formelli, Franca; D'Incalci, Maurizio.

In: Journal of the National Cancer Institute, Vol. 92, No. 20, 18.10.2000, p. 1641-1650.

Research output: Contribution to journalArticle

Gambacorti-Passerini, C, Barni, R, Le Coutre, P, Zucchetti, M, Cabrita, G, Cleris, L, Rossi, F, Gianazza, E, Brueggen, J, Cozens, R, Pioltelli, P, Pogliani, E, Corneo, G, Formelli, F & D'Incalci, M 2000, 'Role of α1 acid glycoprotein in the in vivo resistance of human BCR-ABL + leukemic cells to the Abl inhibitor STI571', Journal of the National Cancer Institute, vol. 92, no. 20, pp. 1641-1650.
Gambacorti-Passerini, Carlo ; Barni, Rossella ; Le Coutre, Philipp ; Zucchetti, Massimo ; Cabrita, Gonçalo ; Cleris, Loredana ; Rossi, Francesca ; Gianazza, Elisabetta ; Brueggen, Josef ; Cozens, Robert ; Pioltelli, Pietro ; Pogliani, Enrico ; Corneo, Gianmarco ; Formelli, Franca ; D'Incalci, Maurizio. / Role of α1 acid glycoprotein in the in vivo resistance of human BCR-ABL + leukemic cells to the Abl inhibitor STI571. In: Journal of the National Cancer Institute. 2000 ; Vol. 92, No. 20. pp. 1641-1650.
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abstract = "Background: Chronic myeloid leukemia is caused by a chromosomal translocation that results in an oncogenic fusion protein, Bcr-Abl. Bcr-Abl is a tyrosine kinase whose activity is inhibited by the antineoplastic drug STI571. This drug can cure mice given an injection of human leukemic cells, but treatment ultimately fails in animals that have large tumors when treatment is initiated. We created a mouse model to explore the mechanism of resistance in vivo. Methods: Nude mice were injected with KU812 Bcr-Abl + human leukemic cells. After 1 day (no evident tumors), 8 days, or 15 days (tumors >1 g), mice were treated with STI571 (160 mg/kg every 8 hours). Cells recovered from relapsing animals were used for in vitro experiments. Statistical tests were two-sided. Results: Tumors regressed initially in all STI571-treated mice, but all mice treated 15 days after injection of tumor cells eventually relapsed. Relapsed animals did not respond to further STI571 treatment, and their Bcr-Abl kinase activity in vivo was not inhibited by STI571, despite high plasma concentrations of the drug. However, tumor cells from resistant animals were sensitive to STI571 in vitro, suggesting that a molecule in the plasma of relapsed animals may inactivate the drug. The plasma protein α1 acid glyco-protein (AGP) bound STI571 at physiologic concentrations in vitro and blocked the ability of STI571 to inhibit Bcr-Abl kinase activity in a dose-dependent manner. Plasma AGP concentrations were strongly associated with tumor load. Erythromycin competed with STI571 for AGP binding, When animals bearing large tumors were treated with STI571 alone or with a combination of STI571 and erythromycin, greater tumor reductions and better long-term tumor-free survival (10 of 12 versus one of 13 at day 180; P",
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T1 - Role of α1 acid glycoprotein in the in vivo resistance of human BCR-ABL + leukemic cells to the Abl inhibitor STI571

AU - Gambacorti-Passerini, Carlo

AU - Barni, Rossella

AU - Le Coutre, Philipp

AU - Zucchetti, Massimo

AU - Cabrita, Gonçalo

AU - Cleris, Loredana

AU - Rossi, Francesca

AU - Gianazza, Elisabetta

AU - Brueggen, Josef

AU - Cozens, Robert

AU - Pioltelli, Pietro

AU - Pogliani, Enrico

AU - Corneo, Gianmarco

AU - Formelli, Franca

AU - D'Incalci, Maurizio

PY - 2000/10/18

Y1 - 2000/10/18

N2 - Background: Chronic myeloid leukemia is caused by a chromosomal translocation that results in an oncogenic fusion protein, Bcr-Abl. Bcr-Abl is a tyrosine kinase whose activity is inhibited by the antineoplastic drug STI571. This drug can cure mice given an injection of human leukemic cells, but treatment ultimately fails in animals that have large tumors when treatment is initiated. We created a mouse model to explore the mechanism of resistance in vivo. Methods: Nude mice were injected with KU812 Bcr-Abl + human leukemic cells. After 1 day (no evident tumors), 8 days, or 15 days (tumors >1 g), mice were treated with STI571 (160 mg/kg every 8 hours). Cells recovered from relapsing animals were used for in vitro experiments. Statistical tests were two-sided. Results: Tumors regressed initially in all STI571-treated mice, but all mice treated 15 days after injection of tumor cells eventually relapsed. Relapsed animals did not respond to further STI571 treatment, and their Bcr-Abl kinase activity in vivo was not inhibited by STI571, despite high plasma concentrations of the drug. However, tumor cells from resistant animals were sensitive to STI571 in vitro, suggesting that a molecule in the plasma of relapsed animals may inactivate the drug. The plasma protein α1 acid glyco-protein (AGP) bound STI571 at physiologic concentrations in vitro and blocked the ability of STI571 to inhibit Bcr-Abl kinase activity in a dose-dependent manner. Plasma AGP concentrations were strongly associated with tumor load. Erythromycin competed with STI571 for AGP binding, When animals bearing large tumors were treated with STI571 alone or with a combination of STI571 and erythromycin, greater tumor reductions and better long-term tumor-free survival (10 of 12 versus one of 13 at day 180; P

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