Role of alpha 1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the Abl inhibitor STI571

Background: Chronic myeloid leukemia is caused by a chromosomal translocati on that results in an oncogenic fusion protein, Bcr-Abl, Bcr-Abl is a tyros ine kinase whose activity is inhibited by the antineoplastic drug STI571. T his drug can cure mice given an injection of human leukemic cells, but trea tment 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 Ber-Abl(+) human leuke mic 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 tes ts were two-sided. Results: Tumors regressed initially in all STI571-treate d mice, but all mice treated 15 days after injection of tumor cells eventua lly relapsed. Relapsed animals did not respond to further STI571 treatment, and their Bcr-Abl kinase activity in vivo was not inhibited by STI571, des pite high plasma concentrations of the drug. However, tumor cells from resi stant animals were sensitive to STI571 in vitro, suggesting that a molecule in the plasma of relapsed animals may inactivate the drug. The plasma prot ein oil acid glycoprotein (AGP) bound STI571 at physiologic concentrations in vitro and blocked the ability of STI571 to inhibit Bcr-Abl kinase activi ty in a dose-dependent manner. Plasma AGP concentrations were strongly asso ciated 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 < . 001) were observed after the combination treatment. Conclusion: AGP in the plasma of relapsed animals binds to STI571, preventing this compound from i nhibiting the Bcr/Abl tyrosine kinase. Molecules such as erythromycin that compete with STI571 for binding to AGP may enhance the therapeutic potentia l of this drug.