In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor

Background: The leukemia cells of approximately 95% of patients with chroni c myeloid leukemia and 30%-50% of adult patients with acute lymphoblastic l eukemia express the Bcr/Abl oncoprotein, which is the product of a fusion g ene created by a chromosomal translocation [(9:22) (q34;q11)]. This oncopro tein expresses a constitutive tyrosine kinase activity that is crucial for its cellular transforming activity. In this study, we evaluated the antineo plastic activity of CGP57148B, which is a competitive inhibitor of the Bcr/ Abl tyrosine kinase. Methods: Nude mice were given an injection of the Bcr/ Abl-positive human leukemia cell lines KU812 or MC3. Tumor-bearing mice wer e treated intraperitoneally or orally with CGP57148B according to three dif ferent schedules. In vitro drug wash-out experiments and in vivo molecular pharmacokinetic experiments were performed to optimize the irt vivo treatme nt schedule. Results: Treatment schedules administering CGP57148B once or t wice per day produced some inhibition of tumor growth, but no tumor-bearing mouse was cured. A single administration of CGP57148B caused substantial ( >50%) but short-lived (2-5 hours) inhibition of Bcr/Abl kinase activity. On the basis of the results from in vitro wash-out experiments, 20-21 hours w as defined as the duration of continuous exposure needed to block cell prol iferation and to induce apoptosis in these two leukemia cell lines. A treat ment regimen assuring the continuous block of the Bcr/Abl phosphorylating a ctivity that was administered over an 11-day period cured 87%-100% of treat ed mice, Conclusion: These data indicate that the continuous block of the o ncogenic tyrosine kinase of Bcr/Abl protein is needed to produce important biologic effects in vivo.