STI571 (formerly known as CGP57148B) is a potent inhibitor of bcr/abl, an oncogenic fusion protein that causes Chronic Myeloid Leukemia (CML). We previously shovfed that STI571 can cure mice injected with human BCR/ABL+ KU812 leukemic cells; if continuous inhibition of the kinase activity of bcr/abl is maintained. In this model, growing leukemic cells induce increased levels of AGP which in turn binds and inhibits STI5J71, causing resistance to it. This phenomenon can be reverted by the co-administration! of ST1571 and erythromycin (E), which competes with STI571 for AGP binding (JNCll in press). In this study the effects of AGP on the intracellular concentrations and tissue distribution of STI571 was evaluated. In vitro experiments using both KU812 cells ; and fresh blasts from CML patients showed that AGP, at 1 mg/ml decreased STI571 intracelhflar concentrations (assessed by HPLC on cell extracts) up to ten times the baseline levels, and did not permit STI571 to inhibit bcr/abl autophosporylation and cell proliferation. El(or the closely related molecule clindamycin [C]) reverted this phenomenon, restoring sensitivity to STI571 and intracellular concentrations. In vivo experiments perforated using tumor bearing mice revealed that the co-administration of E caused a decrease! in STI571 plasma concentrations associated with a statistically significant increase in STIS71 levels (compared with animals treated with ST1571 only) in all organs and tissues examined: tumor (+102%), kidney (+85%), liver (+120%), spleen (+41%). The effects of Elon STI571 levels were evident as early as 15' after its administration. In conclusion E, wh|ich was shown to revert in vivo resistance to STI571 in an animal model, has significant effects of the pharmacokinetics, intracellular concentrations, tissue distribution and biological activity of STI571 in animals.
|Issue number||11 PART I|
|Publication status||Published - 2000|
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