Abstract
Chronic myeloid leukemia (CML) is a stem cell disorder caused by a constitutively activated tyrosine kinase, the BCR-ABL oncoprotein. Imatinib (STI571, Gleevec) is a small-molecule inhibitor of this kinase that produces clinical remissions in CML patients and is now frontline therapy for this disease. While this agent has a high rate of clinical success in early phases of CML, development of resistance to this drug is increasingly becoming problematic, particularly in later stages of the disease. Moreover, growing evidence suggests that imatinib has very poor penetration of the blood brain barrier, likely due at least partly to its being a substrate of P-glycoprotin (Pgp), resulting in subtherapeutic levels in the CNS. As a result, several clinical cases have been reported where CNS relapses occurred in imatinib treated CML patients despite peripheral blood and bone marrow complete responses (Leis et al., Leuk Lymphoma. 2004 Apr;45(4):695–8). This phenomenon has also been recapitulated in at least one preclinical model, where the limited ability of imatinib to cross the blood-brain barrier allowed the CNS to become a sanctuary for BCR-ABL-induced leukemia (Wolff et al., Blood. 2003 Jun 15;101(12):5010–3). BMS-354825, a small-molecule dual-function SRC/ABL tyrosine kinase inhibitor, was designed to overcome many of the limitations associated with imatinib therapy. BMS-354825 has more than 500-fold increased potency relative to imatinib versus BCR-ABL and more importantly retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants (Shah et al., Science, 2004 Jul 16;305(5682):399–401). In addition, BMS-354825 proved to be equally effective against several preclinically- and clinically-derived tumor models of imatinib resistance (Lee et al., Proceedings of the AACR, Volume 45, March 2004). In the current study, we assessed the efficacy of BMS-354825, which is not a Pgp substrate, in a model of established intracranial CML tumors. SCID-beige mice bearing K562 CML tumors implanted intracranially (2x106 cells per animal) were treated with BMS-354825 orally b.i.d. for a period of up to 40 days. BMS-354825 proved to be exceptionally efficacious resulting in increased lifespan of animals by 450% and 268% for the 15 mg/kg and 5 mg/kg dose levels, respectively. In order to more directly assess the anti-tumor activities of BMS-354825 in this intracranial CML model, we implanted K562 cells stably transfected with the firefly luciferase gene intracranially into SCID-beige animals. Bioluminescent imaging (BLI) then allowed the non-invasive monitoring of in vivo growth of these tumors. BMS-354825 at 15 mg/kg (2qdx14;6 po) achieved tumor regressions and subsequent complete stasis of intracranial K562 growth while animals were on therapy. In summary, these results suggest that BMS-354825 may have therapeutic advantages over imatinib in the management of intracranial CML disease and warrants further clinical investigation.
What human blood-brain barrier models can tell us about BBB function and drug discovery?
