Favorable therapeutic index of a p210(BCR-ABL)-specific tyrosine kinase inhibitor; activity on lineage-committed and primitive chronic myelogenous leukemia progenitors.

摘要: Purpose: In order to assess the effect of tyrosine kinase inhibitor CGP57148B on lineage-committed and primitive chronic myelogenous leukemia (CML) progenitor cells, peripheral blood cells (PBPC) mobilized in phase CML were exposed this compound vitro. Methods: Both short-term (≤1 week) long-term exposure (≥2 weeks) investigated using suspension culture, semisolid (methylcellulose) assay or stroma-dependent culture (LTC). The proportion bcr/abl-positive progenitors was determined after direct plating [2 weeks colony-forming cell (CFC) assay] as well 2 6 LTC (LTC always followed by CFC replates). Results: Incubation PBPC over 48 h with 100 μM reduced colonies 4.4 ± 4.3% (n = 5) plating, 6.6 ± 4.2% 5 ± 5.6% 2) LTC. At dose, survival drug-exposed normal 53 ± 4.2%, 51 ± 2.8% 54.5 ± 4.9% 2), respectively. at a concentration 10 μM 1 week under conditions number 11.8 ± 6.1% 12 ± 6.4% 4) 14.3 ± 11.4% 3) LTC; 84.5 ± 2.1%, 93 ± 4.2% 86 ± 1.4% Following 1 μM, remaining 35%, 9% 25% untreated samples LTC, respective values for 10%, 11% 19%. Long-term yielded 98%, 100% 93% (1 μM) 77%, 86% 80% (10 μM), Conclusion: results support use either vitro (e.g. purging) continuous treatment vivo.