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Favorable therapeutic index of a p210BCR-ABL-specific tyrosine kinase inhibitor; activity on lineage-committed and primitive chronic myelogenous leukemia progenitors

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

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Received: 18 January 1999 / Accepted: 3 May 1999

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Kasper, B., Fruehauf, S., Schiedlmeier, B. et al. Favorable therapeutic index of a p210BCR-ABL-specific tyrosine kinase inhibitor; activity on lineage-committed and primitive chronic myelogenous leukemia progenitors. Cancer Chemother Pharmacol 44, 433–438 (1999). https://doi.org/10.1007/s002800051001

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  • DOI: https://doi.org/10.1007/s002800051001

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