Favorable therapeutic index of a p210(BCR-ABL)-specific tyrosine kinase inhibitor

• Verfasst von: Kasper, Bernd [VerfasserIn]
• Verfasst von: Frühauf, Stefan [VerfasserIn]
• Verfasst von: Schiedlmeier, Bernd [VerfasserIn]
• Verfasst von: Buchdunger, Elisabeth [VerfasserIn]
• Verfasst von: Ho, Anthony Dick [VerfasserIn]
• Verfasst von: Zeller, W. Jens [VerfasserIn]
• Titel: Favorable therapeutic index of a p210(BCR-ABL)-specific tyrosine kinase inhibitor
• Titelzusatz: activity on lineage-committed and primitive chronic myelogenous leukemia progenitors
• Verf.angabe: Bernd Kasper, Stefan Fruehauf, Bernd Schiedlmeier, Elisabeth Buchdunger, Anthony D. Ho, W. Jens Zeller
• E-Jahr: 1999
• Jahr: [September 1999]
• Umfang: 6 S.
• Fussnoten: Gesehen am 14.12.2021 ; BCR-ABL ist im Titel hochgestellt
• Titel Quelle: Enthalten in: Cancer chemotherapy and pharmacology
• Ort Quelle: Berlin : Springer, 1978
• Jahr Quelle: 1999
• Band/Heft Quelle: 44(1999), 5, Seite 433-438
• ISSN Quelle: 1432-0843
• DOI: doi:10.1007/s002800051001
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Antineoplastic Agents
• Sach-SW: Benzamides
• Sach-SW: Coculture Techniques
• Sach-SW: Colony-Forming Units Assay
• Sach-SW: Drug Screening Assays, Antitumor
• Sach-SW: Enzyme Inhibitors
• Sach-SW: Fusion Proteins, bcr-abl
• Sach-SW: Hematopoietic Stem Cells
• Sach-SW: Humans
• Sach-SW: Imatinib Mesylate
• Sach-SW: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Sach-SW: Piperazines
• Sach-SW: Protein-Tyrosine Kinases
• Sach-SW: Pyrimidines
• Sach-SW: Stromal Cells
• Sach-SW: Tumor Cells, Cultured
• K10plus-PPN: 1782103325

Abstract

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 microM 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 microM 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 microM, 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 microM CGP57148B were 10%, 11% and 19%. Long-term exposure of normal progenitors to CGP57148B yielded a survival of 98%, 100% and 93% (1 microM) or 77%, 86% and 80% (10 microM), 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.