| Autor: |
Marc G. Berger, Benjamin Lebecque, Thomas Tassin, Louis-Thomas Dannus, Juliette Berger, Mélanie Soucal, Agnès Guerci, Pascale Cony-Makhoul, Hyacinthe Johnson, Gabriel Etienne, Denis Guyotat, Marie-Claude Gagnieu, Bruno Pereira, Sandrine Saugues, Olivier Tournilhac, Eric Hermet, Céline Bourgne |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Scientific Reports, Vol 11, Iss 1, Pp 1-11 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2045-2322 |
| DOI: |
10.1038/s41598-021-85734-0 |
| Popis: |
Abstract Accumulation in target cells is an essential pharmacokinetic step of targeted therapies. Tyrosine Kinase Inhibitors (TKI) against the BCR-ABL fusion protein in Chronic Phase-Chronic Myeloid Leukaemia (CP-CML) cells constitute a unique model in terms of efficacy, specificity, and in vivo demonstration of response heterogeneity by target cells. The overall therapeutic response to nilotinib is heterogeneous with no satisfactory explanation. To better understand the patients’ response heterogeneity, we quantified nilotinib uptake by primary CP-CML cells in standardized conditions using flow cytometry, which allowed also distinguishing mature (polymorphonuclear cells) from immature (CD34+) cells. Nilotinib was undetectable in 13.3% of PMN and 40% of CD34+ cells. Moreover, in CD34+ cells, intracellular nilotinib did not completely abolish BCR-ABL activity (monitored by CrkL phosphorylation inhibition), although nilotinib accumulated well in most CD34+ cell samples. Intracellular nilotinib concentration was inversely correlated with disease burden parameters, Sokal score, and early haematologic response at day 6 ± 1 only in PMN, suggesting an intrinsic ability to limit nilotinib entry in the forms with higher tumor cell burdenat diagnosis. These findings suggest that nilotinib accumulation in CP-CML cells is influenced by individual characteristics and intra-clonal heterogeneity, and might be used for pharmacokinetic studies and to assess the therapeutic response. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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