Yazarlar : Tang C, Schafranek L, Watkins DB, Parker WT, Moore S, Prime JA, White DL, Hughes TP.

Yayın : Leuk Lymphoma.

Yayın Yılı : 2011

Pubmed Linki : http://www.ncbi.nlm.nih.gov/pubmed/21718141

Konu : Lösemi

Literatür İçeriği :

Abstract

Abstract There are three currently identified secondary resistance mechanisms observed in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs). These are BCR-ABL kinase domain (KD) mutations, increased BCR-ABL expression, and overexpression of drug-efflux proteins (ABCB1 and ABCG2). To investigate the interplay between these three modes of resistance, three CML blast crisis cell lines (K562, its ABCB1-overexpressing variant K562 Dox, and KU812) were cultured in gradually increasing concentrations of imatinib to 2 μM, or dasatinib to 200 nM. Eight imatinib- and two dasatinib-resistant cell lines were established. Two imatinib-resistant K562 lines both had increased BCR-ABL expression as the apparent mode of resistance. However, when a dasatinib-resistant K562 culture was generated we observed gradually increasing BCR-ABL expression which peaked prior to identification of the T315I mutation. BCR-ABL overexpression followed by mutation development was observed in a further 4/10 cell lines, each with different KD mutations. In contrast, three imatinib-resistant K562 Dox lines exhibited only a further increase in ABCB1 expression. All TKI-resistant cell lines generated had increased IC(50) (dose of drug required to reduce phosphorylation of the adaptor protein p-Crkl by 50%) to imatinib, dasatinib, and nilotinib, regardless of which TKI was used to induce resistance. This suggests that currently available TKIs share the same susceptibilities to drug resistance.

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