Most cited article - PubMed ID 33783548
Changes in expression of lysosomal membrane proteins in leucocytes of cancer patients treated with tyrosine kinase inhibitors
The lysosomal sequestration of hydrophobic weak-base anticancer drugs is one proposed mechanism for the reduced availability of these drugs at target sites, resulting in a marked decrease in cytotoxicity and consequent resistance. While this subject is receiving increasing emphasis, it is so far only in laboratory experiments. Imatinib is a targeted anticancer drug used to treat chronic myeloid leukaemia (CML), gastrointestinal stromal tumours (GISTs), and a number of other malignancies. Its physicochemical properties make it a typical hydrophobic weak-base drug that accumulates in the lysosomes of tumour cells. Further laboratory studies suggest that this might significantly reduce its antitumor efficacy. However, a detailed analysis of published laboratory studies shows that lysosomal accumulation cannot be considered a clearly proven mechanism of resistance to imatinib. Second, more than 20 years of clinical experience with imatinib has revealed a number of resistance mechanisms, none of which is related to its accumulation in lysosomes. This review focuses on the analysis of salient evidence and raises a fundamental question about the significance of lysosomal sequestration of weak-base drugs in general as a possible resistance mechanism both in clinical and laboratory settings.
- Keywords
- STI571, cancer, drug resistance mechanisms, hydrophobic weak-base drugs, lysosomal drug sequestration, tyrosine kinase inhibitors,
- MeSH
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive * drug therapy MeSH
- Imatinib Mesylate therapeutic use MeSH
- Humans MeSH
- Lysosomes MeSH
- Antineoplastic Agents * therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Names of Substances
- Imatinib Mesylate MeSH
- Antineoplastic Agents * MeSH