Importance of influx and efflux systems and xenobiotic metabolizing enzymes in intratumoral disposition of anticancer agents.

Details

Serval ID
serval:BIB_1B2D228E2FFC
Type
Article: article from journal or magazin.
Publication sub-type
Review (review): journal as complete as possible of one specific subject, written based on exhaustive analyses from published work.
Collection
Publications
Institution
Title
Importance of influx and efflux systems and xenobiotic metabolizing enzymes in intratumoral disposition of anticancer agents.
Journal
Current Cancer Drug Targets
Author(s)
Rochat B.
ISSN
1873-5576[electronic]
Publication state
Published
Issued date
2009
Volume
9
Number
5
Pages
652-674
Language
english
Abstract
In this review, intratumoral drug disposition will be integrated into the wide range of resistance mechanisms to anticancer agents with particular emphasis on targeted protein kinase inhibitors. Six rules will be established: 1. There is a high variability of extracellular/intracellular drug level ratios; 2. There are three main systems involved in intratumoral drug disposition that are composed of SLC, ABC and XME enzymes; 3. There is a synergistic interplay between these three systems; 4. In cancer subclones, there is a strong genomic instability that leads to a highly variable expression of SLC, ABC or XME enzymes; 5. Tumor-expressed metabolizing enzymes play a role in tumor-specific ADME and cell survival and 6. These three systems are involved in the appearance of resistance (transient event) or in the resistance itself. In addition, this article will investigate whether the overexpression of some ABC and XME systems in cancer cells is just a random consequence of DNA/chromosomal instability, hypo- or hypermethylation and microRNA deregulation, or a more organized modification induced by transposable elements. Experiments will also have to establish if these tumor-expressed enzymes participate in cell metabolism or in tumor-specific ADME or if they are only markers of clonal evolution and genomic deregulation. Eventually, the review will underline that the fate of anticancer agents in cancer cells should be more thoroughly investigated from drug discovery to clinical studies. Indeed, inhibition of tumor expressed metabolizing enzymes could strongly increase drug disposition, specifically in the target cells resulting in more efficient therapies.
Keywords
Drug Disposition, Metabolism, Efflux, Cancer, Resistance, SLC, ABC, CYP, Chronic Myeloid-Leukemia, Chronic-Myelogenous-Leukemia, Abl-Kinase Domain, Acute Lymphoblastic-Leukemia, Glutathione-S-Transferase, Resistance Protein-1 Mrp1, Tumor-Specific Expression, Hematopoietic Stem-Cells, Human Liver-Microsomes, Blood-Brain-Barrier
Pubmed
Web of science
Create date
11/11/2009 11:40
Last modification date
20/08/2019 12:51
Usage data