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[Resistance to anticancer drugs]
1Laboratoire de Pharmacologie clinique et moléculaire, Institut Gustave Roussy, Villejuif.
Abstract:
Due to inefficacy of chemotherapy in several cancers, chemoresistance mechanisms which are intrinsic to tumor cells have been extensively described in human cancer cell lines. Detoxifying mechanisms including active efflux pumps (P-gp, MRP or LRP) and/or drug inactivation (glutathione) as well as increased DNA repair have been identified and demonstrated to be involved in chemoresistance processes. Moreover expression of genes implicated in proliferation, differentiation or apoptosis functions has been shown to indicate drug response. Several mechanisms very often coexist within the tumor cell: it is possible even that detoxifying mechanisms are dependent on oncogenes and suppressor genes regulating proliferation, differentiation and/or apoptosis. In human tumor specimens, some of these mechanisms are regularly found and thus lead to develop strategies to block them. In that respect, the first example is the development of modulators of P-gP, a membrane efflux protein, which constitutes the archetype of detoxifying drug mechanisms. In spite of technical difficulties encountered to properly identify and quantify expressions of these biomarkers, ongoing research in cancer chemotherapy now largely relies on chemoresistance mechanisms.
Insights
Chemoresistance mechanisms in cancer cells, including drug efflux pumps and DNA repair, reduce chemotherapy efficacy. Understanding these processes is crucial for developing effective cancer treatments.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Context:
- Chemotherapy inefficacy in various cancers necessitates understanding intrinsic tumor cell chemoresistance.
- Chemoresistance mechanisms are extensively studied in human cancer cell lines.
Purpose:
- To describe the various chemoresistance mechanisms involved in cancer.
- To highlight the role of detoxifying mechanisms, drug inactivation, and DNA repair in chemoresistance.
- To emphasize the link between gene expression, proliferation, differentiation, apoptosis, and drug response.
Summary:
- Detoxifying mechanisms like P-glycoprotein (P-gp), multidrug resistance protein (MRP), and lung resistance-related protein (LRP) efflux pumps, along with drug inactivation via glutathione and enhanced DNA repair, contribute to chemoresistance.
- Coexistence of multiple mechanisms within tumor cells, potentially influenced by oncogenes and suppressor genes regulating cell functions, is common.
- Identification and quantification of these biomarkers in human tumor specimens are ongoing challenges, yet crucial for therapeutic strategies.
Impact:
- Strategies to block chemoresistance mechanisms, such as developing P-gp modulators, are being developed.
- Ongoing research in cancer chemotherapy increasingly focuses on understanding and targeting chemoresistance mechanisms.
- Advances in identifying and quantifying chemoresistance biomarkers will improve the efficacy of cancer chemotherapy.