Related Experiment Videos
[Modulation of chemoresistance: methodology of therapeutic trials]
1Service d'oncologie-hématologie, CHU Lapeyronie, Montpellier.
Abstract:
A certain percentage of cancers are primarily or subsequently resistant to chemetherapeutic agents. Several biological mechanisms are implicated in this phenomenon, including multidrug resistance/P-glycoprotein (mdr1/P-gp), resistance related proteins (P-95 and P-110), multidrug resistance associated protein (P-190), iso-enzymes of gluthatione S-transferase, topo-isomerases, glutathione peroxidase and others. mdr1/P-gp overexpression has been studied in many types of cancer. It represents an inducible, transferable and phylogenetically ancestral biological system. It is expressed at the surface of the cell, and in that way, it participates to several normal functions. The recent introduction of modulators/revertants of mdr1/P-gp may change some concepts in using chemotherapy for cancers. The first step is represented by a better knowledge of the cancers which overexpressed mdr1/P-gp, with determination of the best biological technique, including the gold standards. This allows the clinician to clarify the best impact of such a therapeutic way and to define the criteria of modulator selection. Such criteria includes in vitro selection using a panel of sensitive/resistant cell lines, in vivo tests including transgenic mice, nude or SCID mice, and toxicological studies. Choice of modulated drug is easier and depends on the biological target. For mdr1/P-gp, major drugs included doxorubicin and vinca-alkaloids. Due to the fact that some modulators have an influence on the pharmacokinetic parameters of chemotherapeutic drugs, it is important to verify such parameters. The last choice concerns the strategy of drug development with three levels of action: 1) modulation of clinical chemoresistance, intrinsic or acquired one; 2) modulation of biological resistance; 3) leading to the prevention of the amplification of low levels of chemoresistance. A new therapeutic way is born, which takes care of a dynamic aspect of the tumor, and necessitates a new use of chemotherapy.
Insights
Multidrug resistance (MDR) in cancer, particularly P-glycoprotein (P-gp) overexpression, poses a significant challenge to chemotherapy. New modulators offer a promising approach to overcome chemoresistance and improve cancer treatment strategies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Chemotherapeutic resistance is a major obstacle in cancer treatment.
- Mechanisms include multidrug resistance/P-glycoprotein (mdr1/P-gp), resistance-related proteins, and other enzymes.
- mdr1/P-gp overexpression is a well-studied phenomenon across various cancer types.
Purpose of the Study:
- To explore the role of multidrug resistance/P-glycoprotein (mdr1/P-gp) in cancer chemoresistance.
- To evaluate the potential of mdr1/P-gp modulators in overcoming chemotherapy resistance.
- To define strategies for selecting appropriate modulators and drugs for cancer treatment.
Main Methods:
- Review of existing literature on mdr1/P-gp overexpression and its clinical implications.
- Discussion of in vitro and in vivo methods for evaluating mdr1/P-gp modulators.
- Analysis of pharmacokinetic interactions between modulators and chemotherapeutic agents.
Main Results:
- mdr1/P-gp is an inducible, transferable system expressed on cell surfaces, involved in normal physiological functions.
- Modulators of mdr1/P-gp show potential to alter chemotherapy efficacy.
- Selection criteria for modulators involve in vitro cell line studies, in vivo animal models, and toxicological assessments.
Conclusions:
- Understanding mdr1/P-gp expression is crucial for selecting effective chemotherapy and modulators.
- New therapeutic strategies involving mdr1/P-gp modulation can address intrinsic and acquired chemoresistance.
- This approach necessitates a dynamic view of tumors and a revised use of chemotherapy.