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Multidrug resistance: prospects for clinical management
A Mansouri1, K J Henle, W A Nagle
1Medical Research Service 151, John L. McClellan Memorial Veterans Hospital, Little Rock.
Abstract:
Clinical success in the treatment of tumors with chemotherapy has significantly improved over the past several years. However, treatment failures due to drug resistance of cancer cells has remained a major problem. The classical form of multiple drug resistance is perhaps also the most common type of drug resistance, and represents the overexpression of a transmembrane glycoprotein pump (P-170) that mediates the efflux of a spectrum of structurally and functionally unrelated drugs. Here, we discuss recent evidence that support the concept that the total phenomenon of multiple drug resistance (MDR) involves several other mechanisms in addition to that underlying "classical" MDR. These include the action of other energy-dependent membrane efflux pumps, elevated levels of GSH for drug conjugation and detoxification to facilitate export, enhanced DNA repair facility, gene amplification and oncogene activation. The combination of mechanisms used by any particular cell line is variable and suggests that many of these mechanisms are independent. Successful reversal of drug resistance appears to require the identification of relevant operative resistance mechanisms. An example is the competitive inhibition of P-170 with verapamil, quinine and tamoxifen. A broadly successful strategy for killing drug-resistant cancer cells, however, could be based on either selective energy depletion of cancer cells or the permeabilization of tumor cells with an effective bypass of efflux pumps, since many mechanisms of drug resistance entail the energy-dependent export of toxins. The latter approach may be achieved via membrane lipid modifications or the introduction of membrane pores by biological or physical (electroporation) means.
Insights
Cancer cells develop multiple drug resistance (MDR) through various mechanisms beyond classical P-170 pumps. Targeting these diverse resistance pathways is key to overcoming treatment failures in chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemotherapy has improved cancer treatment, but drug resistance remains a significant challenge.
- Classical multiple drug resistance (MDR) involves P-170 glycoprotein pumps that export drugs.
- MDR is a complex phenomenon involving multiple cellular mechanisms beyond P-170.
Purpose of the Study:
- To review evidence supporting diverse mechanisms of MDR in cancer cells.
- To discuss strategies for overcoming drug resistance by targeting these mechanisms.
Main Methods:
- Literature review of recent evidence on MDR mechanisms.
- Discussion of potential therapeutic strategies targeting MDR.
Main Results:
- MDR involves various mechanisms including other efflux pumps, GSH conjugation, DNA repair, gene amplification, and oncogene activation.
- These mechanisms can be variable and independent across different cancer cell lines.
- Identifying specific resistance mechanisms is crucial for effective treatment reversal.
Conclusions:
- Reversing drug resistance requires targeting the specific operative mechanisms.
- Potential strategies include competitive inhibition of P-170, selective energy depletion, or tumor cell permeabilization to bypass efflux pumps.