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Molecular targets in oncology: implications of the multidrug resistance gene
B L Lum1, M P Gosland, S Kaubisch
1Department of Clinical Pharmacy, University of the Pacific School of Pharmacy, Palo Alto, California.
Abstract:
The curative potential of chemotherapy for a number of tumor types has been obscured by the fact that many patients initially have striking remissions but later relapse and die. At the time of relapse many patients manifest resistance to a wide array of structurally unrelated antineoplastic agents, hence the term multidrug resistance (MDR). Other tumor types, such as those arising in the colon, kidneys, liver, and lungs, tend to exhibit poor response to available cytotoxic drugs. The MDR phenomenon includes cross-resistance among the anthracyclines (doxorubicin, daunorubicin), the epipodophyllotoxins (etoposide, teniposide), the vinca alkaloids (vinblastine, vincristine), taxol, and other compounds. In vitro studies in cell culture indicate that this form of resistance is associated with amplification or overexpression of the mdr1 gene. The mdr1 gene codes for the expression of a cell surface protein, P-glycoprotein (P-gp), which acts as an energy-dependent efflux pump that transports drugs associated with MDR out of the cell before cytotoxic effects occur. The protein is expressed in normal human tissues such as the gastrointestinal tract, liver, and kidneys, where it is thought to serve as an excretory pathway for xenobiotic drugs and toxins. Preliminary studies demonstrated the presence of P-gp in tumor samples from patients with acute leukemia, multiple myeloma, lymphomas, and a variety of solid tumors. A number of drugs are able to reverse MDR, including calcium-channel blockers, phenothiazines, quinidine, antimalarial agents, antiestrogenic and other steroids, and cyclosporine. Limited results from clinical trials with small numbers of patients suggest that the addition of verapamil, diltiazem, quinine, trifluoperazine, or cyclosporine to chemotherapeutic regimens has the potential to reverse MDR; however, toxicities limit their clinical usefulness. A number of trials are under way to identify more active and less toxic modulators of MDR.
Insights
Multidrug resistance (MDR) in cancer chemotherapy occurs when tumors become resistant to multiple drugs, often due to P-glycoprotein (P-gp) efflux pumps. Researchers are exploring modulators to reverse this resistance and improve treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemotherapy often achieves initial tumor remission but is limited by multidrug resistance (MDR), leading to patient relapse and mortality.
- MDR involves cross-resistance to various antineoplastic agents and is particularly prevalent in cancers of the colon, kidneys, liver, and lungs.
- The mdr1 gene and its product, P-glycoprotein (P-gp), are implicated in MDR, functioning as an efflux pump that removes drugs from cells.
Purpose of the Study:
- To investigate the phenomenon of multidrug resistance (MDR) in cancer chemotherapy.
- To understand the role of P-glycoprotein (P-gp) in mediating MDR.
- To explore potential therapeutic strategies for reversing MDR using various drug modulators.
Main Methods:
- In vitro studies using cell cultures to examine MDR mechanisms.
- Analysis of mdr1 gene amplification and P-gp overexpression in resistant cells.
- Review of preliminary clinical trial data on MDR reversal agents.
Main Results:
- MDR is associated with the amplification or overexpression of the mdr1 gene, leading to increased P-gp expression.
- P-gp acts as an energy-dependent efflux pump, expelling cytotoxic drugs from cancer cells.
- Preliminary clinical trials suggest that modulators like verapamil and cyclosporine can reverse MDR, but toxicities are a concern.
Conclusions:
- Multidrug resistance (MDR) is a significant challenge in cancer chemotherapy, mediated by P-glycoprotein (P-gp).
- Several drug classes show potential for reversing MDR, but clinical utility is limited by toxicity.
- Further research is needed to identify safer and more effective MDR modulators for improved cancer treatment.