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[Multidrug resistance (MDR) in oncology]
A Souvirón Rodríguez1, M J Ruiz Gómez, J A Morales Moreno
1Departamento de Radiología y Medicina Física, Facultad de Medicina, Universidad de Málaga.
Abstract:
Multidrug resistance or mdr is a frequent phenomenon for which tumor cells can develop, in only one step, cross-resistance to a different anticancer drugs such as antibiotics, vinca alkaloids and podophylotoxins. This is due to an extrusion of drugs out of the cells, since it is interrelated with the decrease of the intracellular concentration of the drug, compared to sensitive cells. This phenomeno of multidrug resistance (mdr) is considered one of the principal causes of failure in quimiotherapic treatment of cancer, and is associated in many cases to an hyperexpression of mdr-I gene, that codifies for a high molecular weight glycoprotein (p-170) (170-180 Kdaltons), also called p-glycoprotein (pgp). Locadet it in the cellular membrane extracts, like a pump, the quimiotherapic drugs with consumption of ATP. In humans, there are two principal genes that codify for pgp: mdr-I and mdr2/3; being the most important the mdr-I gene. The structure of p-glycoprotein consists in two symmetrical halves anchored in the cellular membrane that includes three extracellular dominances each one, and on intracellular portion with the ATP binding site. Also, has got an for extracellular carbohydrates chain. It is specially important to find drugs that reverse the multidrug resistance. Chemicals such as verapamil, nifedine, quinidine and calmodulin inhibitors are joined to pgp inhibiting it. A Cyclosporine and its non-immunosuppressors derivateds such as SDZ 280-125 and SDZ PSC 833 reverse mdr. At present it is being advancing in clinical trials, but the results are not satisfactory. Most useful chemicals are verapamil, better R-verapamil and A-cyclosporine or its non-immunosuppressors derivates. Futures possibilities are grateful. From diagnostic point of view the mains are: 1. Detection of mdr-I gene. 2. Recognition of the presence of mRNA for pgp. 3. Detection of pgp by flow cytometry or western blot. 4. Immunohistochemistry with monoclonal antibodies to pgp. 5. Rhodamine 123 to study mdr phenotype. 6. Multidrug resistance modulators in vitro. 7. pgp in vivo as a tumor marker. From therapeutic point of view: 1. To assay mdr modulators with higher power and better tolerated. 2. Reversing of mdr with in vivo MoAbs and/or immunotoxins. 3. Gene therapy. 4. New chemicals that joined to tubulin do not be extrused by pgp. 5. Drugs joined to liposomes. 6. Interpheron to increase the efficacy of MoAbs in mdr reversion. 7. Photodynamic therapy. Other possibilities can be the use of MoAbs in diagnostic (immunodetection) by PET and SPECT: and the MoAbs joined to drugs and radioisotopes.
Insights
Multidrug resistance (MDR) in cancer is often caused by the MDR1 gene, which produces p-glycoprotein (Pgp) pumps that expel chemotherapy drugs. Researchers are developing drugs to inhibit these pumps and overcome treatment failure.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) is a significant challenge in cancer chemotherapy, leading to treatment failure.
- MDR is frequently associated with the overexpression of the MDR1 gene, encoding p-glycoprotein (Pgp).
- Pgp acts as an ATP-dependent efflux pump, reducing intracellular drug concentrations and rendering cancer cells resistant.
Purpose of the Study:
- To review the mechanisms of MDR, focusing on Pgp.
- To explore diagnostic strategies for detecting MDR.
- To discuss therapeutic approaches for reversing MDR.
Main Methods:
- Review of literature on MDR mechanisms, diagnostics, and therapeutics.
- Identification of key genes (MDR1) and proteins (Pgp) involved in MDR.
- Analysis of current and potential MDR reversal agents and strategies.
Main Results:
- MDR1 gene and Pgp are central to MDR, acting as drug efflux pumps.
- Various diagnostic methods exist, including gene detection, mRNA analysis, and Pgp detection via flow cytometry, Western blot, and immunohistochemistry.
- Several agents, like verapamil and cyclosporine derivatives, inhibit Pgp, with ongoing clinical trials showing mixed results.
Conclusions:
- MDR remains a major obstacle in cancer treatment, primarily due to Pgp-mediated drug efflux.
- Effective diagnostic tools are available for identifying MDR.
- Further development of potent, well-tolerated MDR modulators, alongside novel therapeutic strategies like gene therapy and targeted drug delivery, is crucial for improving patient outcomes.