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Editorial [ The Reversal of Drug Resistance from Bacteria to Cancer Cells Part - I Guest Editor: Joseph Molnar ]

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"In the field of science, the unknown has no foothold that is absolutely secure. As for those who first step" into this field, they can only hope that the mistake they may make would be a credit to them (A. Szent-Gyorgyi).

Giuseppe Verdi, the great Italian master of dramatic compositions of operas, could not compose his famous La Traviata because the classic tuberculosis had eradicated. Recently, the incurable form of the disease appeared, that rapidly kills the person despite the treatments due to multidrug resistance of mycobacterium.

Resistance develops regularly to a variety of drugs used in the treatment of bacterial, fungal, virus and protozoal infections and cancer. Do these diverse chemicals fail due to common resistance mechanisms? The answer is, yes, based on the 14 papers included in the part I and II of this theme issue. Resistance of bacteria, fungi, viruses, protozoa and cancer to medicinal compounds is now a common occurrence and the mechanism is similar.Accordingly, extrachromosomal DNA elements and membrane efflux proteins happen to be responsible for reduced effectivity of medicines in several systems. The theme issue will show how medicines designed to cure parasites can lose their effectivity and how their efficacy can be preserved by blocking special resistance mechanisms via resistance modifiers.

During the last century, the development of medicinal compounds has been strongly influenced by the Magic Bullet concept of Paul Erhlich.. The theory was based on the concept that each drug would have a specific target and since each organism was distinctly different, a different drug was needed for each infection type. Accordingly, each drug approved by regulatory agencies is to be used for a single entity of disease. Hence, antibiotics are to be used for the management of bacterial or viral or fungal or parasitic infections, neuroleptics for the management of neuroses and psychoses, analgesics for the management of pain and cytotoxins for the management of cancer. The unraveling of the genetic code and subsequent characterization of whole genomes from microorganisms to Man, has shown that the genome of each cell class is nearly 95% similar. Therefore, it is not surprising that drugs that affect prokaryotic cells can also affect the cells of the eukaryote-the latter generally referred to as a "side effect". But what has been surprising is that drugs that affect the eukaryotic cell may also have effects on prokaryotic cells. Prolonged therapy with an inappropriate dose of a single antibiotic therapy that has been long known to provide the basis for the selection of antibiotic mono-resistant bacteria, fungi and parasites is now known to also promote the development of resistance to two or more antibiotics (multidrug resistance). The therapy of cancer has from the early onset involved the use of two or more cytotoxic drugs, since the cancer would quickly become refractory when only one drug would be used. Nevertheless, cancer cells that escape the toxicity of tri-drug therapy become resistant not only to these agents but also to a large gamut of other, non-related compounds. Multidrug resistant cancer is essentially incurable at the moment.

(The development of multidrug resistance of bacteria, fungi, protozoa, parasites and cancer cells, given the fact that 95% of their genomes are similar, suggests that the mechanism or mechanisms by which multidrug resistance takes place may be either similar or identical. What are these mechanisms?)

This theme issue (part I and II) will show how medicines designed to cure parasites and cancer can lose their effectivity and how their efficacy can be preserved by blocking special resistance mechanisms via resistance modifiers. There are examples of overlap of the drug resistance mechanisms in prokaryote and waseukaryote cells. Chemotherapy of infections and cancer shares similar histories and developed side by side for many years. The similarities of some DNA complexing agents that have antiplasmid and antiviral actions can be exploited for rational drug design. Resistance to chemotherapy may be intrinsic or may be induced by previous treatments. It can develop to a specific agent, a class of agents, or multiple compounds. The later, called multidrug resistance (MDR), frequently results from impaired retention of medicine caused by overexpression of particular transport proteins (the so called ABC transporters: MDR, MRP, LRP, BCRP), which function as energy dependent drug efflux pumps. To overcome this type of resistance, which is a major obstacle in chemotherapy of infections and cancer, various classes of reversal agents were developed. Unfortunately, their clinical efficacy was found to be weak, inspite of their remarkable effects in vitro.

Approximately 6 years ago, a group of scientists formed a concerted action under the aegis of the European Commission to overcome drug resistance..........
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Document Type: Research Article

Affiliations: Institute of Medical Microbiology University of Szeged H-6720, Szeged, Dom ter 10. Hungary.

Publication date: July 1, 2006

More about this publication?
  • Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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