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Alternative Mechanisms of Multidrug Resistance in Cancer

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That cancer cell is a complex evolving creature is by now a well-known fact. The understanding of this complexity, although painfully scarce, is not an elusive goal, as in the future, in one way or another, all the therapeutical approaches will rely on this understanding. A current trend in pharmaceutical research and anti-cancer drug design is the discovery of new and new drugs with the hope that one day, one unique drug or a combination of drugs will be able to interrupt or to reverse any potentially malignant process. The same is true about anti-HIV therapy, where every year new compounds are tested or approved, while drug or multidrug resistance seems impossible to be overcome and consequently it is left as it is. The image of cancer cell resistance to our therapeutical attempts would have been incomplete if Dr. Kellen would have not given us a new book, in continuation of the Reversal of Multidrug Resistance in Cancer. Alternative Mechanisms of Multidrug Resistance in Cancer expands our knowledge beyond P-glycoprotein, as the hobby horse mechanism in tumor drug and multidrug resistance. In the same time, the book is a scary panorama of what a cancer cell could become when it has to defend itself against the xenobiotical therapeutics trying to disturb its life and function. References to P-glycoprotein are succinct in this book but one should keep in mind that any of the "nonclassical" MDR mechanisms described here could be associated with an increased P-gp activity in the cancer cell. Some of these mechanisms seem to be specific to malignant cells exposed to chemotherapeutics; among these, MRP protein(s) and function, topoisomerase II and I associated MDR and X-irradiation induced MDR, are discussed in detail. A pleasant surprise is the chapter on taxoids in multidrug resistance, in an era when taxol and taxoid-derived drugs are a most efficient new weapon in previously incurable cancers. Other mechanisms are less specifically induced by cancer chemotherapy and belong to a more general defensive response of cells exposed to various noxious compounds(glutathione S-transferases, DNA repair enzymes induced by DNA-damaging agents) or have an indirect effect on MDR -protein kinase C, as a major player in intracellular signaling, in this way influencing some of the putative MDR mechanisms, or bcl-2, whose contribution to the malignant phenotype is by preventing cell death when this should normally occur. Although not conclusive, one of the final chapters is an attempt to gather under the same roof all these apparently dispersed mechanisms which are, without doubt, tightly interconnected at a molecular level. The book is written in a lively and convincing style. Even if it leaves many questions without an answer, as is the case of the significance of occurrence of all these MDR mechanisms in the living organism, it is a strong pleading for a research which, for the future of cancer therapy, would eventually become even more important than discovering or designing new antitumour agents.