PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Prostate Cancer and Chemotherapy by Alexandre BRIDOUX Postdoctoral Research Fellow Albany College of Pharmacy (ACP) , NY, USA Prostate cancer (PCa) is an adenocarcinoma and is the most frequent of man cancers. Most of the efficient treatments used nowadays act at the early stages of the disease and are unefficacious when cancer turns malignant. The strong existing bibliographical documentation points out it would be possible to step in during several stages of the disease if the disregulations of the biochemical processes of two enzymes: 5-lipoxygenase and cyclooxygenase-2 are considered. An elaborate study of the biology and of the biochemistry of those enzymes allowed to understand the mechanisms of action, their influences on the evolution of cancer and how the use of pharmacological inhibitors can lead the treatment of the disease to an undeniable effect. After a summarized description about PCa and the biological targets of the disease, the design and pharmacological valuations of new « dual inhibitors » of those targets are presented. Prostate cancer and chemotherapy PCa is a leading cause of the aging male (> 50 years old) death worldwide. The frequency of such malignant tumors increased every ten years since 1950 (incidence from 5 to 14%) until the 1990’s (from 40 to 80%) and stabilized since then. The highest incidence estimated is in the United States of America, with 220900 new cancers detected and 280900 deaths in the year 2003. (Those statistics are still valid today.) At the present time, the threatening risk to develop PCa during life is 8%. At the age of 80, the risk rushes to 80%. Etiological studies were performed to determine the origins of the disease and showed that cancers are associated to an abnormal cellular proliferation. Nevertheless, it was found that first stage prostate cancer cells die with testosterone privation. That is the reason why early stage PCa are treated by hormonotherapy. The goal of this treatment is evidently to diminish the quantities of male hormones, testosterone, in the body. Hormonotherapy essentially consists in the administration of analogs of an hormone secreted by the hypophysis (an endocrin cephalic gland) called LH-RH (Luteinizing Hormone-Releasing Hormone). Those analogs stop androgens production by the testis. But it has no effects on cancer itself and is not a substitute for a curative treatment. New drug targets Today, too little is still known about the biological mechanisms of this disease and efficient non-hormonal treatments are lacking. The Pharmaceutical Research is always in search for new biological targets which inhibition would be preventive or curative in order to avoid surgery. Current molecules used are the following: --Cytotoxics are agents which « deceive » the living cell, they substitute to the cell essential products. The latter, bereft of those substances, is inoperative. Representatives of this class are Methotrexate (used in leukemia, breast and lung cancers) and 5-fluorouracil (an antimetabolite used in breast cancer). --Alkylating agents, such as Cisplatin, are capable to link DNA and thus induce cellular death. --Chromatin functions inhibitors are agents which can be divided into three classes: the Vinca alkaloids which way of action is not fully understood, the Topoisomerase II inhibitors, such as Podophyllotoxin, which inhibit one of the cell cycles and the « microtubuls » stabilization agents, such as Paclitaxel (TAXOL®). The latter inhibit the « microtubuls » reorganization which is essential to the normal cell functioning. Two key enzymatic systems in the inflammation process were very recently revealed being implicated in many biological processes linked to cancers (colon, pancreas, breast and lung) and more particularly in PCa. These are the 5-lipoxygenase (5-LO) and the cyclooxygenases (COXs). 5-LO normally monitors the formation of inflammation of allergy mediators. There are two forms of the COX enzyme: COX1 and COX2. The COXs monitor the formation of responsive inflammation mediators. Facing the similarities of the overexpressions of those enzymes in human cancer, they participate to the development of the disease by enhancing the cellular proliferation and the metastases development, a new treatment based on their simultaneous disregulations can be considered. Gamma-carbolines: new 5-LO/COXs dual inhibitors The purpose of this study was to participate to the PCa therapeutical research by the rational design, the synthesis and the pharmacological valuation of _-carbolines , a new class of potential 5-LO/COXs dual inhibitors. The _-carbolines are organic compounds which naturally derive from the tryptophan (often found in red meat) pyrolysis. With this intention, a bibliographical study was first realized to select strong inhibitors of each enzyme. COX inhibitors pre-eminently are the Non-Steroidal Anti-Inflammatory drugs (NSAIDs) which include Aspirin, Ibuprofen, Celebrex and Vioxx. The least two drugs were recently withdrawn from the pharmaceutical market because they were responsible of stroke in patients at risks. Therefore, the new dual inhibitors resulted from the association of two safe drugs described in the litterature: Indometacin (one of the best non selective inhibitor of COXs, commercialized under the name of « Indocin » or « Indobiotic ») and a 5-LO inhibitor developped by the firm Astra Zeneca which code name is ZD2138. (This one was designed at first to treat asthma but never passed the last clinical phases.) A library of differently substituted compounds was then thought and synthesized using common laboratory techniques and synthesis strategies. They were also tested using several pharmacological assays. 5-LO and COX1/COX2 activities were obtained ex vivo on human whole blood. The tests measuring the inhibition of the cellular proliferation were achieved on different cellular issues (breast and prostate cancers, murine leukemia tissues) in order to display the cytotoxic potential of the compounds. At the present time, on the whole, bibliographical data on 5-LO/COXs dual inhibitors and the results of this study don’t provide sufficient proofs to be inconsistent with the use of each class of inhibitors apart. Indeed, in the aim to get a synergic inhibition effect and no matter the secondary effects the choice to use single inhibitors together is more judicious. Nevertheless, this study allowed to select new molecular templates which possess an average dual inhibition of 5-LO/COXs and also showed to be « hit » compounds in the inhibition of the cellular invasiveness of cancer. 5 _-carbolines showed to be very good inhibitors of murine leukemia cells’ proliferation, 1 showed a very good activity against breast cancer cells and 3 against PCa. Thus one may think that with the optimization of their cytotoxic potential, 5_-carbolines might represent new organic entities to develop within more profound therapeutical research studies on PCa. Their real biological target remains still unknown. In the near future new pharmacological tests are needed so as to determine which one is affected. About the author:  Alexandre BRIDOUX received the grade of Doctor of the University of Lille II (Law & Health), France with the Honours Very Honorable on november,4th 2005. His speciality is Medication Sciences. He defended a thesis named « Design, synthesis and pharmacological valuation of gamma-carbolines, potential inhibitors of 5-lipoxygenase and cyclooxygenases ». This study led to the writing of two publications in international journals and one in a french university journal. Those are listed below: 1. Alexandre BRIDOUX, 2005.Conception, synthèse et évaluation pharmacologique de gamma-carbolines, inhibiteurs potentiels de 5-lipoxygénase et de cyclooxygénases. Philosophy Doctorate in Medication Sciences; University of Lille 2 (Law & Health); pp 224. 2. Alexandre BRIDOUX, april 2006.Les gamma-Carbolines, un nouveau traitement du cancer.Le Mensuel de L’Université; Paris; http://www.lemensuel.net 3. Alexandre BRIDOUX, Laurence GOOSSENS, Raymond HOUSSIN et Jean-Pierre HENICHART, 2006.Synthesis of 8-Substituted Tetrahydro-gamma-Carbolines; J. Het. Chem.; 43; 571-578. 4. Alexandre BRIDOUX, Laurence GOOSSENS, Raymond HOUSSIN et Jean-Pierre HENICHART. Design, synthesis and pharmacological valuation of gamma-carbolines, dual inhibitors of 5-lipoxygenase and cyclooxygenases. (In preparation) He is, at the present time, Postdoctoral Research Fellow at the Albany College of Pharmacy (ACP) , NY, USA. ### << Previous Next >> [ View All Perspectives ] |
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