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      β-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma

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          Abstract

          Background:

          The use of β-blockers for the management of hypertension has been recently associated with significant clinical benefits in cancer patients. Herein, we investigated whether β-blockers could be used in combination with chemotherapy for the treatment of neuroblastoma.

          Methods:

          Seven β-blockers were tested for their antiproliferative and anti-angiogenic properties alone, and in combination with chemotherapy in vitro; the most potent drug combinations were evaluated in vivo in the TH-MYCN mouse model of neuroblastoma.

          Results:

          Three β-blockers (i.e., carvedilol, nebivolol and propranolol) exhibited potent anticancer properties in vitro and interacted synergistically with vincristine, independently of P-glycoprotein expression. β-blockers potentiated the anti-angiogenic, antimitochondrial, antimitotic and ultimately pro-apoptotic effects of vincristine. In vivo, β-blockers alone transiently slowed tumour growth as compared with vehicle only ( P<0.01). More importantly, when used in combination, β-blockers significantly increased the tumour regression induced by vincristine ( P<0.05). This effect was associated with an increase in tumour angiogenesis inhibition ( P<0.001) and ultimately resulted in a four-fold increase in median survival, as compared with vincristine alone ( P<0.01).

          Conclusion:

          β-blockers can increase treatment efficacy against neuroblastoma, and their combination with chemotherapy may prove beneficial for the treatment of this disease and other drug-refractory cancers.

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          Most cited references 48

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          Drug combination studies and their synergy quantification using the Chou-Talalay method.

          This brief perspective article focuses on the most common errors and pitfalls, as well as the do's and don'ts in drug combination studies, in terms of experimental design, data acquisition, data interpretation, and computerized simulation. The Chou-Talalay method for drug combination is based on the median-effect equation, derived from the mass-action law principle, which is the unified theory that provides the common link between single entity and multiple entities, and first order and higher order dynamics. This general equation encompasses the Michaelis-Menten, Hill, Henderson-Hasselbalch, and Scatchard equations in biochemistry and biophysics. The resulting combination index (CI) theorem of Chou-Talalay offers quantitative definition for additive effect (CI = 1), synergism (CI 1) in drug combinations. This theory also provides algorithms for automated computer simulation for synergism and/or antagonism at any effect and dose level, as shown in the CI plot and isobologram, respectively.
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            Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.

             P Talalay,  T C Chou (1984)
            A generalized method for analyzing the effects of multiple drugs and for determining summation, synergism and antagonism has been proposed. The derived, generalized equations are based on kinetic principles. The method is relatively simple and is not limited by whether the dose-effect relationships are hyperbolic or sigmoidal, whether the effects of the drugs are mutually exclusive or nonexclusive, whether the ligand interactions are competitive, noncompetitive or uncompetitive, whether the drugs are agonists or antagonists, or the number of drugs involved. The equations for the two most widely used methods for analyzing synergism, antagonism and summation of effects of multiple drugs, the isobologram and fractional product concepts, have been derived and been shown to have limitations in their applications. These two methods cannot be used indiscriminately. The equations underlying these two methods can be derived from a more generalized equation previously developed by us (59). It can be shown that the isobologram is valid only for drugs whose effects are mutually exclusive, whereas the fractional product method is valid only for mutually nonexclusive drugs which have hyperbolic dose-effect curves. Furthermore, in the isobol method, it is laborious to find proper combinations of drugs that would produce an iso-effective curve, and the fractional product method tends to give indication of synergism, since it underestimates the summation of the effect of mutually nonexclusive drugs that have sigmoidal dose-effect curves. The method described herein is devoid of these deficiencies and limitations. The simplified experimental design proposed for multiple drug-effect analysis has the following advantages: It provides a simple diagnostic plot (i.e., the median-effect plot) for evaluating the applicability of the data, and provides parameters that can be directly used to obtain a general equation for the dose-effect relation; the analysis which involves logarithmic conversion and linear regression can be readily carried out with a simple programmable electronic calculator and does not require special graph paper or tables; and the simplicity of the equation allows flexibility of application and the use of a minimum number of data points. This method has been used to analyze experimental data obtained from enzymatic, cellular and animal systems.
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              Guidelines for the welfare and use of animals in cancer research

              Animal experiments remain essential to understand the fundamental mechanisms underpinning malignancy and to discover improved methods to prevent, diagnose and treat cancer. Excellent standards of animal care are fully consistent with the conduct of high quality cancer research. Here we provide updated guidelines on the welfare and use of animals in cancer research. All experiments should incorporate the 3Rs: replacement, reduction and refinement. Focusing on animal welfare, we present recommendations on all aspects of cancer research, including: study design, statistics and pilot studies; choice of tumour models (e.g., genetically engineered, orthotopic and metastatic); therapy (including drugs and radiation); imaging (covering techniques, anaesthesia and restraint); humane endpoints (including tumour burden and site); and publication of best practice.
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                Author and article information

                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                25 June 2013
                21 May 2013
                : 108
                : 12
                : 2485-2494
                Affiliations
                [1 ]Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW , Randwick, New South Wales 2031, Australia
                [2 ]Metronomics Global Health Initiative , Marseille 13005, France
                [3 ]Faculty of Pharmacy, INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University , 27 Boulevard Jean Moulin, Marseille cedex 05 13385, France
                [4 ]Department of Anatomical Pathology (SEALS), Prince of Wales Hospital , Randwick, New South Wales 2031, Australia
                [5 ]Sydney Children's Hospital , Randwick, New South Wales 2031, Australia
                [6 ]Department of Hematology and Pediatric Oncology, La Timone University Hospital of Marseille , 264 Rue Saint Pierre, Marseille cedex 05 13385, France
                [7 ]Australian Centre for Nanomedicine, School of Chemical Engineering, UNSW , Sydney, New South Wales 2052, Australia
                Author notes
                [* ]Dr E Pasquier; E-mail: e.pasquier@ 123456ccia.unsw.edu.au
                [8]

                Current address: Université Pierre et Marie Curie - CNRS UMR 7211 - INSERM U959, Paris, France.

                [9]

                Both authors contributed equally to this work and should both be considered as senior authors.

                Article
                bjc2013205
                10.1038/bjc.2013.205
                3694229
                23695022
                Copyright © 2013 Cancer Research UK

                From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                Categories
                Translational Therapeutics

                Oncology & Radiotherapy

                mitochondria, neuroblastoma, β-blockers, chemotherapy, angiogenesis, vincristine

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