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      Effective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-based Metronomic Chemotherapy: A Bench to Bedside Study

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          Abstract

          Background

          Angiosarcomas are rare malignant tumors of vascular origin that represent a genuine therapeutic challenge. Recently, the combination of metronomic chemotherapy and drug repositioning has been proposed as an attractive alternative for cancer patients living in developing countries.

          Methods

          In vitro experiments with transformed endothelial cells were used to identify synergistic interactions between anti-hypertensive drug propranolol and chemotherapeutics. This led to the design of a pilot treatment protocol combining oral propranolol and metronomic chemotherapy. Seven consecutive patients with advanced/metastatic/recurrent angiosarcoma were treated with this combination for up to 12 months, followed by propranolol-containing maintenance therapy.

          Findings

          Gene expression analysis showed expression of ADRB1 and ADRB2 adrenergic receptor genes in transformed endothelial cells and in angiosarcoma tumors. Propranolol strongly synergized with the microtubule-targeting agent vinblastine in vitro, but only displayed additivity or slight antagonism with paclitaxel and doxorubicin. A combination treatment using bi-daily propranolol (40 mg) and weekly metronomic vinblastine (6 mg/m 2) and methotrexate (35 mg/m 2) was designed and used in 7 patients with advanced angiosarcoma. Treatment was well tolerated and resulted in 100% response rate, including 1 complete response and 3 very good partial responses, based on RECIST criteria. Median progression-free and overall survival was 11 months (range 5–24) and 16 months (range 10–30), respectively.

          Interpretation

          Our results provide a strong rationale for the combination of β-blockers and vinblastine-based metronomic chemotherapy for the treatment of advanced angiosarcoma. Furthermore, our study highlights the potential of drug repositioning in combination with metronomic chemotherapy in low- and middle-income country setting.

          Funding

          This study was funded by institutional and philanthropic grants.

          Highlights

          • A strong synergism was identified between propranolol and vinblastine in an in vitro model of angiosarcoma.
          • Adrenergic receptor expression was detected in angiosarcoma tumors providing a molecular target for propranolol.
          • Propranolol and vinblastine-based metronomic chemotherapy led to 100% response in 7 patients with inoperable angiosarcoma.
          • This treatment resulted in prolonged survival of angiosarcoma patients and warrants further investigation in larger trials.

          Related collections

          Most cited references 32

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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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            Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro.

            In this article we present validation of a real-time RT-PCR method to quantitate mRNA expression levels of atrial natriuretic peptide and c-fos in an in vitro model of cardiac hypertrophy. This method requires minimal sample and no postreaction manipulation. In real-time RT-PCR a dual-labeled fluorescent probe is degraded concomitant with PCR amplification. Input target mRNA levels are correlated with the time (measured in PCR cycles) at which the reporter fluorescent emission increases beyond a threshold level. The use of an oligo(dt) magnetic bead protocol to harvest poly(A) mRNA from cultured cells in 96-well plates minimized DNA contamination. We show that the GAPDH gene chosen for normalization of the RNA load is truly invariant throughout the biological treatments examined. We discuss two methods of calculating fold increase: a standard curve method and the DeltaDelta Ct method. Real-time quantitative RT-PCR was used to determine the time course of c-fos induction and the effect of varying doses of four known hypertrophy agents on atrial naturitic factor messenger RNA expression in cultured cardiac muscle cells. Our results agree with published data obtained from Northern blot analysis. Copyright 1999 Academic Press.
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              • Record: found
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              Propranolol for severe hemangiomas of infancy.

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                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                17 February 2016
                April 2016
                17 February 2016
                : 6
                : 87-95
                Affiliations
                [a ]INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, Marseille, France
                [b ]Metronomics Global Health Initiative, Marseille, France
                [c ]Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia
                [d ]Service d'Hématologie & Oncologie Pédiatrique, AP-HM, Marseille, France
                [e ]Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
                [f ]Department of Pathology, Tata Memorial Centre, Mumbai, India
                [g ]Service d'Oncologie Médicale, AP-HM, Marseille, France
                [h ]Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, UNSW Australia, Sydney, Australia
                Author notes
                [* ]Correspondence to: E. Pasquier, Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, High St, Randwick NSW 2031, Australia.Children's Cancer Institute Australia for Medical ResearchLowy Cancer Research CentreUNSW AustraliaPO Box 81High StRandwickNSW 2031Australia epasquier@ 123456ccia.unsw.edu.au
                [** ]Correspondence to: S. Banavali, Department of Medical and Pediatric Oncology, Tata Memorial Centre, Dr. Ernest Borges Road, Parel, Mumbai 400 012, India.Department of Medical and Pediatric OncologyTata Memorial CentreDr. Ernest Borges Road, ParelMumbai400 012India banavali_2000@ 123456yahoo.com
                Article
                S2352-3964(16)30065-2
                10.1016/j.ebiom.2016.02.026
                4856748
                27211551
                © 2016 The Authors
                Categories
                Original Research

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