Journal
EBIOMEDICINE
Volume 6, Issue -, Pages 87-95Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2016.02.026
Keywords
Angiosarcoma; Vascular tumor; Metronomic chemotherapy; Propranolol; Adrenergic receptor
Funding
- Children's Cancer Institute
- Balnaves Foundation
- Cancer Council New South Wales
- NHMRC Senior Research Fellowships [APP1058299]
- LNlavie
- Les copains de Charles
- Marie Curie-Sklodowska Fellowship from the European Research Council [626794]
- Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology [CE140100036]
Ask authors/readers for more resources
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 beta-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. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available