In-vitro and in-vivo study of arginase in treatment of malignant pleural mesothelioma

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is the commonest form of mesothelioma. Asbestos and erionite fibre exposure are notable causes of MPM. Combination of pemetrexed and cisplatin is the cornerstone chemotherapy in clinical management of MPM with a median overall survival of 12 months far from satisfactory. Arginine is a semi-essential amino acid in tumours, but non-essential in normal cells. Arginine-degrading enzymes (arginase and arginine deiminase) have been used to treat different cancers with inability to synthesize arginine. BCT-100 is a pegylated arginase which is currently undergoing formal phase I/II clinical trials in treatment of hepatocellular carcinoma at Queen Mary Hospital with encouraging results. The effect of BCT-100 has not been investigated in MPM. The aim of this study is to investigate the effect of BCT-100 in MPM in vitro and in vivo. Method: A panel of MPM cell lines (H28, 211H, H226, H2052 and H2452) was used. The effect of BCT-100 on cell viability and protein expression was studied by Crystal Violet assay and Western blot respectively. The in vivo effect of BCT-100 was investigated with nude mice xenograft models. Results: BCT-100 reduced cell viability with IC50 values ranges from 13 - 22 mU/ml in different MPM cell lines after 72 hours incubation. BCT-100 suppressed tumor growth in H226 and 211H nude mice xenografts in a dose dependent manner. The median survival was significantly increased accompanied with induction of apoptosis and cell cycle arrest in BCT-100 treatment group when compared with control group in both xenografts. Conclusion: BCT-100 (pegylated arginase) reduced cell viability in vitro. BCT-100 also suppressed tumor growth and increased median survival which is partially mediated by apoptosis and cell cycle arrest in vivo. Acknowledgment: This research is supported by Pneumoconiosis Compensation Fund Board.