title: Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model.
abstract: Malignant pleural mesothelioma (MPM) is an incurable cancer with an increasing incidence. Currently, pemetrexed (PMX)-based chemotherapy is the mainstay of chemotherapy for MPM, however, the outcome of PMX-based chemotherapy in patients with MPM is dismal. RNA interference (RNAi) technology has been considered as an effective tool to substantially enhance the therapeutic efficacy of chemotherapeutic agents in many preclinical and clinical settings. In this study, therefore, we investigated whether non-viral anti-thymidylate synthase RNAi embedded liposome (TS shRNA lipoplex) would effectively guide the downregulation of TS in human malignant mesothelioma MSTO-211H cells. Consequently, it enhanced the antitumor effect of PMX both in vitro and in vivo. TS shRNA effectively enhanced the in vitro cell growth inhibition upon treatment with PMX via downregulating TS expression in the MSTO-211H cell line. In in vivo orthotopic tumor model, the combined treatment of PMX and TS shRNA lipoplex efficiently combated the progression of orthotopic thoracic tumors and as a result prolonged mouse survival, compared to each single treatment. Our findings emphasize the pivotal relevance of RNAi as an effective tool for increasing the therapeutic efficacy of PMX, a cornerstone in the treatment regimens of MPM, and thereby, raising the possibility for the development of a novel therapeutic strategy, combination therapy of TS-shRNA and PMX, that can surpass many of the currently applied, but less effective, therapeutic regimens against lethal MPM.
authors: Department of Pharmacokinetics and Biopharmaceutics, Institute of Health Biosciences, Tokushima University, Tokushima, Japan.
authors: Amr S
authors: AS
authors: Abu Lila
authors: Department of Pharmacokinetics and Biopharmaceutics, Institute of Health Biosciences, Tokushima University, Tokushima, Japan.
authors: Chihiro
authors: C
authors: Kato
authors: Department of Cancer Metabolism and Therapy, Institute of Health Biosciences, Tokushima University, Tokushima, Japan.
authors: Masakazu
authors: M
authors: Fukushima
authors: Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors: Cheng-Long
authors: CL
authors: Huang
authors: Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors: Hiromi
authors: H
authors: Wada
authors: Department of Pharmacokinetics and Biopharmaceutics, Institute of Health Biosciences, Tokushima University, Tokushima, Japan.
authors: Tatsuhiro
authors: T
authors: Ishida
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D000068437:Pemetrexed / Q000008:administration & dosage*; D034622:RNA Interference; D013940:Thymidylate Synthase / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D008081:Liposomes; D000068437:Pemetrexed; D013940:Thymidylate Synthase