title: Adenovirus-based strategies enhance antitumor capability through p53-mediated downregulation of MGMT in uveal melanoma.
abstract: Uveal melanoma (UM) is an intractable disease with a low survival rates, despite adequate local treatment, as a result of its metastatic characteristics. Thus, new therapeutic strategies, including combinations of novel gene therapy and traditional chemotherapy, are under investigation to improve long-term prognosis. Dacarbazine or DTIC, an alkylating agent which results in DNA methylation, is most commonly used to treat melanoma but the response is very limited. The O6-methylguanine DNA methyl transferase (MGMT), a DNA repair protein, is involved in chemoresistance in DTIC treatment. We previously investigated a combination of oncolytic adenovirus H101 and the alkylating agent DTIC in the treatment of UM cells in vitro and observed a synergistic antitumor effect. In this study, we validated this result and report an enhanced therapeutic effect in vivo. Our findings also demonstrated that the oncolytic adenovirus H101 decreased MGMT levels via accumulation of p53 overcoming DTIC chemoresistance. Therefore, the clinical therapeutic efficacy of DTIC in the treatment of UM might be improved using this adenovirus-based combination therapy.
authors.affiliation: a Department of Clinical Skills Center , Kunming Medical University , Kunming , Yunnan , China.
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.affiliation: b Department of Ophthalmology , The First Affiliated Hospital of Kunming Medical University , Kunming , Yunnan , China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yuan
authors.affiliation: b Department of Ophthalmology , The First Affiliated Hospital of Kunming Medical University , Kunming , Yunnan , China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhao
authors.affiliation: a Department of Clinical Skills Center , Kunming Medical University , Kunming , Yunnan , China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: a Department of Clinical Skills Center , Kunming Medical University , Kunming , Yunnan , China.
authors.forename: Yunzhi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: b Department of Ophthalmology , The First Affiliated Hospital of Kunming Medical University , Kunming , Yunnan , China.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: a Department of Clinical Skills Center , Kunming Medical University , Kunming , Yunnan , China.
authors.forename: Biyun
authors.initials: B
authors.lastname: Cun
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015254:DNA Modification Methylases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014604:Uveal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D023041:Xenograft Model Antitumor Assays; D000098943:Uveal Melanoma
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes
keywords: Dacarbazine; MGMT; oncolytic adenovirus; p53; uveal melanoma