title: Glucose conjugated platinum(II) complex: antitumor superiority to oxaliplatin, combination effect and mechanism of action.
abstract: A glucose-conjugate of (trans-R,R-cyclohexane-1,2-diamine)-2-fluoromalonato-platinum(II) complex (Glu-Pt) is designed to target tumor-specific active glucose transporters (GLUTs). Despite of very high water solubility, Glu-Pt exhibits improved cytotoxicity as compared to oxaliplatin. In this study, we investigated the in vivo toxicity profiles with the maximum tolerated dose (MTD) evaluation followed by antitumor efficacy study in leukemia-bearing DBA/2 mice. Glu-Pt showed 6-fold increase in the MTD and was more efficacious against mouse L1210 ascetic leukemia than oxaliplatin at equitoxic doses. To explore the combination effect of Glu-Pt and compare with oxaliplatin-based FOLFOX chemotherapy, we investigated the two-component synergistic antitumor activity of Glu-Pt with folinic acid (FA) and 5-fluorouracil (5-FU) respectively in five human cancer cell lines followed by a comparison study with oxaliplatin in a fixed three-component in vitro FOFLOX combination. As the result, Glu-Pt exhibited superior synergistic cytotoxicity compared to oxaliplatin. Flow cytometry-based cell cycle and apoptosis study demonstrated that Glu-Pt follows the same mechanistic principles as of oxaliplatin. Glu-Pt monotherapy and its combination with FA and 5-FU may result in improved efficacy over oxaliplatin and FOLFOX regimen. The study provides fundamental data supporting the potential of Glu-Pt as a drug candidate for further (pre)clinical development.
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Gao
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
authors.forename: Menghua
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Laboratory of Immune Micro-environment, Tianjin Medical University, 22, Qi Xiang Tai Road, Heping District, Tianjin 300070, PR China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Central Institute of Pharmaceutical Research, CSPC Pharmaceutical Group, 226 Huanghe Road, Shijiazhuang, Hebei 050035, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Mi
authors.affiliation: Department of Medicinal Chemistry, Gudui BioPharma Technology Inc., 2 Huatian Road, Huayuan Industrial Park, Tianjin 300384, PR China.
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Immunology, Laboratory of Immune Micro-environment, Tianjin Medical University, 22, Qi Xiang Tai Road, Heping District, Tianjin 300070, PR China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China. Electronic address: qingzhi@tju.edu.cn.
authors.forename: Qingzhi
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005947:Glucose / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000077150:Oxaliplatin; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005947:Glucose
keywords: Antitumor efficacy; FOLFOX; Glucose transporter; Glucose-conjugated platinum(II) complex; Oxaliplatin