European journal of medicinal chemistry

Glucose conjugated platinum(II) complex: antitumor superiority to oxaliplatin, combination effect and mechanism of action.

PMID 26177447


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 inxa0vivo 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 inxa0vitro 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.

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Phenazine methosulfate, ≥90% (UV)