PURPOSE: The mechanisms for cisplatin-induced renal cell injury have been the focus of intense investigation for many years with a view to provide a more effective and convenient form of nephroprotection. BNP7787 (disodium 2,2'-dithio-bis ethane sulfonate; dimesna, Tavocept), is a water-soluble disulfide investigational new drug that is undergoing clinical development for the prevention and mitigation of clinically important chemotherapy-induced toxicities associated with platinum-type chemotherapeutic agents. We hypothesized that part of BNP7787's mechanism of action (MOA) pertaining to the potential prevention of cisplatin-induced nephrotoxicity involves the inhibition of gamma-glutamyl transpeptidase (GGT) activity, mediated by BNP7787-derived mesna-disulfide heteroconjugates that contain a terminal gamma-glutamate moiety [e.g., mesna-glutathione (MSSGlutathione) and mesna-cysteinyl-glutamate (MSSCE)]. METHODS: Inhibition studies were conducted on human and porcine GGT to determine the effect of mesna-disulfide heteroconjugates on the enzyme's activity in vitro. These studies utilized a fluorimetric assay that monitored the hydrolysis of L-gamma-glutamyl-7-amino-4-trifluoromethylcoumarin (GG-AFC) to AFC. RESULTS: Mesna-disulfide heteroconjugates that contained gamma-glutamyl moieties were potent inhibitors of human and porcine GGT. An in situ-generated mesna-cisplatin conjugate was not a substrate for GGT. CONCLUSIONS: The GGT xenobiotic metabolism pathway is postulated to be a major toxification pathway for cisplatin nephrotoxicity, and BNP7787 may play a novel and critical therapeutic role in the modulation of GGT activity. We further postulate that there are two general mechanisms for BNP7787-mediated nephroprotection against cisplatin-induced nephrotoxicity involving this pathway. First, the active BNP7787 pharmacophore, mesna, produces an inactive mesna-cisplatin conjugate that is not a substrate for the GGT toxification pathway (GGT xenobiotic metabolism pathway) and, second, BNP7787-derived mesna-disulfide heteroconjugates may serve as selective, potent inhibitors of GGT, possibly resulting in nephroprotection by a novel means.
PURPOSE: The mechanisms for cisplatin-induced renal cell injury have been the focus of intense investigation for many years with a view to provide a more effective and convenient form of nephroprotection. BNP7787 (disodium 2,2'-dithio-bis ethane sulfonate; dimesna, Tavocept), is a water-soluble disulfide investigational new drug that is undergoing clinical development for the prevention and mitigation of clinically important chemotherapy-induced toxicities associated with platinum-type chemotherapeutic agents. We hypothesized that part of BNP7787's mechanism of action (MOA) pertaining to the potential prevention of cisplatin-induced nephrotoxicity involves the inhibition of gamma-glutamyl transpeptidase (GGT) activity, mediated by BNP7787-derived mesna-disulfide heteroconjugates that contain a terminal gamma-glutamate moiety [e.g., mesna-glutathione (MSSGlutathione) and mesna-cysteinyl-glutamate (MSSCE)]. METHODS: Inhibition studies were conducted on human and porcine GGT to determine the effect of mesna-disulfide heteroconjugates on the enzyme's activity in vitro. These studies utilized a fluorimetric assay that monitored the hydrolysis of L-gamma-glutamyl-7-amino-4-trifluoromethylcoumarin (GG-AFC) to AFC. RESULTS:Mesna-disulfide heteroconjugates that contained gamma-glutamyl moieties were potent inhibitors of human and porcine GGT. An in situ-generated mesna-cisplatin conjugate was not a substrate for GGT. CONCLUSIONS: The GGT xenobiotic metabolism pathway is postulated to be a major toxification pathway for cisplatinnephrotoxicity, and BNP7787 may play a novel and critical therapeutic role in the modulation of GGT activity. We further postulate that there are two general mechanisms for BNP7787-mediated nephroprotection against cisplatin-induced nephrotoxicity involving this pathway. First, the active BNP7787 pharmacophore, mesna, produces an inactive mesna-cisplatin conjugate that is not a substrate for the GGT toxification pathway (GGT xenobiotic metabolism pathway) and, second, BNP7787-derived mesna-disulfide heteroconjugates may serve as selective, potent inhibitors of GGT, possibly resulting in nephroprotection by a novel means.
Authors: Barbara Marengo; Mariapaola Nitti; Anna Lisa Furfaro; Renata Colla; Chiara De Ciucis; Umberto Maria Marinari; Maria Adelaide Pronzato; Nicola Traverso; Cinzia Domenicotti Journal: Oxid Med Cell Longev Date: 2016-06-21 Impact factor: 6.543
Authors: C J Henry; B K Flesner; S A Bechtel; J N Bryan; D J Tate; K A Selting; J C Lattimer; M E Bryan; L Grubb; F Hausheer Journal: J Vet Intern Med Date: 2017-10-27 Impact factor: 3.333