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Mechanistic study of BNP7787-mediated cisplatin nephroprotection: modulation of gamma-glutamyl transpeptidase

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Abstract

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.

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Acknowledgments

We thank Vanessa Sandoval and Erika Ramirez for editorial assistance in the preparation of this manuscript. In addition, we appreciate the time and effort of David Margrave and Dr. Scott Whitaker in reviewing these manuscripts and we thank Julie Martin for providing Fig. 1.

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  1. BioNumerik Pharmaceuticals, Inc., 8122 Datapoint Drive, Suite 1250, San Antonio, TX, 78229, USA

    Frederick H. Hausheer, Dakshine Shanmugarajah, Betsy D. Leverett, Xinghai Chen, Quili Huang, Harry Kochat, Pavankumar N. Petluru & Aulma R. Parker

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  1. Frederick H. Hausheer
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  2. Dakshine Shanmugarajah
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Correspondence to Frederick H. Hausheer.

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Hausheer, F.H., Shanmugarajah, D., Leverett, B.D. et al. Mechanistic study of BNP7787-mediated cisplatin nephroprotection: modulation of gamma-glutamyl transpeptidase. Cancer Chemother Pharmacol 65, 941–951 (2010). https://doi.org/10.1007/s00280-009-1101-y

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