Cancer Chemotherapy and Pharmacology

, Volume 65, Issue 5, pp 941–951

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

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

DOI: 10.1007/s00280-009-1101-y

Cite this article as:
Hausheer, F.H., Shanmugarajah, D., Leverett, B.D. et al. Cancer Chemother Pharmacol (2010) 65: 941. doi:10.1007/s00280-009-1101-y

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.

Keywords

BNP7787CisplatinGamma-glutamyl transpeptidase (GGT)GlutathioneMesna–disulfide heteroconjugatesNephrotoxicity

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Frederick H. Hausheer
    • 1
  • Dakshine Shanmugarajah
    • 1
  • Betsy D. Leverett
    • 1
  • Xinghai Chen
    • 1
  • Quili Huang
    • 1
  • Harry Kochat
    • 1
  • Pavankumar N. Petluru
    • 1
  • Aulma R. Parker
    • 1
  1. 1.BioNumerik Pharmaceuticals, Inc.San AntonioUSA