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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)941-951
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume65
Issue number5
DOIs
StatePublished - Apr 1 2010

Fingerprint

Mesna
gamma-Glutamyltransferase
Cisplatin
Modulation
Disulfides
Xenobiotics
Metabolism
Glutamic Acid
Swine
Investigational Drugs
2,2'-dithiodiethanesulfonic acid
Chemotherapy
Enzyme activity
Substrates
Platinum
Glutathione
Toxicity
Hydrolysis
Assays
Kidney

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Mechanistic study of BNP7787-mediated cisplatin nephroprotection : Modulation of gamma-glutamyl transpeptidase. / Hausheer, Frederick H.; Shanmugarajah, Dakshine; Leverett, Betsy D.; Chen, Xinghai; Huang, Quili; Kochat, Harry; Petluru, Pavankumar N.; Parker, Aulma R.

In: Cancer Chemotherapy and Pharmacology, Vol. 65, No. 5, 01.04.2010, p. 941-951.

Research output: Contribution to journalArticle

Hausheer, Frederick H. ; Shanmugarajah, Dakshine ; Leverett, Betsy D. ; Chen, Xinghai ; Huang, Quili ; Kochat, Harry ; Petluru, Pavankumar N. ; Parker, Aulma R. / Mechanistic study of BNP7787-mediated cisplatin nephroprotection : Modulation of gamma-glutamyl transpeptidase. In: Cancer Chemotherapy and Pharmacology. 2010 ; Vol. 65, No. 5. pp. 941-951.
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AU - Leverett, Betsy D.

AU - Chen, Xinghai

AU - Huang, Quili

AU - Kochat, Harry

AU - Petluru, Pavankumar N.

AU - Parker, Aulma R.

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N2 - 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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