Employing pancreatic tumour;-glutamyl transferase for therapeutic delivery
Institution: | University of New South Wales |
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Department: | Clinical School - Prince of Wales Hospital |
Year: | 2014 |
Keywords: | GSAO; γ-glutamyl transferase; Prodrug; Pancreatic cancer; Targeted therapy; Tumour microenvironment; Stellate cells |
Record ID: | 1047189 |
Full text PDF: | http://handle.unsw.edu.au/1959.4/53650 |
γ-glutamyltransferase (γGT) is a cell surface enzyme that catalyses hydrolysis of the bond linking the glutamate and cysteine residues of glutathione and glutathione-S-conjugates. I have observed that human pancreatic tumour cells and tumour-associated stellate cells express high levels of this enzyme when compared to normal pancreatic epithelial and stellate cells. Detection of the protein in tumour sections correlated with γGT activity on the surface of the cultured tumour and stellate cells. I tested whether the tumour γGT could be employed to deliver a therapeutic to the tumour endothelial cells. GSAO is a glutathione-S-conjugate of a trivalent arsenical that is activated to enter endothelial cells by γGT cleavage of the γ-glutamyl residue. The arsenical moiety triggers proliferation arrest and death of the endothelial cells by targeting the mitochondria. Human pancreatic tumour and stellate cell γGT activated GSAO in culture and γGT activity positively correlated with GSAO-mediated proliferation arrest of endothelial cells in transwell and co-culture systems. A soluble form of γGT is found in blood and I measured the rate of activation of GSAO by this enzyme. I calculated that systemically administered GSAO would circulate through the pancreatic blood supply several times before appreciable activation by normal blood levels of γGT. In support of this finding, tumour γGT activity positively correlated with GSAO-mediated inhibition of pancreatic tumour angiogenesis and tumour growth in mice. My findings indicate that pancreatic tumour γGT can be used to deliver a therapeutic to the tumour.