1 research outputs found
Employing Pancreatic Tumor γ‑Glutamyltransferase for Therapeutic Delivery
γ-Glutamyltransferase
(γGT) is a cell surface enzyme
that catalyzes hydrolysis of the bond linking the glutamate and cysteine
residues of glutathione and glutathione-S-conjugates. We have observed
that human pancreatic tumor cells and tumor-associated stellate cells
express high levels of this enzyme when compared to normal pancreatic
epithelial and stellate cells. Detection of the protein in tumor sections
correlated with γGT activity on the surface of the cultured
tumor and stellate cells. We tested whether the tumor γGT could
be employed to deliver a therapeutic to the tumor 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 tumor and stellate cell γGT activated GSAO
in culture and γGT activity positively correlated with GSAO-mediated
proliferation arrest and death of endothelial cells in Transwell and
coculture systems. A soluble form of γGT is found in blood,
and we measured the rate of activation of GSAO by this enzyme. We
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, tumor
γGT activity positively correlated with GSAO-mediated inhibition
of pancreatic tumor angiogenesis and tumor growth in mice. Our findings
indicate that pancreatic tumor γGT can be used to deliver a
therapeutic to the tumor