L-
Canavanine (CAV) is an
arginine (ARG) analog isolated from the jack bean, Canavalia ensiformis. CAV becomes incorporated into cellular
proteins of MIA PaCa-2 human
pancreatic cancer cells and the aberrant, canavanyl
proteins are not preferentially degraded. Hydrolytic cleavage of CAV to
canaline (CAN) and
urea is mediated by
arginase. CAN is a potent metabolite that inactivates
vitamin B6-containing
enzymes and may inhibit cell growth. To determine the presence of
arginase and its specificity for ARG and CAV in MIA PaCa-2 cells, a radiometric assay, which quantifies the 14C released from the hydrolytic cleavage of L-[guanidino-14C]ARG or L-[guanidinooxy-14C]CAV mediated by
arginase, was employed. Insignificant amounts of 14CO2 were released when cells were exposed to [14C]CAV or to [14C]ARG.
Pancreatic cancer cells secrete a negligible amount of
arginase. Cytotoxic effects of CAN and CAV were compared on cells exposed to varying concentrations of ARG. These studies provide evidence that CAV's cytotoxic effects on MIA PaCa-2 cells cannot be attributed to conversion to the active metabolite CAN. A slower and decreased hydrolysis of CAV by
arginase allows CAV to persist and increases its chances of incorporating into
proteins in these cells. Lack of considerable amounts of
arginase in the pancreas makes CAV a worthy candidate for further studies in
pancreatic cancer.