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Inhibition of the Growth of Human Pancreatic Cancer Cells by the Arginine Antimetabolite L-Canavanine¹

Divisions of Pharmacology and Toxicology [D. S. S., C. Y. A.] and Pharmaceutics and Medicinal Chemistry [P. B. D.], School of Pharmacy, Northeast Louisiana University, Monroe, Louisiana 71209-0470, and T. H. Morgan School of Biological Sciences, University of Kentucky, Lexington, Kentucky 40506 [G. A. R.]

L-Canavanine (CAV), the L-2-amino-4-guanidinooxy structural analogue of L-arginine (ARG), is a potent ARG antagonist which occurs in the jack bean, Canavalia ensiformis. This ARG antimetabolite is active against L1210 murine leukemia and a solid colonic tumor in the rat. Our initial studies using a microtiter assay show that CAV exhibits a 50% inhibitory concentration of approximately 2 mM against the human pancreatic adenocarcinoma cell line, MIA PaCa-2, when these cells are grown in Dulbecco's modified Eagle's medium containing 0.4 mM ARG. When the ARG concentration is reduced to 0.4 µM, the 50% inhibitory concentration for CAV falls precipitously to 0.01 mM. The pronounced increase in the ability of CAV to inhibit MIA PaCa-2 cell growth at the lower ARG concentration may result from enhanced CAV competition with ARG for incorporation into newly synthesized cellular proteins. At 0.4 µM ARG, 30 mM CAV almost completely inhibits cell growth by 6 h. In contrast, with 0.4 mM ARG, complete inhibition does not occur until after 48 h. A dramatic reversal of growth inhibition caused by a very high concentration of CAV was observed when cells treated with CAV were replenished with a high concentration of ARG. Our results suggest that CAV has real potential as a lead compound for the development of analogues with enhanced activity against human pancreatic cancer.

¹ This work was supported in part by National Science Foundation Grant IBN-9302875; funds from the Lucille Markey Cancer Center of the University of Kentucky; the School of Pharmacy, Northeast Louisiana University; and the American Society of Pharmacognosy Foundation.

² To whom requests for reprints should be addressed.

Received 7/19/94. Accepted 10/ 3/94.