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Inhibition of Protein Tyrosine Phosphatase by the Antitumor Agent Gallium Nitrate¹

Arizona Cancer Center, The University of Arizona Health Sciences Center, Tucson, Arizona 85724 [M. M. B., G. P.], and Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55902 [L. A. B., R. T. A.]

Protein tyrosine phosphatases (PTPases) play an important role in regulating cell growth and transformation. We report that the antitumor agent gallium nitrate is a potent inhibitor (concentration producing 50% inhibition, 2–6 µM) of detergent-solubilized cellular membrane PTPase from Jurkat human T-cell leukemia cells and HT-29 human colon cancer cells. This is the first report of a selective, small molecule drug inhibitor of PTPase. Gallium nitrate did not inhibit CD45, a PTPase found in the membranes of hemopoietic lineage cells such as Jurkat cells. Studies with gallium nitrate and a series of gallium-containing analogues revealed no correlation between growth-inhibitory activity in Jurkat and HT-29 cells and the ability to inhibit detergent-solubilized PTPase. Gallium nitrate and most of the gallium analogues penetrate poorly into cells. In contrast, a gallium-hydrogen peroxide complex inhibits DNA synthesis in Jurkat cells and induces the accumulation of phosphotyrosines on multiple intracellular proteins in this cell line. Gallium-hydrogen peroxide complex and gallium nitrate have similar inhibitory activity toward detergent-soluble PTPase. This is a new mechanism of action for gallium nitrate but it is not known if the inhibition of PTPase is related to the antitumor activity of gallium nitrate.

¹ Work was supported by NIH Grants CA 52995 and CA 42286. L. A. B. was supported by NIH Postdoctoral Training Grant CA 09127.

² To whom requests for reprints should be addressed, at Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, Arizona 85724.

Received 12/ 7/92. Accepted 2/11/93.

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