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Inhibition of H-ras Oncogene Transformation of NIH3T3 Cells by Protease Inhibitors¹

New York University Medical Center, Institute of Environmental Medicine, New York, New York 10016

The protease inhibitors antipain, leupeptin, ₁-antitrypsin, and -aminocaproic acid were found to inhibit transformation of NIH3T3 cells after transfection with an activated H-ras oncogene.

Inhibition of focus formation by protease inhibitors was concentration dependent and maximal at 50% of control values. Transfection of a gene for neomycin resistance was not affected by protease inhibitors. Antipain was inactive if present only during the first 2 days of the gene transfer protocol or only during the final 10 days of the experiment. However, the full effect was observed when antipain was added at the subculture step on day 3 and during the subsequent cell proliferation. If cells were not subcultured, the yield of the foci per µg of DNA was sharply reduced and addition of antipain did not further suppress the transformation rate. Subculture of NIH3T3 cells 3 days after transfection at lower cell densities resulted in higher transformation efficiency. The results suggest that transformation of NIH3T3 cells by a single mutated oncogene may involve multiple stages including cell proliferation and that part of this process is susceptible to inhibition by protease inhibitors.

¹ This work was supported by Grant CA36342 from the NIH and is part of Center programs ES00260 and CA13343 from the NIH.

² To whom requests for reprints should be addressed.

Received 9/11/86. Revised 1/ 2/87. Accepted 3/24/87.