GENE AMPLIFICATION AND MULTIDRUG-RESISTANCE INDUCED BY THE PHOSPHATASE-INHIBITORY TUMOR PROMOTER, OKADAIC ACID

The mechanism by which tumor promoters contribute to cellular transformation and tumorigenesis is not completely understood. To investigate further the molecular events involved in these processes, we used okadaic acid, a nonphorbol ester type tumor promoter that specifically inhibits certain protein phosphatases. We describe here that the continuous treatment of murine NIH 3T3 fibroblast cell cultures with okadaic acid resulted in a 50-fold amplification of two genes, mdr-1a and mdr-1b, that conferred multidrug resistance. As a consequence, the cells became cross-resistant to the cytotoxic effects of adriamycin, an antineoplastic drug used in the treatment of human tumors. Since genetic changes have been correlated with cell transformation and tumorigenesis, our results suggest that these processes may constitute an additional factor contributing to tumor promotion by okadaic acid.