Loss of amplified genes by poly(ADP-ribose) polymerase inhibitors.

A poly(ADP-ribose) polymerase inhibitor, benzamide (BA), was found to induce flat revertants of NIH 3T3 cells that had been transformed by human Ha-ras, rat Ki-ras, rat c-raf, and human ret-II. These genes had been amplified in original transformants, but they were completely eliminated by BA. Contrary to this, endogenous activated Ha-ras in a human bladder carcinoma cell line, T24, was not eliminated by BA. The gene loss seemed to be restricted to exogenous and/or amplified sequences. BA also eliminated the amplified c-myc gene in HL-60 cells, concomitant with differentiation into granulocytes. We demonstrated that the amplified c-myc gene was not present as episomes. It is probably present as double minutes or a homogeneously staining region. Dimethylsulfoxide also induced differentiation at a concentration that did not inhibit poly(ADP-ribose) polymerase. The cell lost the c-myc gene in association with this differentiation. The amplified c-myc gene in a colon adenocarcinoma cell line, COLO 320HSR, and the amplified mdr-1 gene in an adriamycin-resistant myelogenous leukemia cell line, K562/ADM, were not eliminated by BA. Various poly(ADP-ribose) polymerase inhibitors also eliminated human Ha-ras in the NIH 3T3 transformant and the c-myc gene in HL-60 cells.