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.
Nagao
M
M
Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan.
Nakayasu
M
M
Aonuma
S
S
Shima
H
H
Sugimura
T
T
D016475:3T3 Cells / Q000187:drug effects; D062365:Aminobenzoates / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D019817:Benzoic Acid; D002454:Cell Differentiation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003374:Coumarins / Q000494:pharmacology; D005784:Gene Amplification; D006801:Humans; D008165:Luminol / Q000494:pharmacology; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011519:Proto-Oncogenes; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D062368:meta-Aminobenzoates
D062365:Aminobenzoates; D001549:Benzamides; D001565:Benzoates; D003374:Coumarins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D062368:meta-Aminobenzoates; D008165:Luminol; C037689:benzamide; C025160:3-aminobenzamide; D019817:Benzoic Acid; C030123:coumarin; C044855:3-aminobenzoic acid