PREFERENTIAL PERICENTRIC LESIONS AND ANEUPLOIDY INDUCED IN MOUSE OOCYTES BY THE TOPOISOMERASE-II INHIBITOR ETOPOSIDE

Etoposide (VP-16) is used as an antineoplastic drug in humans. It inhi bits topoisomerase II (topo II) activity by forming a ternary complex (DNA-etoposide-topo II). This complex prevents the DNA-strand rejoinin g activity of topo II, which results in DNA-strand breaks and the form ation of structural chromosome aberrations. Topo II activity is also r equired for removing regions of DNA catenation prior to chromosome seg regation. The possibility exists that patients undergoing etoposide ch emotherapy may incur genetic damage and, consequently, may be at a gre ater risk for developing secondary tumors and having genetically abnor mal offspring. We studied the ability of etoposide for inducing both s tructural chromosome aberrations and aneuploidy in mouse oocytes. Diff erent dosages of etoposide were given to female mice at various times before and after human choronic gonadotrophin injection, and ovulated oocytes were collected 17 h later. The proportions of chromatid acentr ic fragments and of hyperploid metaphase II oocytes were significantly higher (P < 0.01) in the etoposide groups than in concurrent controls . These results indicate that both structural and numerical aberration s can be induced without direct interaction with DNA or with the vario us organelles associated with chromosome segregation. Additionally, un like other compounds (vinblastine, colchicine, benomyl, and griseofulv in) that induce both meiotic delay (ovulated metaphase I oocytes and p olyploidy) and aneuploidy, etoposide did not cause meiotic delay in oo cyte maturation. (C) 1994 Wiley-Liss, Inc.