Jb. Mailhes et al., PREFERENTIAL PERICENTRIC LESIONS AND ANEUPLOIDY INDUCED IN MOUSE OOCYTES BY THE TOPOISOMERASE-II INHIBITOR ETOPOSIDE, Teratogenesis, carcinogenesis, and mutagenesis, 14(1), 1994, pp. 39-51
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.