Cytogenetic risk assessment of etoposide from mouse bone marrow

Increased clinical applications of the anticancer drug etoposide (a non-intercalative epipodophyllotoxin derivative) and the frequent induction of a second malignancy, particularly leukaemia, in post-etoposide-treated cancer survivors warrant detailed genotoxicity testing of etoposide. The genotoxicity test results available on etoposide are either primarily in in vitro test systems or in lower organisms after treatment with unusually high doses, or after chronic exposures, having little extrapolative value to humans. Therefore, a cytogenetic risk assessment study on etoposide in mouse in vivo was undertaken after a low dose (in accordance with the human therapeutic dose) single exposure. The cytogenetic toxicity of etoposide was assessed from bone marrow of mouse at three separate endpoints: chromosomal aberration and mitotic index studies at 24 h post-treatment and the micronucleus test (MNT) at 30 h post-treatment. The flame drying technique using colchicine, hypotonic sodium citrate, methanol-glacial acetic acid and Giemsa was followed for the preparation of slides for the metaphase chromosomal aberration and mitotic index studies and a simple technique was followed for the MNT. Although induction of chromosomal aberrations, excluding gaps, per 100 metaphases by 10 and 15 mg kg(-1) etoposide was not significant statistically, 20 mg kg(-1) of etoposide induced a significantly higher number of chromosomal aberrations in female (P < or = 0.01) and male (P < or = 0.05) mice. There was no significant change in the induced percentages of dividing cells by any of the doses of etoposide tested. The micronucleus induction also was not significant statistically with the lowest dose but it was significant in female (P