Are topoisomerase II inhibitor-induced micronuclei in vitro a predictive marker for the compounds' ability to cause secondary leukemias after treatment?
The inhibition of topoisomerase II (topo II) is a very powerful principle of chemotherapy and topo II inhibiting drugs are the backbone of most chemotherapeutic strategies. However, secondary malignomas can occur after treatment. Typically, secondary acute myeloid leukemia (t-AML) after treatment with topo II inhibitors has a shorter latency period than t-AML following alkylator therapy. Fragments originating from chromosome breakage as well as whole chromosomes which are not correctly distributed during mitosis give rise to micronuclei in the next interphase. Micronucleus formation has become an important endpoint in genotoxicity testing. In an effort to test the suitability of the micronucleus assay for predictive purposes, we have analyzed three human tumor cell lines for cell growth as well as micronucleus induction after treatment with four clinically used topo II inhibitors. Micronuclei were induced at levels of low toxicity by etoposide, mitoxantrone, daunorubicin and idarubicin. The induction of micronuclei was a more sensitive indicator of drug effects than reduction in cell growth. Thus, micronucleus induction may assist in the prediction of the potency of a chemotherapeutic agent for induction of secondary malignomas.
Stopper
H
H
Department of Toxicology, University of Würzburg, Germany. stopper@toxi.uni-wuerzburg.de
Boos
G
G
Clark
M
M
Gieseler
F
F
D000970:Antineoplastic Agents / Q000633:toxicity*; D014408:Biomarkers, Tumor; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006801:Humans; D007938:Leukemia / Q000139:chemically induced*; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects*; D015162:Micronucleus Tests; D013601:T-Lymphocytes / Q000187:drug effects; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002273:Carcinogens; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II