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 o f chemotherapy and topo II inhibiting drugs are the backbone of most chemot herapeutic strategies. However, secondary malignomas can occur after treatm ent. Typically, secondary acute myeloid leukemia (t-AML) after treatment wi th topo II inhibitors has a shorter latency period than t-AML following alk ylator therapy. Fragments originating from chromosome breakage as well as w hole chromosomes which are not correctly distributed during mitosis give ri se to micronuclei in the next interphase. Micronucleus formation has become an important endpoint in genotoxicity testing. In an effort to test the su itability of the micronucleus assay for predictive purposes, we have analyz ed three human tumor cell lines for cell growth as well as micronucleus ind uction after treatment with four clinically used topo II inhibitors. Micron uclei were induced at levels of low toxicity by etoposide, mitoxantrone, da unorubicin and idarubicin. The induction of micronuclei was a more sensitiv e indicator of drug effects than reduction in cell growth. Thus, micronucle us induction may assist in the prediction of the potency of a chemotherapeu tic agent for induction of secondary malignomas. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.