EFFECTS OF FLUORO-DOXORUBICIN (ME2303) ON MICROTUBULES - INFLUENCE OFDIFFERENT CLASSES OF MICROTUBULE-ASSOCIATED PROTEINS

Anthracyclines are among the most useful agents for the treatment of n eoplastic disease, but their clinical use is limited by progressive ca rdiomyopathy. A few studies have suggested the role of microtubules fo r the understanding of this toxicity. By using kinetic and structural studies, we demonstrate the disorganizing action of fluoro-doxorubicin , a novel anthracycline, on the microtubule system. Microtubules have a rich and complex composition in relation to their numerous functions in cells. In the present study, we investigate the role of two major microtubule-associated protein (MAP) families, Tau and MAP2. Both MAP families are responsible for the properties of different classes of mi crotubules. We show the differential effect of fluoro-doxorubicin on t hese two classes of microtubules. Furthermore, we show that fluoro-dox orubicin is able to affect the capacity of purified tubulin to form no rmal microtubules. This study confirms that anthracyclines may interfe r with the microtubule organization. We suggest that some classes of m icrotubules, with regard to their MAP composition, may be affected mor e specifically in cardiac myocytes.