EFFECTS OF THE MICROTUBULE-DISTURBING AGENTS DOCETAXEL (TAXOTERE(R)),VINBLASTINE AND VINCRISTINE ON EPIDERMAL GROWTH FACTOR-RECEPTOR BINDING OF HUMAN BREAST-CANCER CELL-LINES IN-VITRO

Epidermal growth factor (EGF) is a mitogenic peptide that binds to sur face membrane receptors (EGFR) of breast cancer cells. After binding, secondary transmitter molecules are activated by tyrosine phosphorylat ion of the intracellular receptor domaine. The activity of the EGF/EGF R system can be modulated by a variety of chemically unrelated compoun ds including cytostatic agents. The purpose of our present study was t o determine the effects of mitotic inhibitors on EGF receptor binding on human breast cancer cells. We found that MDA-231 and MDA-468 cells bind substantially more [I-125]EGF after preincubation with docetaxel, vinblastine and vincristine. This effect was concentration- and time- dependent, reaching a maximum at 3000 ng/ml and 48 h incubation for do cetaxel, and 100 ng/ml and 48 h incubation for vinca alcaloids. Subseq uent experiments showed an increase in the rate of EGF binding as well as maximal binding capacity. Scatchard analysis of binding experiment s under equilibrium conditions indicated that this was due to an incre ase in the number of apparent EGF binding sites, Modulation of EGF rec eptor binding by docetaxel, vinblastine, and vincristine was not detec table when isolated membranes were used, indicating that intact cytopl asmatic mechanisms are required for the upregulation of EGF receptors.