TARGETING MICROTUBULE-ASSOCIATED PROTEINS IN GLIOBLASTOMA - A NEW STRATEGY FOR SELECTIVE THERAPY

Background: This report presents a summary of preclinical data concern ing the use of estramustine, an antimicrotubule agent against human gl ioblastoma cells. The strategy for the investigation of estramustine i s predicated on the unique affinity of this agent for microtubule-asso ciated proteins (MAPs). Methods: A series of laboratory investigations were used to demonstrate antiproliferative effects (MTT assay, colony forming assay, thymidine incorporation), cell cycle synchronization ( flow cytometry), intracellular localization of binding sites (immunocy tochemistry, electron microscopy), and activity in subcutaneous xenogr afts of human glioblastoma. Results: Estramustine has potent in vitro activity against human glioblastoma cells and can enhance the cytotoxi c effects of ionizing radiation. Estramustine-binding protein was abun dantly expressed in glioblastoma cells and may contribute to the selec tive effects of estramustine on neoplastic cells. This agent has activ ity against subcutaneous xenografts of human glioblastoma. Synthesized novel estrogen carbamates also can inhibit proliferation of glioblast oma cells. Conclusions: Cytoskeletal elements (MAPs) of glioblastoma c ells may provide a useful target for therapy with agents like estramus tine because of the potent antimitotic effects of this agent and its a ffinity to a protein that is expressed in glioma cells. These observat ions have stimulated a search for other estrone carbamates with antimi totic activity that exceeds more conventional antimicrotubule agents.