Glioblastoma multiforme is the most common primary malignant brain tumor and is rapidly fatal for the vast majority of patients. there are few treatment options for this tumor that can significantly improve the length of the patient's life and new forms of therapy are needed. The objective of this proposal is to develop new methods of treatment for this tumor by investigating the effects of a known antimicrotubule drug (estramustine) and other agents with similar chemical structure (estradiol analogs) on cultured glioblastoma cells. There is strong evidence which indicates that estramustine accumulates in cells containing the binding site [estramustine binding protein (EMBP)] and depolymerizes microtubules by binding to microtubule associated proteins (MAPs). A protein which is recognized by an antibody to EMBP has been identified in glioblastoma cells obtained from operative specimens. In vitro treatment of this glioblastoma with estramustine results in rapid inhibition of cell proliferation. This inhibition is associated with significant alterations in the cytoarchitecture of the tumor cells. Based on the chemical structure of estramustine and other microtubule inhibitors, estradiol analogs with a carbamide bond on the A ring were synthesized and also found to have significant antiproliferative effects. Two of these analogs were as effective as estramustine in inhibiting tumor cell proliferation and also caused significant changes in cellular morphology. The proposed experiments will investigate the effect of putative antimicrotubule agents on glioblastoma by: 1, examining the effects of estramustine and estradiol analogs with a variety of glioblastomas as well as with human astrocytes; 2, determining whether estradiol analogs accumulate in cells containing the binding site for estramustine, estramustine binding protein; 3, assaying a variety of glioblastoma cultures and human astrocytes for their constituent MAPs to compare their responses to EM and estradiol analogs with respect to differences in their MAPs. 4, utilizing an in vivo model by implanting human glioblastoma cells into the rat to study of the distribution and potential antiproliferative effects of radioactively labeled agents. The proposed experiments will require techniques currently in use in the Neuro-oncology and Obstetrics and Gynecology laboratories including cell culture, immunohistochemistry, in vitro chemosensitivity testing, [3H] thymidine incorporation assays, Western blots, and implantation of human cells into rats. The results of these experiments may provide valuable information concerning the composition of MAPs in glial cells and malignant glial tumors as well as clinically relevant data on a new form of therapy.
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