Targeting microtubule-associated proteins in glioblastoma: a new strategy for selective therapy.
BACKGROUND
This report presents a summary of preclinical data concerning the use of estramustine, an antimicrotubule agent against human glioblastoma cells. The strategy for the investigation of estramustine is predicated on the unique affinity of this agent for microtubule-associated 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 (immunocytochemistry, electron microscopy), and activity in subcutaneous xenografts of human glioblastoma.


RESULTS
Estramustine has potent in vitro activity against human glioblastoma cells and can enhance the cytotoxic effects of ionizing radiation. Estramustine-binding protein was abundantly expressed in glioblastoma cells and may contribute to the selective effects of estramustine on neoplastic cells. This agent has activity against subcutaneous xenografts of human glioblastoma. Synthesized novel estrogen carbamates also can inhibit proliferation of glioblastoma cells.


CONCLUSIONS
Cytoskeletal elements (MAPs) of glioblastoma cells may provide a useful target for therapy with agents like estramustine because of the potent antimitotic effects of this agent and its affinity to a protein that is expressed in glioma cells. These observations have stimulated a search for other estrone carbamates with antimitotic activity that exceeds more conventional antimicrotubule agents.
Section of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520-8039, USA.
J M
JM
Piepmeier
P E
PE
Pedersen
D
D
Yoshida
C
C
Greer
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000532:radiotherapy; D002352:Carrier Proteins / Q000032:analysis; D002460:Cell Line; D003114:Colony-Forming Units Assay; D004961:Estramustine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005434:Flow Cytometry; D005909:Glioblastoma / Q000737:chemistry* / Q000188:drug therapy / Q000532:radiotherapy; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000187:drug effects*; D009368:Neoplasm Transplantation; D011838:Radiation-Sensitizing Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013936:Thymidine / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; D011838:Radiation-Sensitizing Agents; D004961:Estramustine; D013936:Thymidine