[Proceedings of the 11th NCI · EORTC · AACR Symposium]
Copyright © 2000 Stichting NCI-EORTC Symposium on New Drugs in Cancer Therapy
Published by the AACR.
562 Detection of -tubulin binding in tumor and brain following i.v. administration of the microtubule disrupting agents T138067 and T900607 to mice. S.W. Schwendner, H. Beckmann, E. Santha, Q. Ye, M. Wright, H.D. Knych, T. Wiens, M.J. Thoolen, and P.B.M.W.M. Timmermans. Tularik Inc., South San Francisco, CA 94080.
T138067 (2-fluoro-1-methoxy-4-pentafluorophenylsul-phonamidobenzene) and its analog T900607 prevent tubulin polymerization by covalently binding to -tubulin. These agents both inhibit the growth and clonogenic potential of a number of tumor cell lines, and their activity is not affected by the MDR phenotype of the cells. Both compounds demonstrate efficacy against MX-1 human mammary tumor xenografts in athymic nude mice. T138067 is currently in phase II and T900607 in phase I clinical trials. In the current study, the localization and -tubulin binding in brain and tumor of T138067 or T900607 were assessed following i.v. bolus or i.v. infusion using monoclonal antibodies that specifically recognize either T138067- or T900607-modified -tubulin. Bolus administration of T138067, the more lipophilic of the agents, demonstrated greater compound localization and tubulin binding in the brain relative to tumor while infusion of T138067 resulted in decreased brain localization and tubulin binding. Administration of the more hydrophilic agent T900607 resulted in much less brain localization and -tubulin binding than T138067. Both agents demonstrated greater tumor tubulin binding when administered by infusion over 3 hr rather than by i.v. bolus. Immunostaining of tumor sections reveals that the distribution of tubulin binding of T138067 is homogenous throughout the tumor. |
