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Evidence for Microtubule Target Engagement in Tumors of Patients Receiving Ixabepilone

Authors' Affiliations: ¹ Medical Oncology Branch and ² Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute; ³ Laboratory of Integrative and Medical Biophysics, National Institute of Child Health and Human Development, Bethesda, Maryland

Requests for reprints: Tito Fojo, Center for Cancer Research, National Cancer Institute, Building 10, Room 12N226, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-402-1357; Fax: 301-402-1608; E-mail: tfojo{at}helix.nih.gov.

Purpose: Microtubule-stabilizing agents, such as taxanes, have been shown to be effective anticancer drugs. -Tubulin, a basic unit of microtubules, can undergo several posttranslational modifications after assembly into stabilized microtubules, including acetylation and detyrosination. These modifications have been observed in cell cultures after exposure to microtubule stabilizers. Our objective was to develop a straightforward and dependable assay to show tubulin target engagement in tumor tissue after treatment of patients with ixabepilone(BMS-247550; Ixempra).

Experimental Design: Levels of posttranslationally modified -tubulin were assessed in lysates of cultured malignant cell lines, as well as in both tumor tissue and peripheral blood mononuclear cells derived from patients before and after treatment with ixabepilone. Modification-specific antibodies permitted quantitative Western blot analysis.

Results: In cultured cell lines, the levels of detyrosinated (glu-terminated) and acetylated -tubulin increased after microtubule stabilization induced by ixabepilone. ixabepilone treatment also induced a 2-fold to 25-fold increase in detyrosinated -tubulin levels in 11 of 13 serial biopsies and a 2-fold to 100-fold increase in acetylated -tubulin in 11 of 12 serial biopsies obtained from patients receiving ixabepilone. Overall, little or no difference in tubulin modifications were observed between the before and after ixabepilone treatment in lysates from their peripheral blood mononuclear cells at the time point examined.

Conclusion: Assessing the levels of detyrosinated and/or acetylated -tubulin seems to provide a simple and reliable assay to show target engagement by the microtubule-stabilizing agent ixabepilone. Such analyses may provide further understanding of therapeutic success or failure of microtubule-stabilizing agents in cancer therapy.

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