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Biochemical Genetic Analysis of Indanocine Resistance in Human Leukemia¹

Department of Medicine and The Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, La Jolla, California 92093-0663 [X. H. H., D. G., R. T., H. S., T. J. K., D. A. C., L. M. L.], and Target Structure-Based Drug Discovery Group, Information Technology Branch, National Cancer Institute, NIH, Frederick, Maryland 21702 [R. G.]

Indanocine is a potent tubulin-binding drug that is cytotoxic to multidrug-resistant cancer cell lines. We demonstrated that indanocine specifically induces apoptosis in malignant B cells from patients with chronic lymphocytic leukemia. To address the exact biochemical basis for indanocine toxicity, an indanocine-resistant clone was selected from mutagenized CEM human lymphoblastoid cells. The resistant cells displayed a stable indanocine-resistant phenotype for at least 9 months in drug-free culture. The cloned cells are cross-resistant to colchicine and vinblastine, but not to paclitaxel, and do not have increased expression of the multidrug-resistant p170 glycoprotein. In both parental cells and cell extracts, indanocine treatment caused tubulin depolymerization. In contrast, the tubulin in the resistant clone did not depolymerize under identical conditions. Both extract mixing and cell fusion experiments suggested that a stable structural change in microtubules, rather than a soluble factor, was responsible for indanocine resistance. Sequence analysis of parental and resistant cells revealed a single point mutation in the M40 isotype of ß-tubulin at nucleotide 1050 (GT, Lys³⁵⁰Asn) in the indanocine-resistant clone, in a region close to the putative colchicine binding site.

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