Abstract
3-(Iodoacetamido)-benzoylurea (3-IAABU) is a newly synthesized antitubulin compound with a molecular weight of 347. 3-IAABU exhibited anticancer activity in a variety of tumor cell lines with ID90 in the range of 0.015–0.29 µm for leukemic cells and 0.06–0.92 µm for solid tumors. Higher selectivity against malignant cells was observed with 3-IAABU than that with vinblastine and paclitaxel. It inhibits microtubule assembly in tubulin systems either with or without microtubule-associated proteins (ID50 was 0.1 µm and 1.2 µm, respectively) and microtubule depolymerization was not affected, indicating an inhibition of polymerization by binding of 3-IAABU to the heterodimeric subunit of tubulin. 3-IAABU was shown to inhibit the binding of colchicine, a subunit binding compound, but did not inhibit binding of vinblastine and guanosine 5′-triphosphate/guanosine 5′-diphosphate, indicating that colchicine site corresponds to the site that 3-IAABU locates. Tumor cells treated with 3-IAABU showed scattered chromosomes in metaphase. Normal microtubule architecture or spindle apparatus was absent in these cells; instead, punctuated aggregates of tubulin were found by an immunofluorescent staining. Cell cycle analyses showed an accumulation of tumor cells at M phase after a 4-h treatment with 3-IAABU. The phosphorylated bcl-2 representative of an inactivated form of the oncoprotein was found in the cells 12 h after treatment with 3-IAABU. These cells progressed to apoptosis within 16 h. As a new tubulin ligand, 3-IAABU could be a promising agent in cancer chemotherapy.
Footnotes
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↵1 Supported by the T. J. Martell Foundation for Leukemia, Cancer, and AIDS Research and NIH Small Business Innovative Research Grant GM-53696-03.
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↵2 To whom requests for reprints should be addressed, at Department of Medicine, Division of Neoplastic Diseases, Box 1131, Mount Sinai School of Medicine, New York, NY 10029. Phone: (212) 241-7549; Fax: (212) 996-9801.
- Received August 18, 1998.
- Accepted October 5, 1998.
- ©1998 American Association for Cancer Research.