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Research Articles: Therapeutics, Targets, and Development

Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia

¹ Department of Molecular Biology, The Scripps Research Institute, La Jolla, California and ² Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California

Requests for reprints: Peter B. Dervan, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125. E-mail: dervan{at}caltech.edu or Joel M. Gottesfeld, Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037. E-mail: joelg{at}scripps.edu

Abstract

We recently identified a polyamide-chlorambucil conjugate, 1R-Chl, which alkylates and down-regulates transcription of the human histone H4c gene and inhibits the growth of several cancer cell lines in vitro and in a murine SW620 xenograft model, without apparent animal toxicity. In this study, we analyzed the effects of 1R-Chl in the chronic myelogenous leukemia cell line K562 and identified another polyamide conjugate, 6R-Chl, which targets H4 genes and elicits a similar cellular response. Other polyamide conjugates that do not target the H4 gene do not elicit this response. In a murine model, both 1R-Chl and 6R-Chl were found to be highly effective in blocking K562 xenograft growth with high-dose tolerance. Unlike conventional and distamycin-based alkylators, little or no cytotoxicities and animal toxicities were observed in mg/kg dosage ranges. These results suggest that these polyamide alkylators may be a viable treatment alternative for chronic myelogenous leukemia. [Mol Cancer Ther 2008;7(4):769–78]

Grant support: National Cancer Institute grant CA107311 and Department of Defense grant CM043013 (J.M. Gottesfeld and P.B. Dervan) and predoctoral NIH National Research Service Award training grant (M.E. Farkas).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Current address for D. Alvarez: New Jersey Center for Science, Technology and Math Education, Kean University, 1000 Morris Avenue, Townsend Hall 117-H, Union, NJ 07083-0411.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 2/ 4/08; accepted 2/22/08.