Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia
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.
Additional Information
© 2008 American Association for Cancer Research. Accepted February 22, 2008. Received February 4, 2008. 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). We thank the staff of The Scripps Research Institute Department of Animal Resources, and The Scripps Mass Spectrometry and DNA Microarray facilities for technical assistance. 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.Attached Files
Accepted Version - nihms47642.pdf
Supplemental Material - MCT-08-0130--Suppl_Figs_and_Table.pdf
Supplemental Material - MCT-08-0130--Suppl_Figs_and_Table_Legends.pdf
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Additional details
- PMCID
- PMC2376757
- Eprint ID
- 66737
- Resolver ID
- CaltechAUTHORS:20160509-104236392
- CA107311
- National Cancer Institute
- CM043013
- Department of Defense
- NIH Predoctoral Fellowship
- Created
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2016-05-17Created from EPrint's datestamp field
- Updated
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2021-11-11Created from EPrint's last_modified field