Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia
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. Copyright © 2008 American Association for Cancer Research.
Molecular Cancer Therapeutics
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Chou, C. James; Farkas, Michelle E.; Tsai, Sherry M.; Alvarez, David; Dervan, Peter B.; and Gottesfeld, Joel M., "Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia" (2008). Kean Publications. 2478.