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. [Mol Cancer Ther 2008;7(4):769 -78]

In vivo imaging of pyrrole-imidazole polyamides with positron emission tomography

“…Recently, the phar-macokinetics of a hairpin polyamide-chlorambucil conjugate dosed to mice (500 nmoles per mouse) was evaluated at two time-points (39). Predominant occupancy of the polyamidealkylator conjugate was observed in the lung, spleen, small intestine, and pancreas at 2 and 24 h, as measured by liquid chromatography-mass spectrometry analysis (39). Elimination through the GI tract parallels the results obtained with 1 and 3 in this study.…”

“…It should be noted that GI tract occupancy was not evaluated in the aforementioned study (13). Recently, the phar-macokinetics of a hairpin polyamide-chlorambucil conjugate dosed to mice (500 nmoles per mouse) was evaluated at two time-points (39). Predominant occupancy of the polyamidealkylator conjugate was observed in the lung, spleen, small intestine, and pancreas at 2 and 24 h, as measured by liquid chromatography-mass spectrometry analysis (39).…”

“…Although both of the above-mentioned studies provide insights into polyamide bioavailability (13,39), the necessity of animal killing and organ extraction permits only single timepoint measurements to be conducted per animal. The methodology presented in this study permits examinations of polyamide biodistribution at multiple time points in the same animal, allowing detailed pharmacokinetic measurements to be performed in only a few hours.…”

Pyrrole-Imidazole Polyamides for Gene Therapy: Bioanalytical Methods and Pharmacokinetics

“…It is thought that the concentration in the lungs immediately after the intravenous administration of PI polyamide B is higher than the calculated value. The early-plasma concentration-time profiles after the intravenous administration of a hairpin polyamide-chlorambucil conjugate, duocarmycin, and nitroglycerin are similar to that of PI polyamide B (Alberts et al, 1998;Chou et al, 2008;Wester et al, 1983) Recently, the biodistribution of a hairpin polyamide-chlorambucil conjugate administered into mice has been reported (Chou et al, 2008). The predominant occupancy of the polyamide-chlorambucil conjugate was observed in the lungs, spleen, small intestine, and pancreas 2 and 24 h after the injection.…”

Genome-wide Mapping of Drug-DNA Interactions in Cells with COSMIC (Crosslinking of Small Molecules to Isolate Chromatin)

“…4,5,[7][8][9][10][11] Polyamides have been employed to both repress and activate the expression of specific genes. 4,[12][13][14][15][16][17][18][19] They also have interesting antiviral [20][21][22][23][24] and anticancer 12,13,[25][26][27][28][29][30] properties. One attractive feature of polyamides is their ability to access DNA sequences that are methylated 31,32 and wrapped around histone proteins 9,10,33 .…”