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.
Chou
C James
CJ
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
Farkas
Michelle E
ME
Tsai
Sherry M
SM
Alvarez
David
D
Dervan
Peter B
PB
Gottesfeld
Joel M
JM
D000478:Alkylation; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002699:Chlorambucil / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006657:Histones / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D006657:Histones; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D012333:RNA, Messenger; D002699:Chlorambucil