Antitumor activity of a pyrrole-imidazole polyamide in three tumor xenograft models

Abstract

Background: Pyrrole-imidazole polyamides are synthetic minor groove binders with modular sequence recognition. We developed a polyamide that targets the DNA sequence 5'-WGWWCW-3' (W=A/T). This molecule is cytotoxic in a number of cancer cell lines including LNCaP (prostate cancer), DU145 (prostate cancer), and A549 (lung cancer). Data in cell culture suggests that this molecule interferes with RNA polymerase 2 activity resulting in proteasome-mediated degradation of the RNA Polymerase 2 large subunit, activation of p53 and induction of p53 target genes, and apoptosis. This polyamide demonstrates no detectable DNA damage by alkaline comet assay nor does it induce detectable phosphorylation of YH2A.X, ATM, DNA-PKcs, p53, or Chk2. This polyamide circulates in mice after intravenous and subcutaneous injection in saline vehicle.

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