Abstract 1130: Antitumor activity of a pyrrole-imidazole polyamide in three tumor xenograft models.

Abstract

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 γH2A.X, ATM, DNA-PKcs, p53, or Chk2. This polyamide circulates in mice after intravenous and subcutaneous injection in saline vehicle. Methods: Male immune compromised mice were implanted with LNCaP, DU145, or A549 tumors. Tumors were allowed to grow until approximately 100 mm3 and then stratified into vehicle (5% DMSO/PBS) and treatment arms (1 mg/kg polyamide, in vehicle). Treatment was administered via subcutaneous injection every three days, for a total of three cycles (LNCaP), eight cycles (DU145), or six cycles (A549). At the experimental endpoint, tumors were resected and weighed immediately. For LNCaP xenografts, serum PSA pre- and post-treatment were also measured. In parallel, a group of immune compromised mice without xenografts were treated with an identical regimen for eight cycles and subsequently observed for three months. Results: Tumors resected from polyamide-treated mice were statistically smaller than those of vehicle-treated mice. The effect was greatest on LNCaP tumors (n=12, Treated (T)/Control (C): 32%, p=1.6E-5). DU145 tumors (n=6, T/C: 34%, p=0.013), and A549 tumors (n=8, T/C: 62%, p=0.047) were also affected. Post-treatment serum PSA in the polyamide-treated mice with LNCaP xenografts were lower than for the vehicle treated mice (p = 0.024). Statistical differences between treated and control groups were determined using two-tailed t-tests. Polyamide treatment resulted in no significant weight loss or observable distress in tumor-free mice and these mice appeared healthy for at least three months after treatment was complete. Conclusions: The polyamide demonstrated in vivo antitumor activity in this panel of tumor xenografts with limited host toxicity. Citation Format: Nicholas G. Nickols, Fei Yang, Benjamin C. Li, Georgi K. Marinov, Jonathan W. Said, Peter B. Dervan. Antitumor activity of a pyrrole-imidazole polyamide in three tumor xenograft models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1130. doi:10.1158/1538-7445.AM2013-1130