Abstract 3676: The hypoxia-activated pro-drug tirapazamine suppresses outgrowth of colorectal liver metastases following radiofrequency ablation

Abstract

Abstract Background Radiofrequency ablation (RFA) is a common procedure for the management of colorectal liver metastases. RFA-generated lesions are surrounded by a rim of hypoxia that is associated with aggressive outgrowth of intrahepatic micrometastases. Hypoxia-activated pro-drugs such as tirapazamine (TPZ) are designed to selectively kill tumour cells under hypoxic conditions. Therefore we hypothesised that TPZ may have therapeutic value in limiting hypoxia-associated tumour outgrowth following RFA. Methods Murine C26 and MC38 colorectal cancer cells were grown under hypoxia and normoxia in vitro and were treated with different concentrations of TPZ. Apoptosis and cell cycle distribution were assessed by western blot and FACS analysis. Proliferative capacity was tested by colony formation assays. Mice harbouring microscopic colorectal liver metastases were treated with RFA, followed by a single injection of TPZ (60 mg/kg) or saline. Tumour load was assessed morphometrically 7 days later. Results TPZ induced apoptosis of colorectal tumour cells under hypoxia in vitro, which completely abolished clone-forming capacity. Under normoxia, TPZ caused a G2 cell cycle arrest from which cells recovered partly. This reduced, but did not abolish, colony-forming capacity. A single dose of TPZ largely prevented accelerated outgrowth of hypoxic micrometastases following RFA. TPZ administration was associated with minimal toxicity. Conclusions TPZ kills colorectal cancer cells in a hypoxia-dependent manner and potently suppresses hypoxia-associated outgrowth of liver metastases with limited toxicity. This warrants further studies to assess the potential value of TPZ, or other hypoxia-activated pro-drugs, as adjuvant therapeutics following RFA treatment of colorectal liver metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3676. doi:1538-7445.AM2012-3676