Abstract 4371: RRx-001 modulates intratumor blood flow in SCCVII and U87 tumors

Abstract

Abstract The tumor-specific provascular effects of the anti-cancer agent RRx-001, a novel nitrogen oxide donor and allosteric hemoglobin modifier in Phase 1 clinical trials were investigated using contrast enhanced ultrasound (CEUS) and whole tissue section quantitative immunohistological staining. Changes in tumor blood flow by CEUS in SCCVII tumor bearing mice following RRx-001 (3, 6, 12 mg/kg) were dose and time dependent, reaching maximum perfusion 6 h after treatment, returning to baseline within 72 h. Microregional effects of RRx-001 (15 mg/kg) on tumor blood flow and oxygenation by immunohistological staining were studied in mouse SCCVII and human U87 tumors. SCCVII tumors exhibited regions of intermittent perfusion exemplified by co-localization of vessels with the hypoxia marker pimonidazole commonly occurring throughout the tissue. Only 21% of vessels showed perfusion after a bolus dose of the perivascular stain DiOC7. This increased to 28% 12 h post RRx-001. Paradoxically, an increase in tissue oxygenation was not seen while modestly increased pimonidazole binding was observed. However, preliminary radiobiological assessment suggested tumors were radiosensitized when irradiated 10 min after 12 mg/kg RRx-001. In the U87 tumor a decrease in vessel perfusion at 90 min post RRx-001 administration was observed. Blood flow over large areas of treated tumors was completely shut down. These areas stained positive for CD31 and tissue did not appear necrotic. Analysis indicated 25% reduction in the fraction of perfused vessels and un-perfused tissue by area at 90 min returning to near normal levels at 12 h. There was no significant increase in the fraction of necrosis at 12 h suggesting that the large un-perfused regions seen at 90 min had recovered rather than become necrotic. No significant change in tumor hypoxia was seen at 90 min or 12 h. For both tumor types, RRx-001 appeared to cause the loss of perfusion in large regions of the tumor however, at the 12 h time point, both tumor types showed increase in vessel perfusion but no significant decrease in hypoxia. These data suggest a redistribution of blood flow in both tumor types while differences between the tumors were related to tumor architecture and distribution of α-SMA. RRx-001 shows promise for short-term blood flow redistribution in tumors with a pericyte-rich vasculature with contractile proteins such as α-SMA. Expression of α-SMA in tumor vasculature could therefore be useful for predicting tumor response to RRx-001. 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 4371. doi:1538-7445.AM2012-4371