Abstract #LB-211: CYT997: Preclinical studies on the antivascular effects and mode of action of a phase II vascular disrupting agent.

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO CYT997 is an orally available synthetic small molecule that is currently in phase II clinical studies within different oncology settings. CYT997 has been shown to exhibit potent vascular disrupting activity in vivo at doses well below its maximum tolerated dose. We have modeled this activity in vitro and found that CYT997 potently inhibited the proliferation of HUVEC primary endothelial cells at low nM concentrations. In order to evaluate the acute vascular effect of CYT997 on blood flow through tumour tissue in vivo , we have used Laser Doppler Flowmetry to measure blood flow in a mouse model of metastatic colorectal cancer. Oral administration of CYT997 led to a significant reduction in tumour blood flow 15 minutes post administration and this effect persisted for up to 96hrs post administration. Similarly, in athymic nude mice bearing subcutaneous DLD-1 human colon adenocarcinoma xenografts a single oral dose of CYT997 led to a time and concentration dependent shutdown of tumour vasculature. The observed vascular shutdown was rapid and was detected at 1-hour post administration of CYT997. Significant vascular shutdown was maintained in tumours at 24-hours post administration of CYT997 and subsequent histology demonstrated greater necrosis of the tumour core in mice treated with CYT997. In addition to vascular disrupting activity, CYT997 also causes G2/M cell cycle arrest and apoptosis of tumor cell lines. Time course analysis of the cell cycle in HCT-15 cells was performed and showed that CYT997 (250 nM) markedly and rapidly increased the fraction of cells in G2/M. As CYT997 is under clinical development as a therapy to be used in conjunction with current antitumor therapies we have assessed the combination of CYT997 and a number of clinically used anti-cancer agents with a range of different modes of action, on the proliferation of HCT-15 liver adenocarcinoma cells. CYT997 demonstrated marked synergy with 5FU (CI=0.55 at IC50), paclitaxel (CI=0.60 at IC50), and vincristine (CI=0.35 at IC50). In contrast, the kinase inhibitor sorafenib did not affect CYT997 activity on HCT-15 cell viability. Together, these findings clearly demonstrate that CYT997 is an orally available vascular disrupting agent that reduces tumour blood flow in a dose dependent manner in a two murine cancer models and raises the possibility that CYT997 may exhibit increased efficacy in combination with other common anticancer therapies. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-211.