TLK286 (canfosfamide HCl), a novel glutathione analog prodrug, exhibits antiangiogenic effects including the inhibition of human endothelial cell proliferation and capillary tubule formation in vitro Free

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New cancer treatment regimens that incorporate anti-vascular endothelial growth factor agents such as bevacizumab in combination with chemotherapeutic drugs have shown clinical benefit in several types of cancer including non-squamous non-small cell lung cancer (NSCLC). Conventional cytotoxic agents such as cyclophosphamide, etoposide and taxanes also can inhibit tumor vasculature, and the antiangiogenic activity of these cytotoxics may be optimized by metronomic therapy. TLK286 is a novel glutathione analog prodrug in Phase 3 clinical development for treatment of NSCLC and ovarian cancers. In Phase 2 trials, TLK286 has demonstrated single agent activity in NSCLC, ovarian, breast and colorectal cancers. TLK286 activity in combination regimens was also demonstrated in Phase 2 trials in NSCLC and ovarian cancer. To assess the potential antiangiogenic activity of TLK286, we investigated the effects of TLK286 alone and in combination with bevacizumab on human endothelial cell proliferation and capillary tubule formation in vitro. The data demonstrated that TLK286 was a potent inhibitor of human endothelial cell proliferation with IC50 values ranging from 1-2 μM. Furthermore, TLK286 concentrations of ≥2 μM inhibited endothelial capillary tubule formation when human endothelial cells were co-cultured with diploid fibroblasts. When TLK286 and bevacizumab were combined, the inhibitory effects on endothelial cell proliferation and capillary tubule formation were significantly enhanced. These data suggest that TLK286 may be suitable for combination with bevacizumab and other antiangiogenic agents.