NM-3, an isocoumarin, increases the antitumor effects of radiotherapy without toxicity

We examined the effects of a new antiangiogenic isocoumarin, NM-3, as a rad iation modifier in vitro and in vivo. The present studies demonstrate that NM-3 is cytotoxic to human umbilical vein endothelial cells (HUVECs) but no t to Lewis lung carcinoma (LLC) cells nor Seg-1, esophageal adenocarcinoma cells, in clonogenic survival assays. When HUVEC cultures are treated with NM-3 combined with ionizing radiation (IR), additive cytotoxicity is observ ed. In addition, the combination of NM-3 and IR inhibits HUVEC migration to a greater extent than either treatment alone The effects of treatment with NM-3 and LR were also evaluated in tumor model systems. C57BL/6 female mic e bearing LLC tumors were given injections for 4 consecutive days with NM-3 (25 mg/kg/day) and treated,vith IR (20 Gy) for 2 consecutive days. Combine d treatment with NM-3 and IR significantly reduced mean tumor volume compar ed with either treatment alone. An increase in local tumor control was also observed in LLC tumors in mice receiving NM-3/IR therapy. When athymic nud e mice bearing Seg-1 tumor xenografts were treated with NM-3 (100 mg/kg/day for 4 days) and 20 Gy (four 5 Gy fractions), significant tumor regression was observed after combined treatment (NM-3 and IR) compared with IR alone. Importantly, no increase in systemic or local tissue toxicity was observed after combined treatment (NM-3 and IR) when compared with IR alone. The bi oavailability and nontoxic profile of NM-3 suggests that the efficacy of th is agent should be tested in clinical radiotherapy.