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

Cancer Res. 2000 Dec 15;60(24):6958-63.


We examined the effects of a new antiangiogenic isocoumarin, NM-3, as a radiation modifier in vitro and in vivo. The present studies demonstrate that NM-3 is cytotoxic to human umbilical vein endothelial cells (HUVECs) but not 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 observed. 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 IR were also evaluated in tumor model systems. C57BL/6 female mice bearing LLC tumors were given injections for 4 consecutive days with NM-3 (25 mg/kg/day) and treated with IR (20 Gy) for 2 consecutive days. Combined treatment with NM-3 and IR significantly reduced mean tumor volume compared 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 nude 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 bioavailability and nontoxic profile of NM-3 suggests that the efficacy of this agent should be tested in clinical radiotherapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Animals
  • Carcinoma, Lewis Lung / drug therapy
  • Cell Movement / drug effects
  • Cell Movement / radiation effects
  • Cells, Cultured
  • Collagen / metabolism
  • Coumarins / pharmacology*
  • Coumarins / toxicity
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Drug Combinations
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / radiation effects
  • Esophageal Neoplasms / drug therapy
  • Female
  • Humans
  • Isocoumarins
  • Laminin / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms / drug therapy*
  • Neoplasms / radiotherapy*
  • Proteoglycans / metabolism
  • Radiation, Ionizing
  • Time Factors
  • Tumor Cells, Cultured
  • Umbilical Veins / cytology
  • Umbilical Veins / drug effects
  • Umbilical Veins / radiation effects


  • Coumarins
  • Drug Combinations
  • Isocoumarins
  • Laminin
  • Proteoglycans
  • isocoumarin NM-3
  • matrigel
  • Collagen