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 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.
Salloum
R M
RM
Department of Surgery, University of Chicago, Illinois 60637, USA.
Jaskowiak
N T
NT
Mauceri
H J
HJ
Seetharam
S
S
Beckett
M A
MA
Koons
A M
AM
Hari
D M
DM
Gupta
V K
VK
Reimer
C
C
Kalluri
R
R
Posner
M C
MC
Hellman
S
S
Kufe
D W
DW
Weichselbaum
R R
RR
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003374:Coumarins / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D004938:Esophageal Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D049934:Isocoumarins; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011509:Proteoglycans / Q000378:metabolism; D011839:Radiation, Ionizing; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects
D003374:Coumarins; D004338:Drug Combinations; D049934:Isocoumarins; D007797:Laminin; D011509:Proteoglycans; C453300:isocoumarin NM-3; C059485:matrigel; D003094:Collagen