A nitric oxide synthase inhibitor, N(G)-nitro-l-arginine-methyl-ester, exerts potent antiangiogenic effects on plasmacytoma in a newly established multiple myeloma severe combined immunodeficient mouse model.
Angiogenesis is one of critical factors in sustaining the growth, invasion and metastasis of certain solid tumours and haematological malignancies such as multiple myeloma (MM). In the present study, we examined the anticancer potential of an inhibitor of nitric oxide synthase (NOS), NG-nitro-l-arginine methyl ester (L-NAME), in a novel severe combined immunodeficient mouse model (KHM mouse) that harbours the highly sanguineous plasmacytoma cell line KHM-4, derived from a patient with highly chemoresistant MM. KHM mice were intraperitoneally administered with either L-NAME, doxorubicin, melphalan, or paclitaxel. A significant reduction in tumour sizes was noted in L-NAME-administered KHM mice while no significant reduction was observed in melphalan- or doxorubicin-administered mice. A profound decrease in angiogenesis was observed in tumour tissues from L-NAME- and paclitaxel-administered KHM mice. A marked decrease in human vascular endothelial cell growth factor (VEGF) levels was identified in tumour tissues from L-NAME-administered KHM mice, strongly suggesting that L-NAME suppressed VEGF production by tumour cells through its inhibition of NOS in tumour cells, resulting in reduced neovasculization in mice leading to the regression of tumour sizes. The present data represent the first observations that certain NOS inhibitors potentially serve as experimental agents for the treatment of chemoresistant MM and plasmacytoma.
Uneda
Shima
S
Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto, Japan.
Hata
Hiroyuki
H
Matsuno
Fumihiko
F
Nagasaki
Akitoshi
A
Harada
Naoko
N
Mitsuya
Yumi
Y
Matsuzaki
Hiromitsu
H
Mitsuya
Hiroaki
H
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008222:Lymphokines / Q000096:biosynthesis; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010954:Plasmacytoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester