A novel hypoxia-dependent 2-nitroimidazole KIN-841 inhibits tumour-specific angiogenesis by blocking production of angiogenic factors.
Tumour angiogenesis is initiated by angiogenic factors that are produced in large amounts by hypoxic tumour cells. The inhibition of this step may lead to tumour-specific antiangiogenesis because normal tissues are not usually hypoxic. On the other hand, blocking a biological function of endothelial cells is known to result in angiogenic inhibition. To produce a tumour-specific and powerful antiangiogenesis, we determined whether potent angiogenic inhibition could be achieved by inhibiting the production of angiogenic factors by hypoxic tumour cells and simultaneously blocking certain angiogenic steps in endothelial cells under normoxia. We focused on the 2-nitroimidazole moiety, which is easily incorporated into hypoxic cells and exhibits its cytotoxicity as hypoxic cytotoxin. We designed and synthesised 2-nitroimidazole derivatives designated as KIN compounds, and investigated their antiangiogenic activities under normoxia using a chick embryo chorioallantoic membrane. KIN-841 (2-nitroimidazole 1-acetylhydroxamate) showed a potent angiogenic inhibition in a dose-dependent manner. This compound inhibited the proliferation of bovine pulmonary arterial endothelial (BPAE) cells more strongly than that of tumour cells, such as Lewis lung carcinoma (3LL) cells, under normoxia. The inhibition of cell proliferation by KIN-841 under hypoxia increased about five-fold compared to that under normoxia. Moreover, under hypoxia, KIN-841 significantly decreased the excessive production of vascular endothelial cell growth factors induced by 3LL cells as determined by tritium-labelled thymidine ([(3)H]thymidine) incorporation into BPAE cells and by ELISA. Intraperitoneal administration of KIN-841 suppressed 3LL-cell-induced in vivo angiogenesis in the mouse dorsal air sac system. These results indicate that the regulation of the production of angiogenic factors by hypoxic tumour cells is a useful target for tumour-specific angiogenesis inhibition, and that KIN-841, which causes simultaneous direct inhibition of endothelial cell function and production of angiogenic factors by hypoxic tumour cells, is a very potent inhibitor of tumour-specific angiogenesis. Thus, the potential for clinical use of KIN-841 as an antitumour drug is very high.
Shimamura
M
M
Medical R&D Center, The Tokyo Metropolitan Institute of Medical Science, Japan. mshima@rinshoken.or.jp
Nagasawa
H
H
Ashino
H
H
Yamamoto
Y
Y
Hazato
T
T
Uto
Y
Y
Hori
H
H
Inayama
S
S
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply*; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006877:Hydroxamic Acids; D000860:Hypoxia / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D009574:Nitro Compounds / Q000494:pharmacology*; D009593:Nitroimidazoles; D011651:Pulmonary Artery; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D006877:Hydroxamic Acids; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; C472350:KIN-841; D008222:Lymphokines; D009574:Nitro Compounds; D009593:Nitroimidazoles; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors