Activity of a new vascular targeting agent, ZD6126, in pulmonary metastases by human lung adenocarcinoma in nude mice.
ZD6126 (ANG453) is a novel vascular targeting agent that selectively disrupts the cytoskeleton of endothelial cells in tumor. In mouse s.c. xenograft models, ZD6126 was found to induce selective occlusion of tumor blood vessels, cessation of tumor blood flow, and death of tumor cells because of the starvation of oxygen and nutrition. Here, we investigated whether ZD6126 inhibited the metastatic formation of human non-small cell lung cancer cells. PC14PE6 (adenocarcinoma) and H226 (squamous cell carcinoma) cells were injected into the tail vein of nude mice, and lung metastases were estimated. ZD6126 treatment involved either a single dose on 24 h before killing or daily doses from day 14 until the end of the experiment. Single treatment with i.p. injection of 200 mg/kg ZD6126 caused bleeding and necrotic changes in the tumor by 24 h. Histological analysis revealed that apoptotic tumor cells were markedly increased in the ZD6126-treated group. Moreover, ZD6126 induced the apoptosis of CD31-positive vascular endothelial cells in tumors but not in the normal lung parenchyma. When mice were treated daily with 100 mg/kg ZD6126 from day 14 until the end of the experiment, the lung weight was significantly less in the ZD6126-treated group than that of the control group, despite no difference in the number of metastatic nodules. These data suggest that ZD6126 could demonstrate its antitumor activity against both already established and early phase of lung cancer metastasis by causing the selective apoptosis of tumor endothelial cells and destruction of the tumor vasculature.
Goto
Hisatsugu
H
Department of Internal Medicine and Molecular Therapeutics, Course of Medical Oncology, The University of Tokushima School of Medicine, Tokushima 770-8503, Japan.
Yano
Seiji
S
Zhang
Helong
H
Matsumori
Yuka
Y
Ogawa
Hirohisa
H
Blakey
David C
DC
Sone
Saburo
S
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009943:Organophosphorus Compounds / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D006131:Growth Inhibitors; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds