Antitumor activity of the novel vascular targeting agent ZD6126 in a panel of tumor models.
OBJECTIVE
The purpose of this study was to examine the antitumor effects of the novel vascular targeting agent ZD6126 and to use histology, CD31 immunohistochemistry, and electron microscopy to gain an insight into the mechanism of action of this novel agent.


METHODS
The antitumor effects of ZD6126 were examined using a range of solid tumor models: (a) ras-transformed mouse 3T3 fibroblasts (Hras5); and (b) human lung (Calu-6), colorectal (LoVo and HT-29), prostate (PC-3), ovarian (SKOV-3), and breast (MDA-MB-231) tumors, grown as xenografts in nude mice.


RESULTS
In vivo, a well-tolerated dose of ZD6126 was shown to cause rapid effects on tumor endothelium leading to exposure of the basal lamina after cell retraction and subsequent loss of endothelial cells. This led to thrombosis and vessel occlusion, resulting in extensive tumor necrosis 24 h after ZD6126 administration. Dose-response studies showed that these effects were seen at a dose 8- to 16-fold lower than the maximum tolerated dose, demonstrating that ZD6126 has a wide therapeutic margin in these mouse models. A single dose of ZD6126 (200 mg/kg) led to a significant growth delay in Calu-6 and LoVo tumors. Growth delay was increased when 100 mg/kg ZD6126 was given as a well-tolerated regime in five daily doses. Finally, combining ZD6126 with cisplatin resulted in greater than additive enhancement in growth delay in the Calu-6 model.


CONCLUSIONS
These findings provide direct support that ZD6126 selectively disrupts tumor vasculature, demonstrate that it has activity in a range of tumor xenograft models, and show that it can significantly enhance the antitumor efficacy of cisplatin.
Blakey
David C
DC
Cancer and Infection Bioscience Department, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. david.blakey@astrazeneca.com
Westwood
F Russell
FR
Walker
Mike
M
Hughes
Gareth D
GD
Davis
Peter D
PD
Ashton
Sue E
SE
Ryan
Anderson J
AJ
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D004338:Drug Combinations; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D002945:Cisplatin