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• W2259294386 abstract "A272 Suggested roles of endothelin-1 (ET-1) in prostate cancer include promotion of angiogenesis, tumor cell proliferation, migration and invasion, and osteoblast proliferation driving metastatic disease (Bagnato & Natali 2004). Endothelin A receptors (ET A Rs) appear to drive the pathology of these processes, while endothelin B receptors (ET B Rs) appear to play a beneficial role. Intervention with a specific ET A R antagonist, therefore, might be the basis for effective treatment to ameliorate disease progression and prolong survival. We have evaluated ZD4054, a specific ET A R antagonist (Morris et al 2005), in a range of preclinical models that represent angiogenesis, invasion, and osteoblast proliferation.
 In an in vivo model of angiogenesis, where an assessment of blood vessel development was performed after human tumor cells had been inoculated by intradermal injection into the abdominal area of athymic mice (Alderley Park nu/nu strain), 5 days’ treatment with ZD4054 produced a consistent and highly statistically significant decrease in vessel count, compared with controls.
 In vitro , in A673 rhabdomyosarcoma smooth muscle cells, apoptosis induced by serum-free media was reduced by the selective ET B R antagonist BQ788, but not by either the selective ET A R antagonist BQ123 or ZD4054, implying that apoptosis is driven by ET B Rs. Moreover, ET-1-induced actin reorganization and phosphorylation of paxillin tyr31 and FAK tyr397,tyr861 in these cells were reduced by BQ123 and ZD4054, but not by BQ788. Invasion of these cells through a 3D-Matrigel TM matrix was also reduced by ZD4054 but not by sarafotoxin, implying that the invasive phenotype in these cells is driven by ET A Rs.
 We have shown previously in in vitro osteoblast models that ZD4054 inhibits ET A R-mediated activation of p44/42 MAPK in murine osteoblast cells and blocks ET A R-mediated proliferation of human immature pre-osteoblast cells in response to ET-1 (Curtis et al 2005).
 These preclinical data clearly identify that ZD4054 can modulate angiogenesis, invasion, and osteoblast proliferation, inferring a key role for ET A Rs in the pathology of tumor development and progression. These preclinical effects appear to translate into a clinical benefit as demonstrated by the positive results observed with ZD4054 in patients with prostate cancer (James et al , submitted). Phase III clinical trials are currently being planned.
 Bagnato A & Natali PG. J Transl Med 2004;2:16.
 Morris CD et al . Br J Cancer 2005;92:2148-2152.
 Curtis N et al. Proc Am Assoc Cancer Research 2005;46:abst 1512.
 James N et al. Submitted to ECCO 14 meeting, Barcelona, September 2007." @default.
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• W2259294386 date "2007-11-01" @default.
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• W2259294386 title "The impact of ZD4054, a specific endothelin A receptor antagonist, on tumor blood supply, invasion, and the bone microenvironment" @default.
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