Objectives. The osteoblastic response of bone to metastatic prostate cancer
is both characteristic and enigmatic. The potent vasoconstrictor endotheli
n-1 (ET-1), produced by prostate cancer, has been identified as a potential
factor in new bone formation.
Methods. Using a novel method to quantitate new bone formation induced by t
he WISH tumor, we examined the effects of ET-1 overexpression and endotheli
n receptor antagonists on the osteoblastic response.
Results. WISH, a human tumor cell line derived from amnion, produces ET-1 m
RNA and protein and induces abundant new bone formation and splenomegaly in
vivo. Stable transfection of WISH with an ET-1 overexpression cDNA constru
ct produced clones that secreted 18-fold more bioactive ET-1 than vector-on
ly controls. After 14 days of growth in the lower leg of nu/nu mice, ET-1 o
verexpressing tumors produced significantly more new bone than vector-only
controls. Conversely, areas of new bone formation were significantly less i
n animals treated with a selective endothelin A (ETA) receptor antagonist A
Conclusions. The activity of ET-1 in this osteoblastic model provides a uni
que target for therapy. UROLOGY 53: 1063-1069, 1999. (C) 1999, Elsevier Sci
ence Inc. All rights reserved.