New bone formation in an osteoblastic tumor model is increased by endothelin-1 overexpression and decreased by endothelin A receptor blockade

Nelson, JB Nguyen, SH Wu-Wong, JR Opgenorth, TJ Dixon, DB Chung, LWK Inoue, N

Jb. Nelson et al., New bone formation in an osteoblastic tumor model is increased by endothelin-1 overexpression and decreased by endothelin A receptor blockade, UROLOGY, 53(5), 1999, pp. 1063-1069

31

INGLESE

Article

Urology & Nephrology

UROLOGY

0090-4295 → ACNP

53

5

1999

1063 - 1069

ISI

0090-4295(199905)53:5<1063:NBFIAO>2.0.ZU;2-M

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 127722. 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.