ABT's ET-1 inhibitor, bone mestastases.
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Endothelin A Receptor Blockade Inhibits Osteoblastic Metastases.
Theresa Guise, BG Grubbs, Y Cui, JR Wu-Wong, J Wessale, RJ Padley, TJ Janus, JJ Yin, University of Texas Health Science Center - San Antonio, San Antonio, TX; Abbott Laboratories, Abbott Park, IL.
Osteoblastic bone metastases are common in advanced prostate and breast cancer but the mechanisms by which tumor cells stimulate new bone formation remain unclear. Endothelin-1 (ET-1) is a 21 amino acid peptide produced by breast and prostate cancer and stimulates osteoblast proliferation. Breast cancer lines, ZR-75-1, MCF-7 and T47D, all cause osteoblastic metastases in female nude mice and produce ET-1. Conditioned media from these cell lines, as well as exogenous ET-1, stimulated osteoblast proliferation and new bone formation in cultures of mouse calvariae. These effects were inhibited by nonselective and endothelin A (ETA), but not ETB, receptor antagonists. Mice inoculated with ZR-75-1 and treated with ABT-627, a specific ETA receptor antagonist, had significantly fewer bone metastases compared with untreated ZR-75-1-mice. By histomorphometry of long bones and spine, untreated ZR-75-1-mice had greater total bone area, new bone area and tumor in bone compared with ABT-627-treated ZR-75-1-mice at either dose. There was no effect of ABT-627 on osteolytic bone metastases caused by ET-1-negative breast cancer, MDA-MB-231. ZR-75-1 expressed neither ETA or ETB receptors while MDA-MB-231 expressed both. There was no effect of ABT-627 on 1) in vitro growth of ZR-75-1 or MDA-MB-231 or 2) in vivo growth of ZR-75-1 or MDA-MB-231 mammary fat pad tumors. These data indicate that the effects of ABT-627 to inhibit osteoblastic metastases are not direct effects on these tumor cells, but rather directed against the osteoblastic response of tumor-produced ET-1. In summary, 1) tumor-produced ET-1 stimulates new bone formation in vitro and osteoblastic metastases in vivo and these effects are mediated via ETA receptors; 2) ETA receptor blockade significantly reduced osteoblastic bone metastases and tumor burden in bone. Thus, tumor-produced ET-1 likely has a major role in the establishment of osteoblastic bone metastases by stimulating osteoblast proliferation and new bone formation. ETA receptor blockade may be useful for prevention and the treatment of osteoblastic bone metastases.
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TXB has an ET-1A inhibitor for cancer that is preclinical.
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