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1 Arizona Cancer Center, University of Arizona, Tucson, AZ and 2 ProlX Pharmaceuticals, Tucson, AZ
Requests for Reprints: Garth Powis, Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724-5024. Phone: (520) 626-6408; Fax: (520) 626-4848. E-mail: gpowis{at}azcc.arizona.edu
The hypoxia-inducible factor-1 (HIF-1) transcription factor is an important regulator of tumor response to hypoxia that include increased angiogenesis, glycolytic metabolism, and resistance to apoptosis. HIF-1 activity is regulated by the availability of the HIF-1
subunit, the levels of which increase under hypoxic conditions. PX-478 (S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) is an inhibitor of constitutive and hypoxia-induced HIF-1 levels and thus HIF-1 activity. We report that PX-478 given to mice suppresses HIF-1 levels in HT-29 human colon cancer xenografts and inhibits the expression of HIF-1 target genes including vascular endothelial growth factor and the glucose transporter-1. PX-478 shows antitumor activity against established (0.15–0.40 cm3) human tumor xenografts with cures of SHP-77 small cell lung cancer and log cell kills up to 3.0 for other tumors including HT-29 colon, PC-3 prostate, DU-145 prostate, MCF-7 breast, Caki-1 renal, and Panc-1 pancreatic cancers. Large (0.83 cm3) PC-3 prostate tumors showed 64% regression, which was greater than for smaller tumors. The antitumor response to PX-478 was positively correlated with tumor HIF-1 levels (P < 0.02) and was accompanied by massive apoptosis. The results show that PX-478 is an inhibitor of HIF-1 and HIF-1 transcription factor activity in human tumor xenografts and has marked antitumor activity against even large tumor xenografts, which correlates positively with HIF-1 levels.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 11/25/03; revised 12/29/03; accepted 1/ 9/04.
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