Interactions between Ets family members and a vari-

The hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha are activated in hypoxic tumor regions. However, their role in tumorigenesis remains controversial, as tumor growth promoter and suppressor activities have been ascribed to HIF-1alpha, while the role of HIF-2alpha remains largely unknown. Here, we show that overexpression of HIF-2alpha in rat glioma tumors enhances angiogenesis but reduces growth of these tumors, in part by increasing tumor cell apoptosis. Moreover, siRNA knockdown of HIF-2alpha reduced apoptosis in hypoxic human malignant glioblastoma cells. Furthermore, inhibition of HIF by overexpression of a dominant-negative HIF transgene in glioma cells or HIF-2alpha deficiency in teratomas reduced vascularization but accelerated growth of these tumor types. These findings urge careful consideration of using HIF inhibitors as cancer therapeutic strategies.

Hypoxia inducible factors (HIF) are candidate transcriptional regulators of vascular development. Unlike HIF-1alpha - the founding member of the HIF family - which is expressed more or less ubiquitously, HIF-2alpha (also called HRF, HLF and EPAS1) is highly expressed by vascular endothelial cells and was shown to activate the transcription of endothelial cell-specific receptor tyrosine kinases (tie-2 and flk-1/VEGF receptor 2) and of vascular endothelial growth factor (VEGF). Therefore HIF-2alpha is a candidate dual regulator of vascular development. Here we describe the quail homologue of HIF-2alpha. Sequence analysis reveals that HIF-2alpha is highly conserved between birds and mammals. Like the murine HIF-2alpha, the quail molecule is highly expressed by endothelial cells but also detectable in certain epithelial cells such as in the endoderm.

Bioequivalence could be demonstrated in terms of rate and extent of absorption after administration of test and reference products under naltrexone protection. Concerning the safety evaluation, no negative implications on the possible use of the test formulation could be determined.