THE MOLECULAR-BASIS OF THE HYPOXIA RESPONSE PATHWAY - TUMOR HYPOXIA AS A THERAPY TARGET

Hypoxia induces a cascade of physiological responses that includes gly colysis, erythropoiesis, angiogenesis, changes in adrenergic signal tr ansduction and vascular cellular proliferation. Hypoxia-inducible gene s are relevant to growth and behaviour of cancer as well as the adapta tion and survival of normal tissues. Hypoxia inducible factor-1 (HIF-1 ) is a heterodimeric DNA binding complex composed of two basic-helix-l oop-helix PAS-proteins: HIF-1 beta/ARNT (aryl hydrocarbon receptor nuc lear translocator), which is constitutively expressed, and HIF-1 alpha , which is not present in normoxic cells but induced under hypoxic con ditions. Recently another member of the bHLH-PAS family, EPAS-1 has be en reported and shares similar properties with HIF-1 alpha, although i t is considered endothelial specific. In addition, the presence of oth er DNA-binding motifs in the promoter of hypoxia-inducible genes highl ight the occurrence of cross-talk between transcription factors in the modulation of hypoxic gene expression. In this review we present a su rvey of the hypoxia response pathway and we discuss attempts to use ge ne therapy activated by the low oxygen environment or by necrotic regi ons of tumours.