In psoriatic lesions, epidermal keratinocytes overexpress vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) and transforming growth factor alpha (TGF-alpha). TGF-alpha has been shown to induce VEGF/VPF in normal human epidermal keratinocytes in vitro. By using a 19-mer antisense phosphorothioate oligodeoxynucleotide (PS-ODN) complementary to bases 6-24 relative to the translational start site of the VEGF/VPF mRNA, the control sense and mismatched PS-ODNs, we examined modulation of VEGF/VPF induction by TGF-alpha in vitro. Normal human epidermal keratinocytes were treated with PS-ODNs and Lipofectin for 8 h prior to the addition of TGF-alpha. Inhibition was assayed at the level of secreted protein by capture ELISA and mRNA expression was assayed by Northern blot analysis. The anti-sense PS-ODN was capable of inhibiting VEGF/VPF RNA and protein to near-basal levels. This inhibition was concentration dependent. No effect was observed with the sense or mismatch control PS-ODNs. These studies suggest that antisense oligonucleotide technology may be a potential therapy for the inhibition of angiogenesis associated with certain skin disorders such as psoriasis.