In our previous studies we found that retinoids (ligands of both RAR and RXR nuclear receptors), 1,25-dihydroxyvitamin D3 (VD3, calcitriol) and some cytokines (IFNα, IL-12) exert a strong inhibitory effect on angiogenesis induced by various human tumor cell lines in an experimental murine system. IFNα and retinoids were also found to inhibit proliferation of a majority of tested cell lines (T47D-breast cancer, HeLa - HPV18 harboring cervical adenocarcinoma, Skv - HPV16 associated vulvar carcinoma). Combination of some of these compounds exerted synergistic antiangiogenic and antiproliferative effects which could account for their beneficial effect, as shown in advanced squamous cell carcinomas (SCC) of the skin and uterine cervix. The aim of the present study was to establish, in experimental systems in vivo and in vitro, optimal combinations of retinoids, VD3 and cytokines for their potential use in the treatment of multiple premalignant and malignant skin tumors. Using a murine model of tumor cell-induced angiogenesis, we found the strongest antiangiogenic activity of combined 13-cis retinoic acid (13-cis RA) with VD3 or with IFNα. We applied such combined therapy in 11 patients with multiple actinic keratoses displaying signs of malignant transformation, in early SCC and BCC. The daily dosage of 13-cis RA was 0.3-0.5mg/kg, and VD3 (calcitriol) 0.5-1.0 mcg/day. In 10 of 11 patients, treated for 5-14 months, the lesions decreased by 30-85% in size and numbers, or regressed. Since no significant side effects were seen, this therapy could find application in widespread early cutaneous non-melanoma cancers or premalignant lesions in a high risk, e.g. immunosuppressed population.In most recent study, we showed that combination of IL-12 and VD3 was not only strongly antiangiogenic but also most efficient in the inhibition of growth or eradication of established murine malignant tumors. The combined therapy with IL-12 and VD3, both in small non toxic doses, could find application for more advanced solid tumors.