1,25-Dihydroxyvitamin D3 in lipiodol for the treatment of hepatocellular carcinoma: cellular, animal and clinical studies.

1,25-Dihydroxyvitamin D(3) (1,25-(OH)(2) D(3)) is a potent regulator of cell growth and differentiation, with recent evidence showing inhibition of tumor invasion, angiogenesis and tumor cell death. The growth-inhibitory properties of 1,25-(OH)(2) D(3) could be harnessed in the treatment of patients with cancer if the development of systemic hypercalcemia is avoided. Hepatocellular cancer (HCC) presents a setting where the tumor is accessible for treatment through the hepatic artery and also where the tumor is highly lipiodol avid. On this basis, we hypothesised that, 1,25-(OH)(2) D(3) dissolved in lipiodol and administered through the hepatic artery may prove to be a rational approach to the use of the drug in the treatment of HCCs. In brief, 6 years of work with 1,25-(OH)(2) D(3) at cellular, animal and clinical level has provided us with plenty of support for this hypothesis. Sensitivity of HCCs in cell culture to 1,25-(OH)(2) D(3), growth retardation of human HCC xenografts in nude mice, uptake and retention of 1,25-(OH)(2) D(3)-lipiodol by liver tumors in cell culture and animals, escalation of the 1,25-(OH)(2) D(3) dose by 100x without the development of hypercalcemia in both liver tumor bearing rats and in patients with HCC are some of the evidence that will be discussed in this paper.