A phase one study of the hepatic arterial administration of 1,25-dihydroxyvitamin D-3 for liver cancers

Background and Aims: It is well established that exposure to 1,25-dihydroxy vitamin D-3 (1,25(OH)(2)D-3) inhibits the proliferation of human colorectal cancer and hepatoma cell lines, both in vitro and in vivo. However, clinic al trials of the administration of 1,25(OH)(2)D-3 and analogs for the treat ment of malignancy have been limited by the development of hypercalcemia. 1 ,25-dihydroxyvitamin D-3 is principally excreted in bile following hepatic catabolism. This suggested the hypothesis that hepatic regional administrat ion may allow high doses of 1,25(OH)(2)D-3 to be administered for the treat ment of liver cancers without producing hypercalcemia, caused by a clinical ly significant first pass effect. This phase one study investigates the eff ect of hepatic regional administration of 1,25(OH)(2)D-3 on serum calcium l evels, together with other markers of renal. and liver function. Methods: Six subjects with hepatic colorectal cancer metastases and one wit h primary hepatocellular cancer were given continuous hepatic arterial infu sions of 1,25(OH)(2)D-3, for periods of 1-4 weeks. Blood samples were taken regularly and assayed for calcium levels, liver function tests and urea an d electrolyte levels. Results: Patients remained normocalcemic at dosages of up to 10 mcg/day. No patient experienced any side-effects from the treatment. Conclusions: Administration of 1,25(OH)(2)D-3 as a continuous hepatic arter ial infusion allows a high dosage to be administered without inducing hyper calcemia. This route of administration may allow the potential of 1,25(OH)( 2)D-3 in the treatment of hepatic cancers to be realized. (C) 2001 Blackwel l Science Asia Pty Ltd.