Will analogs of 1,25-dihydroxyvitamin D-3 (calcitriol) open a new era in cancer therapy?

Numerous in vitro and in vivo observations, demonstrating that 1,25-dihydro xyvitamin D-3 is a potent inhibitor of tumor cell growth, provided the rati onale for using this seco-steroid hormone to treat patients with leukemia a nd various types of cancer. However, the therapeutic efficacy of systemical ly applied vitamin D analogs for treating cancer has not yet fulfilled its promise. A main reason for these disappointing results is that the use of s ystemically applied vitamin D analogs is limited by severe side effects, mo stly hypercalcemia, at the supraphysiological doses needed to reach clinica l improvement. New concepts for the development of cancer treatment strateg ies that are based on the use of vitamin D-3 compounds are discussed in thi s manuscript. At the moment, different strategies that may enable the appli cation of vitamin D analogs for the treatment of various malignancies, incl uding malignant skin tumors, are employed. It has been shown that certain v itamin D analogs differ in their intracellular metabolism, nongenomic actio ns, pharmacokinetics, interaction with the vitamin D binding protein (DBP) or the vitamin D receptor (VDR). Several of these new concepts are based on recent laboratory results demonstrating that VDR requires heterodimerisati on with additional nuclear cofactors such as the retinoid-X receptor (RXR) for sufficient DNA-binding or are based on new findings in the metabolism o f vitamin D. Taken together, these new strategies hold promise that analogs of 1,25-dihydroxyvitamin D-3 may herald a new era in the treatment of vari ous malignancies, including skin cancer.