In this issue of Endocrinology, Blutt et al. describe the ability of 1α, 25-dihydroxyvitamin D3 (calcitriol) to stimulate apoptosis in the human prostate cancer (CaP) cell line known as LNCaP (1). The study raises for discussion the subject of the wide spectrum of actions of calcitriol in CaP and its potential therapeutic use in a number of diseases. Over the past several years, it has become clear that calcitriol exhibits antiproliferative, prodifferentiating, and immunosuppressive properties in addition to its well known actions on mineral metabolism (2). This recent recognition of calcitriol’s expanded range of activities has raised the possibility that it may have utility in the treatment of a variety of malignancies, immunemediated diseases, psoriasis, and a number of other conditions, including its more classical uses to treat osteoporosis and renal osteodystrophy. The findings of Blutt et al. support an additional mechanism by which calcitriol may have anticancer activity.

Because the therapeutic application of calcitriol is limited by its predictable proclivity to induce hypercalciuria and hypercalcemia, the advent of new therapeutic indications has spawned intense activity by pharmaceutical companies to develop vitamin D analogs with an improved therapeutic index so that the desired activity can be maximized while the tendency toward hypercalcemia can be minimized. Simultaneously, many laboratories have explored two basic and important biological questions: 1) to determine the various mechanisms by which calcitriol can exhibit cancer-inhibiting activity (which is the subject of the paper by Blutt et al.) as well as 2) the physiologic and molecular mechanisms by which analogs of calcitriol can differentially activate various pathways so that anticancer activity can be increased while calcemic activity can be reduced. In this mini-review of the subject, we shall try to touch on the high points of these two areas of vitamin D research but, because of space limitations, we will limit our comments to CaP and often cite recent reviews of this subject and the references therein (3–6) rather than cite individual reports. In addition, we will begin by summarizing the history of the calcitriol hypothesis for CaP treatment to provide background and conclude by reviewing the clinical studies that have taken place using calcitriol and how we view the future.