Biological evaluation of new vitamin D2 analogues

- We examined activity profiles of double-point modified analogues of vitamin D2.
- The analogues were less toxic in vivo than 1,25D.
- Pro-differentiating activities of analogues were stronger than that of 1,25D.
- The analogues upregulated expression of CYP24A1 and CD14 stronger than 1,25D.
- Neither calcemic, nor pro-differentiation effects were correlated to VDR binding.

1,25-dihydroxyvitamin D3 (1,25D), a steroid hormone which regulates calcium/phosphate homeostasis, has a broad spectrum of anti-cancer activities, including differentiation of acute myeloid leukemia (AML) cells. In order to avoid undesirable side effects such as hypercalcemia, low-calcemic analogues should be produced for therapeutic purposes. In this paper, we describe biological activities of double-point modified analogues of vitamin D2 and we compare them to 1,25D and to paricalcitol, the drug used to treat secondary hyperparathyroidism. In vivo, our new analogues have lower calcemic effects, and lower toxicity in comparison to 1,25D. They have enhanced pro-differentiating and transcription-inducing activities in AML cells. Interestingly, differentiation effects do not correlate with the affinities of the analogues to the vitamin D receptor (VDR).