Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Novel 2-methyl-A-ring analogues of 1a,25-dihydroxy-vitamin D3 and its 20-epimer that modulate cancer cell differentiation and apoptosis

T Okano PhD 1, K Nakagawa 2, M Kurobe 3, K Ozono MD 4, K Konno PhD 5, T Fujishima PhD 6, H Takayama PhD 7

1,2,3 Depertment of Hygienic Sciences, Kobe Pharmaceutical University, Kobe, Japan, 4 Depertment of Environmental Medicine, Research Institute Osaka Medical Ctr for Maternal and Child Health, Osaka, Japan, 5,6,7 Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan,

AIMS:1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3] exhibits antiproliferative, differentiating, and apoptosis-inducing effects on many malignant cells. These properties have raised the possibility of its use as a therapeutic agent in cancer. METHODS:In the present study, we synthesized all possible 2-methyl-A-ring diastereomers of 1α,25(OH)2D3 and its 20-epimer and evaluated their biological activities; (1) at the molecular level, transactivation on target gene promoters, vitamin D receptor(VDR)/retinoid X receptor(RXR) complex formation, VDR/ coactivator interactions were measured in cotransfected mammalian cells. (2) at the cellular level, modulations of cell differentiation, proliferation and apoptosis, and stimulation of telomerase activity were measured in human leukemia HL-60 cells. (3) at the animal level, calcium mobilizing activity from bone was measured in rat. RESULTS:It was found that the potent analogues could be clearly divided into two groups; (1) those bearing the 1α- and 3β-hydroxy groups on the A-ring were potent activators of VDR-mediated genomic actions including target gene expressions, cell differentiation and proliferation, telomerase activity, and calcium mobilization. (2) those bearing the 1beta- and 3α-hydroxy groups on the A-ring were potent stimulator of apoptosis without showing any VDR-mediated actions. Thus, we clearly identified for the first time the structural motifs in recognition of cell differentiation and apoptosis on the basis of the stereochemistry of both hydroxyl groups at positions 1 and 3 of the A-ring of the 1α,25(OH)2D3 molecule. CONCLUSIONS:These findings provide useful information not only for structure-function studies of 1α,25(OH)2D3 analogues but also for the development of therapeutic agents for the treatment of cancer.

KEY WORDS: Structure-function, Calcitriol, Caspases, Bcl-2, Macrophage.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on differentiation therapy.