Disease relevance of Dovonex

• The strong direct effects of MC 903 on cell proliferation and cell differentiation, coupled with its decreased activity as a classical vitamin D makes this compound an interesting candidate for studies in human proliferative disorders such as psoriasis [1].
• MC 903 and 1,25(OH)2D3 have similar effects on cell proliferation and cell differentiation in vitro using the human histiocytic lymphoma cell line U 937, but in vivo MC903 has 100-200 times less effect on calcium metabolism [2].
• Oral or intraperitoneal administration of MC 903 to rats showed that the compound was at least 100 times less active than 1,25(OH)2D3 and 1 alpha (OH)D3 in causing hypercalciuria, hypercalcemia and bone calcium mobilisation [1].
• We have therefore studied, how MC 903 competes for the binding sites of 1,25(OH)2D3, influences the 1,25(OH)2D3 induced synthesis of the most abundant bone non-collagenous protein, osteocalcin, and induces the activity of alkaline phosphatase in MG-63 human osteosarcoma cells [3].
• Calcipotriol (MC 903), a synthetic derivative of vitamin D3 stimulates differentiation of squamous carcinoma cell line in the raft culture [4].

High impact information on Dovonex

• Similar up-regulatory effects on the apoD gene expression were obtained by treatment of T-47D cells with 1,25-dihydroxyvitamin D3 analogues, including MC 903, which is relatively devoid of hypercalcemic side effects in clinical applications [5].
• The affinity of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25-(OH)2D3] and analogs with side-chain modifications [MC 903 or calcipotriol, MC 1147 or 24,24-dihomo-1 alpha,25-(OH)2D3 and 1,25-(OH)2-16ene-23yne-D3] for the vitamin D receptor and the serum vitamin D binding protein (DBP) were compared [6].
• The affinity of MC 903 for the receptor from chick and rat duodenum or from human peripheral blood mononuclear cells or HL-60 cells varied between 60 and 100% relative to the affinity of 1,25-(OH)2D3 [6].
• The relative affinity of MC 903 for human DBP was 30-fold decreased, whereas the two other analogs did not bind to DBP at all even in more than 1000-fold excess [6].
• Calcitriol and its synthetic analogue MC 903 inhibit the interleukin-2-induced migration of human lymphocytes [7].

Chemical compound and disease context of Dovonex

• The efficacy of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and the new analogue calcipotriene (MC 903) in the treatment of psoriasis was investigated [8].
• Psoriasis treatment with vitamin D3 analogue MC 903 [9].
• EB 1089 was somewhat less effective than 1 alpha,25(OH)2D3 and MC 903, which is currently used in the treatment of psoriasis, has only a weak activity on C6.9 cells [10].

Biological context of Dovonex

• MC 903 and 1,25(OH)2D3 have shown similar receptor binding properties and comparable effects on leukemic cell differentiation [3].
• In order to determine the activity of this compound on bone cells, we have compared the effects of MC-903 and 1,25 dihydroxyvitamin D3 (1,25(OH)2D) on parameters of cell proliferation and differentiation in cultured normal human osteoblastic cells derived by migration from trabecular bone fragments [11].
• Calcipotriol (MC 903): pharmacokinetics in rats and biological activities of metabolites. A comparative study with 1,25(OH)2D3 [2].
• KH 1060 was the biologically most potent of the analogues and, compared to KH 1060, the IC50 values were 1.2-, 2.7- and 14-fold higher when 1,25-(OH)2D3, EB 1089 and MC 903, respectively, were used for the displacement of receptor bound [3H]1,25-(OH)2D3 [12].
• The analogue MC 903 was the second most potent inhibitor of cell growth in spite of expressing the lowest affinity for the VDR and the weakest inhibition of TSH-stimulated adenylyl cyclase activity and iodide uptake [12].

Anatomical context of Dovonex

• Vitamin D3 and its analogue, calcipotriol (MC 903), inhibit the proliferation of cultured human and mouse keratinocytes and induce keratinocyte differentiation [13].
• Dose response curves showed that MC-903 was 10 to 100 times less effective than 1,25(OH)2D in stimulating the synthesis of the osteoblast specific protein osteocalcin by human bone cells depending on the basal osteocalcin production [11].
• In addition, MC 903 and MC 1288 were more effective than 1,25(OH)2D3 in stimulating DNA synthesis in proliferating myoblasts and in inhibiting DNA synthesis in differentiating myoblasts [14].
• In enterocytes, at a concentration of 10(-11) M, MC 1288 was significantly more active than 1,25(OH)2D3 in rapidly stimulating 45Ca2+ uptake by enterocytes (80 vs 38% above controls, respectively), whereas MC 903 was devoid of activity [14].

Gene context of Dovonex

• 1,25-(OH)2D3 and the analogue MC 903 inhibited IL-6 production by LPS-stimulated human mononuclear cells [15].
• The production was not affected, but 1,25(OH)2D3 (greater than 10(-11) M) and a synthetic derivative MC 903 (greater than = 10(-10) M) inhibited the proliferation of mouse thymocytes to IL-1 [16].
• During therapy with MC 903 a decline in the staining intensity for IL-6, but not for TNF alpha, was observed in both lesional and unaffected skin [17].
• MC-903 (10(-7) M) reduced CCPR in control tissue by 51%, and in FAP tissue by 52% at 10(-6) M and 51% at 10(-7) M [18].
• The activity of transglutaminase, the enzyme responsible for cross-linking the proteins of the cornified envelope, was maximally stimulated by 388% with MC 903 (10(-8) M), by 328% with 1,25-(OH)2-D3 (10(-8) M), and by 27% with 1 alpha-OH-D3 (10(-8) M) compared with vehicle [19].

Analytical, diagnostic and therapeutic context of Dovonex

• The greater activity of 1,25(OH)2D over MC-903 was observed in human bone cell cultures with elevated basal osteocalcin levels, indicating that the response to 1,25(OH)2D but not to MC-903 was amplified in cells with the higher osteoblastic characteristics [11].
• After treatment for 8 weeks, topical MC 903 alone resulted in marked improvement in 66% of the patients and in clearance in 17% [20].

References