1,25(OH)2-16ENE-vitamin D3 is a potent antileukemic agent with low potential to cause hypercalcemia

Jung, Soo Ja; Lee, Young Yiul; Pakkala, Seppo; Vos, Sven de; Elstner, E; Norman, Anthony W.; Green, J.; Uskoković, Milan R.; Koeffler, H. Phillip

doi:10.1016/0145-2126(94)90081-7

Cited by 55 publications

(32 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recently, a compound which has the well recognized potentiating unsaturation in position 16 of ring D (Jung et al, 1994;Uskokovic et al, 1997) as well as a novel 5,6-trans modification, has been shown to strongly inhibit the proliferation of several types of human cancer cells, including myeloid leukemia HL60 cells (Hisatake et al, 1999). Remarkably, the 5,6-trans-16-ene analog was 40 times less calcemic in mice than the physiological form of vitamin D, 1,25D 3 or the 16-ene analog, suggesting that 5,6-16D 3 may indeed be a useful cancer chemotherapeutic agent.…”

mentioning

confidence: 98%

Signaling of monocytic differentiation by a non‐hypercalcemic analog of vitamin D₃, 1,25(OH)₂‐5,6 trans‐16‐ene‐vitamin D₃, involves nuclear vitamin D receptor (nVDR) and non‐nVDR–mediated pathways

Wang

Donnelly

et al. 2002

Journal Cellular Physiology

View full text Add to dashboard Cite

Exposure of leukemia cells to the physiologically active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25D3) normalizes their phenotype to cells that resemble mature monocytes. One of the earliest detectable events in this process is an upregulation of the nuclear receptor for 1,25D3, the vitamin D receptor (nVDR). In contrast, the novel analog of 1,25D3, 1,25-dihydroxy-5,6 trans-16-ene-vitamin D3 (5,6-16D3), which has recently been reported to have low calcium-mobilizing activity in vivo, rapidly induced the expression of CD14, CD11b, and monocyte-specific esterase (MSE), classical markers of the mature monocyte, but upregulated nVDR expression less than 1,25D3. This upregulation was shown to be the result of altered degradation of the nVDR protein, while the levels of nVDR mRNA were constant. Knock-out of nVDR transcriptional activity by a decoy VDRE double-stranded deoxyoligonucleotide, markedly abrogated 1,25D3-induced differentiation, but incompletely inhibited 5,6-16D3-induced differentiation. These findings suggest that the unique ability of 5,6-16D3 to induce cell differentiation but not systemic hypercalcemia, may be due to the activation of pathways which initiate differentiation independently of nVDR.

show abstract

mentioning

confidence: 98%

Signaling of monocytic differentiation by a non‐hypercalcemic analog of vitamin D₃, 1,25(OH)₂‐5,6 trans‐16‐ene‐vitamin D₃, involves nuclear vitamin D receptor (nVDR) and non‐nVDR–mediated pathways

Wang

Donnelly

et al. 2002

Journal Cellular Physiology

View full text Add to dashboard Cite

show abstract

“…Recently, vitamin D 3 analogs have been developed that have profound effects on a variety of cells but have less ability to cause hypercalcemia than does 1,25(OH) 2 D 3 . These analogs can inhibit proliferation and induce differentiation of cancer cells and decrease the development and progression of carcinoma in vivo without causing hypercalcemia (Zhou et al 1989, Abe et al 1991, Jung et al 1994. These analogs may have utility in a variety of other disease states including psoriasis, immunological abnormalities and bone and endocrine disorders.…”

Section: Introductionmentioning

confidence: 99%

Effects of long-term administration of vitamin D3 analogs to mice

Smith

Frankenburg²,

Goldstein³

et al. 2000

Journal of Endocrinology

View full text Add to dashboard Cite

This study explores the effects of chronic administration of vitamin D 3 compounds on several biological functions in mice. Knowledge of long-term tolerability of vitamin D 3 analogs may be of interest in view of their potential clinical utility in the management of various pathologies such as malignancies, immunological disorders and bone diseases. Four unique vitamin D 3 analogs (code names, compounds V, EO, LH and LA) and 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) were administered i.p. for 55 weeks to Balb/c mice. Each analog had previously been shown to have potent in vitro activities. After 55 weeks of administration, the mice had a profound decrease in their serum levels of interleukin-2 (IL-2). Likewise, several analogs depressed serum immunoglobulin G concentrations (compounds LH and LA), but levels of blood lymphocytes and splenic lymphocyte subsets (CD4, CD8 and CD19) were not remarkably depressed. The percent of committed myeloid hematopoietic stem cells was 4-to 5-fold elevated in the bone marrow of the mice that received analogs LH and V; nevertheless, their peripheral blood white and red cell counts and platelets were not significantly different in any of the groups. The mice that received 1,25(OH) 2 D 3 had a decrease in bone quantity and quality with a decrease in cross-sectional area and cortical thickness, and a 50% reduction in both stiffness and failure load compared with the control group. In contrast, the cohort that received a fluorinated analog (compound EO) developed bones with significantly larger cross-sectional area and cortical thickness as well as stronger mechanical properties compared with the control group. At the conclusion of the study, body weights were significantly decreased in all experimental mice. Their blood chemistries were normal. Extensive gross and microscopic autopsy analyses of the mice at the conclusion of the study were normal, including those of their kidneys. In conclusion, the vitamin D 3 analogs were fairly well tolerated. They did suppress immunity as measured by serum IL-2 and may provide a means to depress the immune response after organ transplantation and for autoimmune diseases. Use of these analogs prevented the detrimental effects of vitamin D 3 administration on mechanical and geometric properties of bone, while one analog (compound EO) actually enhanced bone properties. These results suggest that long-term clinical trials with the analogs are feasible.

show abstract

“…Previous studies of calcitriol derivatives demonstrated that the introduction of the C-16 double-bond in the D-ring affects the conformation of the side-chain, improves the biological stability by arresting the metabolic degradation at the 24-keto stage, 3 generally enhances differentiation and anti-proliferative activity, 4 and reduces the hypercalcemic potential. 5 Structural modifications of the side-chain itself also interfere with the C-24 hydroxylation-initiated cascade of degradation and modify biological activities. [6][7][8] These include C-23-yne or C-23(E,Z)-ene modifications and 26,27-hexafluorination.…”

Section: Introductionmentioning

confidence: 99%

Calcitriol derivatives with two different side-chains at C-20. Part 4: Further chain modifications that alter VDR-dependent monocytic differentiation potency in human leukemia cells

Garay

Jankowski

Lizano

et al. 2007

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Signaling of cell differentiation is one of the important physiological functions of the activated vitamin D receptor (VDR). Activation of the VDR can be achieved not only by 1α,25-dihydroxyvitamin D 3 (1,25D), the natural ligand, but also by a large number of its analogs. These include a category containing two side chains emanating at C-20, generally referred to as Gemini. The introduction of a cyclopropyl moiety as part of the pro-R side chain provides modified Gemini compounds with increased steric requirement and decreased chain flexibility; the biological consequences of this novel structural variant are subject of this investigation. In general, the resulting 1α,25-dihydroxy-(4-hydroxy-4-methyl-pentyl)-21,22-cis-cyclo-cholecalciferols reduced had differentiation and transcriptional potency and induced cell cycle arrest less effciently, as shown by a decrease in G1/S ratio, when compared to 1,25D. Modifying their calcitriol side chain in the form of a 4-hydroxy-4-trifluoromethyl-5,5,5-trifluoropent-2-ynyl moiety, however, resulted in pronounced induction of differentiation in 1,25D-sensitive and moderate level of differentiation in 1,25D-resistant leukemia cells.

show abstract

1,25(OH)2-16ENE-vitamin D3 is a potent antileukemic agent with low potential to cause hypercalcemia

Cited by 55 publications

References 43 publications

Signaling of monocytic differentiation by a non‐hypercalcemic analog of vitamin D₃, 1,25(OH)₂‐5,6 trans‐16‐ene‐vitamin D₃, involves nuclear vitamin D receptor (nVDR) and non‐nVDR–mediated pathways

Signaling of monocytic differentiation by a non‐hypercalcemic analog of vitamin D₃, 1,25(OH)₂‐5,6 trans‐16‐ene‐vitamin D₃, involves nuclear vitamin D receptor (nVDR) and non‐nVDR–mediated pathways

Effects of long-term administration of vitamin D3 analogs to mice

Calcitriol derivatives with two different side-chains at C-20. Part 4: Further chain modifications that alter VDR-dependent monocytic differentiation potency in human leukemia cells

Contact Info

Product

Resources

About

1,25(OH)2-16ENE-vitamin D3 is a potent antileukemic agent with low potential to cause hypercalcemia

Cited by 55 publications

References 43 publications

Signaling of monocytic differentiation by a non‐hypercalcemic analog of vitamin D3, 1,25(OH)2‐5,6 trans‐16‐ene‐vitamin D3, involves nuclear vitamin D receptor (nVDR) and non‐nVDR–mediated pathways

Signaling of monocytic differentiation by a non‐hypercalcemic analog of vitamin D3, 1,25(OH)2‐5,6 trans‐16‐ene‐vitamin D3, involves nuclear vitamin D receptor (nVDR) and non‐nVDR–mediated pathways

Effects of long-term administration of vitamin D3 analogs to mice

Calcitriol derivatives with two different side-chains at C-20. Part 4: Further chain modifications that alter VDR-dependent monocytic differentiation potency in human leukemia cells

Contact Info

Product

Resources

About

Signaling of monocytic differentiation by a non‐hypercalcemic analog of vitamin D₃, 1,25(OH)₂‐5,6 trans‐16‐ene‐vitamin D₃, involves nuclear vitamin D receptor (nVDR) and non‐nVDR–mediated pathways

Signaling of monocytic differentiation by a non‐hypercalcemic analog of vitamin D₃, 1,25(OH)₂‐5,6 trans‐16‐ene‐vitamin D₃, involves nuclear vitamin D receptor (nVDR) and non‐nVDR–mediated pathways