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Review

Promise of vitamin D analogues in the treatment of hyperproliferative conditions

Sonoko Masuda and Glenville Jones
Sonoko Masuda
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Glenville Jones
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DOI: 10.1158/1535-7163.MCT-05-0539 Published April 2006
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  • Figure 1.
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    Figure 1.

    Model of the transcriptional mechanism of action of 1α,25-(OH)2D3 enters the picture at 1 o'clock interacting with the unliganded VDR-retinoid X receptor basal complex and locating the vitamin D–responsive element–containing vitamin D–dependent gene. The initial steps in activation involving conformational changes in the VDR and recruitment of coactivators are shown in the 3 o'clock complex. At this point, a SWI/SWF chromatin remodeling complex affects changes in chromatin allowing recruitment of the transcription initiation complex, including attraction of DRIPs shown at 6 o'clock. Active transcription of the vitamin D–dependent gene occurs. The complex at 9 o'clock is involved in turning over the VDR and recycling the rest of the transcriptional machinery. Note that the ligand 1α,25-(OH)2D3 is also subject to degradation by CYP24A1, an inducible cytochrome P450 found in the target cell. Reproduced from ref. 20; Figure 9 in Chapter 13 in “Vitamin D 2nd Edition” published by Elsevier, New York. With kind permission from G. Kerr Whitfield and Mark R. Haussler and Elsevier.

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    Figure 2.

    Chemical structures of potential anticancer vitamin D analogues referred to in the text are provided. Note that several different strategies have been used by the organic chemist to modify the properties of the vitamin D molecule. The most basic molecule is the prodrug version that is inactive as given but activated by CYPs in vivo. The most popular analogues have modified (hybrid) side chains and these include double side chain versions known as Gemini analogues. Many analogues possess side chains with double or triple bonds in the C-24 position that make them resistant to the actions of CYP24A1. The nonsteroidal vitamin D analogues were designed to occupy the VDR-ligand-binding pocket.

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  • Table 1.

    In vivo effects of vitamin D analogues in animal models of cancer

    Tumor, modelAnalogueDoseEffectHypercalcemiaRef.
    Breast
        N-methyl-N′-nitrosourea inducedEB10891 μg/kg p.o.Tumor suppressionMarked(71)
    Ro24-55311.25 and 2.5 nmol/kg dietReduced tumor incidenceNone(78)
    1α(OH)D558.4 and 116.8 nmol/kg diet*Reduced tumor incidenceNone(79)
        MCF-7 xenografts22-Oxa-1α,25(OH)2D31.0 μg/kg p.o.Tumor suppressionNone(73)
    TX52280 μg/kg/2 d i.p.Tumor suppressionNone(77)
    TX52725 μg/kg/2 d i.p.Tumor suppressionMarked(77)
        MDA-MB-231 xenograftsEB108914 pmol/L/24 h, infusionInhibited skeletal metastasisNone(72)
    Prostate
        LNCaP xenograftsEB10890.5 μg/kg i.p.Tumor suppressionNone(81)
    EB10891 μg/kg p.o.Tumor suppressionMild(86)
    LG1901193 and 10 mg/kg p.o.Tumor suppressionNone(86)
    LG19011910 mg/kg p.o.Reduced tumor incidenceNone(86)
        PC-3 xenograftsRo23-75531.6 μg/animal i.p.Tumor suppressionNone(84)
        MAT LyLu tumors in ratsEB10890.5 and 1.0 μg/kg i.p.Inhibited lung metastasisMarked(82)
        MDA-PCa 2b xenograftsJK-1626-24 μg/kg s.c.Inhibited metastatic bone lesionsNone(83)
    Colon
        1,2-Dimethylhydrazine induced22-Oxa-1α,25(OH)2D330 μg/kg i.p.†Reduced aberrant crypt fociNone(91)
    Ro25-53173.5 nmol/kg dietReduced tumor incidenceNone(88)
    Ro25-90223.0 and 3.5 nmol/kg dietReduced tumor incidenceNone(88)
        Azoxymethane inducedRo24-55312.5 nmol/kg dietReduced tumor incidenceNone(89)
    1α(OH)D558.4 nmol/kg dietReduced aberrant crypt fociNone(79)
        LoVo xenograftsEB10890.1 and 0.5 μg/kg p.o.Tumor suppressionNone(87)
        HT-29 xenograftsRo25-67600.1 and 0.2 μg/animal i.pTumor suppressionNone(90)
        MC-26 xenograftsRO-43835610.02 μg E i.p.Reduced tumor growthNone(92)
    • ↵* 1α(OH)D5 58.4 and 116.8 nmol/kg diet = 25 and 50 μg/kg diet.

    • ↵† 22-Oxa-1α,25(OH)2D3 30 μg/kg i.p. = 72.5 nmol/kg i.p.

  • Table 2.

    Clinical development of 1α,25(OH)2D3 and its analogues for cancer treatment

    StudyTreatmentPatientsProtocolRef.
    Phase II1α,25(OH)2D3 + dexamethasoneProstate cancer before prostatectomyTwice weekly p.o.Ongoing study*
    Phase II1α,25(OH)2D3 + mitoxantrone + prednisoneProstate cancerHigh-dose pulse p.o.Ongoing study*
    Phase II1α,25(OH)2D3 + docetaxelPancreatic cancerWeekly p.o.Ongoing study*
    Phase II1α,25(OH)2D3Prostate cancer before prostatectomyWeekly p.o.(98)
    Phase II1α,25(OH)2D3 + docetaxelProstate cancerWeekly p.o.(99)
    Phase II1α,25(OH)2D3 + carboplatinProstate cancerWeekly p.o.(100)
    Phase II1α(OH)D2Prostate cancer before prostatectomyDaily p.o.Ongoing study*
    Phase II1α(OH)D2Prostate cancerDaily p.o.(105)
    Phase IIEB1089Liver cancerDaily p.o.(103)
    Phase IIEB1089Pancreatic cancerDaily p.o.(104)
    Phase I1α,25(OH)2D3 + ketoconazole + dexamethasoneAdvanced solid tumorsDays 1-3/wk p.o.Ongoing study*
    Phase I1α,25(OH)2D3 + gefitinib + dexamethasoneAdvanced solid tumorsWeekly i.v.Ongoing study*
    Phase I/II1α,25(OH)2D3 + docetaxel + estramustineProstate cancerHigh-dose pulse p.o.(101)
    Phase I1α,25(OH)2D3 + paclitaxelAdvanced solid tumorsDays 1-3/wk p.o.(95)
    Phase I1α,25(OH)2D3Liver cancerDaily hepatic infusion(97)
    Phase I1α,25(OH)2D3Advanced malignancyWeekly p.o.(94)
    Phase I1α,25(OH)2D3Advanced malignancyEvery other day s.c.(93)
    Phase I19-Nor-1α,25(OH)2D2 + gemcitabineAdvanced malignancyWeekly i.v.Ongoing study*
    Phase I16-Ene-23-yne-1α,25(OH)2D3Advanced malignancyDaily p.o.(108)
    Phase I1α(OH)D2Prostate cancerDaily p.o.(106)
    Phase IEB1089Breast and colorectal cancerDaily p.o.(102)
    No phase specified19-Nor-1α,25(OH)2D2 + zoledronateMultiple myeloma or other plasma cell disorderWeekly i.v.Ongoing study*
    • ↵* Cancer clinical trial currently under way in the United States (http://www.cancer.gov).

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Molecular Cancer Therapeutics: 5 (4)
April 2006
Volume 5, Issue 4
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Promise of vitamin D analogues in the treatment of hyperproliferative conditions
Sonoko Masuda and Glenville Jones
Mol Cancer Ther April 1 2006 (5) (4) 797-808; DOI: 10.1158/1535-7163.MCT-05-0539

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Promise of vitamin D analogues in the treatment of hyperproliferative conditions
Sonoko Masuda and Glenville Jones
Mol Cancer Ther April 1 2006 (5) (4) 797-808; DOI: 10.1158/1535-7163.MCT-05-0539
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    • Rationale for Using Vitamin D Analogues in Cancer Therapy
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