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Vitamin D, vitamin D analogs (deltanoids) and prostate cancer Expert Rev. Clin. Pharmacol. 1(6), 803–813 (2008)

William M Brown VaxDesign Corp., 12612 Challenger Parkway, Suite 365, Orlando, FL 32826, USA Tel.: +1 407 249 3650 Fax: +1 407 249 3649 [email protected]

‘Vitamin D’ is a generic term for a family of secosteroids, members of which bind to the vitamin D receptor. Calcitriol, the active form of vitamin D, has antiproliferative effects on many tumor cells. However, clinical use of calcitriol in cancer prevention or therapy is limited because it induces hypercalcemia at the necessary supraphysiological doses. The anti-tumor effects of vitamin D analogs (deltanoids) have been researched extensively; more than 3000 deltanoids have now been described. Prostate cancer is more common in northern geographic regions; mortality decreases with exposure to sunlight. As UV light is necessary for vitamin D synthesis in the skin, it has long been dogma that vitamin D is involved. This review concerns deltanoids that have been assessed for use in treating or preventing prostate cancer. Keywords : calcitriol • deltanoid • prostate cancer • vitamin D

‘Vitamin D’ is a generic term for a family of seco­ steroids with affinity for the vitamin D receptor (VDR). A secosteroid has a structure similar to a steroid (Figure 1) , but with an incomplete ring; in vitamin D, the two B-ring carbon atoms (C9 and 10) of the typical four rings of a steroid are not joined (Figure 2) . Owing to its eight carbon side chain, the incomplete B-ring that allows rotation about the 6–7 carbon–carbon bond and the A-ring that undergoes chair-boat conformational interconversion, vitamin D molecules are extremely conformationally flexible [1] . The human body does not make vitamin D2 ; it is derived from dietary fungal and plant sources. Vitamin D3 is made in the skin when 7-dehydrocholesterol is exposed to UV light. It can also be derived from animal sources in the diet [2,3] . Alfacalcidol (1α-hydroxyvitamin D3) was first approved as a drug in Japan in 1981 to treat vitamin D deficiency, which can cause rickets and osteomalacia. Alfacalcidol is a prodrug for what is now known to be the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) (F igur e 3) . Alfacalcidol has since also been approved as a treatment for osteoporosis. Dietary vitamin D (D3 and/or D2) is biologically inert; it is first modified in the liver by vitamin D3-25-hydroxylase and then in the kidney by 25-hydroxyvitamin D3-1α-hydroxylase (1α(OH)ase), to form the active metabolite, 1α,25(OH)2D3 [4,5] . 1α,25(OH)2D3 is required www.expert-reviews.com

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for calcium and phosphorus homeostasis, and for normal skeletal development and maintenance; 1α,25(OH)2D3 plays a key role in Ca 2+ homeostasis, stimulating Ca 2+ (re)absorption and bone turnover. Vitamin D, its metabolites and analogs (collectively, ‘deltanoids’) have been used in the prevention and treatment of vitamin D deficiency and disorders of mineral homeo­stasis, including osteoporosis, osteomalacia, renal osteodystrophy and parathyroid dysfunction. In addition to its ‘classical’ effects on calcium and bone, 1α,25(OH)2D3 has immuno­ modulatory effects on antigen-presenting cells and T cells. 1α,25(OH)2D3 also appears to be a paracrine factor in several cell and tissue types, including brain, placenta and skin, where it can affect the proliferation and differentiation of many types of immune system and malignant cells. 1α,25(OH)2D3 appears to be involved in determining the transition from proliferation to differentiation. It is involved in stimulating monocyte activity, in inhibiting lymphocyte-specific immunity and in regulating the growth and differentiation of normal cells in embryogenesis. These so-called noncalcemic effects of vitamin D, its metabolites and analogs suggest the possibility of other applications of deltanoids, such as modulating the immune system, modifying hormone secretion, altering calcium transport, influencing intercellular calcium concentrations, inducing cell differentiation and inhibiting cell proliferation.

© 2008 Expert Reviews Ltd

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The anti-tumor effects of various deltanoids have become a major area of research. Indeed, such compounds have been considered for use in treating hyperproliferative disorders, such as cancer, psoriasis and (auto)immune conditions. 1α,25(OH)2D3 itself has antiproliferative effects on many tumor cell types in vitro and in vivo (for recent reviews, see [6–11]). Despite these potent antiproliferative properties, the clinical use of vitamin D3 in cancer prevention or therapy has been limited because it induces hypercalcemia, increasing the risk of soft-tissue and vascular calcification and osteoporosis when administered at the supraphysiological doses necessary to affect cancers [12] . To some degree, this issue has been addressed by intermittent dosing; weekly administration of oral calcitriol has enabled dose escalation, although it seems that pharmacokinetic variables do not increase dose proportionally [12] . Furthermore, in some indications, intravenous calcitriol has higher bioavailability than oral calcitriol [13,14] . Consequently, much effort has been devoted to developing less or noncalcemic and more potent analogs of vitamin D3. To date, more than 3000 analogs have been synthesized and tested [15–17] . Some of these compounds and their properties are discussed later (Figures 4 & 5) . Deltanoids interact with four proteins

The active form of vitamin D (1α,25(OH)2D3), and presumably its many analogs, interacts with four types of proteins: the nuclear VDR (a transcription factor), the plasma membrane receptor that apparently mediates ‘nongenomic’ responses, a serum transporter (the vitamin D-binding protein [DBP]) and metabolic enzymes (especially vitamin D-24-hydroxylase [18]). These will now be discussed briefly. Nuclear VDR

Vitamin D and its many analogs appear to operate by two independent pathways; the first is the genomic pathway, involving the nuclear VDR, a member of the steroid/thyroid hormone/ retinoid receptor superfamily. Binding of 1α,25(OH)2D3 to the nuclear VDR, followed by dimerization of the ligand–VDR with the retinoid X receptor (RXR), and then binding of the 804

ligand–VDR–RXR complex to vitamin D-responsive elements in promoters affects the transcription of many genes. Specifically, the 1α,25(OH)2D3 –VDR–RXR complex binds to response elements, consisting of two directly repeated pairs of motifs, AGGTGA, spaced by three nucleotides. VDRs and vitamin D activity have been reported in calcium-transporting tissues other than the intestine and bone, including the placenta and mammary glands. VDRs and vitamin D actions have also been seen in many cell types not involved in calcium homeostasis, including those of the immune system, skin, colon, brain, endocrine glands and muscles. The antiproliferative effects of 1α,25(OH)2D3 are believed to be mediated through the VDR. Against this, and likely pointing to our still incomplete understanding of the situation, two groups have generated VDRdeficient mice by gene-targeting techniques [19–21]. Yoshizawa et al. ablated exon 2 of the VDR gene, encoding the first zinc finger of the DNA-binding domain [19] , while Li et al. ablated a VDR fragment spanning exons 3–5, encoding the second zinc finger of the DNA-binding domain [20] . While neither mouse strain was normal, the knockouts were also not lethal. Indeed, homo­ zygous littermates from both studies phenotypically resembled the human condition of vitamin D-dependent rickets type II, exhibiting rickets and osteomalacia, and elevated levels of and resistance to 1α,25(OH)2D3. The x-ray crystal structure of the 1α,25(OH) 2D3 -occupied VDR showed that the preferred ligand shape was a twisted 6-s-trans bowl shape [22] . Optimal agonists for VDR binding include 1α,25(OH)2D3 and analogs with conformationally flexible side chains, such as 20-epi-1α,25(OH)2D3, which is 200– 500-fold more potent than 1α,25(OH)2D3 and 21-(3´-hydroxy3-methylbutyl)-1α,25(OH) 2D3, which has two side chains. 23S-25-dehydro-1α,25(OH)D3-26,23-lactone is an antagonist of only the nuclear VDR [23] . From crystal structures, the A-ring of vitamin D compounds exists in the β‑chair form, with the 1α-OH being in an equatorial orientation. Interconversion between A-ring forms can occur in solution. A constrained analog that exists only in the α‑chair form has been studied; it showed almost no VDR binding and very low HL-60-differentiating activity. In mice, the analog was quite calcemic [24] . Crystal structures of the VDR have revealed that all bound compounds are anchored by the same residues in the ligandbinding pocket. An analog with a locked side chain, 21-nor-calcitriol-20(22),23-diyne, has been studied; the crystal structure of the VDR ligand-binding pocket bound to this locked side chain analog suggested a structural basis for the compound’s activity [22] . The E and Z isomers of 17–20 dehydro analogs of 2‑methylene-19-nor-(20S)-1α,25(OH)2D3 (2MD) both bound with high affinity to recombinant rat VDR. The Z isomer had similar activity in vivo and in vitro to 2MD. The in vitro activity of the E isomer was comparable to the natural hormone; in vivo, it was significantly less calcemic. Crystal structures of the rat VDR ligand-binding domain complexed with the analogs demonstrated that the Z analog was oriented similarly to 2MD. The E analog conformation was quite different to both 2MD and calcitriol. Thus, position C21 in the ligand binding site may be important in Expert Rev. Clin. Pharmacol. 1(6), (2008)

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determining biological activity [25] . Some 20-epi and 20-normal vitamin D3 analogs have been studied for their effects on VDR degradation. Transcriptionally active 20-epi analogs protected the VDR against degradation more efficiently than 20-normal analogs or 1α,25(OH)2D3. The 20-epi analogs apparently induced a VDR conformation that reduced VDR degradation [26] .

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1α,25(OH)2D3 is delivered to its target organs by a plasma transport protein, the DBP. While binding, solubilization and serum transport of the vitamin D sterols are apparently the key roles of DBP, DBP is a multifunctional plasma protein also involved in certain immune and inflammatory responses. DBP appears to bind cell surfaces. DBP is structurally related to albumin and α-fetoprotein (AFP); the DBP gene is part of the albumin/AFP gene family. The decreased calcemic activity of many vitamin D analogs is, at least partly, due to the DBP. Owing to lower binding to DBP, relative to the natural molecule, more extensive extracellular metabolism and more rapid clearance occur [29,30] . Vitamin D-metabolizing enzymes

Dietary vitamin D (D3 and/or D2 ) is metabolized, first to 25-hydroxy­v itamin D3 (25OH-D3 ) in the liver and then to 1α,25(OH) 2D3, the active metabolite, in the kidney. 1α,25(OH)2D3 is considered a hormone because it is formed in the kidney and acts in the intestines and bone. 1α,25(OH)2D3 production is feedback controlled by serum calcium and phosphate concentrations. When the synthesis of 1α,25(OH) 2D3 is repressed, 24,25‑dihydroxyvitamin D3 (24,25(OH) 2D3 ) is www.expert-reviews.com

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Vitamin D and other deltanoids can also act more rapidly via a second, nongenomic pathway, by activating ion channels or other membrane-related or second messenger signals. Specifically, in some target tissues there appears to be a cell membrane receptor (∼60 kDa), which has been called the ‘membrane VDR’ (mVDR) [27,28] . Rapid responses mediated via the mVDR include the opening of voltage-gated Ca 2+ and Cl‑ channels in ROS 17/2.8 osteoblast cells, activation of MAPK in human NB4 leukemia cells, release of insulin by rat pancreatic β-cells, and in chick duodenal cells, transcaltachia, the rapid hormonal stimulation of intestinal Ca 2+ transport [23] . Conformationally restricted analogs of 1α,25(OH)2D3 have been studied to determine preferred ligand features for these nongenomic responses. The most preferred is apparently a 6-s-cis shape, such as that of 1α,25(OH)2D3 or analogs, such as 1α,25(OH)2lumisterol3 or 1α,25(OH)2-7-dehydrocholesterol, that are locked in a 6-s-cis shape. 1β,25(OH)2D3 is an antagonist only of responses via the membrane receptor [23] . While the mVDR responds effectively to analogs that are 6-s-cis locked, such as 1α,25(OH)2-previtamin D3 or 1α,25(OH)2-provitamin D3, these same analogs had only 1–2% of the activity of 1α,25(OH)2D3 in regulating transcription. The 6-s-trans analog, 1α,25(OH)2tachysterol3, had less than 0.1% of the activity of 1α,25(OH)2D3 in regulating transcription [24] .

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formed, which can then be converted to 1,24,25‑trihydroxyvitamin D3 (1,24,25(OH) 3D3), which stimulates intestinal calcium transport but not bone calcium mobilization or phosphate transport. Some vitamin D-resistant bone diseases appear to be related to defects in vitamin D metabolism. Bone disease related to chronic kidney disease is probably the result of defective formation of 1α,25(OH)2D3 in the kidney. Treatment with intravenous 1α,25(OH)2D3 can correct this. 25-hydroxyvitamin D3 -24-hydroxylase (also known as CYP24A1) is a bifunctional enzyme that can 24‑hydroxylate 1α,25(OH)2D3, leading to it being excreted as calcitroic acid (1α-hydroxy-23 carboxy-24,25,26,27-tetranorvitamin D3), or 23‑hydroxylate it, leading to 1α,25(OH)2D3-26,23-lactone. The degree to which CYP24A1 catalyzes 23- or 24-hydroxylation varies by species. The human enzyme predominantly 24-hydroxy­ lates the substrate and yet differs from the opossum enzyme that 23-hydroxylates it by only a few amino acids. Mutagenesis of the human enzyme at a single substrate-binding residue (A326G) functionally changed the enzyme from a 24‑ to a 23‑hydroxylase  [31] . 24-hydroxylation by CYP24 leads to excretion of the 24-hydroxylated compound by the kidney. A 24-phenylsulfone analog of 1α,25(OH)2D3, KRC‑24SO2Ph-1 (S‑4a), inhibited 24-hydroxylase activity in colon-, prostateand mammary gland-derived tumor cells. 25-hydroxyvitamin 805

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Figure 3. 1α,25-dihydroxyvitamin D3 (1α,25(OH) 2D3 ).

D3 -1α‑hydroxylase expression was unaffected by S-4a. The COGA-13 colon cancer cell line has very high levels of CYP24 and is largely resistant to the actions of vitamin D. However, S-4a imparted antimitotic activity to 1α,25(OH)2D3 and may thus be a useful combination therapeutic to boost the antiproliferative potential of vitamin D-based anti-tumor activity [32] . While vitamin D may be useful in tumor therapy, epithelial cells from tumor-prone organs, including the colon, prostate and breast, not only express the VDR, but also vitamin D hydroxylases. Indeed, unlike normal cells, many malignant cells have high basal levels of 25‑hydroxyvitamin D3-24-hydroxylase (CYP24) and can further upregulate the level of CYP24 in response to 1α,25(OH)2D3 [32] . There is also evidence for another metabolic pathway for vitamin  D2 in humans, involving the production of 24-hydroxyvitamin D2 (24-OHD2) and 1,24-dihydroxyvitamin D2 (1,24‑(OH)2D2). After a single dose of vitamin D2 (106 IU) or repeated daily doses (103 –5 × 104 IU), these metabolites were found in human serum. Synthesis of 1,24-(OH)2D2 was increased by parathyroid hormone (PTH), suggesting a renal origin. Vitamin D2 apparently gave rise to two biologically active products, 1,24-(OH)2D2 and 1,25(OH)2D2. 1,24-(OH)2D2 may be a useful naturally occurring analog of 1α,25(OH)2D3 [33] . The vitamin D metabolic pathway, including the cytochrome P450s (CYPs) involved in activation and catabolism, illustrates the importance of metabolic considerations in analog design. Some structural features making them more or less resistant to metabolic enzymes have been reported [34] . Vitamin D-related compounds are differentiated, on the basis of side-chain chemical structures, into different series; D2, D3, D4, D5 and D6. Considerable attention has focused on the vitamin D3 series. Prominent D3 analogs include 1α-hydroxyvitamin D3 (1αOHD3, alfacalcidol), an analog of 1α,25(OH) 2D3 that is effective in anephric animals and may have advantages over 1α,25(OH) 2D3 in treating bone diseases [35] . 22-oxacalcitriol (OCT) has profound differentiation-inducing effects and modest calcemic effects. It is now approved as a treatment for secondary 806

hyperparathyroidism (intravenous preparation) and as an ointment for the treatment of psoriasis vulgaris. 1α,25-dihydroxy2β-(3-hydroxypropoxy)vitamin D3 (ED-71) has a hydroxypropoxy group at the 2β position and binds to the VDR with approximately a third of the affinity of 1α,25(OH)2D3. ED-71 has a longer half-life in plasma than 1α,25(OH)2D3 because of a higher affinity for the DBP. ED-71 possesses a profile approximately the inverse of OCT. ED-71 was intended to have strong effects in bone. A Phase  II study demonstrated that ED-71 increased bone mass dose dependently, even with adequate vitamin D supplementation [36] . ED-71 has been assessed in Phase III clinical trials for the treatment of osteoporosis and bone fracture prevention [37] . 3-epi-1,25(OH)2D3 showed equipotent and prolonged activity compared with 1,25(OH)2D3 in suppressing parathyroid hormone (PTH) secretion [38] . Owing to ED-71’s hydroxypropoxy substituent at the 2-position, epimerization at the adjacent, sterically hindered 3-position may be prevented, possibly accounting for its low potency in suppressing PTH, as seen in its clinical development [39] . Synthesis of 3-epi-ED-71 and investigations of in vitro suppression of PTH using bovine parathyroid cells have been reported. Regarding the inhibitory potency of vitamin D3 analogs 1,25(OH)2D3 was found to be more potent than ED-71, which is as potent or more potent than 3-epi-1,25(OH) 2D3, which is much more potent than 3-epiED-71. ED-71 and 3-epi-ED-71 showed weak activity in suppressing PTH in the assays used [39] . 2MD is a bone-selective vitamin D analog developed based on SAR studies. The boneselective action of the analog has been tested and confirmed in vitro and in vivo and it may be useful clinically in bone diseases [40] . 1α-hydroxy-24-ethyl-cholecalciferol (1α(OH)D5) is a less calcemic analog of vitamin D3 [201] . 1α(OH)D5 (Figure 4) has been found to exhibit anti-tumor activity in animals [41–44] and is now being assessed in a Phase I trial (MN-201, Marillion Pharmaceuticals, PA, USA [301]). The analog ZK191784 contains a structurally modified side chain, with a 22,23-double bond, 24R-hydroxy group, 25-cyclopropyl ring and 5-butyloxazole group [45] . ZK191784 bound competitively to the VDR, with an affinity similar to 1α,25(OH) 2D3. The effects of ZK191784 on Ca 2+ homeostasis and the regulation of Ca 2+ transport proteins were investigated in wild-type mice and mice lacking the renal epithelial Ca 2+ channel TRPV5 (TRPV5 – /– ). TRPV5 – /– mice showed hyper­ calciuria, hypervitaminosis D, increased intestinal expression of the epithelial Ca 2+ channel TRPV6, the Ca 2+ -binding protein calbindin-D9K and intestinal Ca 2+ hyperabsorption. ZK191784 normalized the Ca 2+ hyperabsorption and expression of the intestinal Ca 2+ transport proteins in TRPV5 –/– mice. The compound had a 1α,25(OH)2D3-antagonistic action in the intestine and kidney. Since ZK191784 acted as a largely intestine-specific 1α,25(OH) 2D3 antagonist, it may cause fewer hypercalcemic side effects than 1α,25(OH) 2D3 and other analogs. As with 1α,25(OH)2D3, ZK191784 inhibited antigen-induced lymphocyte proliferation and cytokine secretion in vitro and had potent immunosuppressive activity in a murine contact hyper­sensitivity model. ZK191784 also has 1α,25(OH) 2D3 ‑antagonistic effects Expert Rev. Clin. Pharmacol. 1(6), (2008)

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although docetaxel can extend survival length  [57] . There is, Analog Manufacturer Approved indication thus, a continuing need for novel therapies to decrease the 1α,25(OH)2D3 Roche, Abbott Renal osteodystrophy and osteoporosis incidence and the morbidity 1α(OH)D3 Leo, Chugai, Teijin Renal osteodystrophy, and mortality associated with osteoporosis (Japan) prostate cancer. 1α,24(OH)2–24-cyclopropyl-D3 Leo Psoriasis Although the mechanisms 1α,24(OH)2D3 Teijin Psoriasis are not fully understood, 1α,25(OH) 2 D3 reduces cell 19-nor-1α,25(OH)2D2 Abbott Renal osteodystrophy growth in prostate cancer cells in the HL‑60 cell line, a model commonly used to study by affecting several pathways, genomic responses of 1α,25(OH) 2D3 analogs [46] . Antagonism including inducing cell cycle arrest and apoptosis, and alterof HL‑60 differentiation has previously been shown with sev- ing growth factor signaling [58,59] . Furthermore, in some other eral vitamin D analogs that have 1α,25(OH) 2D3 -antagonistic cancer models, it has been found that VDR agonists can reduce profiles in vivo. angiogenesis; there is also some evidence that VDR agonists The vitamin D system offers many drug-development pos- can reduce metastasis [56,60,61] . Calcitriol (1α,25(OH)2D3) can sibilities [47,48] . Indeed, several vitamin D-related compounds also stimulate apoptosis in the LNCaP human prostate cancer are already approved and in clinical use in various jurisdic- cell line [62,63] . Some vitamin D analogs have antiproliferative tions: 1α,25(OH) 2D3 (Roche, Abbott) for renal osteodystro- effects on prostate cancer cells in vitro. EB1089 (0.5–2.5 µg/kg) phy and osteoporosis, 1α(OH)D3 (Leo, Chugai, Teijin) for renal reduced the growth of MAT LyLu Dunning prostate tumors osteodystrophy and (in Japan) osteoporosis, 1α,24(OH) 2-24- in Copenhagen rats and subcutaneous LNCaP xenograft cyclopropyl-D3 (Leo) and 1α,24(OH) 2D3 (Teijin) for psoria- tumors propagated in nude mice, and was less hypercalcemic sis, and 19-nor-1α,25(OH)2D2 (Abbott) for renal osteodystro- than 1α,25(OH)2D3. phy  (Table  1) . This review selectively concerns compounds in The antiproliferative effects of calcitriol and its analogs are clinical development for treating prostate cancer. commonly demonstrated in three human prostate cancer cell lines, LNCaP, PC-3 and DU 145, and xenografts of them in nude Vitamin D & prostate cancer mice. Various studies have demonstrated that synthetic analogs Prostate cancer is the most commonly diagnosed cancer in of vitamin D3, with lower calcemic activity, exhibit antiprolifAmerican men. While it is typically a slow growing malignancy, erative effects and other biological actions in LNCaP and PC-3 mortality is significant; indeed, prostate cancer is the second most prostate cancer cell lines. While VDR binding is involved, analog common cause of cancer deaths in American men. Prostate can- data indicated that other factors are also involved in the biologicer typically metastasizes to bones [49] . Major risk factors include cal response [63] . As a result, deltanoids have been proposed as age, race and geography. The incidence increases markedly with potential prostate cancer treatments. age; more than 70% of all prostate cancer is diagnosed in men That the prostate is a target organ of vitamin D is consistent aged over 65 years. Consequently, the number of cases will prob- with the VDR being expressed in epithelial and stromal cells ably increase as life expectancy continues to rise. The incidence in the normal prostate. The VDR is also expressed by human is highest in African–Americans and lowest in Asians. Prostate cancer is more common in northern geographic regions; mortality decreases with increased exposure to sunlight. As UV light is necessary for vitamin D synthesis in the skin, it is dogma that vitamin D is involved [50] . Indeed, some epidemiological evidence suggests that decreased production of vitamin D is associated with increased prostate cancer risk [3,51] , although not all studies have been consistent and this relationship has recently been questioned [52–54] . Several genetic loci have been linked to prostate cancer risk; in particular, polymorphisms in the VDR gene may increase the risk of prostate cancer [55,56] , although again, not all reports on this are consistent. Localized prostate cancer is typically treated with surgery or radiation therapy, and the standard therapy for metastatic prostate cancer is androgen ablation. While androgen ablation is typically HO OH successful, androgen-independent tumors commonly develop 18–24 months later. There is currently no particularly effective Figure 4. 1α-hydroxy-24-ethyl-cholecalciferol (1α(OH)D5). treatment for these subsequent androgen-independent cancers, Table 1. Traditional (noncancer) approved indications of vitamin D analogs.

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prostate carcinoma cell lines (e.g., LNCaP, PC- 3 and DU-145) and primary cultures of stromal and epithelial cells from malignant prostate tissue. The VDR has been demonstrated to be present in human prostate tissue from patients who underwent radical prostatectomies for urinary bladder cancer; VDR expression was seen in secretory epithelial and some stromal cells, suggesting that the effects of 1α,25(OH)2D3 in these cells may be mediated via the VDR [64] . Prostate cancer cells express the VDR and the androgen receptor (AR). 1α,25(OH) 2D3 increases AR expression. 1α,25(OH)2D3 has antiproliferative activity in both AR-positive and -negative prostate cancer cells [65,66] . The VDR is required for 1α,25(OH)2D3-induced growth inhibition in prostate cancer cells. Furthermore, in the 1α,25(OH)2D3-resistant cell line JCA-1, the resistance can be overcome by transfection of wild-type VDR, producing cells that are again sensitive to the growth-inhibitory effects of 1α,25(OH)2D3 [67,68] . The AR is also important in the regulation of prostate cancer cell growth. Growth inhibition by 1α,25(OH)2D3 is dependent on AR activity in the LNCaP prostate cancer cell line. Additionally, calcitriol (1α,25(OH)2D3) has been shown to inhibit androgen glucuronidation in prostate cancer (LNCaP and 22Rv1) cells. As androgens promote prostate 808

cancer cell proliferation, if calcitriol reduces their inactivation, it may have a limiting effect on the antiproliferative effects in prostate cancer cells [69] . While the kidney is the primary site of 1α,25(OH)2D3 production, the prostate also expresses 1α‑hydroxylase, allowing local synthesis of 1α,25(OH)2D3. Indeed, 25(OH)D3 is as effective as 1α,25(OH)2D3 in inhibiting the growth of normal prostate epithelial cells, presumably because they express 1α‑hydroxylase, allowing local synthesis of 1α,25(OH)2D3. Clinical studies

Several clinical studies have now examined the efficacy of calcitriol (1α,25(OH)2D3) as a therapeutic agent for the treatment of prostate cancer in human patients. Indeed, 1α,25(OH)2D3 can slow the rate of prostate-specific antigen (PSA) rise in prostate cancer patients, providing at least proof of concept that 1α,25(OH)2D3 or its analogs may be clinically effective in prostate cancer therapy  [66] . However, complicating matters, several deltanoids are known to increase PSA  [70,71] . Although 1α,25(OH)2D3 effectively inhibits prostate cancer growth in vitro, the hypercalcemia induced by growth-inhibitory concentrations of 1α,25(OH)2D3 limits its use. Expert Rev. Clin. Pharmacol. 1(6), (2008)

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In a Phase II trial of calcitriol in 13 patients with hormonerefractory metastatic prostate carcinoma, no objective response (>50% reduction in PSA or >30% reduction in measurable tumor mass) was seen and median time to progression was 10.6 weeks. 1,25(OH)2D3 was initiated at an oral dosage of 0.5 µg/day and escalated to 1.5 µg/day. In two patients, PSA decreases of 25 and 45% were observed. Dose escalation was limited by hypercalcemia [72] . In an open-label, nonrandomized pilot trial, increasing doses of calcitriol were administered to seven men with early recurrent prostate cancer following surgery or radiation therapy. The patients had no evidence of metastases and recurrent disease was indicated by rising PSA levels. The doubling time of PSA after calcitriol treatment was compared with the doubling time at baseline. In all seven patients, the rate of PSA increase was decreased by calcitriol. Dose-dependent hypercalciuria limited the 1α,25(OH)2D3 dose that could be administered (1.5–2.5 µg/day; [73]). In another study, after selection of surgical treatment for histologically confirmed prostate adenocarcinoma, patients were randomized to receive 1α,25(OH)2D3 (0.5 µg/kg) or placebo weekly for 4 weeks. Of 39 prostate tumors, 37 were evaluated. VDR expression was reduced in patients treated with 1α,25(OH)2D3 (mean 75% of cells) versus the placebo. Calcitriol treatment did not significantly affect the fraction of cells expressing TGF-β RII, phosphatase and tensin homolog or proliferating cell nuclear antigen [74] . Clinical trials of several vitamin D analogs in prostate cancer patients have been conducted [75] . In a Phase I study, 1α(OH)D2 was administered at 5–15 µg/day to 25 patients with advanced hormone-refractory prostate cancer (HRPC). A common toxicity was hypercalcemia; elevated urinary calcium excretion and serum phosphorus levels were also seen, as was decreased serum PTH. In two patients, there was a partial response, and in five more, the disease was stabilized for at least 6 months [76] . The efficacy of 1α(OH)D2 has been evaluated in a Phase II trial of 26 patients with advanced hormone-refractory prostate cancer. Patients initially received 1α(OH)D2 (12.5 µg/day, orally; the dose was adjusted for hypercalcemia). The primary end point was progression-free survival for at least 6 months. In the intentto-treat population, stable disease was seen for an average of 19.2 weeks. Of the 20 evaluable patients, six (30%) had stable disease for more than 6 months [77] . Paricalcitol (19-nor-1α-25-dihydroxyvitamin D2 ) has been assessed in patients with androgen-independent prostate cancer (AIPC). In total, 18 patients received paricalcitol (three times/week, intravenously, escalating dose of 5–25 µg). PSA level was the primary end point; no patient showed a sustained 50% drop in serum PSA, although elevated serum PTH levels were reduced [78] . While VDR agonists alone do inhibit prostate cancer cell growth in some cases, they may also be useful in combination therapies. That activation of target genes by 1α,25(OH)2D3 involves VDR–RXR heterodimers immediately suggests the combined use of VDR agonists with retinoids. Indeed, the combination of 9-cis retinoic acid and 1α,25(OH)2D3 synergistically inhibited growth of some prostate cancer cells. Combinations with other anticancer drugs have been assessed. www.expert-reviews.com

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Weekly dosed oral 1α,25(OH) 2D3 has been examined in combination with docetaxel in patients with metastatic AIPC. A total of 37 patients received oral 1α,25(OH) 2D3 (0.5 µg/kg) on day 1, followed by docetaxel (36 mg/m 2 ) on day 2, repeated weekly for 6 weeks of an 8-week cycle. The primary end point was the PSA response. Of the 37 patients, 30 (81%) achieved a PSA response; 22 (59%) showed reductions of more than 75%. After 1 year, overall survival was 89%. Neither drug appeared to affect the pharmacokinetics of the other [79,80] . The AIPC Study of Calcitriol Enhancing Taxotere (ASCENT) was a double-blind, placebo-controlled, randomized clinical trial designed to examine whether a high dose of oral 1α,25(OH) 2D3 significantly increased the proportion of patients with a greater than 50% reduction in serum PSA levels in response to docetaxel (taxotere). ASCENT followed a Phase I study showing that weekly dosing allowed substantial dose escalation of 1α,25(OH) 2D3, and Phase II work suggested that adding a weekly high-dose ‘pulse’ of 1α,25(OH)2D3 may enhance the activity of weekly docetaxel in patients with AIPC [81] . The 250 patients were assigned randomly. The primary end point was PSA response (50% reduction confirmed at least 4 weeks later) within 6 months of enrollment. Overall, PSA response rates were 63% (DN-101) and 52% (placebo; p  =  0.07). While survival was not a primary end point, the study suggested that DN-101 treatment was associated with improved survival [82] . In November 2007, Novacea, Inc. announced that the company had ended its Phase III ASCENT‑2 clinical trial of DN-101, which was being investigated for the treatment of patients with AIPC, because of an imbalance in deaths between the two treatment arms, as observed by the data safety monitoring board of the study [202] . No analysis has yet been published. The combination of high-dose pulsed 1α,25(OH) 2D3 and a standard regimen of docetaxel plus estramustine has been examined in patients with metastatic AIPC. Patients received 1α,25(OH)2D3 (60 µg, orally) on day 1, estramustine (280 mg, orally three times/day) on days 1–5 and docetaxel (60 mg/m 2, then 70 mg/m 2 after cycle 1) on day 2 every 21 days for up to 12 cycles. Of 11 evaluable, chemotherapy-naive patients, six (55%) met the PSA response criteria; of 11 patients previously treated with docetaxel, only one (9%) did [83] . The combination of dexamethasone, 1α,25(OH)2D3 and carboplatin has been examined in patients with HRPC because in vitro data using prostate cancer cell lines suggested synergistic effects of these agents. Treatment began with 1 mg/day oral dexamethasone, with 0.5 µg/day 1α,25(OH) 2D3 added at the start of week 5. Carboplatin was added at the beginning of week 7. The median follow-up was 81 weeks. Median overall survival was 98 weeks. Combined dexamethasone, 1α,25(OH) 2D3 and carboplatin produced a PSA response in 13 out of 34 (38%) treated patients with HRPC, with acceptable side effects [84] . High-dose, intermittent 1α,25(OH) 2D3 was evaluated in combination with dexamethasone in 43 men with AIPC, because of evidence that dexamethasone may potentiate the antitumor effects of 1α,25(OH)2D3 and ameliorate hypercalcemia. 809

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Oral 1α,25(OH) 2D3 was administered weekly, on Monday, Tuesday and Wednesday (MTW) at 8 µg for 1 month, at 10 µg every MTW for 1  month, and at 12  µg every MTW thereafter. Dexamethasone (4 mg) was administered each Sunday and MTW weekly. In total, 37 patients received at least 1 month of 1α,25(OH) 2D3 (12  µg/day × 3  days/week). Most patients had bone metastases and increasing PSA values. Eight patients (19%) experienced partial responses (PSA decline of ≥50% for ≥28 days). However, the response rate (19%) was not significantly higher than expected for dexamethasone alone [85] . Another limiting factor in the use of calcitriol is its inactivation by the P450 enzyme 24‑hydroxylase. Calcitriol treatment induces the expression of 24-hydroxylase in some prostate cancer cells upon 1α,25(OH) 2D3 treatment. Thus, combination therapy with a 24-hydroxylase inhibitor, such as ketoconazole, may also be useful. Expert commentary

The idea of a deltanoid drug is not a problem; alfacalcidol (1α-hydroxyvitamin D3) was approved more than 25 years ago, first for treating vitamin D deficiency and later for osteoporosis. Several other vitamin D-related compounds are already approved and in clinical use in various jurisdictions: 1α,25(OH) 2D3 for renal osteodystrophy and osteoporosis, 1α(OH)D3 for renal osteodystrophy and osteoporosis, 1α,24(OH) 2 -24cyclopropyl-D3 and 1α,24(OH) 2D3 for psoriasis and 19-nor1α,25(OH) 2D2 for renal osteodystrophy (see [47,49]). However, the various ‘noncalcemic’ effects of deltanoids, especially the anti-tumor effects, have long suggested their use in other applications [86–90] . Calcitriol (1α,25(OH) 2D3) itself has antiproliferative effects on many tumor cell types in vitro and in vivo. However, the clinical use of calcitriol in cancer prevention or therapy is limited because of the hypercalcemia it induces when administered at the supraphysiological doses necessary to affect cancers. Indeed, in some of the clinical trials reviewed here, and others, dose escalation was limited by hypercalcemia [72,73] . It is clear that we need less or noncalcemic and more potent analogs; many have been developed [15] and some have been examined clinically in connection with prostate cancer [75–79] .

Prostate cancer is more common in northern geographic regions; mortality decreases with increased exposure to sunlight. As UV light is necessary for vitamin D synthesis in the skin, it is dogma that vitamin D is in some way involved [50,91] . Furthermore, several vitamin D-related genetic loci have been linked to prostate cancer risk, including polymorphisms in the VDR gene [39,40] , although not all reports are consistent. Despite recent studies questioning the relationship between decreased production of vitamin D and prostate cancer risk [52–54] and earlier studies that were not always wholly consistent, it seems unlikely that there is no connection and more likely that we simply do not understand it completely. Indeed, while the mechanisms are not fully understood, 1α,25(OH)2D3 reduces cell growth in prostate cancer cells [58,59] . Five-year view

While the idea of using deltanoids to treat cancers is not new, its practical, clinical testing has only begun relatively recently. The first reported clinical trial of a deltanoid (calcitriol) for prostate cancer was that of Osborn et al. in 1995 [70] . It is ­perhaps not surprising that we do not have an approved drug yet. The field is very active, there are now more than 3000 vitamin D analogs, and much clinical work being done [203] , on the back of the basic science briefly reviewed here. 1α,25(OH) 2D3 can slow the rate of PSA rise in prostate cancer patients, providing at least proof of concept that 1α,25(OH)2D3 or its analogs, may be clinically effective in prostate cancer therapy [66] , although some deltanoids are also known to increase PSA [70,71] . Despite the volume of research reviewed here, it is not likely that any deltanoid will be approved for the treatment or prevention of prostate cancer within 5 years, but by 2013 there may well be several good candidates in advanced stages of development. Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • ‘Vitamin D’ is a generic term for a family of secosteroids that bind to the vitamin D receptor. • Calcitriol, the active form of vitamin D, has antiproliferative effects on many tumor cells. • Clinical use of calcitriol in cancer prevention or therapy is limited because it induces hypercalcemia at the supraphysiological doses necessary. • More potent/ less calcemic vitamin D analogs (deltanoids) have been researched extensively; more than 3000 have now been described. • Prostate cancer is more common in northern geographic regions; mortality decreases with exposure to sunlight. As UV light is necessary for vitamin D synthesis in the skin, it is dogma that vitamin D is involved. Furthermore, several vitamin D-related genetic loci have been linked to prostate cancer risk. • While the idea of using deltanoids to treat cancers is not new, its practical, clinical testing has only begun relatively recently. The first reported clinical trial of a deltanoid (calcitriol) for a cancer indication was in 1995. • Various deltanoids have been and are being assessed for use in treating or preventing prostate cancer.

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Marillion Pharmaceuticals, Inc. www.marillionpharma.com

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Novacea www.novacea.com

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Affiliation •

William M Brown VaxDesign Corp., 12612 Challenger Parkway, Suite 365, Orlando, FL 32826, USA Tel.: +1 407 249 3650 Fax: +1 407 249 3649 [email protected]

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