A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial of Radiopaque Islatravir-Eluting Subdermal Implants for Pre-exposure Prophylaxis Against HIV-1 Infection.

BACKGROUND: Islatravir (MK-8591) is a deoxyadenosine analog in development for the treatment and prevention of HIV-1 infection. An islatravir-eluting implant could provide an additional option for pre-exposure prophylaxis (PrEP). SETTING: Previous data support a threshold islatravir triphosphate concentration for PrEP of 0.05 pmol/10 6 cells in peripheral blood mononuclear cells. Prototype islatravir-eluting implants were previously studied to establish general tolerability and pharmacokinetics (PKs) of islatravir relative to the threshold level. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, a next-generation radiopaque islatravir-eluting implant (48 mg, 52 mg, or 56 mg) or placebo implant was placed for a duration of 12 weeks in participants at low risk of HIV infection. Safety and tolerability, as well as PK for islatravir parent and islatravir triphosphate from plasma and peripheral blood mononuclear cells, were assessed throughout placement and 8 weeks after removal. RESULTS: In total, 36 participants (8 active and 4 placebo per dose arm) were enrolled and completed this study. Implants were generally well tolerated, with no discontinuations due to an adverse event, and no clear dose-dependence in implant-related adverse events. No clinically meaningful relationships were observed for changes in laboratory values, vital signs, or electrocardiogram assessments. Mean islatravir triphosphate levels at day 85 (0.101-0.561 pmol/10 6  cells) were above the PK threshold for all dose levels. CONCLUSION: Islatravir administered using a subdermal implant has the potential to be an effective and well-tolerated method for administering PrEP to individuals at risk of acquiring HIV-1.

Impact on Experimental Colitis of Vitamin D Receptor Deletion in Intestinal Epithelial or Myeloid Cells.

Inflammatory bowel diseases are gastrointestinal diseases that include Crohn disease and ulcerative colitis. The chronic inflammation is thought to result from an excessive inflammatory response to environmental factors such as luminal bacteria in genetically predisposed individuals. Studies have revealed that mice with impaired vitamin D signaling are more susceptible to experimental colitis. To better understand the contribution of vitamin D signaling in different cells of the gut to this disease, we investigated the effects of intestinal-specific or myeloid vitamin D receptor deletion. Our study addressed the importance of vitamin D receptor expression in intestinal epithelial cells using intestine-specific vitamin D receptor null mice and the contribution of vitamin D receptor expression in macrophages and granulocytes using myeloid-specific vitamin D receptor null mice in a dextran sodium sulfate model for experimental colitis. Loss of intestinal vitamin D receptor expression had no substantial effect on the clinical parameters of colitis and did not manifestly change mucosal cytokine expression. Inactivation of the vitamin D receptor in macrophages and granulocytes marginally affected colitis-associated symptoms but resulted in increased proinflammatory cytokine and increased ß-defensin-1 expression in the colon descendens of mice with colitis. Intestinal deletion of the vitamin D receptor did not aggravate symptoms of chemically induced colitis. Loss of the vitamin D receptor in macrophages and granulocytes mildly affected colitis-associated symptoms but greatly increased proinflammatory cytokine expression in the inflamed colon, suggesting a prominent role for innate immune cell vitamin D signaling in controlling gut inflammation.

Remodeling of phospholipid composition in colon cancer cells by 1α,25(OH)2D3 and its analogs.

Alterations in cellular phospholipid composition are emerging as important traits in the development and progression of cancer. In this study we investigated the effects of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] and two of its more antiproliferative analogs on the cellular phospholipid composition of various human colon cancer cell lines. Treatment of Caco-2, SW1417 and SW480-ADH cells with 3×10(-8)M 1,25(OH)2D3, CD578 or WU515 evoked significant changes in phospholipid composition, with the analogs being more potent than the natural compound. Observed effects included changes in acyl chain elongation and acyl chain saturation, and were substantially different in the various cell lines. Consistent with the alterations in phospholipid profiles, 1,25(OH)2D3 and its analogs provoked changes in several lipogenic enzymes such as fatty acid synthase (FASN), acetyl-CoA carboxylase (ACACA) and fatty acid elongases (ELOVLs). These effects were also cell line dependent. Taken together these findings indicate that 1,25(OH)2D3 and its analogs have divergent effects on the phospholipid composition of different colon cancer cell lines and warrant further investigation of the effect of 1,25(OH)2D3 and its analogs on lipid metabolism in various subtypes of primary human colon cancers.

The future of vitamin D analogs.

The active form of vitamin D3, 1,25-dihydroxyvitamin D3, is a major regulator of bone and calcium homeostasis. In addition, this hormone also inhibits the proliferation and stimulates the differentiation of normal as well as malignant cells. Supraphysiological doses of 1,25-dihydroxyvitamin D3 are required to reduce cancer cell proliferation. However, these doses will lead in vivo to calcemic side effects such as hypercalcemia and hypercalciuria. During the last 25 years, many structural analogs of 1,25-dihydroxyvitamin D3 have been synthesized by the introduction of chemical modifications in the A-ring, central CD-ring region or side chain of 1,25-dihydroxyvitamin D3 in the hope to find molecules with a clear dissociation between the beneficial antiproliferative effects and adverse calcemic side effects. One example of such an analog with a good dissociation ratio is calcipotriol (Daivonex®), which is clinically used to treat the hyperproliferative skin disease psoriasis. Other vitamin D analogs were clinically approved for the treatment of osteoporosis or secondary hyperparathyroidism. No vitamin D analog is currently used in the clinic for the treatment of cancer although several analogs have been shown to be potent drugs in animal models of cancer. Transcriptomics studies as well as in vitro cell biological experiments unraveled basic mechanisms involved in the antineoplastic effects of vitamin D and its analogs. 1,25-dihydroxyvitamin D3 and analogs act in a cell type- and tissue-specific manner. Moreover, a blockade in the transition of the G0/1 toward S phase of the cell cycle, induction of apoptosis, inhibition of migration and invasion of tumor cells together with effects on angiogenesis and inflammation have been implicated in the pleiotropic effects of 1,25-dihydroxyvitamin D3 and its analogs. In this review we will give an overview of the action of vitamin D analogs in tumor cells and look forward how these compounds could be introduced in the clinical practice.

Antineoplastic effects of 1,25(OH)2D3 and its analogs in breast, prostate and colorectal cancer.

The active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is mostly known for its importance in the maintenance of calcium and phosphate homeostasis. However, next to its classical effects on bone, kidney and intestine, 1,25(OH)2D3 also exerts antineoplastic effects on various types of cancer. The use of 1,25(OH)2D3 itself as treatment against neoplasia is hampered by its calcemic side effects. Therefore, 1,25(OH)2D3-derived analogs were developed that are characterized by lower calcemic side effects and stronger antineoplastic effects. This review mainly focuses on the role of 1,25(OH)2D3 in breast, prostate and colorectal cancer (CRC) and the underlying signaling pathways. 1,25(OH)2D3 and its analogs inhibit proliferation, angiogenesis, migration/invasion and induce differentiation and apoptosis in malignant cell lines. Moreover, prostaglandin synthesis and Wnt/b-catenin signaling are also influenced by 1,25(OH)2D3 and its analogs. Human studies indicate an inverse association between serum 25(OH)D3 values and the incidence of certain cancer types. Given the literature, it appears that the epidemiological link between vitamin D3 and cancer is the strongest for CRC, however more intervention studies and randomized placebo-controlled trials are needed to unravel the beneficial dose of 1,25(OH)2D3 and its analogs to induce antineoplastic effects.

The vitamin D analog TX527 ameliorates disease symptoms in a chemically induced model of inflammatory bowel disease.

The vitamin D system plays a critical role in inflammatory bowel disease as evidenced by the finding that both vitamin D deficient mice and vitamin D receptor knockout mice are extremely sensitive to dextran sodium sulfate (DSS)-induced colitis. Moreover, the active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is an important immunomodulator that ameliorates the pathogenesis of inflammatory bowel disease. However, therapeutic application of 1,25(OH)2D3 is hampered by its calcemic activity. Previous work illustrated that the analog 1α,25(OH)2-19-nor-14,20-bisepi-23-yne-vitamin D3 (TX527) has potent antiproliferative effects with limited calcemic activity. In the present study we demonstrated that TX527 ameliorated disease symptoms in a DSS-induced model of inflammatory bowel disease. TX527 significantly attenuated disease scores, by suppressing bleeding and diarrhea. Colon length was significantly elevated at the end of the experiment. Histological examination indicated that TX527 diminished mucosal damage and crypt loss and suppressed the infiltration of immune cells in DSS-induced colitis mice. Furthermore, transcript levels of inflammatory cytokines such as IL-1, IL-6, IFN-γ and TNF-α were significantly down-regulated in colonic mucosa of mice with colitis. Moreover, transcript levels of the gastrointestinal glutathione peroxidase 2, which acts as a radical scavenger, were significantly down-regulated after TX527 treatment in DSS-colitis mice. These results indicate that TX527 may have a therapeutic value in the setting of inflammatory bowel disease. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

The odd-skipped related genes Osr1 and Osr2 are induced by 1,25-dihydroxyvitamin D3.

The odd-skipped related genes Osr1 and Osr2 encode closely related zinc finger containing transcription factors that are expressed in developing limb. However, their role in osteoblast proliferation and differentiation remains controversial and little is known about their regulation. In this study we showed that both Osr1 and Osr2 were expressed in several murine and human osteoblast cell lines as well as in primary osteoblast cultures. Moreover, their transcript levels were regulated by a number of osteogenic stimuli in murine pre-osteoblast MC3T3-E1 cells. The most robust regulation of Osr1 and Osr2 mRNA levels was observed after stimulation with 1,25-dihydroxyvitamin D3. 1,25-Dihydroxyvitamin D3 induced transcript levels of Osr1 and Osr2 and this up-regulation was confirmed in other osteoblast cultures, both from murine and human origin. This article is part of a Special Issue entitled 'Vitamin D Workshop'.