Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcipotriol (MC903) is a side chain analog of the vitamin D hormone calcitriol, containing a 22-23 double bond, a 24(S)-hydroxyl function, and carbons 25, 26, and 27 incorporated into a cyclopropane ring which has been developed for treating psoriasis. The in vitro metabolism of calcipotriol was studied in two keratinocyte cell models, HPK1A and HPK1A-ras. Calcipotriol was initially converted into the 24-ketone (MC1046) and its 22,23-hydrogenated derivative (MC1080), metabolites observed in osteosarcoma, kidney, and hepatoma cell lines. We also observed the formation of further metabolites, identified as the two 23-hydroxylated derivatives of MC1080 (MC1439 and MC1441), the two 23,24-dihydroxylated compounds (MC1575 and 1577), and the side chain-cleaved compounds, tetranor-1,23-(OH)2D3 and calcitroic acid, the end products of catabolism of calcitriol. These findings suggest that calcitriol and calcipotriol may share catabolic enzymes. The biological activity of each of the principal metabolites of calcipotriol, assessed using a growth hormone reporter gene transcriptional activation system and a vitamin D receptor assay, was found to be lower than that of calcipotriol. If the extensive in vitro metabolism of calcipotriol is also found in normal and psoriatic keratinocytes in vivo, then this may explain the lack of systemic calcemic activity of topically applied drug.
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PMID:In vitro metabolism of the anti-psoriatic vitamin D analog, calcipotriol, in two cultured human keratinocyte models. 810 49

Dihydrotachysterol (DHT), a reduced vitamin D analog in which the A-ring has been rotated through 180 degrees is a biologically active molecule which can be used to study the structural requirements for the calcemic and cell differentiating properties of the vitamin D hormone, 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25-(OH)2D3), as well as to investigate the specificity of the enzyme systems that catalyze the formation of this hormone. In this study we showed that dihydrotachysterol was metabolized in vivo into a significant polar metabolite observed on straight-phase high performance liquid chromatography (HPLC) which subsequently split into two peaks on reverse-phase HPLC. These two metabolites were identified by HPLC and gas chromatography-mass spectrometry techniques as 1 alpha,25-(OH)2DHT and 1 beta,25-(OH)2DHT. This pair of metabolites was formed from either DHT2 or DHT3. Standard 1 alpha,25-(OH)2DHTs were generated in vitro from chemically synthesized 1-hydroxydihydrotachysterol precursors using a liver hepatoma cell system. Both 1 alpha,25-(OH)2D2 and 1 alpha,25-(OH)2DHT3 showed a binding affinity to the mammalian vitamin D receptor only 50-100 less than 1 alpha,25-(OH)2D3 whereas 1 beta,25-(OH)2DHTs showed poor binding. On the other hand 1 beta,25-(OH)2DHT3 bound to the rat vitamin D transport protein (DBP) with stronger affinity than did 1 alpha,25-(OH)2DHT3. When tested in a COS-1 cell transfection assay system using a rat osteocalcin vitamin D responsive element coupled to a growth hormone reporter gene, 1 alpha,25-(OH)2DHT3 showed a biological activity only 10 times lower than 1 alpha,25-(OH)2D3. It is therefore suggested that 1 alpha,25-(OH)2DHT probably represents the metabolite of DHT responsible for some of its in vivo effects although we cannot rule out in vivo effects of other metabolites identified. Our studies suggest that 1 alpha,25-dihydroxylated DHTs represent a promising novel group of vitamin D analogs worthy of study for cell differentiation as well as calcemic properties.
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PMID:In vivo metabolism of the vitamin D analog, dihydrotachysterol. Evidence for formation of 1 alpha,25- and 1 beta,25-dihydroxy-dihydrotachysterol metabolites and studies of their biological activity. 838 Jan 56

Although 1,25-dihydroxyvitamin D3 has been shown to promote the differentiation of cancer cells and cell lines in vitro, its protective effect against a chemical insult known to induce neoplastic growth in vivo has not been evaluated. The aim of this study was to investigate, in vivo, the influence of the vitamin D status on the early response to an insult known to induce morphological and functional changes leading to hepatocarcinogenesis. The influence of vitamin D status on the susceptibility of rat liver to carcinogenesis was studied after the administration of diethylnitrosamine and 2-acetylaminofluorene, in association with a partial hepatectomy (Solt-Farber protocol), to normal or vitamin D-depleted rats. Preneoplastic foci (gamma-glutamyltranspeptidase-positive and glucose-6-phosphatase-negative) appeared in both groups of animals as early as 1 week after 2-acetylaminofluorene withdrawal and continued to increase during the subsequent weeks. Livers from vitamin D-depleted rats exhibited a significant increase in the number of foci over that observed in normal rats at weeks 1 and 5 after 2-acetylaminofluorene withdrawal. However, the main effect of vitamin D depletion was on focus size, which was found to be significantly greater in vitamin D-depleted rat livers at weeks 2 to 6; focus area (volume fraction) was also found to be consistently larger in livers of vitamin D-depleted rats than in those of normal rats. Labeling of oval cells, a cell compartment possibly associated with the repopulation of the liver parenchyma, was significantly reduced by vitamin D depletion. Control rat livers of both groups showed normal liver histology, and no foci, nodules or oval cells were detected in either group. The present data suggest that vitamin D depletion leads to increased in vivo susceptibility to chemicals known to induce hepatocarcinogenesis. Long-term studies must be conducted to evaluate the effect of vitamin D status on the evolution of preneoplastic foci into frank hepatocellular carcinoma.
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PMID:Influence of the vitamin D status on the early hepatic response to carcinogen exposure in rats. 910 32

It is well established that the metabolically active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) plays a key role in the establishment and maintenance of the calcium metabolism in the body. In addition to this classic effect of 1alpha,25(OH)2D3, substantial evidence has emerged demonstrating that 1alpha,25(OH)2D3 is able to regulate cell growth and differentiation in a number of different cell types, including cancer cells. However, the clinical usefulness of 1alpha,25(OH)2D3 is limited by its tendency to cause hypercalcaemia. Much effort has therefore been directed to identifying new vitamin D analogues with potent cell regulatory effects, but with weaker effects on the calcium metabolism than those of 1alpha,25(OH)2D3. One of these new synthetic analogues is Seocalcitol (EB 1089). Despite being 50-200 times more potent than 1alpha,25(OH)2D3 with respect to regulation of cell growth and differentiation in vitro as well as in vivo, EB 1089 displays a reduced calcaemic activity in vivo compared to that of 1alpha, 25(OH)2D3. These characteristics make EB 1089 a potentially useful compound for the treatment of cancer. Recent clinical evaluation of EB 1089 has focused mainly on establishing a maximum tolerated dose in cancer patients. Early results confirm that the low calcaemic activity observed in animals can be reproduced in the clinic. Furthermore, EB 1089 has been shown to induce regression of tumours, especially in hepatocellular carcinoma where complete remission has been obtained. In conclusion, the development of EB 1089 as an anti-cancer drug holds promise. However, its final evaluation must await the completion of ongoing controlled clinical trials.
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PMID:Seocalcitol (EB 1089): a vitamin D analogue of anti-cancer potential. Background, design, synthesis, pre-clinical and clinical evaluation. 1082 9

EB1089, a vitamin D analogue without the acute side effects of 1alpha,25(OH)2D3, the physiologically active form of vitamin D, exerts strong antiproliferative activities in malignant cells, including hepatoma cells in vitro, and in experimental hepatomas in animals as well. It also induces cell cycle arrest and apoptosis in premalignant conditions, suggesting its application in chemopreventive trials. We examined the possible chemopreventive effect of EB1089 on hepatocellular carcinoma (HCC) incidence in C3H/Sy virgin female mice, a strain developing an incidence of 58% spontaneous HCCs. A total of 95 mice, 16 weeks old, were used. EB1089 injections of 0.5 microg/kg of body weight were given IP every other day for 2, 4, and 6 months to 51 mice (18, 19, and 14 mice, respectively). The remaining 44 mice were divided into three control groups, accordingly, and injected with the vehicle solution only. The mice were sacrificed when they appeared moribund because of their disease. The rest were sacrificed at the age of at least 80 weeks. A full autopsy was performed and liver tissue was processed for histological examination. The results obtained show that 3.9% of treated mice developed HCC, exclusively in the 2-month group, compared with 36.4% of HCCs in the control group. Our results suggest that the chemopreventive administration of EB1089 causes a very statistically significant (P < 0.0001) inhibitory effect on HCC incidence of C3H/Sy mice. This effect could be useful in a potential application on the chemopreventive control of HCCs.
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PMID:Significant experimental decrease of the hepatocellular carcinoma incidence in C3H/Sy mice after long-term administration of EB1089, a vitamin D analogue. 1268 77

The liver is generally considered negative for the vitamin D nuclear receptor (VDR(n)), even though several studies have shown significant effects of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) on liver cell physiology. The low abundance of VDR(n) in the liver led us to propose that hepatocytes (the largest hepatic cell population) were most likely negative for the receptor, whereas the small hepatic sinusoidal and ductular cell populations that contain cell types known to express VDR(n) in other tissues should express the receptor. Using freshly isolated cells from normal livers as well as biliary and epithelial hepatic cell lines, our data show that the human, rat, and mouse hepatocytes express very low VDR(n) messenger RNA (mRNA) and protein levels. In contrast, sinusoidal endothelial, Kupffer, and stellate cells of normal rat livers as well as the mouse biliary cell line BDC and rat hepatic neonatal epithelial SD6 cells clearly expressed both VDR(n) mRNA and protein. In addition, specimens of human hepatocarcinoma as well as intrahepatic colon adenocarcinoma metastases were also found to express the VDR(n) gene transcript. Kupffer, stellate, and endothelial cells responded to 1,25(OH)(2)D(3) by a significant increase in the CYP24, indicating that the VDR(n) is fully functional in these cells. In conclusion, selective hepatic cell populations are targets for the vitamin D endocrine/paracrine/intracrine system.
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PMID:The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. 1271 84

Hepatocellular carcinoma (HCC) is a common malignant tumour, which has a poor prognosis. Surgical resection can be curative but most patients are inoperable and most chemotherapy agents have minimal activity in this disease. Seocalcitol, a vitamin D analogue, induces differentiation and inhibits growth in cancer cell lines and in vivo. The vitamin D receptor is expressed in hepatocytes and more abundantly in HCC cells. In total, 56 patients with inoperable advanced HCC were included in an uncontrolled study of oral Seocalcitol treatment for up to 1 year (with possible extension for responders). The dose was titrated according to serum calcium levels. The treatment effect was evaluated by regular CT scans. Out of 33 patients evaluable for tumour response, two had complete response (CR), 12 stable disease and 19 progressive disease. The CRs appeared after 6 and 24 months of treatment, and lasted for 29 and at least 36 months (patient still in remission when data censored). Seocalcitol was well tolerated; the most frequent toxicity was hypercalcaemia and related symptoms. Most patients tolerated a daily dose of 10 micro g of Seocalcitol. This is the first study showing activity, by reduction in tumour dimensions, of a differentiating agent in patients with an advanced bulky, solid tumour. Seocalcitol may have an effect in the treatment of HCC, especially in early disease when a prolonged treatment can be instituted. The survival benefit with or without tumour response should be determined in controlled studies.
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PMID:A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma. 1286 12

Peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been implicated to play an important role in lipid and glucose homeostasis. PPARalpha potentiates fatty acid catabolism in the liver and is activated by the lipid-lowering fibrates, whereas PPARgamma is essential for adipocyte differentiation. Here we report that nuclear vitamin D(3) receptor (VDR) represses the transcriptional activity of PPARalpha but not PPARgamma in a 1,25(OH)(2)D(3)-dependent manner. The analysis using chimeric receptors revealed that ligand binding domain of PPARalpha and VDR was involved in the molecular basis of this functional interaction and that the DNA binding domain of VDR was not required for the suppression, suggesting a novel mechanism that might involve protein-protein interactions rather than a direct DNA binding. Furthermore, the treatment of rat hepatoma H4IIE cells with 1,25(OH)(2)D(3) diminishes the induction of AOX mRNA by PPARalpha ligands, Wy14,643. VDR signaling might be considered as a factor regulating lipid metabolism via PPARalpha pathway. We report here the novel action of VDR in controlling gene expression through PPARalpha signaling.
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PMID:Inhibition of peroxisome proliferator-activated receptor alpha signaling by vitamin D receptor. 1463 67

The results of systemic treatments for hepatocellular carcinoma are currently disappointing. In patients with advanced disease, none of the tested treatments (particularly systemic chemotherapy or hormonal treatment, such as tamoxifen) demonstrated an unequivocal benefit in terms of survival, and the trials including the largest numbers of patients have constantly been negative. After successful treatment of a first tumour, the most promising adjuvant strategy seems to be the use of interferon to treat patients who have hepatitis C infection. Nevertheless, only a few small randomized controlled trials have been performed and this result should be confirmed. Methodological improvement of clinical trials is needed, as major bias has often hampered the interpretation of the results. As recommended at a recent international conference in Barcelona, the most reliable methods for assessing the clinical outcome of a treatment in hepatocellular carcinoma are large randomized trials that each include a control arm of untreated patients, with overall survival as the primary endpoint, and an intention-to-treat analysis. New therapeutic strategies should be developed. Drugs such as vitamin D or vitamin A derivatives and inhibitors of COX-2 or angiogenesis could have a favourable influence on tumour growth. Some of these drugs are currently being tested in preliminary studies or even large randomized trials.
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PMID:Systemic treatment of hepatocellular carcinoma. 1519 90

1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the active metabolite of vitamin D(3), is known for the maintenance of mineral homeostasis and normal skeletal architecture. However, apart from these traditional calcium-related actions, 1,25-(OH)(2)D(3) and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities. These actions of 1,25-(OH)(2)D(3) are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25-(OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, actinic keratosis, seborrheic dermatitis, photoaging), osteoporosis (postmenopausal and steroid-induced osteoporosis), cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), secondary hyperparathyroidism, and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation). As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, encouraging results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma. This review deals with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.
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PMID:Noncalcemic actions of vitamin D receptor ligands. 1579 98


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