Studies on the targeted delivery of the antifibrogenic compound mycophenolic acid to the hepatic stellate cell

Greupink, Rick; Bakker, Hester I.; Reker‐Smit, Catharina; Loenen-Weemaes, Anne-miek van; Kok, Robbert-Jan; Meijer, Dirk K. F.; Beljaars, Leonie; Poelstra, Klaas

doi:10.1016/j.jhep.2005.04.014

Cited by 37 publications

(31 citation statements)

References 32 publications

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“…This is in lower concentrations than a number of other typical inhibitors of HSC proliferation in vitro, such as mycophenolic acid, statins, the selective Na ϩ /H ϩ exchange inhibitor cariporide, and the semisynthetic analog of fumagillin TNP-470 (Wang et al, 2000;Di Sario et al, 2003;Rombouts et al, 2003;Greupink et al, 2005). The higher potency of DOX may be related to the fact that multiple intracellular mechanisms are implicated in its antiproliferative effect, in contrast to these other drugs (Gewirtz, 1999).…”

Section: Discussionmentioning

confidence: 97%

“…Cells were incubated with various concentrations of chlorambucil (Sigma), doxorubicin (Pfizer, Capelle aan den IJssel, The Netherlands), or cisplatin (Sigma) in the presence of 10% FCS, 50 ng/ml platelet-derived growth factor-BB and 10 M 5-bromo-2Ј-deoxyuridine (BrdU; Sigma) for 24 h to allow detection of proliferating cells by immunohistochemistry. BrdU incorporation was subsequently quantified by cell counting as described previously (Greupink et al, 2005).…”

Section: Effect Of Drugs On Hsc Proliferation In Vitromentioning

confidence: 99%

“…General toxicity was monitored by analysis of body weight (BW), whereas intrahepatic toxicity of DOX toward liver cells was examined by analysis of serum AST, ALT, AP, and ␥-GT levels. Inflammatory cell influx in the livers was assessed by diaminobenzidine (DAB) staining as described previously, as well as by evaluation of hematoxylin/eosin-stained liver sections (Poelstra et al, 1990;Greupink et al, 2005). To evaluate the effect of DOX on the bile duct epithelial cell proliferation, staining with a monoclonal antibody raised against cytokeratin 7 (Santa Cruz Biotechnology, Santa Cruz, CA) was performed, according to standard indirect immunohistochemical techniques.…”

Section: Antifibrotic Potential Of Doxorubicin In Bile Duct-ligated Ratsmentioning

confidence: 99%

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The Antiproliferative Drug Doxorubicin Inhibits Liver Fibrosis in Bile Duct-Ligated Rats and Can Be Selectively Delivered to Hepatic Stellate Cells in Vivo

Greupink¹,

Bakker²,

Bouma³

et al. 2006

J Pharmacol Exp Ther

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Hepatic stellate cell (HSC) proliferation is a key event in liver fibrosis; therefore, pharmacological intervention with antiproliferative drugs may result in antifibrotic effects. In this article, the antiproliferative effect of three cytostatic drugs was tested in cultured rat HSC. Subsequently, the antifibrotic potential of the most potent drug was evaluated in vivo. As a strategy to overcome drug-related toxicity, we additionally studied how to deliver this drug specifically to HSC by conjugating it to the HSC-selective drug carrier mannose-6-phosphate-modified human serum albumin (M6PHSA). We investigated the effect of cisplatin, chlorambucil, and doxorubicin (DOX) on 5-bromo-

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Section: Discussionmentioning

confidence: 97%

Section: Effect Of Drugs On Hsc Proliferation In Vitromentioning

confidence: 99%

Section: Antifibrotic Potential Of Doxorubicin In Bile Duct-ligated Ratsmentioning

confidence: 99%

See 1 more Smart Citation

The Antiproliferative Drug Doxorubicin Inhibits Liver Fibrosis in Bile Duct-Ligated Rats and Can Be Selectively Delivered to Hepatic Stellate Cells in Vivo

Greupink¹,

Bakker²,

Bouma³

et al. 2006

J Pharmacol Exp Ther

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“…63 A few exceptions, such as the PDGF␤ receptor or the collagen VI receptor, are mainly expressed on activated HSC and are virtually absent from normal liver. 13,64 Thus, the immunosuppressive and antiproliferative drug mycophenolate mofetil 65 or apoptosis-inducing gliotoxin 66 was coupled to mannose6-phosphate (insulin-like growth factor type II) receptor binding constructs that after intravenous injection mainly targeted HSC and sinusoidal endothelial cells. Coupling proapoptotic gliotoxin to a single-chain antibody against synaptophysin, which is expressed in activated HSC-induced apoptosis of activated HSC, and thus reduced fibrosis in the CCl 4 model.…”

Section: Antifibrotic Drug Developmentmentioning

confidence: 99%

Targeting liver fibrosis: Strategies for development and validation of antifibrotic therapies

2009

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We have made striking progress in our understanding of the biochemistry and cell biology that underlies liver fibrosis and cirrhosis, including the development of strategies and agents to prevent and reverse fibrosis. However, translation of this knowledge into clinical practice has been hampered by (1) the limitation of many in vitro and in vivo models to confirm mechanisms and to test antifibrotic agents, and (2) the lack of sensitive methodologies to quantify the degree of liver fibrosis and the dynamics of fibrosis progression or reversal in patients. Furthermore, whereas cirrhosis and subsequent decompensation are accepted hard clinical endpoints, fibrosis and fibrosis progression alone are merely plausible surrogates for future clinical deterioration. In this review we focus on an optimized strategy for preclinical antifibrotic drug development and highlight the current and future techniques that permit noninvasive assessment and quantification of liver fibrosis and fibrogenesis. The availability of such noninvasive methodologies will serve as the pacemaker for the clinical development and validation of potent antifibrotic agents. (HEPATOLOGY 2009;50:1294-1306

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“…In this case, experiments employing drug targeting protocols could be helpful. 17 Another possibility is that the effects of TZDs are counterbalanced by other profibrogenic pathways that become upregulated. It has been demonstrated that HSC isolated from fibrotic animals treated with TZDs have a greater DNA binding activity of PPARc to its cognate responsive elements.…”

mentioning

confidence: 99%

Thiazolidinediones and hepatic fibrosis: don't wait too long

Marra

2006

Gut

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Studies on the targeted delivery of the antifibrogenic compound mycophenolic acid to the hepatic stellate cell

Cited by 37 publications

References 32 publications

The Antiproliferative Drug Doxorubicin Inhibits Liver Fibrosis in Bile Duct-Ligated Rats and Can Be Selectively Delivered to Hepatic Stellate Cells in Vivo

The Antiproliferative Drug Doxorubicin Inhibits Liver Fibrosis in Bile Duct-Ligated Rats and Can Be Selectively Delivered to Hepatic Stellate Cells in Vivo

Targeting liver fibrosis: Strategies for development and validation of antifibrotic therapies

Thiazolidinediones and hepatic fibrosis: don't wait too long

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