Antiproliferative profile of sirolimus and mycophenolate mofetil: impact of the SI/MPL ratio

Voisard, Rainer; Geçgüner, Levent; Baur, Regine; Herter, Tina; Hombach, Vinzenz

doi:10.1016/j.ijcard.2004.05.039

Cited by 12 publications

(15 citation statements)

References 21 publications

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“…On subsequent days, the adherent cells were harvested and resuspended in PBS. The cell number was estimated in a cell counter CASY TTC (Schaerfe System, Reutlingen, Germany) using two different dilutions (30). Cell numbers per 60 mm dish and SD were calculated from three independent experiments.…”

Section: Methodsmentioning

confidence: 99%

Collagen Type I Induces Disruption of E-Cadherin–Mediated Cell-Cell Contacts and Promotes Proliferation of Pancreatic Carcinoma Cells

Köenig

Mueller²,

Hasel³

et al. 2006

Cancer Research

240

183

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Pancreatic cancer is characterized by its invasiveness, early metastasis, and the production of large amounts of extracellular matrix (ECM). We analyzed the influence of type I collagen and fibronectin on the regulation of cellular adhesion in pancreatic cancer cell lines to characterize the role of ECM proteins in the development of pancreatic cancer. We show that collagen type I is able to initiate a disruption of the E-cadherin adhesion complex in pancreatic carcinoma cells. This is due to the increased tyrosine phosphorylation of the complex protein B-catenin, which correlates with collagen type I-dependent activation of the focal adhesion kinase and its association with the E-cadherin complex. The activation and recruitment of focal adhesion kinase to the E-cadherin complex depends on the interaction of type I collagen with B1-containing integrins and an integrin-mediated activation of the cellular kinase Src. The disassembly of the E-cadherin adhesion complex correlates with the nuclear translocation of B-catenin, which leads to an increasing expression of the B-catenin-Lef/Tcf target genes, cyclin D1 and c-myc. In addition to that, cells grown on collagen type I show enhanced cell proliferation. We show that components of the ECM, produced by the tumor, contribute to invasiveness and metastasis by reducing E-cadherin-mediated cell-cell adhesion and enhance proliferation in pancreatic tumor cells.

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Section: Methodsmentioning

confidence: 99%

Collagen Type I Induces Disruption of E-Cadherin–Mediated Cell-Cell Contacts and Promotes Proliferation of Pancreatic Carcinoma Cells

Köenig

Mueller²,

Hasel³

et al. 2006

Cancer Research

240

183

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show abstract

“…To better characterize the clinical relevance, we calculated the simple SI/MPL ratio between the concentration with a significant inhibition in vitro (SI) and the maximum systemic plasma level (MPL) in vivo. Ratios below 1 indicate clinical relevance of the data [10]. The SI/MPL ratios from our study are all smaller than 1 (the MPL for MPA was 34 ug/ml [10]; the ratios were 0.0094, 0,094 and 0.94 when the concentrations of MPA were 1, 10 and 100 μM, respectively), indicating that the antiproliferative effects can, at least from a theoretical point of view, be achieved in a clinical setting in vivo .…”

Section: Discussionmentioning

confidence: 99%

Effects of Mycophenolic Acid on the Proliferation and Endothelin-1 and Interleukin-6 Secretion of Rat Pulmonary Microvascular Endothelial Cells

Zheng²

2013

Cell Physiol Biochem

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Objective: To investigate the effect of mycophenolic acid (MPA) on the proliferation of rat pulmonary microvascular endothelial cells (PMVECs) and on the secretion of endothelin-1 (ET-1) and interleukin-6 (IL-6) by these cells. Methods: Rat PMVECs were treated with five different final concentrations of MPA (0, 0.1, 1, 10 and 100 μM). The fetal bovine serum-induced proliferation of the PMVECs was detected using the Cell Counting Kit-8 (CCK-8). The levels of ET-1 and IL-6 secretion were assessed by radioimmunoassays. Results: At the 24 h time point, the optical density (OD) values at 450 nm for the five groups showed that there were no significant differences between the groups treated with 0 and 0.1 μM MPA (P=0.388) or between the groups treated with 10 and 100 μM MPA (P=0.292), but the OD values were significantly different between all other pairs of groups (P<0.001). At the 48 h time point, the OD values at 450 nm for the five groups showed that there was no significant difference between the groups treated with 0 and 0.1 μM MPA (P=0.094), but the OD values were significantly different between all the other groups (P<0.001). At the 72 h time point, the OD values at 450 nm for the five groups showed that there was no significant difference between the groups treated with the final concentrations of 0 and 0.1 μM MPA (P=0.931), but the OD values were significantly different between all other pairs of groups (10 μM MPA vs 100 μM MPA: P=0.037; 0 μM MPA vs 1 μM MPA: P=0.006; 1 μM MPA vs 10 μM MPA: P=0.005; all other comparisons: P<0.001). There were no significant differences in ET-1 concentration between the groups treated with 0 and 0.1 μM MPA (P=0.156) or the groups treated with 10 and 100 μM MPA (P=0.262), but there were significant differences between all other pairs of groups (P<0.001). By contrast, there were no significant differences in IL-6 concentrations between any pair of groups (P>0.05). Conclusions: MPA inhibits fetal bovine serum-induced rat PMVEC proliferation and ET-1 secretion in a dose-dependent manner.

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“…Failed systemic restenosis trials in the 80ies and 90ies of the past century have caused an estimated loss of 2.5 billion € to the pharmaceutical industry [13,14], indicating the need for tools to predict the clinical relevance of positive in vitro data. Recently our group has suggested to apply a SI/MPL-ratio, characterizing the relation between a significant antiproliferative effect of a substance in vitro (SI) and the maximal plasma level (MPL) of this substance after systemic administration [13,14].…”

Section: Introductionmentioning

confidence: 99%

“…Recently our group has suggested to apply a SI/MPL-ratio, characterizing the relation between a significant antiproliferative effect of a substance in vitro (SI) and the maximal plasma level (MPL) of this substance after systemic administration [13,14]. A SI/MPL-ratio < 1 characterizes an agent that has at least a theoretical chance to achieve positive effects after systemic administration (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Sirolimus inhibits key events of restenosis in vitro/ex vivo: evaluation of the clinical relevance of the data by SI/MPL- and SI/DES-ratio's

Voisard

Zellmann

Müller

et al. 2007

BMC Cardiovasc Disord

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Antiproliferative profile of sirolimus and mycophenolate mofetil: impact of the SI/MPL ratio

Cited by 12 publications

References 21 publications

Collagen Type I Induces Disruption of E-Cadherin–Mediated Cell-Cell Contacts and Promotes Proliferation of Pancreatic Carcinoma Cells

Collagen Type I Induces Disruption of E-Cadherin–Mediated Cell-Cell Contacts and Promotes Proliferation of Pancreatic Carcinoma Cells

Effects of Mycophenolic Acid on the Proliferation and Endothelin-1 and Interleukin-6 Secretion of Rat Pulmonary Microvascular Endothelial Cells

Sirolimus inhibits key events of restenosis in vitro/ex vivo: evaluation of the clinical relevance of the data by SI/MPL- and SI/DES-ratio's

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