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Therapeutic management of intestinal fibrosis induced by radiation therapy: from molecular profiling to new intervention strategies et vice et versa.

Hamama S, Delanian S, Monceau V, Vozenin MC - Fibrogenesis Tissue Repair (2012)

Bottom Line: Chronic toxicities of locoregional and systemic oncological treatments commonly develop in long-term cancer survivors.Reduction of exposure of normal tissues can be achieved by optimization of radiotherapy.Furthermore, understanding of the fibrogenic mechanisms has provided targets to prevent, mitigate, and reverse late radiation-induced damages.

View Article: PubMed Central - HTML - PubMed

Affiliation: INSERM U-1030 "Molecular Radiotherapy" Institut Gustave Roussy, Villejuif, France ; "Molecular Radiotherapy", Université Paris Sud Paris XI, France.

ABSTRACT
Chronic toxicities of locoregional and systemic oncological treatments commonly develop in long-term cancer survivors. Amongst these toxicities, post-radiotherapeutic complications alter patient's quality of life. Reduction of exposure of normal tissues can be achieved by optimization of radiotherapy. Furthermore, understanding of the fibrogenic mechanisms has provided targets to prevent, mitigate, and reverse late radiation-induced damages. This mini-review shows how (i) global molecular studies using gene profiling can provide tools to develop new intervention strategies and (ii) how successful clinical trials, conducted in particular with combined pentoxifylline-vitamin E, can take benefice of biological and molecular evidences to improve our understanding of fibrogenic mechanisms, enhance the robustness of proposed treatments, and lead ultimately to better treatments for patient's benefice.

No MeSH data available.


Related in: MedlinePlus

A. Effect of combined pentoxifylline-trolox on mRNA expression of profibrotic genes in a kinetic manner: Twenty four hours kinetics of mRNA expression of TGF-β1, PAI-1, Col Iα1, and RhoB. Pentoxifylline and trolox synergize to inhibit TGFβ1 at early point time, subsequent inhibition of TGFβ1 targets such as PAI-1 and Col Iα1. Treatment doesn't affect RhoB mRNA expression. P: Pentoxifylline treatment, T: Trolox treatment, PT: Pentoxifylline-trolox treatment. 10 refers to treatment dose in μg/ml. *: p < 0.05, **: p < 0.01, ***: p < 0.005 according to kruskal-Wallis test. B.Protein expression of PAI-1 in control and pentoxifylline-trolox treated cells: Combined pentoxifylline-trolox treatment for 24 hours inhibits PAI-1 protein expression more effectively than pentoxifylline alone or trolox alone; GAPDH is used as a housekeeping gene. C: control, P: Pentoxifylline treatment, T: Trolox treatment, PT: Pentoxifylline-trolox treatment. 10 refers to treatment dose in μg/ml.
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Figure 2: A. Effect of combined pentoxifylline-trolox on mRNA expression of profibrotic genes in a kinetic manner: Twenty four hours kinetics of mRNA expression of TGF-β1, PAI-1, Col Iα1, and RhoB. Pentoxifylline and trolox synergize to inhibit TGFβ1 at early point time, subsequent inhibition of TGFβ1 targets such as PAI-1 and Col Iα1. Treatment doesn't affect RhoB mRNA expression. P: Pentoxifylline treatment, T: Trolox treatment, PT: Pentoxifylline-trolox treatment. 10 refers to treatment dose in μg/ml. *: p < 0.05, **: p < 0.01, ***: p < 0.005 according to kruskal-Wallis test. B.Protein expression of PAI-1 in control and pentoxifylline-trolox treated cells: Combined pentoxifylline-trolox treatment for 24 hours inhibits PAI-1 protein expression more effectively than pentoxifylline alone or trolox alone; GAPDH is used as a housekeeping gene. C: control, P: Pentoxifylline treatment, T: Trolox treatment, PT: Pentoxifylline-trolox treatment. 10 refers to treatment dose in μg/ml.

Mentions: Studies about the mechanism of action of combined pentoxifylline-vitamin E in radiation fibrosis are awfully limited. An in vitro study was conducted in dermal fibroblast using the water-soluble analogue of vitamin E, trolox, to investigate the effects of combined pentoxifylline-trolox on irradiated cells. This study showed reduction in acute and late ROS formation in cells after irradiation, decrease in DNA strand breaks whenever the drugs were added i.e. before or after irradiation supporting an immediate anti-oxidant action that interfere with the DNA repair process [59]. However, the relevance of this study to fibrosis is unclear since only short term response was investigated, therefore we aimed at investigating the role of combined pentoxifylline-vitamin E on two well know fibrogenic pathway, i.e. TGF-β1 and Rho/Rock using an in vitro model of radiation-induced fibrosis consisting of primary smooth muscle cells derived from human radiation enteropathy samples (RE-SMC). The hydrophilic analogous of α-tocopherol, trolox, was used. Incubation of the cells with combined pentoxifylline-trolox didn't regulate RhoB mRNA expression (Figure 2A) nor influence Actin cytoskeleton in RE-SMC (data not shown) but interestingly negatively modulated TGF-β1 mRNA expression at early time point (one hour post-treatment) and subsequently decrease the expression of TGF-β1 targets such as PAI-1 both at mRNA and protein levels (twenty four hours post-treatment) (Figure 2A and 2B). This suggested that the anti-fibrotic effects of combined pentoxifylline-trolox could be mediated by inhibition of the TGF-β1 pathway. Interestingly, pentoxifylline and trolox appear to enhance the activity of each other; and the effect of the combination was more potent than any of the individual treatments, which is the definition of drugs synergy. Combined pentoxifylline-trolox with a dose of 10 μg/ml decreases protein expression of PAI-1 more effectively than trolox alone (10 μg/ml) or pentoxifylline alone (10 μg/ml) (Figure 2B). Thus, the synergy between the elements of this combination at low concentration could constitute the basis of its efficacy conferring a more appropriate therapeutic window. This study offers for the first time, to our knowledge, a molecular base for rationalization of the clinical use of combined Pentoxifylline-vitamin E in radiation fibrosis. Nevertheless, inhibition of TGF-β1 pathway is unlikely to be the sole anti-fibrotic mechanism of action of combined pentoxifylline-trolox and other novel candidates are actually under investigations.


Therapeutic management of intestinal fibrosis induced by radiation therapy: from molecular profiling to new intervention strategies et vice et versa.

Hamama S, Delanian S, Monceau V, Vozenin MC - Fibrogenesis Tissue Repair (2012)

A. Effect of combined pentoxifylline-trolox on mRNA expression of profibrotic genes in a kinetic manner: Twenty four hours kinetics of mRNA expression of TGF-β1, PAI-1, Col Iα1, and RhoB. Pentoxifylline and trolox synergize to inhibit TGFβ1 at early point time, subsequent inhibition of TGFβ1 targets such as PAI-1 and Col Iα1. Treatment doesn't affect RhoB mRNA expression. P: Pentoxifylline treatment, T: Trolox treatment, PT: Pentoxifylline-trolox treatment. 10 refers to treatment dose in μg/ml. *: p < 0.05, **: p < 0.01, ***: p < 0.005 according to kruskal-Wallis test. B.Protein expression of PAI-1 in control and pentoxifylline-trolox treated cells: Combined pentoxifylline-trolox treatment for 24 hours inhibits PAI-1 protein expression more effectively than pentoxifylline alone or trolox alone; GAPDH is used as a housekeeping gene. C: control, P: Pentoxifylline treatment, T: Trolox treatment, PT: Pentoxifylline-trolox treatment. 10 refers to treatment dose in μg/ml.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368760&req=5

Figure 2: A. Effect of combined pentoxifylline-trolox on mRNA expression of profibrotic genes in a kinetic manner: Twenty four hours kinetics of mRNA expression of TGF-β1, PAI-1, Col Iα1, and RhoB. Pentoxifylline and trolox synergize to inhibit TGFβ1 at early point time, subsequent inhibition of TGFβ1 targets such as PAI-1 and Col Iα1. Treatment doesn't affect RhoB mRNA expression. P: Pentoxifylline treatment, T: Trolox treatment, PT: Pentoxifylline-trolox treatment. 10 refers to treatment dose in μg/ml. *: p < 0.05, **: p < 0.01, ***: p < 0.005 according to kruskal-Wallis test. B.Protein expression of PAI-1 in control and pentoxifylline-trolox treated cells: Combined pentoxifylline-trolox treatment for 24 hours inhibits PAI-1 protein expression more effectively than pentoxifylline alone or trolox alone; GAPDH is used as a housekeeping gene. C: control, P: Pentoxifylline treatment, T: Trolox treatment, PT: Pentoxifylline-trolox treatment. 10 refers to treatment dose in μg/ml.
Mentions: Studies about the mechanism of action of combined pentoxifylline-vitamin E in radiation fibrosis are awfully limited. An in vitro study was conducted in dermal fibroblast using the water-soluble analogue of vitamin E, trolox, to investigate the effects of combined pentoxifylline-trolox on irradiated cells. This study showed reduction in acute and late ROS formation in cells after irradiation, decrease in DNA strand breaks whenever the drugs were added i.e. before or after irradiation supporting an immediate anti-oxidant action that interfere with the DNA repair process [59]. However, the relevance of this study to fibrosis is unclear since only short term response was investigated, therefore we aimed at investigating the role of combined pentoxifylline-vitamin E on two well know fibrogenic pathway, i.e. TGF-β1 and Rho/Rock using an in vitro model of radiation-induced fibrosis consisting of primary smooth muscle cells derived from human radiation enteropathy samples (RE-SMC). The hydrophilic analogous of α-tocopherol, trolox, was used. Incubation of the cells with combined pentoxifylline-trolox didn't regulate RhoB mRNA expression (Figure 2A) nor influence Actin cytoskeleton in RE-SMC (data not shown) but interestingly negatively modulated TGF-β1 mRNA expression at early time point (one hour post-treatment) and subsequently decrease the expression of TGF-β1 targets such as PAI-1 both at mRNA and protein levels (twenty four hours post-treatment) (Figure 2A and 2B). This suggested that the anti-fibrotic effects of combined pentoxifylline-trolox could be mediated by inhibition of the TGF-β1 pathway. Interestingly, pentoxifylline and trolox appear to enhance the activity of each other; and the effect of the combination was more potent than any of the individual treatments, which is the definition of drugs synergy. Combined pentoxifylline-trolox with a dose of 10 μg/ml decreases protein expression of PAI-1 more effectively than trolox alone (10 μg/ml) or pentoxifylline alone (10 μg/ml) (Figure 2B). Thus, the synergy between the elements of this combination at low concentration could constitute the basis of its efficacy conferring a more appropriate therapeutic window. This study offers for the first time, to our knowledge, a molecular base for rationalization of the clinical use of combined Pentoxifylline-vitamin E in radiation fibrosis. Nevertheless, inhibition of TGF-β1 pathway is unlikely to be the sole anti-fibrotic mechanism of action of combined pentoxifylline-trolox and other novel candidates are actually under investigations.

Bottom Line: Chronic toxicities of locoregional and systemic oncological treatments commonly develop in long-term cancer survivors.Reduction of exposure of normal tissues can be achieved by optimization of radiotherapy.Furthermore, understanding of the fibrogenic mechanisms has provided targets to prevent, mitigate, and reverse late radiation-induced damages.

View Article: PubMed Central - HTML - PubMed

Affiliation: INSERM U-1030 "Molecular Radiotherapy" Institut Gustave Roussy, Villejuif, France ; "Molecular Radiotherapy", Université Paris Sud Paris XI, France.

ABSTRACT
Chronic toxicities of locoregional and systemic oncological treatments commonly develop in long-term cancer survivors. Amongst these toxicities, post-radiotherapeutic complications alter patient's quality of life. Reduction of exposure of normal tissues can be achieved by optimization of radiotherapy. Furthermore, understanding of the fibrogenic mechanisms has provided targets to prevent, mitigate, and reverse late radiation-induced damages. This mini-review shows how (i) global molecular studies using gene profiling can provide tools to develop new intervention strategies and (ii) how successful clinical trials, conducted in particular with combined pentoxifylline-vitamin E, can take benefice of biological and molecular evidences to improve our understanding of fibrogenic mechanisms, enhance the robustness of proposed treatments, and lead ultimately to better treatments for patient's benefice.

No MeSH data available.


Related in: MedlinePlus