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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 Pravastatin on mRNA expression of TGFβ1, CTGF and Collagen in a kinetic manner: Twenty four hours kinetics of mRNA expression of TGFβ1, CTGF, and Col Iα2 in control and Pravastatin treated cells show that Pravastatin treatment with a dose of 0.1 mM and up reduces levels of mRNAs of these genes with maximum efficiency at six hours post-treatment; C: control, P: Pravastatin treatment. 0.1, 0.5, and 1 refer to treatment dose in mM. *: p < 0.05, **: p < 0.01, ***: p < 0.005 according to kruskal-Wallis test. B.Protein expression of CTGF in control and Pravastatin treated cells: Pravastatin treatment for 24 hours inhibits CTGF protein expression showing also a dose-response relationship. GAPDH is used as a housekeeping gene. C: control, P: Pravastatin treatment. 0.1, 0.5 refer to treatment dose in mM.
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Figure 1: A. Effect of Pravastatin on mRNA expression of TGFβ1, CTGF and Collagen in a kinetic manner: Twenty four hours kinetics of mRNA expression of TGFβ1, CTGF, and Col Iα2 in control and Pravastatin treated cells show that Pravastatin treatment with a dose of 0.1 mM and up reduces levels of mRNAs of these genes with maximum efficiency at six hours post-treatment; C: control, P: Pravastatin treatment. 0.1, 0.5, and 1 refer to treatment dose in mM. *: p < 0.05, **: p < 0.01, ***: p < 0.005 according to kruskal-Wallis test. B.Protein expression of CTGF in control and Pravastatin treated cells: Pravastatin treatment for 24 hours inhibits CTGF protein expression showing also a dose-response relationship. GAPDH is used as a housekeeping gene. C: control, P: Pravastatin treatment. 0.1, 0.5 refer to treatment dose in mM.

Mentions: Rho GTPases regulate fundamental cellular processes including cell motility, cell cycle progression, cell survival, transcription, membrane trafficking and cytokinesis via their downstream effectors the Rho-associated kinases (ROCKs) [16,17]. Many Rho functions have been elucidated using pharmacological inhibitors, the most prominent ones being Statins, molecules which inhibit isoprenoid intermediates production and Rho activation. In order to investigate whether the Rho/ROCK cascade regulates radiation-induced fibrogenic program in intestinal mesenchymal cells, pharmacological inhibition of Rho and ROCK activation was performed in vitro using pravastatin and Y-27632, a pyrimidine derivative inhibitor of ROCK. We showed that both agents modulated radiation-induced fibrogenic differentiation and the expression of CTGF, TGF-β1, and collagen Iα2 genes (Figure 1), most likely via NF-κB inhibition [10,11,18]. Next, therapeutic experiments were conducted in pre-clinical models. Pravastatin was chosen as, in the case of convincing results, it would be easy to accelerate the transfer of this drug to the clinic, given the fact that the drug is safe and well tolerated [19]. Remarkably, we showed that pravastatin administration with curative intent improves radiation enteropathy in rats, inhibits Rho and ROCK activity in human samples, and subsequently inhibits CTGF production in-vivo, ex-vivo, and in-vitro. In addition, inhibition of type-I-collagen and fibronectin occurred, indicating that pravastatin modulates the secretory phenotype of mesenchymal cells, probably by inhibition of the Rho/ROCK/CTGF/ECM cascade [13]. Mitigation experiments with pravastatin, relevant to clinically well-established fibrosis, improved delayed radiation enteropathy in rats and decreased both CTGF expression and collagen deposition. Interestingly, pravastatin's protective effect was differential, as no tumor protection occurred [20]. Similar results were obtained by others using Simvastatin [21] and anti-fibrotic efficacy of statins was shown in model of radiation-induced lung [22,23]. These pre-clinical findings encouraged us to propose a phase II randomized clinical trial, which received approval from the local ethics committee and started at Institut Gustave Roussy in January 2010 with the support of the French Ministry of Health (PHRC 2010).


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 Pravastatin on mRNA expression of TGFβ1, CTGF and Collagen in a kinetic manner: Twenty four hours kinetics of mRNA expression of TGFβ1, CTGF, and Col Iα2 in control and Pravastatin treated cells show that Pravastatin treatment with a dose of 0.1 mM and up reduces levels of mRNAs of these genes with maximum efficiency at six hours post-treatment; C: control, P: Pravastatin treatment. 0.1, 0.5, and 1 refer to treatment dose in mM. *: p < 0.05, **: p < 0.01, ***: p < 0.005 according to kruskal-Wallis test. B.Protein expression of CTGF in control and Pravastatin treated cells: Pravastatin treatment for 24 hours inhibits CTGF protein expression showing also a dose-response relationship. GAPDH is used as a housekeeping gene. C: control, P: Pravastatin treatment. 0.1, 0.5 refer to treatment dose in mM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: A. Effect of Pravastatin on mRNA expression of TGFβ1, CTGF and Collagen in a kinetic manner: Twenty four hours kinetics of mRNA expression of TGFβ1, CTGF, and Col Iα2 in control and Pravastatin treated cells show that Pravastatin treatment with a dose of 0.1 mM and up reduces levels of mRNAs of these genes with maximum efficiency at six hours post-treatment; C: control, P: Pravastatin treatment. 0.1, 0.5, and 1 refer to treatment dose in mM. *: p < 0.05, **: p < 0.01, ***: p < 0.005 according to kruskal-Wallis test. B.Protein expression of CTGF in control and Pravastatin treated cells: Pravastatin treatment for 24 hours inhibits CTGF protein expression showing also a dose-response relationship. GAPDH is used as a housekeeping gene. C: control, P: Pravastatin treatment. 0.1, 0.5 refer to treatment dose in mM.
Mentions: Rho GTPases regulate fundamental cellular processes including cell motility, cell cycle progression, cell survival, transcription, membrane trafficking and cytokinesis via their downstream effectors the Rho-associated kinases (ROCKs) [16,17]. Many Rho functions have been elucidated using pharmacological inhibitors, the most prominent ones being Statins, molecules which inhibit isoprenoid intermediates production and Rho activation. In order to investigate whether the Rho/ROCK cascade regulates radiation-induced fibrogenic program in intestinal mesenchymal cells, pharmacological inhibition of Rho and ROCK activation was performed in vitro using pravastatin and Y-27632, a pyrimidine derivative inhibitor of ROCK. We showed that both agents modulated radiation-induced fibrogenic differentiation and the expression of CTGF, TGF-β1, and collagen Iα2 genes (Figure 1), most likely via NF-κB inhibition [10,11,18]. Next, therapeutic experiments were conducted in pre-clinical models. Pravastatin was chosen as, in the case of convincing results, it would be easy to accelerate the transfer of this drug to the clinic, given the fact that the drug is safe and well tolerated [19]. Remarkably, we showed that pravastatin administration with curative intent improves radiation enteropathy in rats, inhibits Rho and ROCK activity in human samples, and subsequently inhibits CTGF production in-vivo, ex-vivo, and in-vitro. In addition, inhibition of type-I-collagen and fibronectin occurred, indicating that pravastatin modulates the secretory phenotype of mesenchymal cells, probably by inhibition of the Rho/ROCK/CTGF/ECM cascade [13]. Mitigation experiments with pravastatin, relevant to clinically well-established fibrosis, improved delayed radiation enteropathy in rats and decreased both CTGF expression and collagen deposition. Interestingly, pravastatin's protective effect was differential, as no tumor protection occurred [20]. Similar results were obtained by others using Simvastatin [21] and anti-fibrotic efficacy of statins was shown in model of radiation-induced lung [22,23]. These pre-clinical findings encouraged us to propose a phase II randomized clinical trial, which received approval from the local ethics committee and started at Institut Gustave Roussy in January 2010 with the support of the French Ministry of Health (PHRC 2010).

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