Successful treatment of radiation-induced fibrosis using liposomal superoxide dismutase: clinical trial

Delanian, S.; Baillet, F; Huart, Judith; Lefaix, Jean-Louis; Maulard, C; Housset, M.

doi:10.1016/0167-8140(94)90444-8

Cited by 217 publications

(104 citation statements)

References 25 publications

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“…Intramuscular injections of liposomal Cu/Zn-SOD on 34 patients with palpable RT induced fibrosis, showed some clinical regression of fibrosis, with complete response in 17% of fibrotic areas [39]. Another study using liposomal Cu/Zn-SOD and Mn-SOD in pigs with subcutaneous RT fibrosis also demonstrated regression of fibrotic areas [40].…”

Section: Discussionmentioning

confidence: 96%

Long-Term Administration of a Small Molecular Weight Catalytic Metalloporphyrin Antioxidant AEOL 10150 Protects Lungs From Radiation-Induced Injury

Rabbani

Batinić‐Haberle

Poulton

et al. 2005

International Journal of Radiation Oncology*Biology*Physics

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Purpose-To determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N′-diethylimidazolium-2-yl) porphyrin, AEOL 10150, with SOD mimetic properties reduces the severity of radiation-induced injury to the lung from single dose irradiation (RT) of 28 Gy.Materials/Methods-Animals were randomly divided into four different dose groups (0, 1, 10 and 30 mg/kg/day of AEOL 10150), receiving either short (1 week) or long-term (10 weeks) drug administration via osmotic pumps. Animals received single dose irradiation (RT) of 28 Gy to the right hemithorax. Breathing rates, body weights, blood samples, histopathology and immunohistochemistry were used to assess lung damage.Results-There was no significant difference in any of the study endpoints between the irradiated controls and the 3 groups receiving RT and short-term administration of AEOL 10150. For the long term administration functional determinants of lung damage 20 weeks post radiation were significantly worse for RT+PBS and RT+1mg/kg/day of AEOL 10150 as compared to the irradiated groups treated with higher doses of AEOL 10150 (10 or 30mg/kg/day), Lung histology at 20 weeks revealed a significant decrease in structural damage and collagen deposition in animals receiving 10 or 30mg/kg/day after radiation in comparison to RT+PBS and 1mg/kg/day groups. Immunohistochemistry demonstrated a significant reduction in macrophage accumulation, oxidative stress and hypoxia in animals receiving AEOL 10150 (10 or 30mg/kg/day) after lung irradiation compared to RT+PBS and 1mg/kg/day groups. Conclusion-The chronic administration of novel catalytic antioxidant, AEOL 10150, demonstrates a significant protective effect from radiation-induced lung injury. AEOL 10150 has its primary impact on the cascade of events following irradiation and adding drug prior to irradiation and its short-term administration have no significant additional benefits.

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Section: Discussionmentioning

confidence: 96%

Long-Term Administration of a Small Molecular Weight Catalytic Metalloporphyrin Antioxidant AEOL 10150 Protects Lungs From Radiation-Induced Injury

Rabbani

Batinić‐Haberle

Poulton

et al. 2005

International Journal of Radiation Oncology*Biology*Physics

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“…There is a growing body of evidences that SOD could be a potential antifibrotic drug, as proved by clinical results on radiation-induced fibrosis [54,55] and its therapeutic effect could be related to a down-regulation of TGF-β1 expression and activity [27,56]. Superoxide dismutases exhibit potent anti-inflammatory properties [57], and all isoforms (SOD1, SOD2, and SOD3) induced 70% regression of a well-established fibrotic tissue and its replacement by regenerated normal tissue [54].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-generated superoxide induces the development of the adhesion phenotype

Fletcher

Jiang

Diamond

et al. 2008

Free Radical Biology and Medicine

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Adhesion fibroblasts exhibit higher TGF-β1 and type I collagen expression as compared to normal peritoneal broblasts. Furthermore, exposure of normal peritoneal fibroblasts to hypoxia results in an irreversible increase in TGF-β1 and type I collagen. We postulated that the mechanism by which hypoxia induced the adhesion phenotype is through the production of superoxide either directly or through the formation of peroxynitrite. To test this hypothesis, normal peritoneal and adhesion fibroblasts were treated with superoxide dismutase (SOD), a superoxide scavenger, and xanthine/ xanthine oxidase, a superoxide-generating system, under normoxic and hypoxic conditions. Also, cells were treated with peroxynitrite. TGF-β1 and type I collagen expression was determined before and after all treatments using real-time RT/PCR. Hypoxia treatment resulted in a time-dependent increase in TGF-β1 and type I collagen mRNA levels in both normal peritoneal and adhesion fibroblasts. Similarly, treatment with xanthine oxidase, to endogenously generate superoxide, resulted in higher mRNA levels of TGF-β1 and type I collagen in both normal peritoneal and adhesion fibroblasts. In contrast, treatment with SOD, to scavenge endogenous superoxide, resulted in a decrease in TGF-β1 and type I collagen expression in adhesion fibroblasts to levels seen in normal peritoneal fibroblasts; no effect on the expression of these molecules was seen in normal peritoneal fibroblasts. Exposure to hypoxia in the presence of SOD had no effect on mRNA levels of TGF-β1 and type I collagen in either normal peritoneal or adhesion fibroblasts. Peroxynitrite treatment alone significantly induced both adhesion phenotype markers. In conclusion, hypoxia, through the production of superoxide, causes normal peritoneal fibroblasts to acquire the adhesion phenotype. Scavenging superoxide, even in the presence of hypoxia, prevented the development of the adhesion phenotype. These findings further support the central role of free radicals in the development of adhesions.

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“…Pharmacologic interventions and biologic response modifiers have recently been focused on pulmonary radiation protection. Intravenous or systemic delivery of compounds such as WR2721 (Amifostine), [9][10][11][26][27][28][29]32 colony stimulating factors, 31 or other antioxidant molecules 30,33,34 has the potential problem of distribution to tumor vasculature within the target volume. 27,29 Simultaneous tumor and normal tissue radiation protection would not alter the therapeutic ratio or shift to a desirable effect of normal tissue radiation protection.…”

Section: Discussionmentioning

confidence: 99%

Inhalation delivery of manganese superoxide dismutase-plasmid/liposomes protects the murine lung from irradiation damage

et al. 2005

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Intratracheal injection of manganese superoxide dismutaseplasmid/liposome (MnSOD-PL) complexes has been demonstrated to delay the onset and reduce the extent of ionizing irradiation-induced murine pulmonary organizing alveolitis/ fibrosis. To facilitate translation of this modality to clinical fractionated radiotherapy, inhalation delivery of MnSOD-PL was developed using an ultrasonic nebulizer. Transgene product was quantitated by immunohistochemical quantitation and pulmonary tissue levels of MnSOD biochemical activity. C57BL/6NHsd female mice demonstrated a plasmid dose-dependent increased expression of MnSOD transgene product over the range of 250 mg-2.5 mg of MnSOD-PL administered over a constant 5 min interval. Delivery of a constant concentration of 500 mg of MnSOD-PL with varying times of administration ranging from 0.5 to 10 min demonstrated optimal MnSOD expression at 5 min. Mice pretreated by inhalation delivery of MnSOD-PL demonstrated significantly improved survival after 20 Gy single fraction irradiation to both lungs compared to LacZ-PL inhalation-treated or irradiated control mice. Mice receiving 10 fractions of 3.5 cGy demonstrated increased pulmonary MnSOD transgene product activity by a protocol of every Monday-Wednesday or daily inhalation of MnSOD-PL. Thus, inhalation radioprotective gene therapy using MnSOD-PL provides a practical and effective method for delivery of lung-specific radioprotection during fractionated radiotherapy protocols in a mouse model. Gene Therapy (2005) 12, 685-693.

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Successful treatment of radiation-induced fibrosis using liposomal superoxide dismutase: clinical trial

Cited by 217 publications

References 25 publications

Long-Term Administration of a Small Molecular Weight Catalytic Metalloporphyrin Antioxidant AEOL 10150 Protects Lungs From Radiation-Induced Injury

Long-Term Administration of a Small Molecular Weight Catalytic Metalloporphyrin Antioxidant AEOL 10150 Protects Lungs From Radiation-Induced Injury

Hypoxia-generated superoxide induces the development of the adhesion phenotype

Inhalation delivery of manganese superoxide dismutase-plasmid/liposomes protects the murine lung from irradiation damage

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