Acridine Orange Excited by Low-Dose Radiation Has a Strong Cytocidal Effect on Mouse Osteosarcoma

Hashiguchi, Shin; Kusuzaki, Katsuyuki; Murata, Hiroaki; Takeshita, Hideyuki; Hashiba, Mitsuoki; Nishimura, Tsunehiko; Ashihara, Tsukasa; Hirasawa, Yasusuke

doi:10.1159/000048251

Cited by 54 publications

(67 citation statements)

References 26 publications

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“…Since the beginning of the 20th century, acridine family compounds have been well known for their pharmacological properties. 19 Acriflavine hydrochloride has been used as a topical antiseptic, and acridine derivatives have been used for antimalarial and anticancer therapy. Pharmacological properties of these agents are closely related to reversible binding of these compounds to DNA regulatory enzymes.…”

Section: Rapid Fluorescent Dyes Suitable For Ex Vivo Imagingmentioning

confidence: 99%

Potential application of a handheld confocal endomicroscope imaging system using a variety of fluorophores in experimental gliomas and normal brain

Martirosyan

Georges

Eschbacher

et al. 2014

FOC

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Object The authors sought to assess the feasibility of a handheld visible-wavelength confocal endomicroscope imaging system (Optiscan 5.1, Optiscan Pty., Ltd.) using a variety of rapid-acting fluorophores to provide histological information on gliomas, tumor margins, and normal brain in animal models. Methods Mice (n = 25) implanted with GL261 cells were used to image fluorescein sodium (FNa), 5-aminolevulinic acid (5-ALA), acridine orange (AO), acriflavine (AF), and cresyl violet (CV). A U251 glioma xenograft model in rats (n = 5) was used to image sulforhodamine 101 (SR101). A swine (n = 3) model with AO was used to identify confocal features of normal brain. Images of normal brain, obvious tumor, and peritumoral zones were collected using the handheld confocal endomicroscope. Histological samples were acquired through biopsies from matched imaging areas. Samples were visualized with a benchtop confocal microscope. Histopathological features in corresponding confocal images and photomicrographs of H & E–stained tissues were reviewed. Results Fluorescence induced by FNa, 5-ALA, AO, AF, CV, and SR101 and detected with the confocal endomicroscope allowed interpretation of histological features. Confocal endomicroscopy revealed satellite tumor cells within peritumoral tissue, a definitive tumor border, and striking fluorescent cellular and subcellular structures. Fluorescence in various tumor regions correlated with standard histology and known tissue architecture. Characteristic features of different areas of normal brain were identified as well. Conclusions Confocal endomicroscopy provided rapid histological information precisely related to the site of microscopic imaging with imaging characteristics of cells related to the unique labeling features of the fluorophores. Although experimental with further clinical trial validation required, these data suggest that intraoperative confocal imaging can help to distinguish normal brain from tumor and tumor margin and may have application in improving intraoperative decisions during resection of brain tumors.

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Section: Rapid Fluorescent Dyes Suitable For Ex Vivo Imagingmentioning

confidence: 99%

Potential application of a handheld confocal endomicroscope imaging system using a variety of fluorophores in experimental gliomas and normal brain

Martirosyan

Georges

Eschbacher

et al. 2014

FOC

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“…Furthermore, we found that low-dose X-ray irradiation at 5 Gy after exposure to AO of a mouse osteosarcoma yielded the same strong cytocidal effect in vitro and in vivo as that of by AO-PDT [22]. This radiation effect with AO was independently demonstrated by an Iowa University group in the USA in 2006 [23].…”

Section: Ao-pdt and Ao-rdtmentioning

confidence: 59%

“…In an in-vivo study carried out using a mouse osteosarcoma model, tumor growth was significantly inhibited by AO injection at 10 mg/kg into the peritoneum followed by light illumination of the tumor. This result suggested the potential usefulness of AO for photodynamic therapy in patients with musculoskeletal sarcomas [20][21][22].…”

Section: Ao-pdt and Ao-rdtmentioning

confidence: 72%

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Intraoperative Photodynamic Surgery (iPDS) with Acridine Orange for Musculoskeletal Sarcomas

Kusuzaki¹,

Matsubara²,

Satonaka³

et al. 2014

Cureus

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We recently established the new limb salvage modality of acridine orange (AO) therapy (AOT), in an attempt to develop minimally invasive limb salvage surgery with minimal damage of normal tissues and a low risk of local recurrence. The treatment modality consists of intraoperative photodynamic surgery (iPDS) and photodynamic therapy (iPDT), followed by postoperative radiodynamic therapy (RDT) using AO for patients with high-grade malignant musculoskeletal sarcomas. Clinical results have shown that the treatment is associated with a low risk of local recurrence, the risk being almost the same as that following conventional wide resection, and yields superior limb function as compared to that obtained after wide resection.In this review, we present the detailed mechanism of selective accumulation of AO in sarcomas, which is related to the acidic environment and lysosomal acidity of the tumor cells induced by cancer-specific glycolysis not involving the define tricarboxylic acid (TCA) cycle (Warburg's effect). We also describe the clinical uses of AOT and the procedure for intraoperative photodynamic surgery (iPDS) using local administration of AO.

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“…Consequently, this in vivo study was conducted. Previously, we reported that the intraperitoneal administration of AO at 10 mg/ kg followed by blue light excitation inhibited the tumor growth of osteosarcoma developing from a different cell line (MOS) than LM8 in vivo (14,15,18,19). Recently, we also found that the intravenous administration of AO at 1.0 mg/kg is useful for PDD of mouse osteosarcomas in nude mice.…”

Section: Discussionmentioning

confidence: 98%

In vivo anti-tumor activity of photodynamic therapy with intravenous administration of acridine orange, followed by illumination with high-power flash wave light in a mouse osteosarcoma model

Satonaka

Kusuzaki²,

Matsubara³

et al. 2010

Oncology Letters

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Abstract. In a recent study, we demonstrated that a high-power flash wave light (FWL) from a xenon lamp exerted a stronger cytocidal effect against a mouse osteosarcoma cell line than continuous wave light (CWL) in photodynamic therapy with acridine orange (AO-PDT). Based on our in vitro results, we investigated the in vivo anti-tumor activity of AO-PDT using flash wave light from a xenon lamp in a mouse osteosarcoma model. Mouse osteosarcoma cells (LM8) were injected into the subcutaneous tissue of the back of C3H mice, and tumors that grew to approximately 3 mm in diameter were treated by AO-PDT using FWL. AO was administered by intravenous injection and 2 h later the entire body of the mouse was illuminated with FWL from a xenon lamp. Significant growth inhibition of the tumor xenografts was observed as compared with that in the control group, suggesting that AO-PDT with FWL may be useful in the treatment of osteosarcoma. An immunohistochemical study of the tumors treated by AO-PDT showed that the underlying mechanism of the tumor growth inhibition involved both apoptosis and necrosis. In conclusion, it appears that following the intravenous administration of AO, AO-PDT in combination with FWL exerts strong anti-tumor activity. Inhibitory effects against growth of the primary tumor in human patients with osteosarcoma as well as other musculoskeletal sarcomas were also observed.

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Acridine Orange Excited by Low-Dose Radiation Has a Strong Cytocidal Effect on Mouse Osteosarcoma

Cited by 54 publications

References 26 publications

Potential application of a handheld confocal endomicroscope imaging system using a variety of fluorophores in experimental gliomas and normal brain

Potential application of a handheld confocal endomicroscope imaging system using a variety of fluorophores in experimental gliomas and normal brain

Intraoperative Photodynamic Surgery (iPDS) with Acridine Orange for Musculoskeletal Sarcomas

In vivo anti-tumor activity of photodynamic therapy with intravenous administration of acridine orange, followed by illumination with high-power flash wave light in a mouse osteosarcoma model

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