Bioluminescence Imaging of the Response of Rat Gliosarcoma to ALA‐PpIX‐mediated Photodynamic Therapy<sup>¶</sup>

Moriyama, Eduardo H.; Bisland, Stuart K.; Lilge, Lothar; Wilson, Brian C.

doi:10.1111/j.1751-1097.2004.tb00078.x

Cited by 15 publications

(12 citation statements)

References 65 publications

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“…All cells were grown in DMEM/F12 with 10% fetal bovine serum. The firefly luciferase gene plasmid (pGL3 enhancer vector; Promega) was cotransfected into RG2 cells as reported before (37). All the viruses used in this study were constructed in the laboratory of G. McFadden, and virus was propagated and titrated by focus formation on BGMK cells as described previously (5,16,21,22,38,39).…”

Section: Methodsmentioning

confidence: 99%

Myxoma Virus Virotherapy for Glioma in Immunocompetent Animal Models: Optimizing Administration Routes and Synergy with Rapamycin

et al. 2010

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Oncolytic myxoma virus (MYXV) is being developed as a novel virotherapeutic against human brain cancer and has promising activity against human brain tumor models in immunocompromised hosts. Because an intact immune system could reduce its efficacy, the purpose of this study was to evaluate the oncolytic potential of MYXV in immunocompetent racine glioma models. Here, we report that MYXV infects and kills all racine cell glioma lines and that its effects are enhanced by rapamycin. Intratumoral administration of MYXV with rapamycin improved viral replication in the tumor and significantly prolonged host survival. Similarly, coadministration via a method of convection-enhanced delivery (CED) enhanced viral replication and efficacy in vivo. Mechanisms by which rapamycin improved MYXV oncolysis included an inhibition of type I IFN production in vitro and a reduction of intratumoral infiltration of CD68 + microglia/macrophages and CD163 + macrophages in vivo. Our findings define a method to improve MYXV efficacy against gliomas by rapamycin coadministration, which acts to promote immune responses engaged by viral delivery. CancerRes; 70(2); 598-608. ©2010 AACR.

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Section: Methodsmentioning

confidence: 99%

Myxoma Virus Virotherapy for Glioma in Immunocompetent Animal Models: Optimizing Administration Routes and Synergy with Rapamycin

et al. 2010

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“…Freshly excised glioma cells from patients were obtained with approval from the Montreal Neurological Institute and cultured as described (21). To generate the luciferase-RG2 cell line, the modified firefly luciferase gene plasmid (pGL3 enhancer vector; Promega) was cotransfected into RG2 cells as previously reported (38). Firefly luciferase plasmid was provided by B. Wilson and E. Moriyama (Toronto, ON, Canada).…”

Section: Methodsmentioning

confidence: 99%

Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

Alain

Lun

Martineau

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

121

108

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Oncolytic viruses constitute a promising therapy against malignant gliomas (MGs). However, virus-induced type I IFN greatly limits its clinical application. The kinase mammalian target of rapamycin (mTOR) stimulates type I IFN production via phosphorylation of its effector proteins, 4E-BPs and S6Ks. Here we show that mouse embryonic fibroblasts and mice lacking S6K1 and S6K2 are more susceptible to vesicular stomatitis virus (VSV) infection than their WT counterparts as a result of an impaired type I IFN response. We used this knowledge to employ a pharmacoviral approach to treat MGs. The highly specific inhibitor of mTOR rapamycin, in combination with an IFN-sensitive VSV-mutant strain (VSV ΔM51 ), dramatically increased the survival of immunocompetent rats bearing MGs. More importantly, VSV ΔM51 selectively killed tumor, but not normal cells, in MG-bearing rats treated with rapamycin. These results demonstrate that reducing type I IFNs through inhibition of mTORC1 is an effective strategy to augment the therapeutic activity of VSV ΔM51 .innate antiviral immunity | malignant gliomas | mTORC1 | oncolytic viruses M alignant gliomas (MGs) are by far the most frequent, aggressive, and lethal primary brain tumor variants (1, 2). Patients with MGs have a median survival time of approximately 1 y and respond poorly to most available therapeutic modalities (3-5). Thus, more effective treatments are needed.Recent evidence implicates the PI3K/mammalian target of rapamycin (mTOR) signaling pathway as one of the main oncogenic signaling pathways whose deregulation may underlie gliomagenesis (6, 7). mTOR exists in two complexes: mTOR complex 1 (mTORC1), which is sensitive to the drug rapamycin and regulates mRNA translation, and mTORC2, which is rapamycininsensitive and regulates the organization of the actin cytoskeleton (reviewed in refs. 8-10). mTORC1 stimulates type I IFN production via phosphorylation of its target proteins 4E-BPs and S6K1/2 (11). Evidence for the critical role of the mTORC1 signaling pathway in innate immunity emerged from the findings that the mTORC1 inhibitor rapamycin suppresses type I IFN in plasmacytoid dendritic cells (pDCs), which are the major producers of systemic type I IFN (12). In addition, genetic deletion of the mTOR downstream target S6K1/2 leads to impaired type I IFN response (see Results). In contrast, we recently found that the lack of the translational repressors 4E-BP1/2 leads to enhanced type I IFN production (13).Oncogenic transformation is associated with a deficient type I IFN response, which constitutes the first line of defense against virus infection (14,15). Oncolytic viruses are studied as effective anticancer agents because they exploit this selective defect (16)(17)(18)(19). One of the best characterized oncolytic viruses, whose replication is extremely sensitive to the inhibition by IFN, is vesicular stomatitis virus (VSV) (20). However, there are several reasons that limit the use of oncolytic viruses for the treatment of MGs. First, some MGs exhibit a robust type I I...

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“…Quantitative bioluminescence imaging has also been used in previous studies of PDT treatment response 18 and was further validated here [ Fig. 3(a)] Figure 3(b) shows how the cumulative 1 O 2 luminescence counts in individual animals, as well as the averages over all animals, di®ers between the response groups.…”

Section: Resultsmentioning

confidence: 97%

Correlation of in vivo tumor response and singlet oxygen luminescence detection in mTHPC-mediated photodynamic therapy

Wilson

Patterson

et al. 2015

J. Innov. Opt. Health Sci.

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Excited-state singlet oxygen ( 1 O 2 ), generated during photodynamic therapy (PDT), is believed to be the primary cytotoxic agent with a number of clinically approved photosensitizers. Its relative concentration in cells or tissues can be measured directly through its near-infrared (NIR) luminescence emission, which has correlated well with in vitro cell and in vivo normal skin treatment responses. Here, its correlation with the response of tumor tissue in vivo is examined, using the photosensitizer meso-tetrahydroxyphenylchlorin (mTHPC) in an animal model comprising luciferase-and green°uorescent protein (GFP)-transduced gliosarcoma grown in a dorsal window chamber. The change in the bioluminescence signal, imaged pretreatment and at 2, 5 and 9 d post treatment, was used as a quantitative measure of the tumor response, which was classi¯ed in individual tumors as \non", \moderate" and \strong" in order to reduce the variance in the data. Plotting the bioluminescence-based response vs the 1 O 2 counts demonstrated clear correlation, indicating that 1 O 2 luminescence provides a valid dosimetric technique for PDT in tumor tissue.

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Bioluminescence Imaging of the Response of Rat Gliosarcoma to ALA‐PpIX‐mediated Photodynamic Therapy^¶

Cited by 15 publications

References 65 publications

Myxoma Virus Virotherapy for Glioma in Immunocompetent Animal Models: Optimizing Administration Routes and Synergy with Rapamycin

Myxoma Virus Virotherapy for Glioma in Immunocompetent Animal Models: Optimizing Administration Routes and Synergy with Rapamycin

Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

Correlation of in vivo tumor response and singlet oxygen luminescence detection in mTHPC-mediated photodynamic therapy

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Bioluminescence Imaging of the Response of Rat Gliosarcoma to ALA‐PpIX‐mediated Photodynamic Therapy¶

Cited by 15 publications

References 65 publications

Myxoma Virus Virotherapy for Glioma in Immunocompetent Animal Models: Optimizing Administration Routes and Synergy with Rapamycin

Myxoma Virus Virotherapy for Glioma in Immunocompetent Animal Models: Optimizing Administration Routes and Synergy with Rapamycin

Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

Correlation of in vivo tumor response and singlet oxygen luminescence detection in mTHPC-mediated photodynamic therapy

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Bioluminescence Imaging of the Response of Rat Gliosarcoma to ALA‐PpIX‐mediated Photodynamic Therapy^¶