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Molecular Cancer Therapeutics
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A heterotypic bystander effect for tumor cell killing after adeno-associated virus/phage–mediated, vascular-targeted suicide gene transfer

Martin Trepel, Charlotte A. Stoneham, Hariklia Eleftherohorinou, Nicholas D. Mazarakis, Renata Pasqualini, Wadih Arap and Amin Hajitou
Martin Trepel
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Charlotte A. Stoneham
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Hariklia Eleftherohorinou
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Nicholas D. Mazarakis
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Renata Pasqualini
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Wadih Arap
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Amin Hajitou
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DOI: 10.1158/1535-7163.MCT-09-0110 Published August 2009
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    Figure 1.

    EF43-FGF4 tumor growth is inhibited by targeted RGD-4C adeno-associated virus/phage–HSVtk independently of expression of the target receptor on tumor cells. A, EF43-FGF4 tumor cells barely express αv integrins. EF43-FGF4 cells grown in vitro were detached and subjected to fluorescence-activated cell sorting analysis with an anti-αv integrin antibody (right) or a species-matched immunoglobulin G control antibody (left). Kaposi's sarcoma (KS1767) cells served as a positive control. B, systemic administration of αv integrin-targeted RGD-4C adeno-associated virus/phage–HSVtk vector mediates marked suppression of EF43-FGF4 tumors after ganciclovir treatment. EF43-FGF4 tumors were established in BALB/c immunocompetent mice (∼100 mm3). A single dose of RGD-4C adeno-associated virus/phage–HSVtk vector (5 × 1010 transducing units) was administered i.v. Treatment with ganciclovir (80 mg/kg/d) i.p. started 2 d later. A comprehensive panel of negative experimental control groups, including vehicle alone, vehicle plus ganciclovir, nontargeted adeno-associated virus/phage–HSVtk, nontargeted adeno-associated virus/phage–HSVtk plus ganciclovir, targeted RGD-4C adeno-associated virus/phage–HSVtk, targeted RGD-4C adeno-associated virus/phage–GFP, and targeted RGD-4C adeno-associated virus/phage–GFP plus ganciclovir (mock transduction) is shown. Data are presented as the volumes of five individual tumors and their medians before and at day 13 after treatment.

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    Figure 2.

    In vitro bystander effect between HSVtk-transduced SVEC4-10 endothelial cells and nontransduced tumor cells. HSVtk-transduced endothelial SVEC4-10 cells were mixed at a 1:9 ratio with nontransduced SVEC4-10 cells (A), EF43-FGF4 breast cancer cells (B), 9L malignant glioma cells (C), or MDA-MB435 breast cancer cells (D) in 24-well plates. After 24 h, the cocultures were treated with 20 μmol/L ganciclovir (right) or vehicle (left) for 5 d. Phase-contrast microscopy 5 d after initiation of drug treatment.

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    Figure 3.

    The heterotypic bystander effect is mediated by gap junctional intercellular communication. Heterotypic cocultures in a 1:9 ratio of HSVtk-expressing SVEC4-10 cells and HSVtk-negative EF43-FGF4 or 9L tumor cells were treated for 5 d with either 20 μmol/L ganciclovir alone or a combination of 20 μmol/L ganciclovir plus 70 μmol/L 18α-glycyrrhetinic acid. Homotypic cocultures in a 1:9 ratio of HSVtk-expressing SVEC4-10 cells and HSVtk-negative SVEC4-10 were treated similarly. After treatment, cell survival was assessed by trypan blue exclusion and compared with that of the untreated control coculture (set to 100%). Data are means ± SD (n = 3).

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    Figure 4.

    Connexin expression in tumor cells and endothelial cells involved in bystander killing. EF43-FGF4 cells, 9L glioma cells, and SVEC4-10 endothelial cells as indicated were grown to saturation, after which they were fixed. Immunofluorescence with primary rabbit polyclonal anti–connexin 26, anti–connexin 43, or control antibodies was done. The MDA-MB435 cell line, which is not susceptible to bystander killing, served as a negative control.

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    Figure 5.

    The heterotypic bystander effect between SVEC4-10–HSVtk cells and EF43-FGF4 tumor cells can be induced in vivo. Mixtures of 105 cells containing 50% each of HSVtk-expressing SVEC4-10 endothelial cells and EF43-FGF4 or parental SVEC4-10 cells, respectively, were injected s.c. into 6-wk-old female athymic nude mice at day 0. Starting at day 6, all mice received ganciclovir (80 mg/kg/d). Note the selective ablation of tumors containing HSVtk-transduced endothelial cells.

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Molecular Cancer Therapeutics: 8 (8)
August 2009
Volume 8, Issue 8
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A heterotypic bystander effect for tumor cell killing after adeno-associated virus/phage–mediated, vascular-targeted suicide gene transfer
Martin Trepel, Charlotte A. Stoneham, Hariklia Eleftherohorinou, Nicholas D. Mazarakis, Renata Pasqualini, Wadih Arap and Amin Hajitou
Mol Cancer Ther August 1 2009 (8) (8) 2383-2391; DOI: 10.1158/1535-7163.MCT-09-0110

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A heterotypic bystander effect for tumor cell killing after adeno-associated virus/phage–mediated, vascular-targeted suicide gene transfer
Martin Trepel, Charlotte A. Stoneham, Hariklia Eleftherohorinou, Nicholas D. Mazarakis, Renata Pasqualini, Wadih Arap and Amin Hajitou
Mol Cancer Ther August 1 2009 (8) (8) 2383-2391; DOI: 10.1158/1535-7163.MCT-09-0110
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Molecular Cancer Therapeutics
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