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Journal of the National Cancer Institute, Vol. 98, No. = 21,=20 1546-1557, November 1, 2006
DOI: 10.1093/jnci/djj413
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=A9= =20 2006 The Author(s). This is an Open Access article distributed = under the=20 terms of the Creative Commons Attribution Non-Commercial License=20 (http://creativecommons.org/licenses/by-nc/2.0/uk/), which permits = unrestricted non-commercial use, distribution, and reproduction in = any=20 medium, provided the original work is properly cited. =

ARTICLE

Effects of Intravenously Administered Recombinant Vesicular = Stomatitis=20 Virus (VSV3D{Delta}=20M51) on Multifocal and Invasive Gliomas =

XueQing Lun, Donna L. Senger,=20 Tommy Alain, Andra Oprea, Kelley=20 Parato, Dave Stojdl, Brian = Lichty,=20 Anthony Power, Randal N. Johnston, = Mark=20 Hamilton, Ian Parney, John C. = Bell,=20 Peter A. Forsyth=20

Affiliations of authors: Departments of = Oncology,=20 Clinical Neurosciences, and Biochemistry and Molecular Biology, = Tom Baker=20 Cancer Centre (XL, DLS, TA, AO, RNJ, IP, PAF), Clark H. Smith = Integrative=20 Brain Tumor Research Center (XL, DLS, TA, AO, MH, IP, PAF), = Department of=20 Neurosurgery (MH), University of Calgary, AB, Canada; Ottawa = Regional=20 Cancer Centre Research Laboratories, Ottawa, ON, Canada (KP, AP, = JCB);=20 Apoptosis Research Center, Children's Hospital of Eastern Ontario, = Ottawa,=20 ON, Canada (DS); Centre for Gene Therapeutics, Department of = Pathology and=20 Molecular Medicine, McMaster University, Hamilton, ON, Canada (BL) =

Correspondence to: Peter A. Forsyth, MD, = Clark H.=20 Smith Integrative Brain Tumor Research Center, Rm. 372A, Heritage = Medical=20 Research Building, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1, = Canada=20 (e-mail: pforsyth{at}ucalgary.ca ).


  =20 ABSTRACT =
Top
Notes
3D"Abstract
Introduction
Materials and methods
Results
Discussion
References
 
<= I>Background:=20 An ideal virus for the treatment of cancer should have=20 effective delivery into multiple sites within the tumor, = evade=20 immune responses, produce rapid viral replication, spread=20 within the tumor, and infect multiple tumors. Vesicular=20 stomatitis virus (VSV) has been shown to be an = effective=20 oncolytic virus in a variety of tumor models, and = mutations in=20 the matrix (M) protein enhance VSV's effectiveness in = animal=20 models. Methods: We evaluated the susceptibility = of 14=20 glioma cell lines to infection and killing by mutant = strain=20 VSV3D{Delta}=20M51, which contains a single=96amino = acid deletion=20 in the M protein. We also examined the activity and = safety of=20 this strain against the U87 and U118 experimental = models of=20 human malignant glioma in nude mice and analyzed the=20 distribution of the virus in the brains of U87 = tumor=96bearing=20 mice using fluorescence labeling. Finally, we examined the=20 effect of VSV3D{Delta}=20M51 on 15 primary human gliomas cultured from = surgical=20 specimens. All statistical tests were two-sided. = Results:=20 All 14 glioma cell lines were susceptible to = VSVM51 infection and killing. = Intratumoral=20 administration of VSV3D{Delta}=20M51 produced marked regression of = malignant=20 gliomas in nude mice. When administered systemically, = live=20 VSV3D{Delta}=20M51 virus, as compared with dead virus,=20 statistically significantly prolonged survival of mice = with=20 unilateral U87 tumors (median survival: 113 versus 46 = days,=20 P =3D .0001) and bilateral U87 tumors (median = survival: 73=20 versus 46 days, P =3D .0025). VSV3D{Delta}=20M51 infected multifocal gliomas, invasive = glioma=20 cells that migrated beyond the main glioma, and all 15 = primary=20 human gliomas. There was no evidence of toxicity. = Conclusions:=20 Systemically delivered VSV3D{Delta}=20M51 was an effective and safe oncolytic = agent=20 against laboratory models of multifocal and invasive = malignant=20 gliomas, the most challenging clinical manifestations of = this=20 disease.


  =20 INTRODUCTION =
Top
Notes
Abstract
3D"Introduction
Materials and methods
Results
Discussion
References
 
H= uman=20 malignant glioma is one of the most common primary central=20 nervous system tumors in adults. The ability to treat = patients=20 with malignant gliomas remains poor. Despite dramatic=20 improvements in neuroimaging and neurosurgical = techniques, the=20 prognosis of patients with malignant glioma has not = improved=20 substantially during the past 30 years (1).=20 The most aggressive treatment available for patients = with=20 malignant glioma is surgical resection followed first = by=20 conventional radiotherapy administered with concomitant = chemotherapy and then by adjuvant chemotherapy (2).=20 Despite successful initial treatment of patients with = malignant=20 glioma, the median survival of patients with glioblastoma=20 multiforme thus treated is just over 1 year (2),=20 and virtually all patients die of recurrent disease = (3=965).=20

Malignant gliomas are diffuse, highly invasive, and often=20 multifocal. The core tumor is surrounded by a penumbra = of=20 invasive tumor cells that are detectable several = centimeters=20 away from the main tumor mass. These locally invasive = glioma=20 cells, which are often found at the margins of the = tumor=20 resection, are the most common site of malignant glioma = recurrence. In addition, these invasive glioma cells = activate=20 several cellular signaling pathways that render them = more=20 resistant to conventional chemotherapies than their = noninvasive=20 counterparts (6).=20 Therefore, malignant glioma must be considered as a = cerebral=20 disease that requires treatment not only of a single, = main=20 tumor mass but also of invasive cells and multiple = tumor=20 foci.

Recently, several oncolytic viruses have shown promising = results=20 in preclinical models of brain tumors. These viruses = include=20 reovirus (7=969),=20 recombinant herpes simplex virus (10=9614),=20 Newcastle disease virus (15=9617),=20 recombinant poliovirus (18,19),=20 myxoma virus (20),=20 modified adenovirus (21=9623),=20 and wild-type vesicular stomatitis virus (VSV) (24=9628).=20 Despite impressive preclinical data, there are potential=20 limitations to the use of these viruses in patients, = such as=20 inadequate distribution and/or delivery and = insufficient levels=20 of gene transfer or virus replication (29=9632).=20 Indeed, no dramatic results have been reported in the = small=20 number of early clinical trials in humans using = oncolytic=20 viruses against malignant glioma (15,16,33=9636).=20 Case reports of long-term survivors (35)=20 and a patient with a complete response (17)=20 have been described, and a clinical trial in patients = with=20 recurrent malignant gliomas treated with reovirus has = been=20 completed (37),=20 but a final report has not been published.

Oncolytic viruses exploit a number of genetic defects in = tumor=20 cells (38=9642).=20 A common genetic defect occurring during tumor = evolution is=20 diminished responsiveness to interferon (43,44).=20 This common defect reflects the important role of=20 interferon-regulated pathways in the control of normal = growth=20 and apoptosis. Interferon is also a key mediator of the = individual cell's innate antiviral response. When tumor = cells=20 acquire mutations that allow them to escape = interferon-mediated=20 growth control pathways (e.g., those controlling = proliferation=20 or apoptosis), the tumor cells simultaneously = compromise their=20 innate viral responses, permitting a lethal viral = infection=20 within the tumor cell. In addition, tumor cells may = have=20 defects in signaling pathways such as the Myc, Ras, or = p53=20 pathways that render them susceptible to VSV = replication (26,28,45).=20 Thus, tumor cells undergo growth and proliferation at = the=20 expense of losing their resistance to viral infection, = and a=20 lethal oncolytic infection occurs.

We and others have found that wild-type VSV is a potent = oncolytic=20 virus in a number of tumor cell types, including gliomas = (24,28,43=9645)=20 but is lethal to animals that have not been treated with=20 interferon (43).=20 Hence, we used a VSV mutant called VSV3D{Delta}=20M51. VSV3D{Delta}=20M51 has a single amino acid deletion = of=20 methionine-51 (M51) of the matrix (M) protein. One of = the=20 functions of the M protein is to block the nuclear to=20 cytoplasmic transport of interferon-beta mRNA, thereby=20 circumventing the cellular interferon response. The = deletion of=20 methionine-51 from the M protein of VSV3D{Delta}=20M51 abolishes this block and restores=20 interferon-mediated responses in normal cells. This = mutant=20 theoretically has an improved therapeutic value (that = is, safer=20 but retaining the same efficacy) compared with = wild-type VSV=20 because it induces a marked interferon response in = normal cells=20 but retains its full oncolytic effect against tumor = cells both=20 in vitro and in vivo (43).=20

During the past several years of oncolytic virus = development,=20 it has become apparent that insufficient viral delivery = can=20 be a key limitation in the treatment of brain tumors (29,38,40,43).=20 Direct inoculation of virus into a tumor may be = advantageous=20 in the treatment of localized tumor, but focal necrosis, = tissue=20 planes, and high intratumoral pressure will still limit = viral=20 distribution. Intravascular administration is an = attractive=20 alternative and may allow for multiple administrations = over=20 a long period of time. Although an intact blood=96brain = barrier will affect delivery to the normal brain, the=20 blood=96tumor barrier is somewhat permeable and may = provide a=20 potential advantage over direct intratumoral = inoculation in=20 delivery to multifocal tumors and invasive tumor cells. = In=20 addition, intravascular injection is simpler, less = expensive,=20 and less invasive clinically than direct local = delivery. A=20 number of preclinical studies have shown that virus = treatments=20 can be delivered to brain tumors via intracarotid = delivery=20 (46=9650),=20 but only two studies have shown intravenous delivery of = an=20 oncolytic virus for the treatment of brain tumors = (51,52).=20 The systemic/vascular delivery of VSV mutants has = previously=20 been shown to be effective in animal models of cancer,=20 including those that had already widely metastasized = (43,53)=20 or were multifocal (54).=20

In this study, we investigated the effects of intravenous = delivery=20 of VSV3D{Delta}=20M51 for the treatment of brain tumors. We carried = out=20 a detailed evaluation of the oncolytic properties of = VSVM51 in vitro, in vivo, and ex vivo in = human=20 malignant glioma surgical specimens. We also compared = the=20 effects of VSV3D{Delta}=20M51 to those of another oncolytic = virus,=20 reovirus. Reovirus has activity against experimental = models of=20 malignant glioma, but a small number of glioma cell = lines are=20 highly resistant to infection and killing by this virus = (8,9).=20


  =20 MATERIALS AND METHODS=20
Top
Notes
Abstract
Introduction
3D"Materials and=20 methods
Results
Discussion
References
 
<= STRONG>Cell=20 Lines

Fourteen human glioma cell lines (U87, U118, U251, U343, = U373,=20 U563, SF126, SF188, SNB19, UC12, UC13, UC14, RG2, and 9L) = and=20 murine NIH3T3 and L929 fibroblast cells were purchased = from=20 the American Type Culture Collection (ATCC, Manassas, VA). = HS68=20 human foreskin fibroblast cells were a gift from Karl = Riabowol=20 (University of Calgary, Canada). All cells were propagated = in=20 Dulbecco's modified Eagle medium/F12 (DMEM/F12, = Hybri-care;=20 ATCC, Manassas, VA) containing 10% fetal bovine serum = (FBS)=20 at 37 =B0C in a humidified, 5% CO2 incubator. = Each cell=20 line was tested regularly for mycoplasma = contamination.=20

Transfection of Glioma Cells With Red Fluorescent=20 Protein

FuGene transfection reagent (Roche Diagnostic Co, = Indianapolis,=20 IN) and an expression plasmid containing red fluorescent=20 protein (RFP) (Clontech, Palo Alto, CA) were used for=20 transfection of a glioma cell line (U87) with RFP, as=20 previously described (7).=20 Briefly, FuGene transfection reagent and RFP:DNA vector = were=20 incubated together for 30 minutes at room temperature in=20 serum-free media. The DNA mixture was applied to U87 = cells for=20 4 hours at 37 =B0C in serum-free media. FBS was then = added to a=20 final concentration of 10%. Cells were grown at 37 =B0C = and 5%=20 CO2, and the culture medium was changed = daily. After=20 4 days, transfected cells were selected for G418 = antibiotic=20 resistance (400 =B5g/mL) and identified by fluorescent=20 microscopy. RFP expression was found in more than 95% = of cells=20 as determined by fluorescence-activated cell sorting; = this=20 method confirmed the purity of the U87-RFP=96expressing=20 cells.

Viruses and Cell Infection

VSV3D{Delta}=20M51 is derived from the Indiana serotype of VSV = and is=20 propagated in Vero cells (African green monkey kidney = cells).=20 VSV3D{Delta}=20M51 has a single amino acid deletion = of=20 methionine-51 of the M protein and contains an extra = cistron=20 that encodes green fluorescent protein (GFP) inserted = between=20 the G and L sequences. This recombinant genome was used = to=20 generate a replication-competent, GFP-expressing VSV = clone=20 (43).=20 Dead virus was prepared by exposing live virus to = ultraviolet=20 (UV) irradiation for l hour. Reovirus serotype 3 = (strain=20 Dearing or T3D) was grown in L929 mouse fibroblast = cells and=20 purified as previously described (55);=20 it was similarly UV inactivated to generate dead virus. = Tumor=20 or normal cells grown to 50%=9660% confluence in = 96-well plates=20 were infected in 50 =B5L of serum-free medium and = incubated for 1=20 hour at 4 =B0C for reovirus or 37 =B0C for VSV3D{Delta}=20M51. Medium (150 =B5L) was then added = to each=20 well, and cells were returned to 37 =B0C at 5% = CO2 for=20 use in subsequent experiments. =

3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyl-2H-Tetrazolium=20 Bromide Assay

Viability of tumor or normal cells infected as above with=20 different doses (multiplicity of infection [MOI] =3D 0, = 1, and=20 10) of VSV3D{Delta}=20M51 or reovirus-T3D was measured 24 = hours=20 (VSV3D{Delta}=20M51) and 72 hours (reovirus) after = infection by=20 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium=20 bromide (MTT) assay, as previously described (55).=20 Briefly, cells were incubated with MTT (1 mg/mL) at 37 = =B0C and=20 5% CO2 for 1 hour and lysed with dimethyl = sulfoxide,=20 and the absorbance was read with an ultra microplate = reader=20 (Bio-Tek Instruments, Inc, Burlington, VT).

Assays to Measure Cytopathic Effect of VSV3D{Delta}=20M51 or Reovirus Infection

All glioma and normal cell lines were seeded at 5 x 104 cells = per well in=20 six-well plates and incubated at 37 =B0C in 5% = CO2=20 overnight. After infection with live or dead VSV3D{Delta}=20M51 at an MOI of 1.0 or 10 for 24=9672 = hours, the=20 cells were examined using a Zeiss inverted microscope = (Axiovert=20 200M) mounted with a Carl Zeiss camera (AxioCam MRc, = Carl Zeiss=20 Inc, Thornwood, NY) to obtain both phase contrast and=20 fluorescent images (using a fluorescein isothiocyanate = filter=20 to visualize virus-encoded GFP).

Western Blot to Detect Viral Proteins

All cell lines were seeded at 5 x=20 104 cells per well in six-well plates and = incubated=20 at 37 =B0C in 5% CO2 overnight. Cells were = then=20 treated with either dead or live VSV3D{Delta}=20M51 virus at an MOI of 1. Twenty-four = hours=20 after infection, the cells were collected by scraping = and were=20 lysed in 500 =B5L of lysis buffer (20 mM Tris pH 8.0, = 136 mM=20 NaCl, 10% glycerol, 1% NP40, 0.02% leupeptin, 0.5% = aprotinin,=20 and 1.5% sodium orthovanadate) for 20 minutes. Cellular = debris=20 was removed by low-speed centrifugation (1000g = for 10=20 minutes) at 4 =B0C. Protein concentration of cell = lysates was=20 determined using the BCA protein assay kit (Biolynx, = Inc,=20 Brockville, ON, Canada). Supernatants were frozen at = =9680 =B0C for=20 long-term storage. For electrophoresis, equal amounts = of=20 protein were separated on 7.5% sodium dodecyl=20 sulfate=96polyacrylamide gels and transferred to = nitrocellulose=20 membranes. Membranes were incubated with polyclonal = anti-VSV=20 antibody (1 : 1000) overnight at 4 =B0C, washed three = times=20 with 1x Tris buffered = saline, and=20 incubated for 1 hour with horseradish peroxidase=20 (HRP)=96conjugated secondary antibody (1 : 3000 = dilution,=20 Biosciences, Amersham, Piscatoway, NJ) at room = temperature=20 (John C. Bell, unpublished). Antibody binding was = detected=20 using an enhanced chemiluminescence reagent (Biosciences,=20 Amersham) according to the manufacturer's instructions. =

Mice

CD-1 nude mice (female, 6=968 weeks old) were purchased = from=20 Charles River Canada, Constant, PQ, Canada. Three to four = mice=20 were caged together in each vivarium with a 12-hour = light/dark=20 schedule at 22 =B1 1 =B0C and a relative humidity of = 50 =B1 5%.=20 Food and water were available ad libitum. In all = experiments,=20 mice were killed by cervical dislocation when they had=20 difficulty ambulating, feeding, or grooming or had lost = at=20 least 20% of their body weight. All animal procedures = were=20 reviewed and approved by the University of Calgary Animal = Care=20 Committee.

In Vivo Oncolysis in Subcutaneous Tumor Model

Female CD-1 nude mice (n =3D 21) were each implanted with 1 = x 106 U87 (n = =3D 11) or=20 U118 (n =3D 10) malignant glioma cells on the right = flank to=20 establish subcutaneous tumors. Tumor size (length x width) was measured daily using = calipers.=20 When palpable tumors reached approximately 25 = mm2,=20 mice were treated intratumorally with live or dead = VSVM51 virus (three injections of VSV3D{Delta}=20M51 1 x=20 107 plaque-forming units [PFU] at 2-day intervals) = (8).=20 Tumor size was then measured until sacrifice was=20 indicated.

Determination of the Toxicity of the Intracerebral=20 Administration of VSV3D{Delta}=20M51 in Nude Mice

Female CD-1 nude mice (n =3D 8) were injected = intracerebrally=20 with either dead or live VSV3D{Delta}=20M51 (5 x = 102,=20 1 x 103, 1 x 104 PFU per = mouse, two=20 mice per dose) at a depth of 3 mm under guidance of a=20 stereotactic frame (Kopf Instruments, Tujanga, CA), as=20 described previously (7,20,56).=20 Briefly, virus was injected intracerebrally into the = right=20 putamen. A 0.5-mm burr hole was made 1.5=962 mm right = of the=20 midline and 0.5=961 mm posterior to the coronal suture = through a=20 scalp incision. Stereotactic injection used a 5-=B5L = syringe=20 (Hamilton Co, Reno, NV) with a 30-gauge needle, = inserted=20 through the burr hole to a depth of 3 mm, mounted on a = Kopf=20 stereotactic apparatus (Kopf Instruments). After 10 = seconds,=20 the needle was withdrawn and the incision was sutured. = Mice=20 were followed daily for toxic effects. After the mice = were=20 killed, their brains, lungs, kidneys, hearts, and = livers were=20 removed, fixed in 10% formalin, embedded in paraffin, = and=20 sectioned with a microtome. Sections were stained with=20 hematoxylin and eosin for histologic analysis, analyzed = for VSV=20 antigens by immunohistochemistry, or analyzed for the = presence=20 of DNA fragments by terminal transferase deoxyuridine=20 triphosphate nick-end labeling (TUNEL) assay.

Immunohistochemistry to Detect VSV Antigens

Frozen sections of mouse brain and major organs (heart, = liver,=20 lung, and kidney) were fixed in 4% paraformaldehyde for 20=20 minutes and washed three times in phosphate-buffered = saline=20 (PBS). Sections were then exposed to primary polyclonal = rabbit=20 anti-VSV antibody at a 1 : 3000 dilution in PBS = containing 2%=20 bovine serum albumin, for 24 hours at 4 =B0C. = Biotinylated=20 anti-rabbit IgG (Vector Laboratories, Burlingame, CA) = was used=20 as the secondary antibody. Sections were then incubated = with=20 avidin conjugated to HRP (Vectastain ABC = immunohistochemistry=20 kit, Vector Laboratories), and staining was visualized = by=20 addition of the DAB (3,3'-diaminobenzidine) substrate. = To=20 visualize VSV antigens, sections were mounted and = viewed with a=20 Zeiss inverted microscope (Axiovert 200M) and a Carl = Zeiss=20 camera (AxioCam MRc) to obtain both phase contrast and=20 fluorescent images.

TUNEL Assay

The presence of fragmented DNA was analyzed with the TUNEL=20 technique using the ApopTag plus fluorescein in situ = apoptosis=20 detection kit (Chemicon, Inc, Temecula, CA) according = to the=20 manufacturer's instructions. Briefly, paraffin-embedded = brain=20 sections were dewaxed in xylene, rehydrated in an = ethanol=20 gradient, and treated with proteinase K (Invitrogen, = Carlsbad,=20 CA; 20 =B5g/mL in PBS) for 20 minutes at room = temperature.=20 Sections were washed in PBS, incubated with reaction = mixture=20 including terminal deoxynucleotidyl transferase and=20 fluorescein-dUTP for 1 hour at 37 =B0C, washed in PBS, = incubated=20 with the antidigoxigenin conjugate for 30 minutes at 37 = =B0C, and=20 then counterstained with 4'-6-diamidino-2-phenylindole. =

Sequencing of M Protein in VSV3D{Delta}=20M51

At 48 hours after intracerebral injections of 1 x 104 PFU of=20 VSV3D{Delta}=20M51, mice were killed by cervical dislocation and = their=20 brains were homogenized in PBS (pH 7.2). Virus was = amplified by=20 a single passage of brain homogenate on Vero cells for = 24=20 hours. Virions were purified from the Vero cell = supernatant by=20 passage through a 0.2-=B5m filter followed by = centrifugation at=20 30 000g for 90 minutes. The virus pellet was = resuspended=20 in PBS, and genomic RNA was extracted by sequential = addition of=20 Trizol (Invitrogen) and chloroform (57),=20 except that rather than lysing and extracting RNA from = the=20 cells, we extracted it from purified VSV particles. = Samples=20 were then centrifuged at 10 000g for 10 minutes, and = the=20 aqueous phase was removed and washed on an RNEasy spin column = (Qiagen, Mississouga, Ontario, Canada) per the = manufacturer's=20 instructions. The RNA product was used as a template in a=20 random hexamer=96primed reaction using Superscript II = reverse=20 transcriptase to generate single-stranded viral cDNA. = From this=20 cDNA template, specific primers (sense:=20 ACGAATTCAAATTAGGGATCGCACCACC, antisense:=20 ACGGATCCCGTGATACTCGGGTTGACCT) were used in the polymerase = chain=20 reaction to amplify a 377-bp fragment spanning bases = 61=96438=20 of the VSV M gene. This product was purified on an agarose = gel=20 and sequenced directly from the above sense primer using = an=20 Applied Biosystems 3730 DNA Analyzer (Ottawa Genomics=20 Innovation Centre).

Determination of the Appropriate VSV3D{Delta}=20M51 Dose for Intravenous Administration in Nude=20 Mice

Female CD-1 nude mice (n =3D 24) received intravenous = injection=20 of dead or live virus (at doses of 5 x 107, 5 x 108, 1 x 109, or 5 = x 109 PFU per mouse) via = the tail=20 vein. Mice were followed for up to 60 days, and their = body=20 weights were recorded every other day. After the mice = were=20 killed by cervical dislocation, their brains and major = organs=20 (liver, lung, heart, and kidney) were saved either for = virus=20 recovery assays in liquid nitrogen or pathologic = analysis in=20 formalin as described above. For the in vivo = therapeutic=20 experiments, we selected a dose that was one dose level = below=20 the dose at which 50% of the mice died; we refer to = this dose=20 as the maximum tolerated.

Virus Recovery Assays

Mice were killed by cervical dislocation, and saline was=20 immediately infused into the left ventricle of the = heart.=20 Tissues were extracted and then homogenized in liquid = nitrogen=20 using a Pellet Pestles Kit (VWR International, = Edmonton,=20 Alberta, Canada) followed by repeated freeze=96thawing = to release=20 virus from the cells. Supernatants were used for plaque = titration on Vero cells as previously described (58).=20 Briefly, Vero cells were plated in six-well plates and = infected=20 with serial dilutions of sample supernatant. = Forty-eight hours=20 after incubation at 37 =B0C in 5% CO2, cells = were=20 overlaid with 2x MEM = (Mediatech,=20 Herndon, VA) and 2x = Noble=20 agar (Difco Laboratories, Detroit, MI) containing 0.2 = mL=20 neutral red (Sigma Chemical, Oakville, Ontario, Canada). = Virus=20 plaques were counted, and PFU were calculated by the number = of=20 plaques multiplied by the dilution factor.

Survival Studies in an Orthotopic Human Glioma Model of = Nude=20 Mice

To investigate the antitumor efficacy of VSV3D{Delta}=20M51 in mice, an orthotopic unilateral = glioma=20 animal model was established with the human glioma cell = line=20 U87. The stereotactic techniques used to implant glioma = cells=20 in the right putamen have been described previously = (7,20).=20 Briefly, female CD-1 nuce mice (n =3D 13) were = anesthetized, and=20 U87 glioma cells (1 x = 105=20 cells per mouse) were implanted under the guidance of a = stereotactic frame, as described above. After 15 days, = mice=20 were injected intravenously via the tail vein with = multiple=20 doses of live (n =3D 8) or dead (n =3D 5) virus (5 = x 108 PFU per mouse every = 2=20 days, for a total of three injections). Mice were = monitored=20 every other day for survival. After the mice were killed, = their=20 brains and major organs were prepared as described above = for=20 histologic analysis, immunohistochemical analysis of VSV=20 antigen, and TUNEL assay to assess apoptosis. =

Survival was also assessed in mice with bilateral brain = tumors.=20 To prepare these mice, we implanted U87 cells (5 x 104cells per = mouse per=20 side in both sides of the brain) in CD-1 nude mice (n = =3D 11).=20 After 11 days, mice were injected intravenously, via = the tail=20 vein, with live (n =3D 6) or dead (n =3D 5) virus (5 = x 108 PFU per mouse) = every other=20 day for three injections and every 5 days for another = three=20 injections for a total of six injections. Survival was=20 followed, and organs were analyzed as above. =

VSV3D{Delta}=20M51 Viral Distribution Stufdies

To determine if VSV3D{Delta}=20M51 targets multifocal gliomas in the brain, = we=20 established a dual tumor model using U87 tumor cells. Cells=20 were implanted by stereotactic techniques as described = above=20 in CD-1 nude mice (n =3D 18). After 15 days, each mouse was=20 injected intravenously, via the tail vein, with a = single dose=20 of VSV3D{Delta}=20M51 (5 x=20 108 PFU per mouse). Mice were killed at the following = time=20 points after virus injection (three mice at each time = point):=20 0 hour, 10 hours, 24 hours, 72 hours, 7 days, and 15 days.=20 After sacrifice by cervical dislocation, a whole brain = picture=20 was taken with a Leica MZ-FLIII fluorescence = stereomicroscope=20 using a standard GFP filter set (6,20).=20 Photoshop 6.0 (Adobe) was used to process the images. = After=20 imaging, the brain and other major organs were removed = and=20 frozen in liquid nitrogen for virus recovery = assays.=20

To determine the ability of VSV3D{Delta}=20M51 to target invasive cells, we = implanted=20 U87-RFP cells (3 x = 105 per=20 mouse) into the brains of mice (n =3D 6) to generate = tumors.=20 After 15 days, we injected VSV3D{Delta}=20M51 (5 x = 108=20 PFU per mouse) intravenously, via the tail vein, into=20 tumor-bearing mice. After 72 hours, mice were perfused = with 5=20 mL of saline and killed by cervical dislocation. The = brains=20 were removed and embedded in OCT embedding medium. = RFP-expressing=20 tumors and GFP-labeled viruses were visualized in frozen = brain=20 sections by a Zeiss inverted microscope (Axiovert 200M) = with=20 a fluorescent GFP or rhodamine filter set (20).=20 Immunohistochemical staining of VSV antigen was = performed on=20 tissue sections. A Carl Zeiss camera (AxioCam MRc) was = used to=20 obtain both phase contrast and fluorescent images of = the tumor=20 cell=96expressed RFP and the virus-expressed GFP. =

Primary Human Glioma Culture

Short-term cultures were established from patient samples = of=20 human gliomas (n =3D 15) obtained following brain tumor = surgery=20 at the Foothills Hospital (Calgary); this study was = approved=20 by the Conjoint Medical Ethics Committee. Briefly, each = patient=20 specimen was split in two pieces; one portion of the = specimen=20 was fixed in 10% formalin and the other portion of the = specimen=20 was used for short-term cultures. The tumor tissue that = was=20 used to establish short-term cultures was washed several = times=20 in sterile saline, transferred to a 35-mm tissue culture = dish,=20 cut into small pieces (approximately 0.5=961 mm in = diameter),=20 and dissociated with trypsin (0.25%) and 50 =B5g/mL=20 deoxyribonuclease (Roche Diagnostics, Laval, PQ, = Canada) for 30=20 minutes at 37 =B0C. After filtering and washing with = DMEM/F12=20 (containing 20% FBS), cells were resuspended in 20% FBS = in=20 DMEM/F12 and plated (at 10 000=96100 000 cells per = well) in=20 96-well plates. Cells were infected the following day = with=20 VSV3D{Delta}=20M51 virus, both live and UV = inactivated, at MOIs=20 of 0.1, 1, and 10. Cell viability was measured 72 hours = later=20 by MTT and cytopathic effect assays [as above and in = (20)].=20

Primary Tumor Immunocytochemistry for Glial Fibrillary = Acid=20 Protein Expression

Primary tumor cells obtained from surgical specimens were = grown=20 in eight-well chamber slides (50 000=96200 000 cells = per=20 well) and fixed for 15 minutes in 4% paraformaldehyde. = Cells=20 were then blocked with 10% goat serum and 0.1% Triton = X-100=20 in PBS for 30 minutes. Primary antibody (glial fibrillary=20 acidic protein [GFAP] monoclonal antibody 1 : 1000, = Chemicon,=20 Inc) was then added. After 24 hours at 4 =B0C, cells = were=20 washed with PBS and then incubated with anti-mouse = IgG-Cy3=20 (Vector Laboratories) for 1 hour. Sections were mounted = with=20 Geltol mounting medium (Fisher scientific Co, = Pittsburgh, PA)=20 and viewed with a Zeiss microscope (Axiovert 200M), and = pictures were taken with a Zeiss inverted microscope = and a Carl=20 Zeiss camera (Axiocam MRC).

Statistical Analyses

Statistical Analysis Software (SAS Institute, Inc, Cary, = NC)=20 and GraphPad Prism (version 4; GraphPad Software Inc, San=20 Diego, CA) were used for statistical analyses. Survival = curves=20 were generated by the Kaplan=96Meier method. The = log-rank=20 test and two-way analysis of variance (ANOVA) were used = to=20 compare the effect of different forms of treatment = (live virus=20 versus dead virus) and the time since administration on = tumor=20 size. All reported P values were two-sided and = were=20 considered to be statistically significant at=20 P<.05.


  =20 RESULTS =
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Notes
Abstract
Introduction
Materials and methods
3D"Results
Discussion
References
 
<= STRONG>Susceptibility=20 of Human Malignant Glioma Cell Lines to Infection and Killing by=20 VSV3D{Delta}=20M51

Fourteen malignant glioma cell lines were tested for=20 susceptibility to infection and killing by VSV3D{Delta}=20M51 and reovirus T3D by cytopathic = effect and=20 MTT assays (representative examples in Fig.=20 1). All 14 cell lines were susceptible to infection = and=20 killing by VSV3D{Delta}=20M51, whereas only 12 (85%) of the = lines were=20 susceptible to infection and killing by reovirus (U118 = and U343=20 were resistant). In contrast, neither of the normal = cell lines=20 tested (HS68 and NIH3T3) was killed by VSV3D{Delta}=20M51 or reovirus. Cells were infected with = either=20 1 MOI of VSV3D{Delta}=20M51 or 10 MOI of reovirus; complete cell death = was=20 observed in all glioma cell lines 48 hours after infection = with=20 VSV3D{Delta}=20M51 (Fig.=20 1, A) but not until 144 hours after infection with = reovirus=20 (Fig.=20 1, B). Untreated cells and cells treated with=20 UV-inactivated (dead) virus did not exhibit any cytopathic=20 effect at any time point assessed.



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  = 		Fig. 1. Effects of = vesicular=20 stomatitis virus strain 3D{Delta}=20M51 (VSV3D{Delta}=20M51) and reovirus T3D in vitro on = established=20 human malignant glioma cell lines. A) = Cytopathic=20 effects on glioma (U87, U118, U251, U373, U343) and = normal=20 (NIH3T3, HS68) cell lines of dead and live = VSVM51 at multiplicity of infection = (MOI) =3D 1, 48=20 hours after infection (magnification: x100). B) = Cytopathic=20 effects on the same cell lines of dead and live = reovirus at 10=20 MOI, 144 hours after infection, when the full = cytopathic=20 effect of reovirus was produced (magnification: x100). C)=20 = 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium=20 bromide assay comparing the effects of VSVM51 or reovirus on the viability of = glioma cell=20 lines (U87, U118, U251, U373, U343) and normal cell = lines=20 (NIH3T3, HS68); ultraviolet-inactivated viruses were = used as a=20 negative control. D) Detection of VSV proteins = by=20 western blot after infection of glioma cell lines with = VSV3D{Delta}=20M51. =

 = ;
The=20 MTT viability assay confirmed the results from the cytopathic = effect assays (Fig.=20 1, C). VSV3D{Delta}=20M51 produced more rapid glioma cell = killing and=20 at a lower (1 MOI, 24 hours) MOI than reovirus T3D (10 = MOI, 72=20 hours) (Fig.=20 1, C). Extensive cell killing was found in all = glioma cell=20 lines in the presence of VSV3D{Delta}=20M51. The normal cell lines NIH3T3 and = HS68 were=20 not susceptible to either reovirus or VSV3D{Delta}=20M51 (Fig.=20 1, C). To ensure that cell killing following = treatment with=20 VSV3D{Delta}=20M51 was due to viral infection rather = than a=20 nonspecific effect, viral protein production was assessed = by=20 western blotting. All glioma lines exhibited viral protein=20 production 24 hours after infection, in accordance with = their=20 susceptibility to killing by VSV (Fig.=20 1, D), whereas no viral protein production was seen = in=20 normal cell lines (Fig.=20 1, D).

Effects of Intratumoral Administration of VSVM51 on a Glioma Cell Line Resistant to Infection = by=20 Reovirus

We next investigated if VSV3D{Delta}=20M51 would infect and kill a cell line = resistant=20 to reovirus in a subcutaneous tumor in CD-1 nude mice. = We=20 treated mice bearing subcutaneous human malignant glioma=20 xenografts of U87 (susceptible to reovirus) and of U118=20 (resistant to reovirus). These cells were implanted in = the hind=20 flanks of mice, which were treated intratumorally with = live or=20 dead virus after palpable tumors had formed (1 x 107 PFU per mouse, = every other day, for a period of 6 days). We observed=20 statistically significant inhibition of tumor growth in = the=20 live virus=96treated mice compared with the dead = virus=96treated=20 control mice bearing either U87 (ANOVA, = P<.0001) (Fig.=20 2, A) or U118 (two-way ANOVA, P<.0001) = tumors (Fig.=20 2, B).



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  = 		Fig. 2. Effects of = vesicular=20 stomatitis virus strain 3D{Delta}=20M51 (VSV3D{Delta}=20M51) on growth of = reovirus-susceptible (U87)=20 and reovirus-resistant (U118) glioma in a subcutaneous = model=20 of malignant gliomas in CD-1 nude mice. Mice bearing=20 subcutaneous glioma implants were treated = intratumorally with=20 live or dead VSV3D{Delta}=20M51 virus when a palpable tumor = reached=20 approximately 25 mm2; tumor size (length = x width) was measured = using a=20 caliper. A) U87-derived gliomas, live virus = (closed=20 circles, n =3D 6) versus dead virus (open = diamonds, n=20 =3D 5). B) U118-derived gliomas, live virus = (closed=20 circles, n =3D 6) versus dead virus (open = diamonds, n=20 =3D 4). Results shown are the means and 95% confidence = intervals=20 of the tumor size. =

 = ;
Toxicity=20 of Intracerebrally Administered VSV3D{Delta}=20M51 in CD-1 Nude Mice

We evaluated the toxicity of VSV3D{Delta}=20M51 in vivo when administered = intracerebrally. A=20 single intracerebral administration of VSV3D{Delta}=20M51 was lethal, even at a dose as low = as 5 x 102 PFU per mouse (Fig.=20 3, A). This experiment was repeated three times = with=20 similar results (data not shown). Following = intracerebral=20 administration we found a diffuse meningoencephalitis, = a marked=20 tropism for neurons, and neuronal apoptosis. This was = severe in=20 the hippocampus (Fig.=20 3, B) and brain stem (data not shown), and the = affected=20 areas were positive for VSV antigen expression and = TUNEL=20 staining (Fig.=20 3, B).



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  = 		Fig. 3. = Determination of the=20 maximum tolerated intracerebral dose of vesicular = stomatitis=20 virus strain 3D{Delta}=20M51 (VSV3D{Delta}=20M51). A) Intracerebral = administration:=20 Normal CD-1 nude mice received a single administration = of=20 either ultraviolet-inactivated (dead virus) = VSVM51 or live VSV3D{Delta}=20M51 at doses of 5 x 102,1 x 103, or 1 = x 104 = plaque-forming=20 units (PFU) per mouse, two mice per dose. Mice were = monitored=20 for a period of 20 days. B) Neurotoxicity in = mouse=20 brain treated with VSV3D{Delta}=20M51 (1 x=20 104 PFU per mouse) administered = intracerebrally=20 (magnification: x25 and=20 x400). = Representative images=20 show mouse brain stained for hematoxylin and eosin = (H&E)=20 (top row), by immunohistochemistry (IHC) for = VSV=20 antigen (middle row), and by terminal = transferase=20 deoxyuridine triphosphate nick-end labeling (TUNEL) = assay=20 (bottom row). Right column is a = higher-magnification=20 view of the hippocampus region of the brain. =

 = ;
We=20 were surprised that the mutant VSV3D{Delta}=20M51, which was engineered to enhance = the=20 antiviral responses in normal cells, retained = substantial=20 neurotoxicity when administered intracerebrally. To = exclude the=20 possibility that the VSV3D{Delta}=20M51 had reverted to wild-type VSV = (i.e., lost=20 the mutation in the M protein), we sequenced the M = protein of=20 virus collected from mice after intracerebral = administration.=20 We confirmed that the virus cultured from the brains = retained=20 the mutation in the M protein and had not reverted to = wild-type=20 VSV.

Safety Evaluation of Intravenous Administration of = VSVM51 in Nude Mice

We next evaluated the toxicity and maximum tolerated dose = of=20 VSV3D{Delta}=20M51 administered intravenously. The mice = tolerated much=20 higher doses of intravenously than intracerebrally = administered=20 VSV3D{Delta}=20M51. All mice (n =3D 4 per group) = administered=20 intravenously, via the tail vein, with doses of 3D≤=201=20 x 109 PFU survived = and=20 appeared normal for up to 60 days (Fig.=20 4, A), when we terminated the experiment by killing = all=20 mice that were still alive. At a dose of 5 x 109 PFU (the = highest=20 dose we were technically capable of preparing), = however, only=20 50% (two of four) of the mice survived for 60 days (Fig.=20 4, A). A transient and not statistically significant = weight=20 loss was observed 3=9611 days after intravenous virus=20 administration in surviving mice of both the 5 x 109 PFU and = the 1=20 x 109 PFU groups = (Fig.=20 4, B). Control mice treated with dead virus = appeared=20 normal. Hence, 1 x = 109 PFU=20 was the maximum tolerated dose when administered = intravenously,=20 and we used one dose level below this dose for all = subsequent=20 therapeutic experiments.



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  = 		Fig. 4. Safety and = toxicity=20 evaluation of vesicular stomatitis virus strain M51 (VSV3D{Delta}=20M51) when administered intravenously = to nude=20 mice. A) Intravenous administration of = VSVM51 in CD-1 nude mice at doses of 5 = x 107, 5 = x 108, 1 = x 109, or 5 = x 109 = plaque-forming=20 units (PFU) per mouse (n =3D 4 per group). Mice were = given a=20 single injection of dead or live VSV3D{Delta}=20M51 intravenously, via the tail vein, = and=20 monitored for 60 days. B) Mean body weight over = time of=20 mice intravenously administered VSV3D{Delta}=20M51. =

 = ;
The=20 histology of major organs (brain, liver, lung, kidney, and=20 heart) of mice treated with a dose of 5 x 108 PFU was = normal,=20 and there was no histologic evidence of apoptosis by TUNEL=20 assay (data not shown). In addition, we detected no = viral=20 antigen expression in liver, lung, kidney, or heart by=20 immunohistochemistry, although in the brain there was = minor VSV=20 antigen staining within the meninges or ventricle at 24 = and 72=20 hours after intravenous administration of virus (data = not=20 shown). Similar results were obtained by virus recovery = assay.=20 Virus was detected in the brain (but not in any other = organs)=20 only beginning 4 hours after intravenous = administration,=20 peaking at 24 hours, and declining thereafter (data not = shown).

Survival Following Systemic Intravenous Administration = of=20 VSV3D{Delta}=20M51 in CD-1 Nude U87 Tumor=96Bearing = Mice

We evaluated the effect of VSV3D{Delta}=20M51 delivered intravenously to mice = with=20 unilateral or bilateral brain tumors. Unilateral or = bilateral=20 U87 glioma orthotopic xenograft models were established = by=20 intracerebral inoculation of U87 cells into the brains of = CD-1=20 nude mice. Mice were treated intravenously with multiple = doses=20 of VSV3D{Delta}=20M51 either 15 days (for unilateral tumors) or = 11=20 days (for bilateral tumors) after tumor implantation. Mice = with=20 unilateral tumors treated with live virus survived=20 statistically significantly longer (mean =3D 113 days, = 95% CI =3D=20 96 to 130 days) than those treated with dead virus = (mean =3D 46=20 days, 95% CI =3D 39 to 53 days, log-rank test, P = =3D .0001)=20 (Fig.=20 5, A). All mice eventually died from recurrent = tumors=20 between 35 and 140 days after tumor implantation. = Similar,=20 although less dramatic, results were found in mice = harboring=20 bilateral U87 human malignant gliomas. The median = survival of=20 dead versus live virus=96treated mice was 46 versus 73 = days,=20 respectively (difference =3D 27 days, 95% CI =3D 38 to = 54 days, and=20 95% CI =3D 62 to 84 days, respectively, log-rank test, = P =3D=20 .0025; Fig.=20 5, B). Similar results were obtained when these = experiments=20 were repeated (data not shown).



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  = 		Fig. 5. Systemic=20 administration of vesicular stomatitis virus strain = M51 (VSV3D{Delta}=20M51) and survival of nude mice with = unilateral=20 and bilateral U87 cell=96derived brain tumors. = A)=20 Unilateral tumor model. Kaplan=96Meier survival = analysis of mice=20 implanted with U87 cells (1 x 105 cells = per mouse)=20 and treated with either dead (n =3D 5) or live (n =3D = 8) virus=20 every 2 days for a total of three doses. One = intravenous=20 injection contained 5 x=20 108 plaque-forming units (PFU) per mouse. = All=20 P values are two-sided. B) Bilateral = tumor=20 model. Kaplan=96Meier survival analysis of mice = implanted with=20 U87 cells (5 x=20 104 cells per mouse per side) and injected = with=20 either dead (n =3D 5) or live (n =3D 6) virus (5 x 108 PFU per = mouse=20 three times every 2 days followed by three times every = 5 days=20 for a total of six injections. All P values are = two-sided. Arrows in (A) and (B) = indicate=20 virus injections. C) Representative = photomicrographs of=20 a whole brain slice from a live virus=96treated mouse=20 (magnification: left, x25;=20 right, x400). = Top row=20 of panels shows hematoxylin and eosin staining = (H&E) of=20 the hippocampus region, middle row of panels = shows=20 immunohistochemical (IHC) staining of the VSV antigen = in the=20 hippocampus region, and bottom row of panels = shows=20 terminal transferase deoxyuridine triphosphate = nick-end=20 labeling (TUNEL) assay of the hippocampus. Adjacent = brain=20 sections were used. Arrows indicate the tumor. =

 = ;
Histologic=20 analysis showed that all live virus=96 and dead = virus=96treated=20 mice died from a large tumor in the brain, with some = live=20 virus=96treated mice having slightly larger ventricles = than dead=20 virus=96treated mice (data not shown). There was no=20 histologically evident change in the hippocampus region = of the=20 brain, immunohistochemical staining evidence of viral = infection=20 of the hippocampus, or evidence of apoptosis by TUNEL = staining=20 of the hippocampus (Fig.=20 5, C).

Infection of Multifocal Gliomas and Invasive Tumor = Cells With=20 Intravenous VSV3D{Delta}=20M51

Having shown that intravenous VSV3D{Delta}=20M51 prolonged survival of mice bearing = gliomas,=20 we evaluated whether a productive infection occurred in = the=20 tumors and characterized the distribution of infection = in the=20 tumor margin and invasive glioma cells. Mice (n =3D 18) = were=20 implanted in both brain hemispheres with U87 cells and = were=20 administered a single intravenous dose of 5 x 108 PFU per = mouse=20 GFP-labeled VSV3D{Delta}=20M51 15 days after tumor implantation. = Mice were=20 killed at multiple time points (three mice per time = point), and=20 their brains were examined in detail. GFP-expressing = virus, as=20 visualized by fluorescence microscopy, was confined to = the=20 tumor, with no expression elsewhere in the normal brain, = lung,=20 kidney, liver, or heart. Viral expression of GFP began = 10 hours=20 after infection, increased up to 72 hours, decreased = slightly=20 by day 7, and was undetectable by 15 days after viral=20 administration (Fig.=20 6, A). The viral titers from the tumor tissues, as=20 determined by virus recovery assays (Fig.=20 6, B), confirmed that a productive viral infection = occurred=20 in these tissues and that the infection had a similar = temporal=20 profile to the results based on fluorescence = microscopy. No=20 evidence of replicating virus was found in=20 non=96tumor-containing brain tissue (data not shown) or = dead=20 virus=96treated brains (data not shown).



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  = 		Fig. 6. = Distribution of=20 intravenously administered vesicular stomatitis virus = strain=20 3D{Delta}=20M51 (VSV3D{Delta}=20M51) expressing green fluorescent = protein (GFP)=20 in multifocal gliomas and invasive tumor cells. Mice = bearing=20 intracerebral bilateral U87 tumors were treated = intravenously=20 with live or dead VSV3D{Delta}=20M51 virus. Mice were killed at = several=20 timepoints, and localization of tumor and virus was = assessed.=20 A) Photomicrograph of GFP-expressing virus in = bilateral=20 tumors. Arrows indicate GFP-virus expression. = B)=20 Titer of virus present in the bilateral tumors (n =3D = 3 mice per=20 time point). Tumors on each side of the brain were = harvested=20 for virus extraction, and the samples were analyzed by = virus=20 recovery assay. The error bars indicate upper = 95%=20 confidence intervals. C) Localization of = VSVM51 expression in experimental = invasive gliomas=20 using fluorescence microscopy and immunohistochemistry = (IHC)=20 VSV antigen staining. Mice bearing U87-RFP=96labeled = tumors were=20 injected intravenously, via the tail vein, with a = single dose=20 of VSV3D{Delta}=20M51 and were killed 72 hours later. = Left=20 three panels of the top row show fluorescent = images of a=20 representative RFP-labeled tumor and GFP virus = expression in=20 frozen sections (magnification: x25); left three = panels of the=20 center and bottom rows show representative GFP = virus=20 targeting the invasive RFP-glioma cells (rows show = increasing=20 magnification of the same section: top row, = x25; center row, = x200; bottom row, = x400). White = arrows=20 indicate the edge of the tumor. Merged refers to a=20 superimposed image of tumor and virus (third = column).=20 IHC of VSV3D{Delta}=20M51 protein on consecutive sections = (right=20 column) confirms the presence of viral proteins in = the=20 invasive glioma cells (brown staining; magnification, = top to=20 bottom: x25, x200, x400). =

 = ;
To=20 determine whether VSV3D{Delta}=20M51 infects invasive glioma cells that = have=20 migrated beyond the main glioma mass, we inoculated U87 = cells=20 that had been transfected with an expression plasmid = containing=20 RFP into the brains of six CD-1 nude mice. Fifteen days = after=20 implantation, a single intravenous dose of VSV3D{Delta}=20M51 was administered, and (based on = the in vivo=20 viral distribution results above) the mice were killed = 72 hours=20 later. We then examined the sections of the brain using = fluorescence microscopy and immunohistochemistry. We = found that=20 viral GFP colocalized with the tumoral RFP using = fluorescence=20 microscopy and colocalization of VSV proteins and tumor = cells=20 by immunohistochemistry (Fig.=20 6, C). In addition, viral GFP expression = colocalized with=20 isolated invasive tumor cells at the margins of the = tumor (Fig.=20 6, C).

Infection and Killing by VSV3D{Delta}=20M51 of Primary Human Malignant Gliomas Cultured = From=20 Surgical Specimens

We next determined whether the in vitro cell line results = would=20 also apply to glioma samples from patients. Accordingly, = we=20 tested whether VSV3D{Delta}=20M51 could infect and kill short-term glioma=20 cultures derived from glioma surgical specimens. We = examined=20 the susceptibility to VSV3D{Delta}=20M51 of 15 ex vivo brain tumor surgical = specimens=20 derived from four glioblastomas, five oligodendrogliomas, = five=20 astrocytomas, and one gliosarcoma. All specimens tested = (15/15)=20 were killed by VSV3D{Delta}=20M51 infection (Fig.=20 7, A) and to a degree that was similar to infection = and=20 killing of U87. A widespread cytopathic effect and = viral GFP=20 expression was seen in live virus=96treated glioma = cells (Fig.=20 7, B-ii, iii, v, vi). In contrast, short-term = cultures=20 treated with dead virus showed no cytopathic effect or = viral=20 GFP expression (Fig.=20 7, B-i, iv). GFAP staining confirmed the glial = lineage of=20 the astrocytic specimens (e.g., a glioblastoma) (Fig.=20 7, C-i), which was also apparent morphologically = using=20 hematoxylin and eosin staining (Fig.=20 7, C-ii, iii).



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  = 		Fig. 7. Effect of = vesicular=20 stomatitis virus strain 3D{Delta}=20M51 (VSV3D{Delta}=20M51) on human primary tumor samples. = A)=20 The viability of the glioma samples was measured by = the=20 = 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium=20 bromide assay, 72 hours after infection with = VSVM51 (0.1=9610 multiplicity of = infection).=20 Error bars indicate 95% confidence intervals of = three=20 independent experiments performed in triplicate. = Samples of=20 dissociated tumor cells from a surgical sample of = glioma were=20 plated and 24 hours later infected with either live or = dead=20 virus. U87 malignant glioma and HS68 (nontransformed = human=20 fibroblasts) were used as positive and negative = controls for=20 VSV3D{Delta}=20M51susceptibility. B) Virus = infectivity=20 and cell killing were confirmed by assessing the = cytopathic=20 effect (CPE) and virus green fluorescent protein (GFP) = expression; shown are phase contrast (upper = panel) and=20 fluorescent GFP (lower panel) images from a=20 representative human glioblastoma taken 24 hours after = infection (magnification: ii and v, x100; iii and vi, x400). Dead virus was = used as a=20 negative control (i and iv, x100). C) Glial = fibrillary=20 acidic protein (i) and hematoxylin and eosin staining = (ii and=20 iii) of the same sample as above (magnification: i, = x400; ii, x100; iii, x400). =

 = ;

  =20 DISCUSSION =
Top
Notes
Abstract
Introduction
Materials and methods
Results
3D"Discussion
References
 
W= e=20 found that an attenuated VSV mutant, designated VSV3D{Delta}=20M51, infected and killed all malignant = glioma=20 cell lines tested and did not infect normal cells in = vitro.=20 When administered intravenously to CD-1 nude mice = bearing human=20 gliomas, VSV3D{Delta}=20M51 dramatically prolonged their = survival and=20 infected both multifocal gliomas and invasive glioma = cells. The=20 invasive and multifocal natures of glioma are major = clinical=20 challenges in treating this disease.

An ideal oncolytic virus for cancer should have several=20 characteristics (38,42,59).=20 It should have effective delivery into multiple sites = within=20 the tumor, evade innate and acquired immune responses, = produce=20 rapid viral replication, spread within the tumor, and = infect=20 multifocal tumors. It should also be "engineerable" so = that it=20 can be modified to, for example, improve its efficacy = or tumor=20 targeting. This is precisely what we found using the = attenuated=20 live virus we constructed (VSV3D{Delta}=20M51). Its efficacy was maintained and = the=20 antiviral responses were enhanced in normal cells, = thereby=20 improving its therapeutic index (43).=20 In addition, we found that VSV3D{Delta}=20M51 infects both multifocal gliomas = and invasive=20 glioma cells. Conventional therapies such as surgery = and=20 radiotherapy are ineffective in treating invasive glioma = cells=20 because these cells may have become more resistant to = these=20 therapies than the tumor cells in the main tumor mass = by=20 adopting a number of cellular characteristics (e.g., = increasing=20 expression of survival pathways, decreasing expression of=20 apoptotic programs, reduced proliferation, etc.) (60).=20 Hence, VSV3D{Delta}=20M51 may represent an effective = treatment for=20 these chemotherapy-resistant tumor cells.

We compared the effectiveness and toxicities of VSVM51 to reovirus in this study on the = basis of=20 our previous work (8,9,55).=20 We found that VSV3D{Delta}=20M51 was superior in several ways to reovirus = for=20 treating gliomas. VSV3D{Delta}=20M51 killed all glioma lines we tested = (including=20 two that were resistant to reovirus), was effective in = vivo=20 when administered systemically, infected invasive glioma = cells,=20 and killed multifocal gliomas. By contrast, reovirus did = not=20 cause regression of bilateral gliomas in an = immunocompetent=20 racine glioma model (55).=20 However, reovirus is superior to VSV3D{Delta}=20M51 in many other ways. When = administered=20 intratumorally, reovirus "cures" experimental gliomas = in the=20 majority of glioma-bearing mice (i.e., mice survived = until the=20 experiment was arbitrarily terminated 90 days after = tumor=20 implantation, often without histologic evidence of = residual=20 tumor) (8),=20 whereas we found that intravenous VSV3D{Delta}=20M51 did not cure any mice. Finally, unlike = VSVM51, reovirus is benign when = administered=20 intracerebrally in adult nude mice (8)=20 or immunocompetent rats (55).=20 Comparisons between oncolytic viruses of putative = efficacy or=20 toxicities in animal models at present are very limited = (61).=20 Definitive conclusions regarding efficacy or toxicity = await the=20 testing of these oncolytic viruses in clinical trials = in=20 malignant glioma patients.

Our study has several limitations. First, we have not yet=20 evaluated VSV3D{Delta}=20M51 in immunocompetent models of gliomas. Such=20 evaluation is important because immune responses = (partially=20 ablated in the immunocompromised mice we used here) may = limit=20 delivery of the virus to the tumor when administered=20 intravenously. Immune responses may also limit the = distribution=20 of the virus within the tumor. Second, the precise = mechanism by=20 which intravenous VSV3D{Delta}=20M51 accesses the invasive glioma cells, which in = many=20 cases appear to be single cells, is unknown. The main = tumor=20 mass of U87 is highly vascularized and has a "leaky"=20 blood=96brain barrier, which would allow intravenously = delivered=20 virus access to the main tumor mass (62,63).=20 In contrast, invasive glioma cells are not believed to = be=20 extensively vascularized (64)=20 and would therefore have limited contact with = systemically=20 delivered virus. We assume that higher pressure within = the=20 tumor mass (65)=20 and high concentrations of virus within the tumor, under=20 pressure, may move the virus out along tracts of white = matter.=20 Because these invasive cells may be in a hypoxic = environment,=20 it should be noted that VSV is able to infect and kill = hypoxic=20 glioma cells both in vitro and in vivo (24).=20 Alternatively, peritumoral increases in neovascularity = and=20 tissue edema can increase the permeability of the = blood=96brain=20 barrier (66,67),=20 allowing the virus to leak out into the perivascular=20 interstitium around the vessels. Third, all the = glioma-bearing=20 mice ultimately died from recurrent tumor. We are now = exploring=20 strategies to understand the causes of treatment = failure with=20 the goal of improving its efficacy (e.g., using live = imaging of=20 viral delivery, improving blood=96brain barrier = breakdown and=20 intra-arterial delivery, etc.).


  =20 NOTES =
Top
3D"Notes
Abstract
Introduction
Materials and methods
Results
Discussion
References
 
<= A=20 name=3D"">This work was funded by the National = Cancer=20 Institute of Canada with funds raised by the Canadian = Cancer=20 Society (D. Stojdl and P. A. Forsyth), a Program = Project Grant=20 from the Terry Fox Foundation (J. C. Bell and P. A. = Forsyth),=20 and the Clark Smith Integrative Brain Tumor Research = Center (P.=20 A. Forsyth and D. L. Senger). T. Alain is funded by the = Alberta=20 Heritage Foundation for Medical Research and a = fellowship by=20 the Canadian Institutes of Health Research. The = sponsors had no=20 role in the design, analysis, writing, or decision to = submit=20 the study for publication.

Funding to pay the Open Access = publication=20 charges for this article was provided by the Clark = Smith=20 Integrative Brain Tumor Center.


  =20 REFERENCES =
Top
Notes
Abstract
Introduction
Materials and methods
Results
Discussion
3D"References
&nb= sp;

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Manuscript received December 16, 2005; revised August 18, 2006; = accepted September 8, 2006.



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=0A= if (isIE6) {=0A= var dx =3D 0, dy =3D -42;=0A= document.all["searchmenu"].style.pixelTop +=3D dy;=0A= document.all["searchmenu"].style.pixelLeft +=3D dx;=0A= document.all["closerMain"].style.pixelTop +=3D dy;=0A= document.all["closerMain"].style.pixelLeft +=3D dx;=0A= document.all["closerTop"].style.pixelTop +=3D dy;=0A= document.all["closerTop"].style.pixelLeft +=3D dx;=0A= document.all["closerLeft"].style.pixelTop +=3D dy;=0A= document.all["closerLeft"].style.pixelLeft +=3D dx;=0A= document.all["closerRight"].style.pixelTop +=3D dy;=0A= document.all["closerRight"].style.pixelLeft +=3D dx;=0A= }=0A= }=0A= init =3D true=0A= }=0A= =0A= // returns left coordinate of the magnet=0A= function getRelativeX() {=0A= var iLeft=3D0;=0A= var objName=3D"magnet"=0A= if (isNS) {=0A= iLeft =3D document.layers[objName].pageX // include the width of the = spacer=0A= } else {=0A= var ieObj =3D document.all[objName]=0A= var oCurrentNode=3DieObj=0A= while(oCurrentNode.tagName !=3D "BODY"){=0A= iLeft 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document.all.closerMain.style.visibility=3D"hidden"=0A= document.all.closerTop.style.visibility=3D"hidden"=0A= document.all.closerLeft.style.visibility=3D"hidden"=0A= document.all.closerRight.style.visibility=3D"hidden"=0A= }=0A= }=0A= =0A= // show the invisible pads that closes the menu=0A= function showCloser() {=0A= if(isNS){=0A= document.layers["closerMain"].visibility =3D "visible"=0A= document.layers["closerTop"].visibility =3D "visible"=0A= document.layers["closerLeft"].visibility =3D "visible"=0A= document.layers["closerRight"].visibility =3D "visible"=0A= } else {=0A= document.all["closerMain"].style.visibility =3D "visible"=0A= document.all["closerTop"].style.visibility =3D "visible"=0A= document.all["closerLeft"].style.visibility =3D "visible"=0A= document.all["closerRight"].style.visibility =3D "visible"=0A= }=0A= }=0A= =0A= // show a given menu=0A= function show(which){=0A= if (!init) return true;=0A= var obj =3D (isNS) ? document.layers[which] : document.all[which].style=0A= // alert(obj.visibility)=0A= if (obj.visibility !=3D "visible") {=0A= hideAll()=0A= obj.visibility =3D "visible"=0A= showCloser()=0A= }=0A= return true;=0A= }=0A= =0A= // fix NS resize problem=0A= function WM_netscapeCssFix() {=0A= =0A= if (document.WM.WM_netscapeCssFix.initWindowWidth !=3D = window.innerWidth || document.WM.WM_netscapeCssFix.initWindowHeight !=3D = window.innerHeight) document.location =3D document.location;=0A= }=0A= =0A= function WM_netscapeCssFixCheckIn() {=0A= if ((navigator.appName =3D=3D 'Netscape') && = (parseInt(navigator.appVersion) =3D=3D 4)) {=0A= if (typeof document.WM =3D=3D 'undefined') {=0A= document.WM =3D new Object;=0A= }=0A= =0A= if (typeof document.WM.WM_scaleFont =3D=3D 'undefined') {=0A= document.WM.WM_netscapeCssFix =3D new Object;=0A= document.WM.WM_netscapeCssFix.initWindowWidth =3D = window.innerWidth;=0A= document.WM.WM_netscapeCssFix.initWindowHeight =3D = window.innerHeight;=0A= }=0A= =0A= window.onresize =3D WM_netscapeCssFix;=0A= }=0A= }=0A= =0A= WM_netscapeCssFixCheckIn()=0A= =0A= ------=_NextPart_000_0000_01C7068F.2ABF5260 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://jncicancerspectrum.oxfordjournals.org/javascript/ajax/xmlhttprequest.js /*=0A= =0A= Cross-Browser XMLHttpRequest v1.2=0A= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=0A= =0A= Emulate Gecko 'XMLHttpRequest()' functionality in IE and Opera. Opera = requires=0A= the Sun Java Runtime Environment .=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_0000_01C7068F.2ABF5260 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://jncicancerspectrum.oxfordjournals.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name =3D=3D "border-top-color") {=0A= e.style.borderTopColor =3D value;=0A= }=0A= else if (name =3D=3D "border-top-style") {=0A= e.style.borderTopStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top-width") {=0A= e.style.borderTopWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-width") {=0A= e.style.borderWidth =3D value;=0A= }=0A= else if (name =3D=3D "bottom") {=0A= e.style.bottom =3D value;=0A= }=0A= else if (name =3D=3D "clear") {=0A= e.style.clear =3D value;=0A= }=0A= else if (name =3D=3D "clip") {=0A= e.style.clip =3D value;=0A= }=0A= else if (name =3D=3D "color") {=0A= e.style.color =3D value;=0A= }=0A= else if (name =3D=3D "cssText") {=0A= e.style.Sets =3D value;=0A= }=0A= else if (name =3D=3D "cursor") {=0A= e.style.cursor =3D value;=0A= }=0A= else if (name =3D=3D "direction") {=0A= e.style.direction =3D value;=0A= }=0A= else if (name =3D=3D "display") {=0A= e.style.display =3D value;=0A= }=0A= else if (name =3D=3D "font") {=0A= e.style.font =3D value;=0A= }=0A= else if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-type") {=0A= e.style.layoutGridType =3D value;=0A= }=0A= else if (name =3D=3D "left") {=0A= e.style.left =3D value;=0A= }=0A= else if (name =3D=3D "letter-spacing") {=0A= e.style.letterSpacing =3D value;=0A= }=0A= else if (name =3D=3D "line-break") {=0A= e.style.lineBreak =3D value;=0A= }=0A= else if (name =3D=3D "line-height") {=0A= e.style.lineHeight =3D value;=0A= }=0A= else if (name =3D=3D "list-style") {=0A= e.style.listStyle =3D value;=0A= }=0A= else if (name =3D=3D "list-style-image") {=0A= e.style.listStyleImage =3D value;=0A= }=0A= else if (name =3D=3D "list-style-position") {=0A= e.style.listStylePosition =3D value;=0A= }=0A= else if (name =3D=3D "list-style-type") {=0A= e.style.listStyleType =3D value;=0A= }=0A= else if (name =3D=3D "margin") {=0A= e.style.margin =3D value;=0A= }=0A= else if (name =3D=3D "margin-bottom") {=0A= e.style.marginBottom =3D value;=0A= }=0A= else if (name =3D=3D "margin-left") {=0A= e.style.marginLeft =3D value;=0A= }=0A= else if (name =3D=3D "margin-right") {=0A= e.style.marginRight =3D value;=0A= }=0A= else if (name =3D=3D "margin-top") {=0A= e.style.marginTop =3D value;=0A= }=0A= else if (name =3D=3D "min-height") {=0A= e.style.minHeight =3D value;=0A= }=0A= else if (name =3D=3D "overflow") {=0A= e.style.overflow =3D value;=0A= }=0A= else if (name =3D=3D "overflow-x") {=0A= e.style.overflowX =3D value;=0A= }=0A= else if (name =3D=3D "overflow-y") {=0A= e.style.overflowY =3D value;=0A= }=0A= else if (name =3D=3D "padding") {=0A= e.style.padding =3D value;=0A= }=0A= else if (name =3D=3D "padding-bottom") {=0A= e.style.paddingBottom =3D value;=0A= }=0A= else if (name =3D=3D "padding-left") {=0A= e.style.paddingLeft =3D value;=0A= }=0A= else if (name =3D=3D "padding-right") {=0A= e.style.paddingRight =3D value;=0A= }=0A= else if (name =3D=3D "padding-top") {=0A= e.style.paddingTop =3D value;=0A= }=0A= else if (name =3D=3D "page-break-after") {=0A= e.style.pageBreakAfter =3D value;=0A= }=0A= else if (name =3D=3D "page-break-before") {=0A= e.style.pageBreakBefore =3D value;=0A= }=0A= else if (name =3D=3D "pixelBottom") {=0A= e.style.pixelBottom =3D value;=0A= }=0A= else if (name =3D=3D "pixelHeight") {=0A= e.style.pixelHeight =3D value;=0A= }=0A= else if (name =3D=3D "pixelLeft") {=0A= e.style.pixelLeft =3D value;=0A= }=0A= else if (name =3D=3D "pixelRight") {=0A= e.style.pixelRight =3D value;=0A= }=0A= else if (name =3D=3D "pixelTop") {=0A= e.style.pixelTop =3D value;=0A= }=0A= else if (name =3D=3D "pixelWidth") {=0A= e.style.pixelWidth =3D value;=0A= }=0A= else if (name =3D=3D "posBottom") {=0A= e.style.posBottom =3D value;=0A= }=0A= else if (name =3D=3D "posHeight") {=0A= e.style.posHeight =3D value;=0A= }=0A= else if (name =3D=3D "position") {=0A= e.style.position =3D value;=0A= }=0A= else if (name =3D=3D "posLeft") {=0A= e.style.posLeft =3D value;=0A= }=0A= else if (name =3D=3D "posRight") {=0A= e.style.posRight =3D value;=0A= }=0A= else if (name =3D=3D "posTop") {=0A= e.style.posTop =3D value;=0A= }=0A= else if (name =3D=3D "posWidth") {=0A= e.style.posWidth =3D value;=0A= }=0A= else if (name =3D=3D "right") {=0A= e.style.right =3D value;=0A= }=0A= else if (name =3D=3D "ruby-align") {=0A= e.style.rubyAlign =3D value;=0A= }=0A= else if (name =3D=3D "ruby-overhang") {=0A= e.style.rubyOverhang =3D value;=0A= }=0A= else if (name =3D=3D "ruby-position") {=0A= e.style.rubyPosition =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-3dlight-color") {=0A= e.style.scrollbar3dLightColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-arrow-color") {=0A= e.style.scrollbarArrowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-base-color") {=0A= e.style.scrollbarBaseColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-darkshadow-color") {=0A= e.style.scrollbarDarkShadowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-face-color") {=0A= e.style.scrollbarFaceColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-highlight-color") {=0A= e.style.scrollbarHighlightColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-shadow-color") {=0A= e.style.scrollbarShadowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-track-color") {=0A= e.style.scrollbarTrackColor =3D value;=0A= }=0A= else if (name =3D=3D "float") {=0A= e.style.styleFloat =3D value;=0A= }=0A= else if (name =3D=3D "table-layout") {=0A= e.style.tableLayout =3D value;=0A= }=0A= else if (name =3D=3D "text-align") {=0A= e.style.textAlign =3D value;=0A= }=0A= else if (name =3D=3D "text-align-last") {=0A= e.style.textAlignLast =3D value;=0A= }=0A= else if (name =3D=3D "text-autospace") {=0A= e.style.textAutospace =3D value;=0A= }=0A= else if (name =3D=3D "text-decoration") {=0A= e.style.textDecoration =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationBlink") {=0A= e.style.textDecorationBlink =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationLineThrough") {=0A= e.style.textDecorationLineThrough =3D value;=0A= }=0A= else if (name =3D=3D 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"vertical-align") {=0A= e.style.verticalAlign =3D value;=0A= }=0A= else if (name =3D=3D "visibility") {=0A= e.style.visibility =3D value;=0A= }=0A= else if (name =3D=3D "white-space") {=0A= e.style.whiteSpace =3D value;=0A= }=0A= else if (name =3D=3D "width") {=0A= e.style.width =3D value;=0A= }=0A= else if (name =3D=3D "word-break") {=0A= e.style.wordBreak =3D value;=0A= }=0A= else if (name =3D=3D "word-spacing") {=0A= e.style.wordSpacing =3D value;=0A= }=0A= else if (name =3D=3D "word-wrap") {=0A= e.style.wordWrap =3D value;=0A= }=0A= else if (name =3D=3D "writing-mode") {=0A= e.style.writingMode =3D value;=0A= }=0A= else if (name =3D=3D "z-index") {=0A= e.style.zIndex =3D value;=0A= }=0A= else if (name =3D=3D "zoom") {=0A= e.style.zoom =3D value;=0A= }=0A= }=0A= catch (e) {=0A= /* ignore error on attempt to set e.style.[property] */=0A= }=0A= }=0A= }=0A= }=0A= ------=_NextPart_000_0000_01C7068F.2ABF5260 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://jncicancerspectrum.oxfordjournals.org/javascript/entrez/callback.js /************************************************************************= *****=0A= * javascript/entrez/callback.js=0A= *=0A= * Entrez Linking callback to populate content box.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Execute callback to fill content box with Entrez Linking information.=0A= */=0A= function entrez_callback(pmid, callback_url) {=0A= /*=0A= * MSIE 5.5 and below have issues with the JavaScript=0A= * used for Entrez Linking. For now we have to disable=0A= * the callback until we can track down a proper fix=0A= * (or everybody sanely upgrades to version 6 or 7!).=0A= */=0A= if (navigator) {=0A= var appname =3D navigator.appName;=0A= if (appname =3D=3D "Microsoft Internet Explorer") {=0A= var userAgent =3D navigator["userAgent"];=0A= var s =3D "MSIE ";=0A= var n =3D -1; =0A= if ((n =3D userAgent.indexOf(s)) !=3D -1) {=0A= var v =3D parseFloat(userAgent.substring(n+s.length));=0A= if (v < 6) {=0A= return;=0A= }=0A= }=0A= }=0A= }=0A= =0A= /*=0A= * Acquire table row element to update, initiate callback=0A= * to update table with Entrez Links.=0A= */=0A= var tr =3D document.getElementById('entrez_callback_'+pmid);=0A= if (!tr) {=0A= return;=0A= }=0A= var req =3D new XMLHttpRequest();=0A= if (!req) {=0A= return;=0A= }=0A= req.onreadystatechange =3D function() {=0A= if (req.readyState =3D=3D 4 && (req.status =3D=3D 200 || req.status = =3D=3D 304)) {=0A= var src =3D req.responseXML.documentElement;=0A= var dst =3D document.createDocumentFragment();=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], dst);=0A= }=0A= var tbl =3D tr.parentNode;=0A= tbl.replaceChild(dst, tr);=0A= }=0A= }=0A= req.open('GET', callback_url, true);=0A= req.send(null);=0A= }=0A= ------=_NextPart_000_0000_01C7068F.2ABF5260--