Clinical Cancer Research Versailles No Abst Metabolism
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ochiai, H.
Right arrow Articles by Sampson, J. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ochiai, H.
Right arrow Articles by Sampson, J. H.
Clinical Cancer Research Vol. 12, 1349-1354, February 2006
© 2006 American Association for Cancer Research

Cancer Therapy: Preclinical

Targeted Therapy for Glioblastoma Multiforme Neoplastic Meningitis with Intrathecal Delivery of an Oncolytic Recombinant Poliovirus

Hidenobu Ochiai1, Stephanie A. Campbell2, Gary E. Archer1, Tracy A. Chewning1, Eugenia Dragunsky4, Alexander Ivanov4, Matthias Gromeier2 and John H. Sampson1,3

Authors' Affiliations: 1 Division of Neurosurgery, Department of Surgery; Departments of 2 Molecular Genetics and Microbiology and 3 Pathology, Duke University Medical Center, Durham, North Carolina; and 4 Center of Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland

Requests for reprints: John H. Sampson, Division of Neurosurgery, Duke University Medical Center, Box 3050, Durham, NC 27710. Phone: 919-684-9041; Fax: 919-684-9045; E-mail: john.sampson{at}duke.edu.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: The toxicity and antitumor activity of regional intrathecal delivery of an oncolytic recombinant poliovirus, PVS-RIPO, was evaluated in rodent models of glioblastoma multiforme neoplastic meningitis.

Experimental Design: To evaluate for toxicity, PVS-RIPO was administered into the spinal cord of transgenic mice that express the human poliovirus receptor, CD155, and into the intrathecal space of athymic rats without tumor. To evaluate efficacy, two different doses of PVS-RIPO were administered intrathecally 3 days after athymic rats were inoculated intrathecally with an aggressive human glioblastoma multiforme xenograft.

Results: No clinical or histologic evidence of toxicity was found. In efficacy studies, median survival was increased by 174.47% from 8.5 days in the group treated with UV light-inactivated virus to 15 days in the rats treated with 1.0 x 107 plaque-forming units (pfu) of PVS-RIPO (P < 0.0001). A similar increase in median survival was seen in the group receiving 1.0 x 109 pfu PVS-RIPO (P < 0.0001); however, there was no statistically significant dose-response relationship (P = 0.345). In addition, 1 of 10 rats in lower-dose PVS-RIPO–treated group and 3 of 10 rats in higher-dose PVS-RIPO–treated group survived >60 days after tumor cell inoculation and had no evidence of residual tumor at autopsy.

Conclusion: These results suggest that intrathecal treatment with PVS-RIPO may be useful for treatment of neoplastic meningitis in patients with glioblastoma multiforme and provides a rationale for clinical trials in this area.

Despite aggressive surgical resection, radiotherapy, and chemotherapy, patients with glioblastoma multiforme suffer persistent recurrences that frequently culminate in leptomeningeal spread (1). Because systemically delivered therapeutics penetrate the intrathecal compartment poorly and because only a limited number of agents are approved for intrathecal use, treatment strategies for neoplastic meningitis have been limited (2–9), and novel strategies are desperately needed (10–12). Oncolytic viruses that are being developed for intraparenchymal solid tumors, however, may provide a unique tool for therapy of neoplastic meningitis as well (13). Although a great number of viral agents are under consideration for use in such strategies (14–23), an attenuated poliovirus has a number of intrinsic properties that render it particularly suitable for targeting neoplastic lesions within the central nervous system (CNS; ref. 24), including a natural propensity to invade the subarachnoid space and destroy CD155-expressing cells in this compartment (25).

Poliovirus is a nonenveloped, plus-stranded RNA virus belonging to the Picornaviridae family and is the causative agent of paralytic poliomyelitis. In poliomyelitis selective targeting of motor neurons is determined by the distribution of the poliovirus cellular receptor (26), the immunoglobulin superfamily molecule, CD155 (27). We have previously shown that a number of tumors, including glioblastoma multiforme, also express this cellular receptor making it an ideal tumor associated target for oncolytic viral therapy (13, 28). Moreover, CD155 recently has been identified as a key determinant of tumor cell migration, invasion, and metastasis (29), and transcriptional activation of the CD155 gene has been linked to signaling pathways commonly deregulated in malignancy, including sonic hedgehog/gli (30), fibroblastic growth factor, and oncogenic ras (31).

To apply poliovirus to tumor therapy, we eliminated its inherent neuropathogenicity by manipulating an essential cis-acting regulatory element involved in gene expression control (32). Poliovirus, like all picornaviruses, uses an internal ribosomal entry site contained within its extensively structured 5' untranslated region to initiate translation in a cap-, 5' end-independent manner (33, 34). Replacing the cognate poliovirus internal ribosomal entry site with its counterpart from human rhinovirus type 2 eliminated the virus' ability to cause poliomyelitis in mice transgenic for CD155 and Cynomolgus macaques (32, 35). However, this alteration does not reduce the cytopathogenicity of the lytic virus for malignant cell types that express CD155, such as glioblastoma multiforme.

In this study, we evaluated the toxicity and efficacy of intrathecal administration of a novel clinical grade recombinant poliovirus, PVS-RIPO, developed through the NIH Rapid Access to Inventional Development program, in transgenic mice expressing the human poliovirus receptor, CD155, and in an athymic rat model of human glioblastoma multiforme neoplastic meningitis. Intraspinal and intrathecal administrations of PVS-RIPO were found to be nontoxic in both the transgenic mice and athymic rats. PVS-RIPO was also highly effective against human glioblastoma multiforme xenografts growing in the subarachnoid space of athymic rats.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Cell line. The human glioblastoma multiforme cell line, U87MG{Delta}EGFR, was obtained from W. Cavenee (University of California at San Diego; ref. 36). These cells are grown in zinc option medium with 0.23% HEPES, 0.22% NaCO3, and 10% fetal bovine serum.

Preparation and inactivation of virus. PVS-RIPO was derived from a previous version of the recombinant virus, PV1(RIPO), by substituting the coding region of poliovirus type 1 (Mahoney) with its counterpart from the type 1 live attenuated Sabin [PV1(S)] vaccine strain. The synthesis of PVS-RIPO was reported previously (13). In brief, infectious PV1(S) cDNA [clone pS1 (T7)], kindly provided by A. Nomoto (University of Tokyo, Japan), was digested with AvaI. The resulting 7.0-kb restriction fragment was ligated with a PCR fragment amplified from PV1 (RIPOS) using primers (a) 5'-GGGTCGACTAATACGACTCCTATAGTAAAACAGCTCTGGGGTTGT-3' and (b) 5'-CCATTTCTCGGGCACTGGAGCG-3' and pBS vector DNA (New England Biolabs, Beverly, MA) digested with AvaI and SalI. PVS-RIPO cDNA was processed for rederivation of virus as described before (32).

Virus inactivation by UV irradiation was carried out in a Stratagene UV-linker according to previously established procedures. The absence of virus infectivity after UV treatment of samples was confirmed by plaque assay as described below.

Plaque assay. Cell monolayers, grown in DMEM with 10% fetal bovine serum, penicillin (10 units/mL), and streptomycin (100 µg/mL), were inoculated with a viral suspension at a multiplicity of infection of 10 and incubated for 30 minutes at room temperature. Culture dishes were thoroughly rinsed with five changes of growth medium to remove unbound particles and plated at 37°C thereafter. At the indicated intervals, culture dishes were removed and treated with three consecutive freeze/thaw cycles. Virus titers in infected monolayer cultures were quantified by plaque assay as described previously (24). The PVS-RIPO titers that we used in this study were determined based on our previous preclinical studies in experimental animals evaluating i.t. delivery of the agent (13, 24).

Antigen capture analysis of CD155 expression. The method of antigen capture for CD155 has been reported previously (13, 28). In brief, cells were grown in monolayer culture and homogenized in lysis buffer. The protein concentrations in cell lysates were determined using the Bradford method. ELISA plates were treated over night with monoclonal anti-CD155 antibody, D171, and suspended in carbonate buffer. Treated plates were rinsed thrice with PBS and individual wells were filled with cell lysate diluted with PBS to achieve the desired protein concentration. Plates were incubated for 4 hours at room temperature while gently rocking. Subsequently, the wells were thoroughly rinsed thrice with PBS and treated with SDS-PAGE loading buffer at 95°C to release the captured antigen. The recovered material was analyzed by SDS-PAGE, transferred to nitrocellulose membranes, and subjected to Western blot. Filters were blocked over night in TBST [10 mmol/L Tris (pH 8), 150 mmol/L NaCl, 0.05% Tween 20] containing 3% dry milk. After treatment with the polyclonal anti-CD155 antibody, D480 (diluted in TBST, 3% dry milk at 1:1,000) for 1 hour at room temperature, the blots were rinsed thrice in TBST and incubated for 1 hour at room temperature with secondary biotinylated anti-rabbit IgG antibody (diluted in TBST, 3% dry milk at 1:500; Vector Labs, Burlingame, CA). After three washes with TBST, the filters were treated with streptavidin-horseradish peroxidase complex (diluted in TBST, 3% dry milk at 1:2,000; Roche, Indianapolis, IN) and developed with a chemoluminescent substrate (enhanced chemiluminescence; Amersham, Arlington Heights, IL).

Toxicity study in CD155 transgenic mice. The evaluation of neurovirulence of poliovirus strains in CD155 transgenic mice has been described previously (37). Serotype 1 PV reference strain (WHO/I) and two clinical lots of PVS-RIPO (0402018, 2nd passage; 0404007, 5th passage in Vero cells) were administered intraspinally to CD155 transgenic mice (TgPVR21) and neurologic symptoms were evaluated using a standard clinical score as follows: grade 0, no neurologic symptoms; grade 1, paralysis of limb; grade 2, death. Evaluation of neurologic symptoms was done from days 0 to 14 after intraspinal PVS-RIPO inoculation. The rodent model for paralytic poliomyelitis in TgPVR21 mice was developed as a replacement for the traditional monkey neurovirulence assay in Cynomolgus macaques. It is a rigorous and standardized clinical assay. It has been established that clinical observation alone is sufficient to predict the neurovirulent potential of live attenuated poliovirus strains, as the sole neurologic manifestation of poliovirus infection in the CNS of TgPVR21 mice is motor neuron death (38). Therefore, and because of the large number of animals enrolled in our assay, we did not evaluate the spinal cords of infected TgPVR21 mice histopathologically.

Athymic rat model of neoplastic meningitis. Subarachnoid catheters were implanted into female athymic rats using an established procedure described previously (39). Briefly, the rats (BIG:NIMRrnu; 190-260 g) were anesthetized by an i.p. injection of ketamine (55 mg/mL) and xylazine (9 mg/mL) and placed in a stereotactic frame (David Kopf Instruments, Tujunga, CA) with their necks flexed at a 70-degree angle using the tilt adapter. A midline sagittal incision was made from the inion to the laminar arch of C1, atlanto-occipital membrane was exposed and incised using a 20-gauge needle, and the underlying cisterna magna dura matter was opened. A PE-10 catheter (Intramedic, Franklin Lakes, NJ) with a 5-0 stainless steel wire stylet was then inserted into the subarachnoid space to the lumbar region (8.5 cm) by passing it along the posterior aspect of the spinal cord. The stylet was removed, a loose knot was tied in the catheter just above the opening of the dura, and the knot was secured in place with dental epoxy (Lang Dental Manufacturing Co., Chicago, IL). The exposed catheter end was then passed through the skin lateral to the incision. The incision was closed in three layers using 6-0 Ethilon (Ethicon, Somerville, NJ), and the catheter was temporarily occluded with 2-0 stainless steel wire. The rats were allowed to recover at least 7 days, and only rats showing normal weight and neurologic function and no evidence of infection were used in the experiments.

Neoplastic meningitis was induced by injecting tumor cells through the indwelling subarachnoid catheter. After anesthetizing rats with isoflurane, the wire stylet was removed, and 5.0 x 106 U87MG{Delta}EGFR cells were injected in 40 µL of PBS using a 1,000-µL Hamilton syringe and injector (Hamilton Co., Reno, NV). The catheter was then flushed with 20 µL of PBS and reoccluded with 2-0 wire.

Toxicity and efficacy studies in athymic rats. For intrathecal toxicity studies, athymic rats were injected with 1.0 x 109 pfu PVS-RIPO in 60 µL of PBS. The weight, neurologic status, survival, and histologic examination of the neural axis and internal organs were compared with a control group treated with PBS. For efficacy studies, rats in the treatment groups were injected with 1.0 x 107 or 1.0 x 109 pfu PVS-RIPO in 60 µL of PBS, and rats in the control groups were injected with 1.0 x 109 pfu UV-inactivated PVS-RIPO in the same volume of PBS or just a PBS. Clinical neurologic function included testing of the stepping and placing reflex and the ability to climb a 60-degree incline ramp. Histologic examination was conducted on six representative cross-sections of the CNS, including the forebrain at level of lateral ventricles, hindbrain at the level of occipital lobe, and four equally spaced spinal sections, including the cauda equina. These sections were evaluated microscopically for hemorrhage, necrosis, edema, demyelination, and arachnoid fibrosis.

Statistical analysis. Survival estimates and median survival was determined by using the method of Kaplan and Meier (40). Survival data were compared using the log-rank test.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Intrathecal toxicity in CD155-expressing transgenic mice. Because rodents do not express the human poliovirus receptor, CD155, we initially evaluated the intrathecal toxicity of PVS-RIPO in CD155 transgenic mice (TgPVR21). WHO/I and two clinical lots of PVS-RIPO (0402018, 2nd passage; 0404007, 5th passage in Vero cells) were administered intraspinally, and neurologic symptoms were evaluated from days 0 to 14 after the PVS-RIPO inoculation. In this toxicity study, two different concentrations of virus (1.75 log10 TCD50 and 2.75 log10 TCD) were tested. In the mice inoculated with low-titer WHO/I, 31.2% of female mice (5 of 16) and 31.2% of male mice (5 of 16) showed paralysis, and all symptomatic animals died as a result of virus infection (Table 1). Similarly, in mice inoculated with high-titer WHO/I, 68.7% of female mice (11 of 16) and 87.5% of male mice (14 of 16) showed paralysis and subsequent fatal involvement of respiratory musculature. However, in the low-titer and high-titer PVS-RIPO (0402018 and 0404007) inoculated groups, none of the mice developed neurologic symptoms, and all animals survived the experiment (Table 1).


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical score frequencies of a serotype 1 PV reference strain (WHO/I) and two lots of PVS-RIPO (0402018, 2nd passage; 0404007, 5th passage) in CD155 transgenic mice (TgPVR21)

 
Intrathecal toxicity in non–tumor-bearing rats. To evaluate any possible toxicity of PVS-RIPO after intrathecal delivery in athymic rats, we also injected 1.0 x 109 plaque-forming units (pfu) of PVS-RIPO into the intrathecal space. At this dose, neither weight loss of >10% nor neurologic deficits were observed. Histologic examination of the neuroaxis revealed only mild pericatheter demyelination of spinal cord in both the PBS-treated group and in the PVS-RIPO–treated group (Table 2). This asymptomatic histologic finding is observed in all of studies using this model and is likely due to catheter placement (13). No evidence of hemorrhage, necrosis, edema, or arachnoid fibrosis was identified in the brain or spinal cord of PVS-RIPO–treated rats. Additional histologic examination of internal organs, including heart, lung, liver, spleen, and kidney, of each rat showed no specific pathologic changes attributed to PVS-RIPO treatment.


View this table:
[in this window]
[in a new window]
  		Table 2. Toxicologic analysis of intrathecal PVS-RIPO on athymic rats without tumor

 
U87MG{Delta}EGFRvIII expresses CD155 and is susceptible to PVS-RIPO. To evaluate the level of expression of the poliovirus receptor, CD155, in the human glioblastoma multiforme cell line U87MG{Delta}EGFR, we used an antigen capture/Western blot assay. This assay showed that CD155 was detected in the U87MG{Delta}EGFR cell line (Fig. 1). Next, we evaluated whether or not PVS-RIPO could be propagated in cultured U87MG{Delta}EGFR cells and found that PVS-RIPO propagated at levels comparable with cell lines commonly used for large-scale propagation of virus in the laboratory (i.e., HeLa cells; ref. 32; Fig. 2). These results indicated that U87MG{Delta}EGFR cells were appropriate targets for oncolytic PVS-RIPO therapy.


Figure 1
View larger version (8K):
[in this window]
[in a new window]
  		Fig. 1. Expression of the poliovirus receptor CD155 in human glioblastoma multiforme cell line (U87MG{Delta}EGFR). Other glioblastoma multiforme cell lines and primary explants displayed a similar range of CD155 expression levels (28).

 

Figure 2
View larger version (11K):
[in this window]
[in a new window]
  		Fig. 2. Propagation of PVS-RIPO in human glioblastoma multiforme cell line, U87MG{Delta}EGFR. One-step growth curves of PVS-RIPO were obtained after synchronized infection of monolayer cultures at a multiplicity of infection (MOI) of 10. Y-axis, pfu. This indicates efficient viral replication in PVS-RIPO stably propagated in glioblastoma multiforme cells.

 
Efficacy of PVS-RIPO against neoplastic meningitis with a human glioblastoma multiforme xenograft. The therapeutic efficacy of intrathecal PVS-RIPO in an athymic rat model of human glioblastoma multiforme neoplastic meningitis induced by U87MG{Delta}EGFR was investigated at two different doses, and survival was compared with groups of rats treated with PBS or UV light-inactivated PVS-RIPO. After inoculation of 5.0 x 106 U87MG{Delta}EGFR cells, median survival was increased by 187.5% from 8 days in the PBS-treated group to 15 days in the group treated with 1.0 x 107 pfu PVS-RIPO (P < 0.0001; Fig. 3). Similarly, the median survival time was increased by 174.47% when compared with the group treated with the UV light-inactivated PVS-RIPO. In the group receiving the higher dose of PVS-RIPO (1.0 x 109 pfu), the median survival was increased by 200% compared with the PBS-treated group and 188.23% compared with the group treated with UV-inactivated PVS-RIPO (P < 0.0001). There was, however, no statistically significant dose-response relationship (P = 0.345). In addition to the increase in median survival, 1 of 10 rats in lower-dose PVS-RIPO–treated group and 3 of 10 rats in higher-dose PVS-RIPO–treated group survived over 60 days after tumor cell inoculation. Histologic examination of their brains and spinal cords showed no evidence of residual tumor.


Figure 3
View larger version (13K):
[in this window]
[in a new window]
  		Fig. 3. Intrathecal treatment of human glioblastoma multiforme neoplastic meningitis with PVS-RIPO in an athymic rat model. Groups of athymic rats (n = 10) harboring intrathecal U87MG{Delta}EGFR xenografts were treated with PVS-RIPO administered at a dose of 1.0 x 107 pfu/40 µL (bullet) or 1.0 x 109 pfu/40 µL ({blacksquare}), 3 days after tumor cell inoculation. Control animals were treated with UV-inactivated PVS-RIPO ({blacktriangleup}; 1.0 x 107 pfu) or PBS ({diamondsuit}).

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Regional delivery of therapeutic agents into the subarachnoid space for the treatment of neoplastic meningitis is an attractive strategy because it bypasses the blood-brain barrier and provides high concentrations of the therapeutic agent at the tumor site while minimizing systemic exposure and toxicity. Intrathecal delivery may be even more advantageous in the context of oncolytic virus therapy because it shields the virus from host immunity, allowing the virus to infect and spread more effectively within the tumor. Leptomeningeal involvement can occur in up to 10% to 14% of high-grade gliomas. Nevertheless, the indications for intrathecal treatment remain extremely rare. However, as therapies improve for intraparenchymal disease, the incidence of treatable leptomeningeal spread may increase. The data presented here then provide proof of the principle that oncolytic viral therapy may be a viable option to investigate in these patients. We believe that this is important given the continued lack of chemotherapeutic agents available for this problem. In addition, the transgenic mouse data herein provide information on the potential unique toxicities of this approach in an immunocompetent model.

In our previously published work, we showed that the poliovirus receptor, CD155, is stably expressed in established glioblastoma multiforme cell lines as well as primary explant cultures (28). We have also previously shown that the oncolytic recombinant poliovirus, PVS-RIPO, is efficacious in an athymic rat model of intracerebral breast cancer metastasis (13). We now present new data based on our investigations with a clinical grade recombinant poliovirus, PVS-RIPO, prepared for human use by the NIH Rapid Access to Inventional Development program, that this oncolytic viral approach may also have efficacy in glioblastoma multiforme neoplastic meningitis after intrathecal delivery.

Although we show here that intrathecal PVS-RIPO therapy may be effective against human glioblastoma multiforme neoplastic meningitis in an athymic rat model, there may still be significant limitations to its success in humans that will need to be evaluated. For example, in our preclinical study, a two log increase in virus dose had no effect on the efficacy of intrathecal viral treatment. Although the lower dose of virus may be "saturating," it remains possible that treatment failures are due to the existence of resistant subpopulations of cells, perhaps those not expressing CD155, or tumor locales not accessible to inoculated virus, notwithstanding the dose.

Another potential obstacle is the fact that all patients that might receive this therapy will have been previously vaccinated against poliovirus. However, available evidence suggests that neutralizing antibodies do not exist in the CNS of vaccinated individuals, and only patients who experience neurologic symptoms of poliovirus infection, indicating intraspinal replication of virus, produce neutralizing antibodies in the cerebrospinal fluid. Still, given the disruption of the blood-brain barrier in patients with glioblastoma multiforme, conclusive evidence for or against existing neutralizing antibodies within the CNS will need to await human studies.

Similarly, monkeys have been shown to be able to contract poliomyelitis after intracerebral administration of pathogenic poliovirus, even if they had been previously vaccinated, suggesting that prior vaccination does not limit viral spread within the CNS (41). Although this is concerning for toxicity, with PVS-RIPO, our preclinical work has shown it to be devoid of neuropathogenic potential even in the complete absence of a preexisting immune response. This is partially due to the heterologous HRV2 internal ribosomal entry site that selectively abrogates viral replication in neuronal cells. Perhaps more important then, is the role that preexisting immunity may play in thwarting i.t. propagation of PVS-RIPO, and whether such a response will limit the efficacy of this approach.

Another potential concern with regard to human application is the potential for deleterious adaptation of the virus by mutation because all RNA viruses are inherently genetically unstable. All of our previous experiments have shown that adaptation to neurovirulence does not occur under the circumstances proposed for our clinical trials (13, 24). Nonetheless, such events will need to be monitored carefully during clinical trials as they can never be categorically excluded with replicating RNA viruses.

In conclusion, intrathecal delivery of PVS-RIPO seems to have promise as a safe and efficacious agent for human glioblastoma multiforme neoplastic meningitis and should be investigated in phase I clinical trials.


   Footnotes
 
Grant support: NIH grant 2P50 NS 20023-21 (M. Gromeier and J.H. Sampson).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/25/05; revised 10/19/05; accepted 12/ 5/05.


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

  1. Arita N, Taneda M, Hayakawa T. Leptomeningeal dissemination of malignant gliomas. Incidence, diagnosis and outcome. Acta Neurochir (Wien) 1995;126:84–92.
  2. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982;49:759–72.[CrossRef][Medline]
  3. Grossman SA, Moynihan TJ. Neoplastic meningitis. Neurol Clin 1991;9:843–56.[Medline]
  4. Ongerboer T, de Visser BW, Somers R, et al. Intraventricular Methotrexate therapy of leptomeningeal metastasis from breast carcinoma. Neurology 1983;33:1565–72.[Abstract/Free Full Text]
  5. Theodore WH, Gendelman S. Meningeal carcinomatosis. Arch Neurol 1981;38:696–9.[Abstract/Free Full Text]
  6. Olson ME, Chernik NL, Posner JB. Infiltration of the leptomeninges by systemic cancer. A clinical and pathologic study. Arch Neurol 1974;30:122–37.[Abstract/Free Full Text]
  7. Berry MP, Jenkin RD, Keen CW, Nair BD, Simpson WJ. Radiation treatment for medulloblastoma: a 21-year review. J Neurosurg 1981;55:43–51.[Medline]
  8. Levin VA, Vestnys PS, Edwards MS, et al. Improvement in survival produced by sequential therapies in the treatment of recurrent medulloblastoma. Cancer 1983;51:1364–70.[CrossRef][Medline]
  9. Markesbery WR, Brooks WH, Gupta GD, Young AB. Treatment for patients with cerebral metastases. Arch Neurol 1978;35:754–6.[Abstract/Free Full Text]
  10. Sampson JH, Archer GE, Villavicencio AT, et al. Treatment of neoplastic meningitis with intrathecal temozolomide. Clin Cancer Res 1999;5:1183–8.[Abstract/Free Full Text]
  11. Archer GE, Sampson JH, McLendon RE, et al. Intrathecal Busulfan treatment of human neoplastic meningitis in athymic nude rats. J Neurooncol 1999;44:233–41.[CrossRef][Medline]
  12. Archer GE, Sampson JH, Lorimer IAJ, et al. Regional treatment of epidermal growth factor receptor vIII-expressing neoplastic meningitis with a single-chain immunotoxin, MR-1. Clin Cancer Res 1999;5:2646–52.[Abstract/Free Full Text]
  13. Ochiai H, Moore SA, Archer GE, et al. Treatment of intracerebral neoplasia and neoplastic meningitis with regional delivery of oncolytic recombinant poliovirus. Clin Cancer Res 2004;10:4831–8.[Abstract/Free Full Text]
  14. Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 1991;252:854–6.[Abstract/Free Full Text]
  15. Bischoff JR, Kirn DH, Williams A, et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996;274:373–6.[Abstract/Free Full Text]
  16. Coffey MC, Strong JE, Forsyth PA, Lee PW. Reovirus therapy of tumors with activated Ras pathway. Science 1998;282:1332–4.[Abstract/Free Full Text]
  17. Stojdl DF, Lichty B, Knowles S, et al. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat Med 2000;6:821–5.[CrossRef][Medline]
  18. Market JM, Medlock MD, Rabkin SD, et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther 2000;7:867–74.[CrossRef][Medline]
  19. Rampling R, Cruickshank G, Papanastassiou V, et al. Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Ther 2000;7:859–66.[CrossRef][Medline]
  20. Papanastassiou V, Rampling R, Fraser M, et al. The potential for efficacy of the modified (ICP 34.5(–)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study. Gene Ther 2002;9:398–406.[CrossRef][Medline]
  21. Csatary LK, Bakacs T. Use of Newcastle disease virus vaccine (MTH-68/H) in a patient with high-grade glioblastoma. JAMA 1999;281:1588–9.[Free Full Text]
  22. Wilcox ME, Yang W, Senger D, et al. Reovirus as an oncolytic agent against experimental human malignant gliomas. J Natl Cancer Inst 2001;93:903–12.[Abstract/Free Full Text]
  23. Timiryasova TM, Chen B, Haghighat P, Fodor I. Vaccinia virus-mediated expression of wild-type p53 suppresses glioma cell growth and induces apoptosis. Int J Oncol 1999;14:845–54.[Medline]
  24. Gromeier M, Lachmann S, Rosenfeld MR, Gutin PH, Wimmer E. Intergeneric poliovirus recombinants for the treatment of malignant glioma. Proc Natl Acad Sci U S A 2000;97:6803–8.[Abstract/Free Full Text]
  25. Rotbart HA. Viral meningitis. Semin Neurol 2000;20:277–92.[CrossRef][Medline]
  26. Gromeier M, Solecki D, Patel D, Wimmer E. Expression of the human poliovirus receptor/CD155 gene during development of the CNS: implications for the pathogenesis of poliomyelitis. Virology 2000;273:259–68.
  27. Mendelsohn CL, Wimmer E, Racaniello VR. Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell 1989;56:855–65.[CrossRef][Medline]
  28. Merrill MK, Bernhardt G, Sampson JH, Wikstrand CJ, Bigner DD, Gromeier M. Poliovirus receptor CD155-targeted oncolysis of glioma. Neuro-oncol 2004;6:208–17.[Abstract]
  29. Sloan KE, Eustace BK, Stewart JK, et al. CD155/PVR plays a key role in cell motility during tumor cell invasion and migration. BMC Cancer 2004;4:73–82.[CrossRef][Medline]
  30. Solecki D, Gromeier M, Bernhardt G, Wimmer E. Expression of the human poliovirus receptor/CD155 gene is activated by sonic hedgehog. J Biol Chem 2002;277:25697–702.[Abstract/Free Full Text]
  31. Hirota T, Irie K, Okamoto R, Ikeda W, Takai Y. Transcriptional activation of the mouse Necl-5/Tage4/PVR/CD155 gene by fibroblast growth factor or oncogenic Ras through the Raf-MEK-ERK-AP-1 pathway. Oncogene 2005;24:2229–35.[CrossRef][Medline]
  32. Gromeier M, Alexander L, Wimmer E. Internal ribosomal entry site substitution eliminates neurovirulence in intergeneric poliovirus recombinants. Proc Natl Acad Sci U S A 1996;93:2370–5.[Abstract/Free Full Text]
  33. Jang SK, Kraeusslich HG, Nicklin MJ, Duke GM, Palmenberg AC, Wimmer E. A segment of the 5' non translated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J Virol 1988;62:2636–43.[Abstract/Free Full Text]
  34. Pelletier J, Sonenberg N. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature 1988;334:320–5.[CrossRef][Medline]
  35. Gromeier M, Bossert B, Arita M, Nomoto A, Wimmer E. Dual stem loop within the poliovirus internal ribosomal entry site control neurovirulence. Virology 1999;72:958–64.
  36. Nishikawa R, Ji X, Harmon RC, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci U S A 1994;91:7727–31.[Abstract/Free Full Text]
  37. Dragunsky E, Taffs R, Chernokhvostova Y, et al. A poliovirus-susceptible transgenic mouse model as a possible replacement for the monkey neurovirulence test of oral poliovirus vaccine. Biologicals 1996;24:77–86.[CrossRef][Medline]
  38. Dragunsky E, Chernokhvostova Y, Taffs R, et al.. TgPVR21 mice for testing type-3 oral poliovirus vaccines: role of clinical observation and histologicalexamination. Vaccine 1997;15:1863–6.[CrossRef][Medline]
  39. Fuchs HE, Archer GE, Colvin MO, et al. Activity of intrathecal 4- hydroperoxycyclophosphamide in a nude rat model of human neoplastic meningitis. Cancer Res 1990;50:1954–9.[Abstract/Free Full Text]
  40. Kaplan EL, Meyer P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–81.[CrossRef]
  41. Ponnuraj EM, John TJ, Levin MJ, Simoes EA. Sabin attenuated LSc/2ab strain of poliovirus spreads to the spinal cord from a peripheral nerve in bonnet monkeys (Macaca radiata). J Gen Virol 2001;82:1329–38.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Gen. Virol.Home page
L. M. Hales, N. J. Knowles, P. S. Reddy, L. Xu, C. Hay, and P. L. Hallenbeck
Complete genome sequence analysis of Seneca Valley virus-001, a novel oncolytic picornavirus
J. Gen. Virol., May 1, 2008; 89(5): 1265 - 1275.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. Toyoda, J. Yin, S. Mueller, E. Wimmer, and J. Cello
Oncolytic Treatment and Cure of Neuroblastoma by a Novel Attenuated Poliovirus in a Novel Poliovirus-Susceptible Animal Model
Cancer Res., March 15, 2007; 67(6): 2857 - 2864.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
S. A. Campbell, M. Mulvey, I. Mohr, and M. Gromeier
Attenuation of Herpes Simplex Virus Neurovirulence with Picornavirus cis-Acting Genetic Elements
J. Virol., January 15, 2007; 81(2): 791 - 799.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ochiai, H.
Right arrow Articles by Sampson, J. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ochiai, H.
Right arrow Articles by Sampson, J. H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online