Distribution kinetics of targeted cytotoxin in glioma by bolus or convection-enhanced delivery in a murine model

Kawakami, Koji; Kawakami, Mariko; Kioi, Mitomu; Husain, Syed R.; Puri, Raj K.

doi:10.3171/jns.2004.101.6.1004

Cited by 69 publications

(45 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, a single intratumoral administration of the protein formulations led to lower antitumor efficacy; that is, Cintredekin Besudotox doubled the median survival and all of the animals succumbed to tumor burden, and the second-generation mhIL-13-PE protein formulation elicited ∼40% long-term survival. These results suggest that the short half-life of the protein formulations (16,17) can be overcome by Ads, which allow sustained local expression.…”

Section: Discussionmentioning

confidence: 79%

“…Due to the short half-life of the hIL-13-PE protein formulation (16,17), multiple injections or continued delivery was necessary to achieve therapeutic levels (1,16,18). This approach was tested preclinically and in phase I-III clinical trials (16)(17)(18). However, in spite of high expectations, the phase III trial failed to achieve clinical endpoints (http://www.fiercebiotech.…”

mentioning

confidence: 99%

“…Because IL13Rα2 is virtually absent from normal brain cells (14), human IL-13 was fused to a truncated Pseudomonas exotoxin (hIL-13-PE; Cintredekin Besudotox) to target IL13Rα2-expressing GBM cells (15). Due to the short half-life of the hIL-13-PE protein formulation (16,17), multiple injections or continued delivery was necessary to achieve therapeutic levels (1,16,18). This approach was tested preclinically and in phase I-III clinical trials (16)(17)(18).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics

Candolfi

Xiong

Yagiz

et al. 2010

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

View full text Add to dashboard Cite

Restricting the cytotoxicity of anticancer agents by targeting receptors exclusively expressed on tumor cells is critical when treating infiltrative brain tumors such as glioblastoma multiforme (GBM). GBMs express an IL-13 receptor (IL13Rα2) that differs from the physiological IL4R/IL13R receptor. We developed a regulatable adenoviral vector (Ad.mhIL-4.TRE.mhIL-13-PE) encoding a mutated human IL-13 fused to Pseudomonas exotoxin (mhIL-13-PE) that specifically binds to IL13Rα2 to provide sustained expression, effective anti-GBM cytotoxicity, and minimal neurotoxicity. The therapeutic Ad also encodes mutated human IL-4 that binds to the physiological IL4R/IL13R without interacting with IL13Rα2, thus inhibiting potential binding of mhIL-13-PE to normal brain cells. Using intracranial GBM xenografts and syngeneic mouse models, we tested the Ad.mhIL-4.TRE.mhIL-13-PE and two protein formulations, hIL-13-PE used in clinical trials (Cintredekin Besudotox) and a second-generation mhIL-13-PE. Cintredekin Besudotox doubled median survival without eliciting long-term survival and caused severe neurotoxicity; mhIL-13-PE led to ∼40% long-term survival, eliciting severe neurological toxicity at the high dose tested. In contrast, Ad-mediated delivery of mhIL-13-PE led to tumor regression and long-term survival in over 70% of the animals, without causing apparent neurotoxicity. Although Cintredekin Besudotox was originally developed to target GBM, when tested in a phase III trial it failed to achieve clinical endpoints and revealed neurotoxicity. Limitations of Cintredekin Besudotox include its short half-life, which demanded frequent or continued administration, and binding to IL4R/IL13R, present in normal brain cells. These shortcomings were overcome by our therapeutic Ad, thus representing a significant advance in the development of targeted therapeutics for GBM.

show abstract

Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics

Candolfi

Xiong

Yagiz

et al. 2010

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

View full text Add to dashboard Cite

show abstract

“…Thus, recent studies show that convection-enhanced delivery (CED) of IT is superior to bolus injection of IT. 49 Investigators compared the concentration of 14 Csucrose in rat brain via intravenous, intrathecal and convectionenhanced delivery and found that convection-enhanced delivery resulted in 10,000-fold increase in tissue concentration of 14 Csucrose versus intravenous delivery. 50 Others have demonstrated that CED of 125 I-boronated epidermal growth factor into rat brains with glioma tumor resulted in 47.4% injected dose/gram (IDg) of the IT being detected within the tumor bed even after 24 hr, whereas intratumoral injection of the IT resulted in only 33% ID/g being detected within the tumor bed 24 hr after injection.…”

Section: Discussionmentioning

confidence: 99%

Intracranial therapy of glioblastoma with the fusion protein DTIL13 in immunodeficient mice

Rustamzadeh

Hall

Todhunter

et al. 2006

Intl Journal of Cancer

View full text Add to dashboard Cite

A fusion protein consisting of human interleukin-13 and the first 389 amino acids of diphtheria toxin was assembled in order to target human glioblastoma cell lines in a murine intracranial model. In vitro studies to determine specificity indicated that the protein called DTIL13 was highly selective for human glioblastoma. In vivo, the maximum tolerated dose of DTIL13 was 1 lg/injection given every other day and repeated for 3 days. Doses that exceeded this amount resulted in weight loss and liver damage as determined by histology and enzyme assay. Experiments in IL-4 receptor knockout mice revealed that liver toxicity was receptorrelated. This same dose given to nude mice with established U373 MG brain tumors resulted in significant reductions in tumor volume and significantly prolonged survival (p < 0.0001). Magnetic resonance imaging (MRI) proved to be extremely useful in (i) determining the ability of DTIL13 to reduce tumor size and (ii) for studying toxicity since diffusion-weighted and gradient echoweighted MRI revealed that vascular leak syndrome was not a limiting toxicity at this dose. These results suggest that DTIL13 is as effective in an intracranial rodent model as it was in a flank model in previous studies and that DTIL13 might be an effective treatment for glioblastoma multiforme. ' 2005 Wiley-Liss, Inc.Key words: diphtheria toxin; glioblastoma; interleukin-13; brain tumor; immunotoxin Glioblastoma multiforme (GBM) is an incurable, heterogeneous, high-grade astrocytic glioma, thought to originate from glial nonneuronal cells. 1 More recent studies have identified a subpopulation of cancer stem-cells within GBM that retain the capacity for self-renewal and the ability to differentiate into a phenotypically diverse population of cells. 2-4 With a 2-year-patient survival rate of <30%, 5 effective treatment has been hindered by the lack of tumor-specific markers in the majority of patients. Recently, the IL-13 receptor (IL-13R) has been found to be overexpressed on cultured human GBM cell lines and surgical GBM specimens, but is not detectable in normal brain tissue. [6][7][8] Targeting the IL-13 receptor with an immunotoxin (IT) has already proven to have potential for treating brain tumors. [8][9][10][11][12] ITs are not mainstream pharmaceuticals, and treatment of systemic tumors with ITs has been limited by their failure to localize in tumor. The promise of these drugs is considerably greater for brain-cancer therapy, since IT can be directly administered intracranially. In an earlier study, we assembled an IL-13 IT made by fusing gene fragments encoding for human IL-13 and the first 389 amino acids of diphtheria toxin. 13 In vivo studies with this agent showed that it had a potent antitumor effect against IL-13R-positive GBM cells grown in the flanks of nude mice without significant toxicity.Although encouraging, the flank model has limitations as a model for intracranial therapy. First, intratumoral pressure within the flank model does not reach the pressures that occur in intracranial tumors ...

show abstract

“…The IL-13 toxin has been shown to exert a potent cytotoxic effect in most human glioblastoma cells tested in culture (174,178,180) and in vivo, in human xenografts consisting of glioma cells implanted in the flank of nude mice (181). Moreover, the intratumoral administration of ILI3-PE toXin into intracranial human glioma xenografts in mice showed highly cytotoxic effects without undesirable side effects (182). To optimize the targeting of GBM associated IL-13cx2 receptor, human IL-13 (hIL-13) gene has been engineered leading to a mutated fonD of hIL-13 that exhibits 50 fold higher affinity for the IL13cx2 receptor present in human glioma cells when compared to the wild type IL-13 (183,184).…”

Section: Targeted Toxins For Glioma Therapymentioning

confidence: 99%