Interleukin-13 Receptors on Human Prostate Carcinoma Cell Lines Represent a Novel Target for a Chimeric Protein Composed of IL-13 and a Mutated Form of Pseudomonas Exotoxin

Maini, Atul; Hillman, Gilda G.; Haas, Gabriel P.; Wang, Ching Y.; Montecillo, Emily; Hamzavi, Fasahat; Pontes, Edson; Leland, Pamela; Pastan, Ira; Debinski, Waldemar; Puri, Raj K.

doi:10.1016/s0022-5347(01)64369-6

Cited by 52 publications

(31 citation statements)

References 18 publications

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“…administrations of IL-13 cytotoxin were needed for pronounced antitumor activity, we examined the extent of apoptosis by this schedule, which has also shown marked antitumor activity in many solid tumor xenograft models including Kaposi's sarcoma, glioblastoma and other head-and-neck tumors. [1][2][3][4][5][6][7] Mice were injected with 100 g/kg of IL-13 cytotoxin in established tumors on days 4, 6 and 8; then, tumor size, caspase activity and apoptotic cells were determined. Tumors were resected 6 hr after each IL-13 cytotoxin injection for caspase and apoptotic cell assay.…”

Section: Accumulation Of Apoptotic Molecules In Scchn Tumors Treated mentioning

confidence: 99%

“…[1][2][3][4][5][6][7] To target these receptors, a recombinant IL-13R-targeted cytotoxin (IL-13PE38, also termed IL-13 cytotoxin) consisting of 2 major components, recombinant human IL-13 and a mutated form of PE, was generated. Over the years, we have shown that IL-13 cytotoxin is extremely cytotoxic to tumor cell lines that express IL-13R in vitro and in vivo.…”

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confidence: 99%

“…Over the years, we have shown that IL-13 cytotoxin is extremely cytotoxic to tumor cell lines that express IL-13R in vitro and in vivo. [1][2][3][4][5][6][7] Based on preclinical studies, we have begun phase I clinical trials for possible treatment of recurrent malignant glioma and advanced renal cell carcinoma. 8,9 To understand the mechanism of cell death caused by IL-13 cytotoxin, we have demonstrated that IL-13 cytotoxin can mediate apoptosis in headand-neck tumor cell lines in vitro.…”

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confidence: 99%

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Tumor regression mechanisms by IL‐13 receptor–targeted cancer therapy involve apoptotic pathways

Kawakami

Puri

2002

Intl Journal of Cancer

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Section: Accumulation Of Apoptotic Molecules In Scchn Tumors Treated mentioning

confidence: 99%

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confidence: 99%

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Tumor regression mechanisms by IL‐13 receptor–targeted cancer therapy involve apoptotic pathways

Kawakami

Puri

2002

Intl Journal of Cancer

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“…Previous studies have proved that IL-13 cytotoxin is highly selective and potent in killing cancer cells that overexpress IL-13R 2 chain. 3,[5][6][7][8][9][10][11][12]14,16,17 Preclinical studies regarding the safety and toxicity of IL-13 cytotoxin have been performed in mice, rats and monkeys; and all animals tolerated this therapy well, with minimal toxicity to vital organs. 18 Based on these results, 3 phase I/II clinical trials of this cytotoxin in adults with malignant glioma have been initiated, and all are currently ongoing in the United States.…”

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confidence: 99%

Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

Saitô

Murata

Watanabe

et al. 2005

Intl Journal of Cancer

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Previous studies demonstrated that IL-13Ra2 chain-overexpressing cancer cells were highly sensitive to IL-13 cytotoxin (IL13-PE38QQR) and could be targeted by cytotoxin treatment. However, the majority of human tumors do not express high levels of IL-13Ra2 chain. To expand the IL-13 cytotoxin-mediated cancer targeting therapy, we combined cytotoxin treatment with gene transfer of IL-13Ra2 chain. We constructed a recombinant adenoviral vector carrying the human IL-13Ra2 gene (Ad-IL-13Ra2), which expresses high levels of IL-13Ra2 chain on infected cells. Human cancer cell lines A549 and HOS, which originally show no IL-13Ra2 expression and little sensitivity to IL-13 cytotoxin, were effectively converted to become sensitive to this cytotoxin after Ad-IL-13Ra2 infection. The CC 50 of IL-13 cytotoxin for Ad-IL13Ra2-infected A549 cells was <10 ng/ml, whereas the CC 50 for uninfected or control vector-infected cells was >500 ng/ml. We also examined the antitumor activity of IL-13 cytotoxin in an established xenograft model of cytotoxin-resistant human lung tumor. Only a single i.t. injection of Ad-IL-13Ra2 markedly enhanced the sensitivity of established tumors to IL-13 cytotoxin treatment; furthermore, this antitumor effect was significantly sustained for more than 1 month after the last treatment with IL-13 cytotoxin. Taken together, these results suggest the combination of adenoviral vector-mediated IL-13Ra2 gene transfer and IL-13 cytotoxin administration can be an effective targeting approach for several types of IL-13 cytotoxin-resistant cancers which show no or little expression of IL-13Ra2 chain. ' 2005 Wiley-Liss, Inc.

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“…We have previously documented that the activity of this cytotoxin is highly specific, killing a variety of human tumor cells that overexpress IL-13 receptors. 25,30,31 The PM-RCC cell line was used as a positive control, since this cell type has been shown to express high levels of IL-13R␣2 protein and is extremely sensitive to the IL13-PE38 toxin (IC 50 , 0.1 ng/ml; data not shown). 27 Two human and 2 rat AM-expressing PC-3 clones showed an IC 50 (concentration of IL-13 toxin causing 50% inhibition of protein synthesis) of 1-4 ng/ml (Fig.…”

Section: Am Induction Of Il-13r␣2 Results In Functionally Active Proteinmentioning

confidence: 99%

Gene expression profiling identifies IL‐13 receptor α2 chain as a therapeutic target in prostate tumor cells overexpressing adrenomedullin

Gonzalez-Moreno

Calvo

Joshi

et al. 2004

Intl Journal of Cancer

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Human adrenomedullin (AM) is a 52 amino acid peptide, which shares homology with the calcitonin gene-related peptide. Overexpression of AM in the prostate carcinoma cell line PC-3 results in growth inhibition with a 20% (for human AM) and 35% (for rat AM) increase in doubling time compared to parental or mocktransfected cells. We demonstrate by gene expression profiling that AM overexpression results in the dysregulation of approximately 100 genes. Examples of such genes include many involved in the formation of the cytoskeleton, cell adhesion and the extracellular matrix, as well as regulators of the cell cycle and apoptosis, cytokines and transcription factors. Several genes related to cell growth arrest, such as GADD45, IGF-BP6 and RUNX-3, are upregulated by AM. Interestingly, interleukin-13 receptor ␣2 (IL-13R␣2) transcripts were significantly increased in clones overexpressing AM, which was confirmed by semiquantitative RT-PCR analysis. In addition, PC-3 cells treated with AM showed an overexpression of IL-13R␣2, which was abolished when cells were preincubated with an anti-AM blocking antibody. When PC-3 cells overexpressing AM and the IL-13R␣2 were treated with the highly specific IL13-PE38 cytotoxin, which binds to this receptor, a concentration-dependent inhibition of protein synthesis was observed. The IC 50 (concentration of cytotoxin inhibiting protein synthesis by 50%) ranged from 1 to 4 ng/ml. This cytotoxicity was specific as it was neutralized by the excess of IL-13 and confirmed by clonogenic assays. This study describes a novel AM-induced mechanism of tumor sensitization through the upregulation of functional IL-13R␣2 chain, an ideal target for the highly specific recombinant chimeric cytotoxin IL13-PE38. © 2004 Wiley-Liss, Inc.Key words: cDNA microarrays; prostate cancer; adrenomedullin; IL-13R␣2; gene expression profiling Prostate carcinoma is the second leading cause of cancer mortality among men in the United States. 1 The 5-year relative survival rate for the patients whose tumors are diagnosed with local or regional disease approaches 100%, but the relative 10-and 15-year survival rates are reduced to 75% and 54%, respectively. 1 Although localized prostate cancer may be successfully treated, 70% of patients eventually progress and develop metastasis. The current nonsurgical therapeutic regimens for treating prostate carcinoma include radio-, hormonal-and chemotherapy, as well as a combination of these regimens, depending on specific circumstances of the patient. The limited success of treating particular forms of prostate cancer requires that additional targets for therapy be identified and tested.Expression of adrenomedullin, an amidated peptide that was originally isolated from human pheochromocytoma, 2 has been documented in both the human and rat prostate, 3 human prostate carcinoma 4 and prostate cancer cell lines, 4 where it has been suggested that adrenomedullin (AM) may act as an autocrine/ paracrine factor. Human AM consists of 52 amino acids (50 amino acids for rat AM) and shar...

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Interleukin-13 Receptors on Human Prostate Carcinoma Cell Lines Represent a Novel Target for a Chimeric Protein Composed of IL-13 and a Mutated Form of Pseudomonas Exotoxin

Cited by 52 publications

References 18 publications

Tumor regression mechanisms by IL‐13 receptor–targeted cancer therapy involve apoptotic pathways

Tumor regression mechanisms by IL‐13 receptor–targeted cancer therapy involve apoptotic pathways

Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

Gene expression profiling identifies IL‐13 receptor α2 chain as a therapeutic target in prostate tumor cells overexpressing adrenomedullin

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