Abstract
Cytotoxins directed to interleukin-4 receptors have shown to mediate relatively selective cytotoxicity against a variety of human cancer cells in vitro and in vivo. In an ongoing Phase I clinical trial, a recombinant protein comprised of circularly permuted IL-4 fused to a mutated form of Pseudomonas exotoxin (the fusion protein termed IL-4(38-37)-PE38KDEL or cpIL4-PE) has shown antitumour activity against malignant glioma. Human medulloblastomas are neuroectodermal tumours that occur in children and have a poor prognosis. The goal of this study was to determine whether human medulloblastoma derived cell lines express interleukin-4 receptor and whether interleukin-4 receptor expression is accompanied by sensitivity to cpIL4-PE. Medulloblastoma cell lines express interleukin-4 receptor at the protein and mRNA levels as determined by binding, indirect immunofluorescence and RT–PCR studies. These cells expressed IL-4Rα (also known as IL-4Rβ) and IL-13Rα1 (also known as IL-13Rα′) chains, however common γc, a component of the interleukin-4 receptor system in immune cells was not detected. Consistent with the expression of IL-4R, cpIL4-PE was found to be highly and specifically cytotoxic to four of five medulloblastoma cell lines. Susceptibility of medulloblastoma cell lines to cpIL4-PE seemed to correlate closely to the functional IL-4 binding sites in general as demonstrated by 125I-IL-4 binding, but did not seem to correlate with mRNA or cell surface immunoreactive receptor protein expression. The sensitivity of medulloblastoma cells to cpIL4-PE could be eliminated by concurrent incubation with IL-4 or IL-13, but not with IL-2. None of these cell lines showed any change in proliferation upon treatment with exogenous IL-4. These studies establish the interleukin-4 receptor as a medulloblastoma-associated target for possible tumour-directed cancer therapy. Further studies are warranted to investigate interleukin-4 receptor expression in primary medulloblastoma tumours and sensitivity to cpIL-4PE in vitro and in vivo.British Journal of Cancer (2002) 86, 285–291. DOI: 10.1038/sj/bjc/6600034 www.bjcancer.com© 2002 The Cancer Research Campaign
Highlights
Cytotoxin directed to IL-4R for human medulloblastoma BH Joshi et al286 neck cancer, renal cell carcinoma and others (Murata et al, 1998a)
We examined the expression of various IL-4R receptor chains by indirect immunofluorescence assays in five different medulloblastoma cells lines
We demonstrate that medulloblastoma cell lines express IL-4R that serve as a sensitive target for IL-4R-targeted agent, cpIL4-PE
Summary
Cytotoxin directed to IL-4R for human medulloblastoma BH Joshi et al286 neck cancer, renal cell carcinoma and others (Murata et al, 1998a). IL-4 primarily signals through Jak and Jak tyrosine kinases while in non-immune cells IL-4 signals through Jak and Jak tyrosine kinases (Murata et al, 1995, 1998a). All types of IL-4R phosphorylate and activate STAT-6 protein (Murata et al, 1995, 1998a,b). The significance of expression of IL-4R on solid tumour cells is not known. It is not known whether human medulloblastoma cells express IL-4R and, if they do, which chains of these receptors are present on medulloblastoma tumour cells. We have examined the mRNA and protein expression of various receptor subunits of IL-4R by RT – PCR, radiolabelled binding, and indirect immunofluorescence assays in different medulloblastoma cell lines. We have tested the cyototoxic effect of cpIL4-PE on various medulloblastoma cell lines
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