Interleukin-13 receptor as a unique target for anti-glioblastoma therapy.

Abstract

Surgery, radiotherapy and chemotherapy have minimally altered survival of glioblastoma patients. We explored a specific approach for glioblastoma therapy in which cellular interleukin-13 (IL-13) receptors were targeted by an IL-13 cytotoxin. A wide array of human glioblastoma cell lines expressing the receptor for IL-13 were effectively killed by an IL-13 cytotoxin, a chimeric protein composed of human IL-13 and a mutated form of Pseudomonas exotoxin (termed IL13-PE38QQR or IL-13 toxin). Daily (qd) intratumoral injections of IL-13 toxin (50 and 100 microg/kg/day) for 5 consecutive days into subcutaneous human U251 glioblastoma tumors (approx. 30 mm(2)) in nude mice resulted in complete regression of tumors in 4/5 and 5/5 mice, respectively. Tumor regression persisted for at least 221 days postimplantation. Three alternate day injections (qod) of IL-13 toxin (250 microg/kg/day) into other subcutaneous U87 glioblastoma tumors also produced durable complete responses (CR) in all 5 mice. Twice daily (bid) intraperitoneal injections of IL-13 toxin at 25 or 50 microg/kg/dose for 5 days (total doses = 10) regressed U251 tumors by 45% and 58% with 1/5 and 2/5 CRs, respectively, on day 54. Intraperitoneal administration of IL-13 toxin with an identical schedule at a dose of 50 microg/kg injected into mice bearing U87 xenografts reduced tumor burden by one-half on day 36. Similar doses (25 or 50 microg/kg) with a daily schedule (qd x 5) by the intravenous route also suppressed growth of U251 subcutaneous tumors by 75% and 81% with 1/6 CR in either group by day 34. All mice tolerated therapy well without any visible signs of toxicity. On the basis of these studies, we have initiated a Phase I clinical trial using IL13-PE38QQR in patients with recurrent glioblastoma. Published 2001 Wiley-Liss, Inc.

• Authors: S R Husain, B H Joshi, R K Puri
• Journal: International journal of cancer (Int J Cancer) Vol. 92 Issue 2 Pg. 168-75 (Apr 15 2001) ISSN: 0020-7136 [Print] United States
• PMID: 11291041 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Bacterial Toxins
• Exotoxins
• IL13RA1 protein, human
• Il13ra1 protein, mouse
• Interleukin-13
• Interleukin-13 Receptor alpha1 Subunit
• Receptors, Interleukin
• Receptors, Interleukin-13
• Recombinant Fusion Proteins
• Virulence Factors
• ADP Ribose Transferases
• Pseudomonas aeruginosa exotoxin A

Topics

• ADP Ribose Transferases
• Animals
• Bacterial Toxins
• Brain Neoplasms (drug therapy)
• Cell Division (drug effects)
• Exotoxins (administration & dosage, genetics, therapeutic use)
• Glioblastoma (pathology, therapy)
• Humans
• Injections, Intralesional
• Injections, Intraperitoneal
• Injections, Intravenous
• Interleukin-13 (genetics, therapeutic use)
• Interleukin-13 Receptor alpha1 Subunit
• Kinetics
• Mice
• Mice, Nude
• Receptors, Interleukin (metabolism)
• Receptors, Interleukin-13
• Recombinant Fusion Proteins (therapeutic use)
• Tumor Cells, Cultured
• Tumor Stem Cell Assay
• Virulence Factors
• Xenograft Model Antitumor Assays