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Overexpression of Interleukin-13 Receptor-2 in Neuroendocrine Malignant Pheochromocytoma: A Novel Target for Receptor Directed Anti-Cancer Therapy

Section on Medical Neuroendocrinology (E.W.L., L.M., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Tumor Vaccines and Biotechnology Branch (B.H.J., R.D., T.F., P.L., R.K.P.), Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Cancer Diagnosis Program (I.A.L.), National Cancer Institute, National Human Genome Research Institute (A.G.E.), Metabolism Branch (J.C.M.), and Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892; and Department of Pathology (R.R.d.K.), Josephine Nefkens Institute, Erasmus Medical Centre-University Medical Centre, 3000-DR Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Karel Pacak, M.D., Ph.D., D.Sc., Section on Medical Neuroendocrinology, Reproductive and Adult Endocrinology Program, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, CRC, Room 1-3140, 10 Center Drive, Bethesda, Maryland 20892-1109. E-mail: karel{at}mail.nih.gov; or Raj K. Puri, M.D., Ph.D., Division of Cellular and Gene Therapies, Food and Drug Administration, Center for Biologics Evaluation and Research, National Institutes of Health, Building 29B, Room 2NN20, 29 Lincoln Drive, Bethesda, Maryland 20892-4555. E-mail: raj.puri{at}fda.hhs.gov.

Context: Pheochromocytomas and paragangliomas are rare catecholamine-secreting neuroendocrine tumors arising from the adrenal medulla and sympathetic tissues. When complete surgical resection is not an option, the treatment of pheochromocytoma is limited.

Objective: The objective of the study was to identify and characterize overexpression of IL-13 receptor-2 (IL-13R2) gene expression in human and murine tumors and verify xenograft mouse pheochromocytoma cell (MPC)-derived tumor’s response to a selective cytotoxin.

Design/Setting/Patients: Expression of IL-13R2 was evaluated in a panel of 25 human pheochromocytoma clinical samples by RT-PCR and eight MPC tumors by indirect immunofluorescence assay and RT-PCR.

Intervention: The function of IL-13R2 in these tumor cells was examined by evaluating tumor sensitivity to a recombinant IL-13-Pseudomonas exotoxin (IL-13PE). Subcutaneous small and large MPC tumors in athymic nude mice (n = 10) were treated intratumorally with IL-13PE (100 µg/kg).

Main Outcome Measures: IC₅₀ and tumor size were measured.

Results: IL-13PE immunotoxin was highly cytotoxic to IL-13R2-overexpressing MPC cells (IC₅₀ <2.5 ng/ml) in vitro. Furthermore, IL-13PE was highly cytotoxic to sc tumors. Our results showed a statistically significant decrease in tumor size as early as 3 d after initial treatment and further suppressed growth of MPC tumors. All tumors displayed a histological evidence of necrosis in response to IL-13 immunotoxin without any adverse effects in host at this dose.

Conclusions: Human and murine neuroendocrine pheochromocytoma overexpress the IL-13R2 chain, and an IL-13PE-based receptor-directed anticancer approach may prove useful in treatment for metastatic pheochromocytoma patients.