Overexpression of Interleukin-13 Receptor-α2 in Neuroendocrine Malignant Pheochromocytoma: A Novel Target for Receptor Directed Anti-Cancer Therapy

Section on Medical Neuroendocrinology, Reproductive and Adult Endocrinology Program, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1109, USA.
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 06/2009; 94(8):2952-7. DOI: 10.1210/jc.2009-0309
Source: PubMed


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.
The objective of the study was to identify and characterize overexpression of IL-13 receptor-alpha2 (IL-13Ralpha2) gene expression in human and murine tumors and verify xenograft mouse pheochromocytoma cell (MPC)-derived tumor's response to a selective cytotoxin.
Expression of IL-13Ralpha2 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-13Ralpha2 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 m icrog/kg).
IC(50) and tumor size were measured.
IL-13PE immunotoxin was highly cytotoxic to IL-13Ralpha2-overexpressing MPC cells (IC(50) <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.
Human and murine neuroendocrine pheochromocytoma overexpress the IL-13Ralpha2 chain, and an IL-13PE-based receptor-directed anticancer approach may prove useful in treatment for metastatic pheochromocytoma patients.

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    • "Conversely, normal adrenal medulla tissue did not reveal expression of IL-13Rα2. IL-13PE treatment resulted in significant suppression of subcutaneous tumors compared with placebo after 3 days initial treatment (P = 0.0021), but not of liver tumors, which required intratumoral delivery of IL-13PE [83]. This treatment could still be used, due to the high specificity for most of human PCCs with all gene mutations, however, in limited number of cases. "
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