Overexpression of interleukin-13 receptor-alpha2 in neuroendocrine malignant pheochromocytoma: a novel target for receptor directed anti-cancer therapy.
BACKGROUND
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-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.


METHODS
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.


METHODS
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).


METHODS
IC(50) and tumor size were measured.


RESULTS
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.


CONCLUSIONS
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.
Lai
Edwin W
EW
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. karel@mail.nih.gov
Joshi
Bharat H
BH
Martiniova
Lucia
L
Dogra
Ritika
R
Fujisawa
Toshio
T
Leland
Pamela
P
de Krijger
Ronald R
RR
Lubensky
Irina A
IA
Elkahloun
Abdel G
AG
Morris
John C
JC
Puri
Raj K
RK
Pacak
Karel
K
D000310:Adrenal Gland Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001426:Bacterial Proteins / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D010673:Pheochromocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D001426:Bacterial Proteins; D000922:Immunotoxins; D053663:Interleukin-13 Receptor alpha2 Subunit; C111749:pseudomonas exoprotein A protein, Pseudomonas aeruginosa