Suppression of renal cell carcinoma growth and metastasis with sustained antiangiogenic gene therapy

Matthew J. Mellon, Kyung Hee Bae, Catherine E. Steding, Juan A. Jiménez, Chinghai Kao, Thomas Gardner

Research output: Contribution to journalArticle

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Abstract

Renal cell carcinoma (RCC) is the third most common urologic neoplasm. This aggressive malignancy has proven refractory to conventional treatment options. Antiangiogenic agents have shown early success in treating metastatic disease. The highly vascular nature of RCC appears particularly susceptible to this approach. This study investigates the potential of sustained expression of an endostatin-angiostatin fusion protein in an early-stage model of RCC to inhibit tumor growth and metastasis. Subcutaneous RCC-29 tumors were induced in athymic nude mice. Once tumors reached volumes of 10 and 25 mm3, subjects received intratumoral injections of a nonreplicating adenoviral vector every 20 days until the conclusion of the trial. The mice were randomly assigned to three treatment groups: saline control, viral Ad-GFP control, and Ad-EndoAngio. Tumor volumes were measured twice weekly for 80 days. During days 40-50 of the trial, subjects underwent dual-photon optical imaging of the tumor vasculature to ascertain angiogenic changes. All animals underwent postmortem histopathogical analysis to assess for metastatic disease in the kidney, lung, liver, brain, and spleen. Results indicate that tumors treated with Ad-EndoAngio displayed 97% growth reduction compared with controls (p < 0.001). Further, in vivo tumor vascular imaging illustrated a reduction in blood vessel number and lumen diameter size. Kaplan-Meier analysis suggested dramatic survival advantage with Ad-EndoAngio treatment. Importantly, histopathological examination demonstrated marked lung and liver metastasis suppression in the treatment arms. These results suggest that sustained EndoAngio gene therapy has effective antiangiogenic action against human RCC tumors and possesses potential as a novel treatment for metastatic renal cell carcinoma.

Original languageEnglish
Pages (from-to)487-495
Number of pages9
JournalHuman Gene Therapy
Volume19
Issue number5
DOIs
StatePublished - May 1 2008

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Renal Cell Carcinoma
Genetic Therapy
Neoplasm Metastasis
Growth
Neoplasms
Blood Vessels
Tumor Burden
Nude Mice
Angiostatins
Endostatins
Urologic Neoplasms
Therapeutics
Lung
Angiogenesis Inhibitors
Liver
Optical Imaging
Kaplan-Meier Estimate
Kidney Diseases
Photons
Spleen

ASJC Scopus subject areas

  • Genetics

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Suppression of renal cell carcinoma growth and metastasis with sustained antiangiogenic gene therapy. / Mellon, Matthew J.; Bae, Kyung Hee; Steding, Catherine E.; Jiménez, Juan A.; Kao, Chinghai; Gardner, Thomas.

In: Human Gene Therapy, Vol. 19, No. 5, 01.05.2008, p. 487-495.

Research output: Contribution to journalArticle

Mellon, Matthew J. ; Bae, Kyung Hee ; Steding, Catherine E. ; Jiménez, Juan A. ; Kao, Chinghai ; Gardner, Thomas. / Suppression of renal cell carcinoma growth and metastasis with sustained antiangiogenic gene therapy. In: Human Gene Therapy. 2008 ; Vol. 19, No. 5. pp. 487-495.
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