Suppression of renal cell carcinoma growth and metastasis with sustained antiangiogenic gene therapy.
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 mm(3), 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 histopathological 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.
Department of Urology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Matthew J
MJ
Mellon
Kyung-Hee
KH
Bae
Catherine E
CE
Steding
Juan A
JA
Jiménez
Chinghai
C
Kao
Thomas A
TA
Gardner
D043168:Angiostatins / Q000235:genetics*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000556:secondary / Q000628:therapy*; D045744:Cell Line, Tumor; D043169:Endostatins / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000097:blood / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000235:genetics*
D043169:Endostatins; D011993:Recombinant Fusion Proteins; D043168:Angiostatins