Endostatin- and interleukin-2-expressing retroviral bicistronic vector for gene therapy of metastatic renal cell carcinoma

Background Metastatic renal cell carcinoma (mRCC) is one of the most treatment‐resistant malignancies. Despite all new therapeutic advances, almost all patients develop resistance to treatment and cure is rarely seen. In the present study, we evaluated the antitumor effect of a bicistronic retroviru...

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Published in:	The journal of gene medicine Vol. 13; no. 3; pp. 148 - 157
Main Authors:	Rocha, Flávia Gomes de Góes, Calvo, Fernanda B., Chaves, Karen C., Peron, Jean P. S., Marques, Rodolfo F., de Borba, Tânia R., Braga, Marina S., Pereira, Cleide B., Vicente, Elisabete J., Chammas, Roger, Schor, Nestor, Bellini, Maria H.
Format:	Journal Article
Language:	English
Published:	Chichester, UK John Wiley & Sons, Ltd 01-03-2011 Wiley Periodicals Inc
Subjects:	Animals Carcinoma, Renal Cell - blood supply Carcinoma, Renal Cell - mortality Carcinoma, Renal Cell - secondary Carcinoma, Renal Cell - therapy Cell Line Cell Proliferation Disease Models, Animal endostatin Endostatins - blood Endostatins - genetics Endostatins - secretion Gene therapy Genetic Therapy Genetic Vectors - genetics Humans interleukin-2 Interleukin-2 - blood Interleukin-2 - genetics Interleukin-2 - secretion Kaplan-Meier Estimate Kidney Neoplasms - blood supply Kidney Neoplasms - mortality Kidney Neoplasms - pathology Kidney Neoplasms - therapy Lung Neoplasms - blood supply Lung Neoplasms - mortality Lung Neoplasms - secondary Lung Neoplasms - therapy Male Mice Mice, Inbred BALB C Neovascularization, Pathologic - prevention & control Random Allocation retroviral bicistronic vector Retroviridae - genetics Retrovirus Tumor Burden
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Summary:	Background Metastatic renal cell carcinoma (mRCC) is one of the most treatment‐resistant malignancies. Despite all new therapeutic advances, almost all patients develop resistance to treatment and cure is rarely seen. In the present study, we evaluated the antitumor effect of a bicistronic retrovirus vector encoding both endostatin (ES) and interleukin (IL)‐2 using an orthotopic metastatic RCC mouse model. Methods Balb/C‐bearing Renca cells were treated with NIH/3T3‐LendIRES‐IL‐2‐SN cells. In the survival studies, mice were monitored daily until they died. At the end of the in vivo experiment, serum levels of IL‐2 and ES were measured, the lung was weighed, and the number of metastatic nodules, nodule area, tumor vessels and proliferation of tumor‐infiltrating Renca cells were determined. Results Inoculation of NIH/3T3‐LendIRES‐IL‐2‐SN cells resulted in an increase in ES and IL‐2 levels in the treated group (p < 0.05). There was a significant decrease in lung wet weight, lung nodule area and tumor vessels in the treated group compared to the control group (p < 0.001). The proliferation of Renca cells in the bicistronic‐treated group was significantly reduced compared to the control group (p < 0.05). Kaplan–Meier survival curves showed that the probability of survival was significantly higher for mice submitted to bicistronic therapy (log‐rank test, p = 0.0016). Bicistronic therapy caused an increase in the infiltration of CD4, CD4 interferon (IFN)γ‐producing, CD8, CD8 IFNγ‐producing and natural killer (CD49b) cells. Conclusions Retroviral bicistronic gene transfer led to the secretion of functional ES and IL‐2 that was sufficiently active to: (i) inhibit tumor angiogenesis and tumor cell proliferation and (ii) increase the infiltration of immune cells. Copyright © 2011 John Wiley & Sons, Ltd.
Bibliography:	ArticleID:JGM1547 FAPESP - No. 2007/54253-6 CNPq - No. 481888/2008 istex:969E643E7AA389A170BD321F35F5CA4721602C04 CAPES/PNPD - No. 0188085 ark:/67375/WNG-DWJ2RHWH-8 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	1099-498X 1521-2254 1521-2254
DOI:	10.1002/jgm.1547