title: Endostatin- and interleukin-2-expressing retroviral bicistronic vector for gene therapy of metastatic renal cell carcinoma.
abstract: 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.
authors.affiliation: Biotechnology Department, IPEN-CNEN, São Paulo, Brazil.
authors.forename: Flávia Gomes de Góes
authors.initials: FG
authors.lastname: Rocha
authors.forename: Fernanda B
authors.initials: FB
authors.lastname: Calvo
authors.forename: Karen C
authors.initials: KC
authors.lastname: Chaves
authors.forename: Jean P S
authors.initials: JP
authors.lastname: Peron
authors.forename: Rodolfo F
authors.initials: RF
authors.lastname: Marques
authors.forename: Tânia R
authors.initials: TR
authors.lastname: de Borba
authors.forename: Marina S
authors.initials: MS
authors.lastname: Braga
authors.forename: Cleide B
authors.initials: CB
authors.lastname: Pereira
authors.forename: Elisabete J
authors.initials: EJ
authors.lastname: Vicente
authors.forename: Roger
authors.initials: R
authors.lastname: Chammas
authors.forename: Nestor
authors.initials: N
authors.lastname: Schor
authors.forename: Maria H
authors.initials: MH
authors.lastname: Bellini
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D002460:Cell Line; D049109:Cell Proliferation; D004195:Disease Models, Animal; D043169:Endostatins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000098:blood supply / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008175:Lung Neoplasms / Q000098:blood supply / Q000401:mortality / Q000556:secondary* / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011897:Random Allocation; D012190:Retroviridae / Q000235:genetics; D047368:Tumor Burden
chemical_list: D043169:Endostatins; D007376:Interleukin-2