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Anti-tumor effect of endostatin mediated by retroviral gene transfer in mice bearing renal cell carcinoma

Enia Lúcia Coutinho^*, Luciana Nogueira de Sousa Andrade, Roger Chammas, Ligia Morganti, Nestor Schor^* and Maria Helena Bellini^*,

^* Division of Nephrology, Department of Medicine, Universidade Federal de São Paulo;

Instituto de Pesquisas Energéticas e Nucleares, Cidade Universitária IPEN-CNEN/SP; and

Laboratório de Oncologia Experimental, Departmento de Radiologia, Faculdade de Medicina da Universidade de São Paulo and Centro de Terapia Celular, CEPID/FAPESP, São Paulo, Brazil

¹Correspondence: Instituto de Pesquisas Energéticas e Nucleares, Cidade Universitária IPEN-CNEN/SP, Av. Lineu Prestes, 2242, 05508–900 São Paulo – SP- Brazil. E-mail: mhmarumo{at}terra.com.br

We investigated whether transfer of the gene encoding the angiogenesis inhibitor endostatin into the NIH/3T3 fibroblast cell line could inhibit renal tumor growth in vivo. NIH/3T3 cells were transduced with retroviral vectors containing the murine endostatin (ES) gene. SCID mice bearing CaKi-1 derived tumors were given a subcutaneous injection of either ES-transduced cells or control cells and were monitored for tumor growth. At the end of the in vivo experiment, the mean tumor volume of treated mice was 51.6 ± 2.4 mm³, while the tumor volume of control was 234.5 ± 14.8 mm³. Microvascular density was significantly decreased on treatment (control 9.79 vs. ES 2.53%, <0.001) accompanied by a 23-fold increase in intraturmoral necrotic area and a 2.94-fold increase in the apoptotic index, determined by immunohistochemistry with anti- activated caspase-3. Apoptotic cells were found in foci enriched in infiltrating leukocytes. In conclusion, retroviral endostatin gene transfer led to secretion of functional endostatin that was sufficiently active to inhibit tumor angiogenesis and tumor growth. A second mechanism may also be implied in endostatin-dependent tumor regression, associated with tumor infiltration of leukocytes. Besides its antiangiogenic properties, endostatin may be a promising adjuvant to immunotherapy.—Coutinho, E. L., Nogueira de Sousa Andrade, L., Chammas, R., Morganti, L., Schor, N., Bellini, M. H. Anti-tumor effect of endostatin mediated by retroviral gene transfer in mice bearing renal cell carcinoma.

Key Words: gene therapy • cancer • bioassay • antiangiogenesis