| Autor: |
David TIP; Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia, Instituto Do Câncer Do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo, 251, 8th floor, São Paulo, SP, Brazil., Cerqueira OLD; Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia, Instituto Do Câncer Do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo, 251, 8th floor, São Paulo, SP, Brazil., Lana MG; Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia, Instituto Do Câncer Do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo, 251, 8th floor, São Paulo, SP, Brazil., Medrano RFV; Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia, Instituto Do Câncer Do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo, 251, 8th floor, São Paulo, SP, Brazil.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA., Hunger A; Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia, Instituto Do Câncer Do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo, 251, 8th floor, São Paulo, SP, Brazil.; Cristalia, Biotecnologia Unidade 1, Rodoviária SP 147, Itapira, SP, Brazil., Strauss BE; Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia, Instituto Do Câncer Do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo, 251, 8th floor, São Paulo, SP, Brazil. bstrauss@usp.br. |
| Abstrakt: |
Since melanomas often retain wild type p53, we developed an adenoviral vector, AdRGD-PG, which provides robust transduction and transgene expression in response to p53. Previously, this vector was used for interferon-β gene transfer in mouse models of melanoma, resulting in control of tumor progression, but limited cell killing. Here, the AdRGD-PG-hIFNβ vector encoding the human interferon-β cDNA (hIFNβ) was used to transduce human melanoma cell lines SK-MEL-05 and SK-MEL-147 (both wild type p53). In vitro, cell death was induced in more than 80% of the cells and correlated with elevated annexinV staining and caspase 3/7 activity. Treatment with hIFNβ promoted cell killing in neighboring, non-transduced cells, thus revealing a bystander effect. In situ gene therapy resulted in complete inhibition of tumor progression for SK-MEL-147 when using nude mice with no evidence of hepatotoxicity. However, the response in Nod-Scid mice was less robust. For SK-MEL-05, tumor inhibition was similar in nude and Nod-Scid mice and was less efficient than seen for SK-MEL-147, indicating both cell type and host specific responses. The AdRGD-PG-hIFNβ vector provides extensive killing of human melanoma cells in vitro and a potent anti-tumor effect in vivo. This study provides a critical advance in the development of our melanoma gene therapy approach. |
