The potent antitumor effects of combined p16 gene and GM-CSF gene therapy through efficient induction of antitumor immunity |
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Authors: | Lin Hui Wang Dian Wen Ju Yinghao Sun Qun Tao Songxi Qian Jing Mi Hirofumi Hamada Xuetao Cao |
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Affiliation: | (1) Department of Immunology, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, P.R. China e-mail: caoxt@public3.sta.net.cn; Fax: +86-21-65382502, CN;(2) Department of Molecular Medicine, Sapporo Medical University, Sapporo 060-8556, Japan, JP |
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Abstract: | Purpose: Tumor suppressor gene therapy and cytokine gene therapy have limited antitumor effects when used alone. Thus, in the present study, we investigated the antitumor potentials of the combined transfer of the p16 tumor suppressor gene and the murine granulocyte-macrophage colony-stimulating factor (GM-CSF) gene. Methods: The adenovirus-harboring p16 gene (Adp16) and adenovirus-harboring GM-CSF (AdGMCSF) gene were utilized for the treatment of established tumors in vivo. The mice were inoculated s.c. with Renca renal carcinoma cells and 3 days later received an intratumoral injection of Adp16 in combination with AdGMCSF. Results: The results demonstrated that tumor-bearing mice treated with Adp16 and AdGMCSF showed more potent inhibition of tumor growth and a prolonged survival period than mice treated with Adp16, AdGMCSF, adenovirus-expressing β-galactosidase or PBS (P < 0.01). Treatments of the mice with Adp16 alone or AdGMCSF alone also showed obvious antitumor effects as compared with those mice treated with PBS (P < 0.05). After combined p16 and AdGMCSF gene therapy, the expression of H-2Kd and Fas molecules on freshly isolated tumor cells increased markedly, and more CD4 + T cells and CD8 + T cells infiltrated in the tumor sites. The cytotoxicity of natural killer cells and specific cytotoxic T lymphocytes increased more significantly after the combined therapy. Conclusions: Our results demonstrated that combination p16 gene and GM-CSF gene therapy could inhibit the growth of established tumors in mice more significantly through efficient induction of antitumor immunity. Received: 11 April 2000 / Accepted: 19 July 2000 |
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Keywords: | Gene therapy p16 Granulocyte-macrophage colony-stimulating factor Renal carcinoma Antitumor immunity |
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