The potent antitumor effects of combined p16 gene and GM-CSF gene therapy through efficient induction of antitumor immunity

• Published in: Journal of cancer research and clinical oncology Vol. 127; no. 2; pp. 101 - 108
• Main Authors: LIN HUI WANG, DIAN WEN JU, YINGHAO SUN, QUN TAO, SONGXI QIAN, JING MI, HAMADA, Hirofumi, XUETAO CAO
• Format: Journal Article
• Language: English
• Published: Berlin Springer 2001; Springer Nature B.V
• Subjects: Adenoviridae; Adenoviruses; Animals; Antineoplastic agents; Antitumor activity; Biological and medical sciences; Blotting, Western; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - therapy; CD4 antigen; CD8 antigen; Colony-stimulating factor; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Cytokines; Cytotoxicity; Female; Gene therapy; Gene Transfer Techniques; Genes, p16; Genetic Therapy - methods; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Histocompatibility antigen H-2; Kidney cancer; Lymphocytes T; Medical sciences; Mice; Mice, Inbred BALB C; Natural killer cells; p16 Protein; Pharmacology. Drug treatments; Renal cell carcinoma; Transfection; Tumor cells; Tumor Cells, Cultured; Tumor suppressor genes; Tumors; β-Galactosidase; Antineoplastic agent; Adenoviridae; Carcinoma; Gene product; Cytotoxicity; CDKN2 gene; Kidney; Immunotherapy; T-Lymphocyte; Vector; Tumor suppressor gene; Kidney disease; Urinary system disease; Immune response; Treatment efficiency; Rodentia; Cytokine; Intratumoral administration; Malignant tumor; Gene expression; Virus; Natural killer cell; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Combined treatment; Gene therapy; Granulocyte macrophage colony stimulating factor
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s004320000187

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. 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. The results demonstrated that tumor-bearing mice treated with Adp16 and Ad-GMCSF showed more potent inhibition of tumor growth and a prolonged survival period than mice treated with Adp16. AdGMCSF, adenovirus-expressing beta-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 H2Kd and Fas molecules on freshly isolated tumor cells increased markedly, and more CD(4)+ T cells and CD(8)+ 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. 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.