Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.
Potentiation of E7 antisense RNA-induced antitumor immunity by co-delivery of IL-12 gene in HPV16 DNA-positive mouse tumor.
Gene Ther. 1998 Nov;5(11):1462-71. Unique Identifier : AIDSLINE MED/99129160 He YK; Lui VW; Baar J; Wang L; Shurin M; Almonte C; Watkins SC; Huang L; Department of Pharmacology, University of Pittsburgh, School of; Medicine, PA 15261, USA.
Abstract:
Down-regulation of oncogene expression by antisense-based gene therapy has been extensively studied, and in some cases, therapeutic effects have been demonstrated. We have previously shown that down-regulation of HPV16 E6 and E7 gene expression inhibited HPV DNA-positive C3 mouse tumor growth. Although not all of the tumor cells were transfected by pU6E7AS plasmid, complete tumor regression was achieved if the tumor size was small at the start of therapy in a syngeneic host. This suggests that some other antitumor mechanisms may be involved in addition to the direct down-regulation of HPV16 E7 oncogene expression by the antisense effect of E7AS. In the current study, we demonstrated that E7AS induces tumor cell apoptosis. More importantly, a strong antitumor immune response was elicited in the pU6E7AS-treated and tumor-regressed mice. There was no tumor growth after rechallenging the tumor-regressed mice with 1 million C3 cells. This E7AS-induced antitumor immune response was augmented by co-delivery of mIL-12 cytokine gene. The combination therapy strategy resulted in complete regression of 26 of 28 (93%) tumors. Only 12 of 31 (38%) tumors from the group treated with pU6E7AS alone and 14 of 28 (50%) tumors from the group treated with pCMVmIL-12 alone had completely regressed. Complete regression was also demonstrated in tumors located 1 cm from the treated tumors, which indicates that a systemic antitumor effect was induced by E7AS and mIL-12. Immunohistochemistry demonstrated that a significant amount of CD4+ and CD8+ cells infiltrated into tumors treated with pU6E7AS, pCMVmIL-12 and pU6E7AS+pCMVmIL-12. These data indicate that host immunity is an important factor for antisense-based gene therapy approach which can be further enhanced by combination with cytokine gene therapy.
Keywords: JOURNAL ARTICLE Animal Apoptosis Comparative Study CD4-Positive T-Lymphocytes/IMMUNOLOGY CD8-Positive T-Lymphocytes/IMMUNOLOGY Gene Expression Regulation Gene Therapy/*METHODS Genetic Vectors Interleukin-12/*GENETICS Mice Microscopy, Fluorescence Neoplasms, Experimental/IMMUNOLOGY/PATHOLOGY/THERAPY Oncogene Proteins, Viral/*GENETICS Papillomavirus, Human/*GENETICS *RNA, Antisense Support, U.S. Gov't, P.H.S. Transfection/METHODS Tumor Virus Infections/IMMUNOLOGY/PATHOLOGY/*THERAPY 990530
A9950933
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.
