TNF-alpha gene and proton radiotherapy in an orthotopic brain tumor model

• Published in: International journal of oncology Vol. 21; no. 2; p. 251
• Main Authors: Gridley, Daila S, Baer, James R, Cao, Jeffrey D, Miller, Glen M, Kim, Dong Won, Timiryasova, Tatyana M, Fodor, Istvan, Slater, James M
• Format: Journal Article
• Language: English
• Published: Greece 01.08.2002
• Subjects: Animals; Body Weight; Brain Neoplasms - pathology; Brain Neoplasms - radiotherapy; Brain Neoplasms - therapy; Combined Modality Therapy; Disease Models, Animal; Genetic Therapy - methods; Genetic Vectors; Glioma - pathology; Glioma - radiotherapy; Glioma - therapy; Killer Cells, Natural; Lymphocyte Subsets; Male; Neoplasm Transplantation; Plasmids; Protons - therapeutic use; Rats; Rats, Nude; Spleen - immunology; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - genetics
• ISSN: 1019-6439
• DOI: 10.3892/ijo.21.2.251

The major goal of this study was to evaluate the safety and efficacy of TNF-alpha gene therapy (pGL1-TNF-alpha) in combination with proton radiation in an orthotopic brain tumor model. C6 glioma cells were implanted into the left hemibrain of athymic rats (day 0). On day 5, pGL1-TNF-alpha (19 microg/10 microl) was injected into the same site; appropriate control groups were included. Proton irradiation (10 Gy, single fraction) was performed 18-20 h thereafter and, on day 10, a portion of animals from each group was assayed. Nearly all tumor-bearing groups had lower body mass compared to those without tumor; brain mass was somewhat increased with plasmid (pGL1-TNF-alpha or pWS4) injection (p<0.05). Histopathological analysis of brain sections revealed that rats receiving pGL1-TNF-alpha/proton irradiation had the smallest tumors and lowest number of mitotic tumor cells, although survival time for animals kept long-term was not significantly prolonged. A decline in leukocyte populations was noted with combination treatment compared to controls (p<0.05), but no differences were found compared to groups receiving each modality alone. Based on DNA synthesis, the pGL1-TNF-alpha/proton irradiated group had the highest levels of leukocyte activation. The highest percentage of lymphocytes expressing the CD71 activation marker occurred with pGL1-TNF-alpha, whereas the proton-irradiated group had the highest percentage of activated NK cells (NK1.1+/CD71+). No significant differences were found in erythrocyte and thrombocyte numbers, hemoglobin, and hematocrit. Overall, the data indicate that pGL1-TNF-alpha/proton treatment results in a measurable antitumor effect and is safe under the conditions used.