TNF-alpha gene and proton radiotherapy in an orthotopic brain tumor model.
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.
Department of Radiation Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA. dgridley@dominion.llumc.edu
Daila S
DS
Gridley
James R
JR
Baer
Jeffrey D
JD
Cao
Glen M
GM
Miller
Dong Won
DW
Kim
Tatyana M
TM
Timiryasova
Istvan
I
Fodor
James M
JM
Slater
D000818:Animals; D001835:Body Weight; D001932:Brain Neoplasms / Q000473:pathology / Q000532:radiotherapy* / Q000628:therapy*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005910:Glioma / Q000473:pathology / Q000532:radiotherapy* / Q000628:therapy*; D007694:Killer Cells, Natural; D016131:Lymphocyte Subsets; D008297:Male; D009368:Neoplasm Transplantation; D010957:Plasmids; D061766:Proton Therapy; D051381:Rats; D011923:Rats, Nude; D013154:Spleen / Q000276:immunology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D014409:Tumor Necrosis Factor-alpha