Combination of pGL1-TNF-alpha gene and radiation (proton and gamma-ray) therapy against brain tumor.
The major goal of this study was to determine if treatment with the newly constructed plasmid vector for tumor necrosis factor-alpha (pGL1-TNF-alpha) could enhance the radiation-induced growth reduction of C6 rat glioma. In addition, two different forms of ionizing radiation (gamma-rays and protons) were utilized. Body and spleen mass, leukocyte blastogenesis, and flow cytometry analysis of cell populations in blood and spleen were performed to detect toxicity, if any, and to identify mechanisms that may correlate with the anti-tumor action of combination therapy. C6 tumor cells were implanted subcutaneously into athymic mice and allowed to become established before treatment initiation. pGL1-TNF-alpha was injected into the implanted tumors, which were then irradiated 16-18 hr later; each modality was administered three times over 8-9 days. The addition of pGL1-TNF-alpha significantly enhanced the anti-tumor effect of radiation (p < 0.05). The effect was more than additive, since pGL1-TNF-alpha alone did not slow tumor progression and radiation alone had only a modest effect. Administration of pGL1-TNF-alpha together with proton radiation resulted in tumor volumes that were 23% smaller than those following pGL1-TNF-alpha + gamma-ray treatment; a similar differential in tumor size was observed in the groups receiving only radiation. Body weights and blood and spleen cell analyses did not reveal treatment-related toxicity. High basal proliferation of blood leukocytes and increased B cell levels in the spleen were associated with pGL1-TNF-alpha + 60Co (gamma-radiation) or proton treatment. Overall, the results suggest that the pGL1-TNF-alpha/radiation combination is effective and safe under the conditions employed. This is the first study to combine gene and proton radiation therapy and to show, under controlled experimental conditions, that proton radiation may have a greater effect against malignant tumors compared to the same physical dose of gamma-radiation.
Gridley
D S
DS
Department of Radiation Medicine (Radiobiology Program), Loma Linda University and Medical Center, Loma Linda, CA 92354, USA. dgridley@dominion.llumc.edu
Li
J
J
Kajioka
E H
EH
Andres
M L
ML
Moyers
M F
MF
Slater
J M
JM
D000818:Animals; D001835:Body Weight; D001932:Brain Neoplasms / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D003037:Cobalt Radioisotopes / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use*; D005910:Glioma / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D007694:Killer Cells, Natural; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017785:Photons / Q000627:therapeutic use*; D061766:Proton Therapy; D051381:Rats; D013154:Spleen / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000627:therapeutic use*
D003037:Cobalt Radioisotopes; D014409:Tumor Necrosis Factor-alpha