Gridley Daila S, Li Jun, Kajioka Eric H, Dutta-Roy Radha, Andres Melba L, Timiryasova Tatyana M, Fodor Istvan
Department of Radiation Medicine, Radiobiology Program, Loma Linda University and Medical Center, Loma Linda, CA 92354, USA.
Oncology. 2002;62(1):66-77. doi: 10.1159/000048249.
The major goal of this study was to evaluate the effects of tumor necrosis factor-alpha (TNF-alpha), delivered as pGL1-TNF-alpha, on hematological variables, as well as C6 tumor growth in athymic mice treated with and without radiation. pGL1-TNF-alpha was administered intratumorally at low to high doses (15, 150 and 450 microg) in all three phases of this study. In phase A, pGL1-TNF-alpha expression within tumors was dose dependent and transient, with highest levels seen at 18 h after injection, whereas no TNF-alpha protein was detected in plasma. Low erythrocyte counts, hemoglobin, and hematocrit were associated with tumor presence, but the reduction in these variables was most striking in the group receiving 450 microg of pGL1-TNF-alpha, the group that also exhibited thrombocytopenia at 72 h. In phase B, treatment with pGL1-TNF-alpha at 15 or 150 microg resulted in the greatest degree of splenomegaly, increased spontaneous blastogenesis by splenocytes, and high leukocyte and lymphocyte numbers in the spleen. In these same two groups, flow cytometry analyses of spleen cells showed that high levels of natural killer (panNK+) cells, B (CD19+) lymphocytes, and cells expressing the CD71 and CD25 activation markers were present (p < 0.05). An enhancing effect was also noted in some of the measurements with parental plasmid p WS4 and tumor presence. In phase C, the slowest tumor progression was observed in the groups receiving 15 and 150 microg pGL1-TNF-alpha together with radiation; tumor volumes were 51 and 43% smaller, respectively, than for PBS-injected controls by the end of the study. Collectively, these results show that localized treatment with pGL1-TNF-alpha is hematologically nontoxic at low doses and support the premise that activation of lymphocytes may contribute to the antitumor effects of radiation against a highly aggressive brain tumor.
本研究的主要目的是评估以pGL1 - 肿瘤坏死因子 - α（TNF - α）形式递送的TNF - α对血液学变量以及在接受和未接受辐射的无胸腺小鼠中C6肿瘤生长的影响。在本研究的所有三个阶段，均以低至高剂量（15、150和450微克）瘤内注射pGL1 - TNF - α。在A阶段，肿瘤内pGL1 - TNF - α的表达呈剂量依赖性且短暂，注射后18小时达到最高水平，而血浆中未检测到TNF - α蛋白。红细胞计数、血红蛋白和血细胞比容降低与肿瘤存在有关，但在接受450微克pGL1 - TNF - α的组中，这些变量的降低最为显著，该组在72小时时还出现了血小板减少症。在B阶段，15或150微克的pGL1 - TNF - α治疗导致脾脏肿大程度最大，脾细胞自发增殖增加，脾脏中白细胞和淋巴细胞数量增多。在这两组中，对脾细胞的流式细胞术分析表明存在高水平的自然杀伤（panNK +）细胞、B（CD19 +）淋巴细胞以及表达CD71和CD25激活标志物的细胞（p < 0.05）。在一些使用亲本质粒p WS4和肿瘤存在的测量中也观察到增强作用。在C阶段，在接受15和150微克pGL1 - TNF - α并联合辐射的组中观察到肿瘤进展最慢；到研究结束时，肿瘤体积分别比注射PBS的对照组小51%和43%。总体而言，这些结果表明低剂量的pGL1 - TNF - α局部治疗在血液学上无毒，并支持淋巴细胞激活可能有助于辐射对高度侵袭性脑肿瘤的抗肿瘤作用这一前提。
