Salmon S E, Young L, Scuderi P, Clark B
Arizona Cancer Center, University of Arizona College of Medicine, Tucson.
J Clin Oncol. 1987 Nov;5(11):1816-21. doi: 10.1200/JCO.1987.5.11.1816.
Tumor colony-forming cells were grown from fresh biopsy specimens from 102 patients with a variety of nonhematologic malignant neoplasms and exposed in vitro to pharmacologically achievable doses of recombinant human tumor necrosis factor (rTNF). In 68 instances, the tumor specimens were also tested against recombinant human gamma-interferon (rIFN-gamma), as well as the combination of rTNF and rIFN-gamma. rTNF exhibited dose-dependent and tumor-type-dependent antitumor effects. Sensitivity to rTNF at doses of less than 100 U was observed in 28% of the tumors tested. A higher than average frequency of sensitivity was observed in colorectal and lung cancer. Resistance to rTNF was observed in 42% of the tumors, including 52% of the ovarian cancer specimens tested. In paired experiments, exposure of tumor specimens to rTNF and rIFN-gamma in combination often resulted in a greater antitumor effect than was observed with either agent alone, with at least subadditive effects seen in 62% of the specimens tested against the combination. Antagonism between rTNF and rIFN-gamma was observed in 18% of the studies. Overall, exposure to the combination of rTNF and rIFN-gamma reduced the dose of rTNF required for significant antitumor activity by about threefold. Normal bone marrow granulocyte-macrophage colony-forming cells were also tested against both rTNF and rIFN-gamma and the combination. The bone marrow progenitors were more sensitive to rTNF and the combination with rIFN-gamma than were the tumor cells; however, the significance of this comparison between two different in vitro assay systems is indeterminate. Based on our observations, rTNF warrants phase II clinical trials in selected solid tumors with definite emphasis on colorectal and lung cancer. Additionally, studies of the combination of rTNF and rIFN-gamma are indicated and will be of particular interest in endometrial and breast cancer.
从102例患有各种非血液系统恶性肿瘤的患者新鲜活检标本中培养肿瘤集落形成细胞，并在体外将其暴露于药理学上可达到剂量的重组人肿瘤坏死因子（rTNF）。在68例病例中，肿瘤标本还接受了重组人γ干扰素（rIFN-γ）以及rTNF与rIFN-γ联合用药的检测。rTNF表现出剂量依赖性和肿瘤类型依赖性的抗肿瘤作用。在所检测的肿瘤中，28%的肿瘤在剂量小于100 U时对rTNF敏感。在结直肠癌和肺癌中观察到高于平均水平的敏感频率。42%的肿瘤对rTNF耐药，包括所检测的52%的卵巢癌标本。在配对实验中，肿瘤标本联合暴露于rTNF和rIFN-γ通常比单独使用任何一种药物产生更大的抗肿瘤作用，在所检测联合用药的标本中，至少62%出现亚相加效应。在18%的研究中观察到rTNF与rIFN-γ之间存在拮抗作用。总体而言，联合暴露于rTNF和rIFN-γ可使产生显著抗肿瘤活性所需的rTNF剂量降低约三倍。正常骨髓粒细胞-巨噬细胞集落形成细胞也接受了rTNF、rIFN-γ及其联合用药的检测。骨髓祖细胞比肿瘤细胞对rTNF及其与rIFN-γ的联合用药更敏感；然而，这两种不同体外检测系统之间比较的意义尚不确定。基于我们的观察结果，rTNF值得在选定的实体瘤中进行II期临床试验，尤其着重于结直肠癌和肺癌。此外，rTNF与rIFN-γ联合用药的研究也很有必要，对子宫内膜癌和乳腺癌将特别有意义。
