Lorence R M, Rood P A, Kelley K W
Department of Animal Sciences, University of Illinois, Urbana 61801.
J Natl Cancer Inst. 1988 Oct 19;80(16):1305-12. doi: 10.1093/jnci/80.16.1305.
The oncolytic strain 73-T of Newcastle disease virus (NDV) has been reported to be beneficial in the treatment of cancer patients, but little is known about its mechanism of action. In this study, NDV strain 73-T and a wild-type isolate of NDV were found to be potent inducers of tumor necrosis factor (TNF) production by both human peripheral blood mononuclear cells (PBMCs) and rat splenocytes. Antibody inhibition experiments identified TNF-alpha as the major species of TNF induced by NDV in PBMCs. The effect of recombinant human TNF-alpha (rHuTNF-alpha) on human cancer cells was then examined. Neither rHuTNF-alpha nor supernatants from NDV-stimulated PBMCs were cytotoxic toward the TNF-resistant human malignant melanoma cell line MEL-14. However, when MEL-14 cells were treated with NDV strain 73-T, both rHuTNF-alpha and supernatants from NDV-stimulated PBMCs killed 48% and 55%, respectively, of these tumor cells. Treatment with NDV also conferred TNF susceptibility to the TNF-resistant human malignant melanoma cell line MEL-21 and the human myelogenous leukemia cell line K562. In contrast to its enhanced cytotoxicity toward NDV-treated cancer cells, rHuTNF-alpha had no effect on NDV-treated normal human PBMCs proliferating in response to concanavalin A. These results suggest two important mechanisms for the antineoplastic activity of NDV: (a) induction of TNF-alpha secretion by human PBMCs and (b) enhancement of the sensitivity of neoplastic cells to the cytolytic effects of TNF-alpha.
据报道，新城疫病毒（NDV）的溶瘤株73-T对癌症患者的治疗有益，但其作用机制尚不清楚。在本研究中，发现NDV株73-T和一种NDV野生型分离株均可有效诱导人外周血单核细胞（PBMC）和大鼠脾细胞产生肿瘤坏死因子（TNF）。抗体抑制实验确定TNF-α是NDV在PBMC中诱导产生的主要TNF种类。随后检测了重组人TNF-α（rHuTNF-α）对人癌细胞的作用。rHuTNF-α和NDV刺激的PBMC上清液对TNF耐药的人恶性黑色素瘤细胞系MEL-14均无细胞毒性。然而，当用NDV株73-T处理MEL-14细胞时，rHuTNF-α和NDV刺激的PBMC上清液分别杀死了48%和55%的这些肿瘤细胞。用NDV处理还使TNF耐药的人恶性黑色素瘤细胞系MEL-21和人髓性白血病细胞系K562对TNF敏感。与对NDV处理的癌细胞增强的细胞毒性相反，rHuTNF-α对经NDV处理后因伴刀豆球蛋白A而增殖的正常人PBMC没有影响。这些结果提示了NDV抗肿瘤活性的两个重要机制：（a）诱导人PBMC分泌TNF-α；（b）增强肿瘤细胞对TNF-α细胞溶解作用的敏感性。
