Joseph W R, Cao Z, Mountjoy K G, Marshall E S, Baguley B C, Ching L M
Auckland Cancer Society Research Centre, University of Auckland School of Medicine, New Zealand.
Cancer Res. 1999 Feb 1;59(3):633-8.
The selective induction of tumor vascular collapse represents an exciting approach to cancer treatment. However, clinical evaluation of tumor necrosis factor-alpha (TNF), an agent that accomplishes this goal, has been limited by systemic toxicity, and clinical approaches using bacterial components to induce TNF production have also been disappointing. Our laboratory has developed synthetic low molecular weight inducers of TNF, including 5,6-dimethylxanthenone-4-acetic acid (DMXAA), as an alternative strategy. DMXAA induces rapid vascular collapse in transplantable murine tumors and induces TNF synthesis in vitro in both murine and human systems. We show here that the extent of DMXAA-induced TNF synthesis is greater in tumors than that in the spleen, liver, or serum. As shown by in situ hybridization studies of the murine Colon 38 tumor, DMXAA induced tumor as well as host cells to express TNF mRNA. The distribution of cells containing TNF mRNA in tumor tissues after DMXAA administration contrasted significantly with that obtained after lipopolysaccharide (LPS) treatment, although splenic and hepatic tissues showed a similar distribution of TNF mRNA-positive cells. In the Colon 38 tumor, the action of LPS was limited to host cells in the periphery of the vessels. DMXAA treatment induced 7-fold higher peak TNF levels in tumor than in serum. In contrast, LPS treatment induced 9-fold higher TNF levels in serum than in tumor. DMXAA induced 35-fold higher TNF activity in the Colon 38 tissue than did LPS. One ovarian, one squamous, and three melanoma human tumor xenografts implanted in athymic nude mice expressed TNF mRNA of human and murine origin in response to DMXAA, confirming that DMXAA can activate both host and tumor cells. The use of low molecular weight agents to induce TNF synthesis in situ in the tumor represents a novel approach to TNF-mediated therapy of cancers.
选择性诱导肿瘤血管塌陷是一种令人兴奋的癌症治疗方法。然而，肿瘤坏死因子-α（TNF）作为实现这一目标的药物，其临床评估受到全身毒性的限制，并且使用细菌成分诱导TNF产生的临床方法也令人失望。我们实验室已开发出合成的低分子量TNF诱导剂，包括5,6-二甲基呫吨酮-4-乙酸（DMXAA），作为一种替代策略。DMXAA可使可移植的小鼠肿瘤迅速发生血管塌陷，并在小鼠和人类系统中体外诱导TNF合成。我们在此表明，DMXAA诱导的TNF合成程度在肿瘤中比在脾脏、肝脏或血清中更高。如对小鼠结肠38肿瘤的原位杂交研究所示，DMXAA诱导肿瘤以及宿主细胞表达TNF mRNA。DMXAA给药后肿瘤组织中含有TNF mRNA的细胞分布与脂多糖（LPS）处理后显著不同，尽管脾脏和肝脏组织中TNF mRNA阳性细胞的分布相似。在结肠38肿瘤中，LPS的作用仅限于血管周围的宿主细胞。DMXAA处理诱导肿瘤中的TNF峰值水平比血清中高7倍。相比之下，LPS处理诱导血清中的TNF水平比肿瘤中高9倍。DMXAA在结肠38组织中诱导的TNF活性比LPS高35倍。植入无胸腺裸鼠体内的一个卵巢、一个鳞状和三个黑色素瘤人类肿瘤异种移植物在DMXAA作用下表达人和鼠源的TNF mRNA，证实DMXAA可激活宿主和肿瘤细胞。使用低分子量药物在肿瘤中原位诱导TNF合成代表了一种TNF介导的癌症治疗新方法。
