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Tumoricidal activity of high‐dose tumor necrosis factor‐α is mediated by macrophage‐derived nitric oxide burst and permanent blood flow shutdown

This study investigates the role of tumor nitric oxide (NO) and vascular regulation in tumor ulceration following high‐dose tumor necrosis factor‐α (TNF) treatment. Using TNF‐responsive (MethA) and nonresponsive (LL2) mouse tumors, tumor NO concentration was measured with an electrochemical sensor and tumor blood flow by Doppler ultrasound. Mice were also pretreated with a selective inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. Tumors harvested from TNF‐treated mice were cryosectioned and immunostained for murine macrophages, or/and iNOS. MethA tumor‐bearing mice were depleted of macrophages. Pre‐ and post‐TNF tumor NO levels were measured continuously, and mice were followed for gross tumor response. In MethA tumors, TNF caused a 96% response rate, and tumor NO concentration doubled. Tumor blood flow decreased to 3% of baseline by 4 hr and was sustained at 24 hr and 10 days post‐TNF. Selective NO inhibition with 1400 W blocked NO rise and decreased response rate to 38%. MethA tumors showed tumor infiltration by macrophages post‐TNF and the pattern of macrophage immunostaining overlapped with iNOS immunostaining. Depletion of macrophages inhibited tumor NO increase and response to TNF. LL2 tumors had a 0% response rate to TNF and exhibited no change in NO concentration. Blood flow decreased to 2% of baseline by 4 hr, recovered to 56% by 24 hr and increased to 232% by 10 days. LL2 tumors showed no infiltration by macrophages post‐TNF. We conclude that TNF causes tumor infiltrating, macrophage‐derived iNOS‐mediated tumor NO rise and sustained tumor blood flow shutdown, resulting in tumor ulceration in the responsive tumor. © 2008 Wiley‐Liss, Inc.