Mechanism of Antitumor Activity of Tumor Necrosis Factor With Hyperthermia in a Tumor Necrosis Factor -Resistant Tumor

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Abstract
Cells from a radiation-induced fibrosarcoma (RIF-1) are exceedingly resistant to tumor necrosis factor a (TNF-α) in vitro. We tested whether the addition of mild hyperthermia (42.5°C, 30 minutes) could enhance TNF-α activity against RIF-1 tumors growing in syngeneic hosts (C3H mice). TNF-α was administered intratumorally. Tumor cell killing essentially was not measurable following TNF-α, hyperthermia, or a combination of the two. Single-modality treatments also had no effect on tumor growth delay or on the x-ray dose (given 24 hours after the primary treatment) required to sterilize 50% of the tumors. The combination of TNF-α and hyperthermia, however, resulted in a marked increase in tumor doubling time and a highly significant reduction in the x-ray dose required to sterilize the tumors. Syngeneic lymph nodal lymphocytes and blood leukocytes did not appear to mediate the action of TNF-α on RIF-1 cells in vitro. Necrosis and hemorrhage were the most prominent histopathological alterations in the treated tumors. Electron microscopic studies 6 hours after therapy showed increased damage to capillary endothelial cells and accumulation of neutrophils in the capillaries of tumors treated with TNF-α with or without heat, suggesting that neutrophils may mediate the endothelial cell injury. These observations indicate a greater than additive tumoricidal effect of TNF-α with hyperthermia. Furthermore, they support the concept that the interaction between the two agents damages the vasculature, compromising the microcirculation and ultimately causing ischemic tumor necrosis. [J Natl Cancer Inst 82:1904–1910,1990]

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