Mechanism of antitumor activity of tumor necrosis factor alpha with hyperthermia in a tumor necrosis factor alpha-resistant tumor.
Cells from a radiation-induced fibrosarcoma (RIF-1) are exceedingly resistant to tumor necrosis factor alpha (TNF-alpha) in vitro. We tested whether the addition of mild hyperthermia (42.5 degrees C, 30 minutes) could enhance TNF-alpha activity against RIF-1 tumors growing in syngeneic hosts (C3H mice). TNF-alpha was administered intratumorally. Tumor cell killing essentially was not measurable following TNF-alpha, 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-alpha 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-alpha 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-alpha with or without heat, suggesting that neutrophils may mediate the endothelial cell injury. These observations indicate a greater than additive tumoricidal effect of TNF-alpha 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.
Srinivasan
J M
JM
Department of Radiation Oncology, Stanford University School of Medicine, Calif. 94305-5468.
Fajardo
L F
LF
Hahn
G M
GM
D000818:Animals; D002196:Capillaries / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D004727:Endothelium / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D006470:Hemorrhage / Q000139:chemically induced; D006979:Hyperthermia, Induced; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008854:Microscopy, Electron; D009336:Necrosis / Q000139:chemically induced; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000494:pharmacology*
D014409:Tumor Necrosis Factor-alpha