title: Temporal dependence of hyperthermic augmentation of macrophage-TNF production and tumor cell-TNF sensitization.
abstract: Hyperthermia in the therapeutic (greater than or equal to 42-43 degrees C) and febrile (less than or equal to 39-40.5 degrees C) ranges modulated the cytotoxic activities of macrophages cocultured with tumour cells and of the monokine tumour necrosis factor (TNF) against tumour cells. These modulatory interactions had clear treatment-sequence dependencies, and some sequences markedly augmented cytotoxic activities. Heated murine bacillus Calmette-Guerin-activated macrophages retained their cytotoxic activities better in coculture with unheated tumour cells if triggering with the endotoxin lipopolysaccharide preceded 1 h of heating at 42 or 43 degrees C than they did if heating to the same extent was concomitant with, or preceded, triggering. Retention of cytotoxicity in coculture during 24 h of 39 or 40.5 degrees C heating was less dependent on pre-heating triggering. The triggering/heating sequence also had modulatory effects on the secretion by heated macrophages of TNF which is involved in cytotoxic manifestations in coculture. Production of TNF by macrophages heated for 1 h at 40.5-43 degrees C or 24 h at 39 or 40.5 degrees C was augmented 1.5- to 6-fold (depending on the heat dose) when triggering preceded heating, whereas sequences in which heating was concomitant with triggering or preceded triggering were detrimental to TNF secretion. Profound treatment-sequence dependencies were also seen when timing of the addition of recombinant human TNF was varied in relation to the heat treatment of tumour cells. Sensitization of TNF-responsive L-929 and TNF-resistant EMT-6 tumour cells occurred if monokine addition preceded heating, whereas the reverse treatment-sequence reduced or eliminated sensitization. Both tumour cell types were also sensitized to TNF if monokine treatment preceded 24 h heating at 40.5 degrees C. These results support the hypothesis that appropriately constructed sequences for either macrophage priming/triggering or monokine treatment of tumour cells, combined with hyperthermia, could augment the cytotoxic actions of macrophages and the cytotoxicity of endogenously added monokines.
authors.affiliation: Department of Tumor Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
authors.forename: S P
authors.initials: SP
authors.lastname: Tomasovic
authors.forename: M
authors.initials: M
authors.lastname: Barta
authors.forename: J
authors.initials: J
authors.lastname: Klostergaard
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D006358:Hot Temperature / Q000627:therapeutic use*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009163:Mycobacterium bovis / Q000276:immunology; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000494:pharmacology
chemical_list: D014409:Tumor Necrosis Factor-alpha