title: Cytotoxic interactions of tumor necrosis factor, melphalan and 41.8 degrees C hyperthermia.
abstract: Experience with limb perfusion-hyperthermia, TNF, and L-PAM suggests dramatic clinical responses in sarcoma and malignant melanoma. To extrapolate these results to clinical 41.8 degrees C whole-body hyperthermia (WBH) and systemic therapy, we studied the cytotoxic interactions of TNF, L-PAM and hyperthermia in L929 cells. The optimal sequence was TNF preceding 41.8 degrees C hyperthermia by 48 h, and L-PAM given simultaneously with heat. Trimodality synergism between TNF, hyperthermia and L-PAM was demonstrated. Non-cytotoxic doses of TNF had a super-additive interaction with L-PAM/heat. Conversely, non-cytotoxic doses of L-PAM had super-additive interactions with TNF followed by hyperthermia. Relative to therapeutic index, we studied WBH, L-PAM and TNF in non-tumor bearing mice. The optimal trimodality sequence did not result in increased normal tissue toxicity compared to L-PAM alone. The concentrations and sequencing of TNF and L-PAM studied are consistent with clinical application to WBH.
authors.affiliation: University of Wisconsin Comprehensive Cancer Center, Department of Human Oncology, Madison 53792-6164.
authors.forename: H I
authors.initials: HI
authors.lastname: Robins
authors.forename: F
authors.initials: F
authors.lastname: d'Oleire
authors.forename: M
authors.initials: M
authors.lastname: Kutz
authors.forename: A
authors.initials: A
authors.lastname: Bird
authors.forename: C L
authors.initials: CL
authors.lastname: Schmitt-Tiggelaar
authors.forename: J D
authors.initials: JD
authors.lastname: Cohen
authors.forename: D R
authors.initials: DR
authors.lastname: Spriggs
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D003131:Combined Modality Therapy; D004347:Drug Interactions; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000628:therapy; D006979:Hyperthermia, Induced; D008558:Melphalan / Q000008:administration & dosage / Q000633:toxicity; D051379:Mice; D008806:Mice, Inbred AKR; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000633:toxicity
chemical_list: D014409:Tumor Necrosis Factor-alpha; D008558:Melphalan