title: Characterization of the antitumor activities of human tumor necrosis factor-alpha and the comparison with other cytokines: induction of tumor-specific immunity.
abstract: We have investigated the in vitro and in vivo antitumor activities of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) against Meth A sarcoma. Meth A sarcoma cells were found to a) be relatively insensitive in vitro to rHuTNF-alpha, and b) express low numbers of TNF-alpha receptors. Intraperitoneally implanted Meth A sarcoma was insensitive to the antitumor effects of rHuTNF-alpha. In contrast, rHuTNF-alpha was highly efficacious against subcutaneously implanted Meth A sarcoma. Biodistribution studies with 125I- or 3H-labeled rHuTNF-alpha demonstrated that, after intravenous administration, the majority of the labeled rHuTNF-alpha localized in the kidney, lungs, and liver. Only low levels of radiolabel were found in subcutaneous Meth A implants. These results support the in vitro data on the low number of TNF-alpha receptors on Meth A sarcoma cells. The ability of rHuTNF-alpha to induce regression of established (7 days) subcutaneous Meth A implants, positively correlated with the degree of both macroscopic and microscopic tumor necrosis. In addition, recombinant human tumor necrosis factor-beta (lymphotoxin) and recombinant murine tumor necrosis factor-alpha induced similar levels of necrosis. Other lymphokines with known antitumor activities, recombinant human interferon-gamma, murine interferon-gamma, and human interleukin 1 alpha, failed to induce detectable necrosis of Meth A sarcoma. Mice which had rejected subcutaneous Meth A sarcoma implants after rHuTNF-alpha treatment and which were later challenged subcutaneously with Meth A sarcoma or other noncross-reacting chemically induced sarcomas were found to be specifically immune to Meth A sarcoma. In addition, low levels of cytotoxic antibodies reactive to Meth A sarcoma were detected in the sera of 21 of 30 Meth A immune mice. Histological evaluation of the hemorrhagic tumor necrosis induced by rHuTNF-alpha suggests that the primary lesion is vascular, possibly directly on the endothelial cells. The mechanisms involved in the generation of specific cell-mediated antitumor immunity in this model are at present unknown.
authors.forename: M A
authors.initials: MA
authors.lastname: Palladino
authors.forename: M R
authors.initials: MR
authors.lastname: Shalaby
authors.forename: S M
authors.initials: SM
authors.lastname: Kramer
authors.forename: B L
authors.initials: BL
authors.lastname: Ferraiolo
authors.forename: R A
authors.initials: RA
authors.lastname: Baughman
authors.forename: A B
authors.initials: AB
authors.lastname: Deleo
authors.forename: D
authors.initials: D
authors.lastname: Crase
authors.forename: B
authors.initials: B
authors.lastname: Marafino
authors.forename: B B
authors.initials: BB
authors.lastname: Aggarwal
authors.forename: I S
authors.initials: IS
authors.lastname: Figari
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D001688:Biological Products / Q000494:pharmacology*; D016207:Cytokines; D003602:Cytotoxicity, Immunologic; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007109:Immunity; D007167:Immunotherapy; D009336:Necrosis; D011994:Recombinant Proteins / Q000276:immunology; D012513:Sarcoma, Experimental / Q000473:pathology / Q000628:therapy*; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D016207:Cytokines; D006023:Glycoproteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha