title: Increased antitumor effect of immunoconjugates and tumor necrosis factor in vivo.
abstract: The potential of specifically targeting antineoplastic drugs and toxins to tumors with the use of monoclonal antibodies (MoAbs) reactive with tumor-associated antigens is currently being examined. N-Acetyl-melphalan-MoAb (N-AcMEL-MoAb) conjugates have previously been shown to have greater antitumor activity than N-AcMEL, melphalan, or MoAb alone against both subcutaneous and ascites murine thymomas in mice (1). Although this conjugate is also a highly selective tumor inhibitor in vitro, it may not reach all the tumor cells in a high concentration, and consequently larger tumors (greater than 0.4 cm2) cannot be eradicated. This conjugate is representative of many drug-MoAb conjugates in that they are unable to gain adequate access to the tumor site to exert their cytotoxic effect. To potentiate the antitumor effect of the N-AcMEL-MoAb conjugate, studies were undertaken to analyze its action in combination with recombinant human tumor necrosis factor alpha (rTNF-alpha), a monokine, capable of causing acute necrosis of syngeneic tumor transplants in mice. Treatment of mice with murine thymomas (0.4 to 0.6 cm2 in size) demonstrated that 30% of the tumors in mice receiving conjugate and rTNF-alpha partially or completely regressed, while no regressions were observed in the tumors of mice receiving N-AcMEL-anti-Ly-2.1 conjugate or rTNF-alpha alone. This and other experiments indicated that the antitumor effect and tumor localization of N-AcMEL-MoAb conjugates can be enhanced in vivo by rTNF-alpha, thereby enabling successful eradication of larger established subcutaneous murine tumors.
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: G A
authors.initials: GA
authors.lastname: Pietersz
authors.forename: I F
authors.initials: IF
authors.lastname: McKenzie
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents; D007167:Immunotherapy; D000922:Immunotoxins / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D011994:Recombinant Proteins / Q000627:therapeutic use; D013945:Thymoma / Q000628:therapy*; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000922:Immunotoxins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha