title: Antitumor effect of 2'-deoxy-5-fluorouridine conjugates against a murine thymoma and colon carcinoma xenografts.
abstract: The conjugation of antineoplastic drugs to monoclonal antibodies reactive with tumor associated antigens conveys selective cytotoxicity, overcoming the systemic toxicities caused by drugs during standard chemotherapy. 2'-Deoxy-5-fluorouridine, a more potent derivative of 5-fluorouracil, is an antimetabolite which exerts its cytotoxic action by inhibiting the enzyme thymidylate synthetase and as a result inhibits DNA synthesis. 2'-Deoxy-5-fluorouridine was successfully conjugated to anti-Ly-2.1 reactive with the murine thymoma ITT(1)75NS E3, I-1, and 250-30.6 reactive with human colon cancer cells using the active ester of 2'-deoxy-5-fluoro-3'-O-succinoyluridine (5FdUrdsucc). In vitro, 5Fd-Urdsucc-anti-Ly-2.1 was selectively cytotoxic against ITT(1)75NS E3 murine thymoma cells at nanomolar concentrations. The human colon carcinoma cell LIM1899 was inhibited by 5FdUrdsucc-I-1 conjugates in the range of 10(-7)-10(-8) M, as were Colo 205 cells by 5FdUrdsucc-250-30.6 conjugates. In vivo, 5FdUrdsucc conjugates were more effective than equivalent amounts of free 5FdUrdsucc. Against the ITT(1)75NS E3 murine thymoma, a single dose of 100 micrograms (5FdUrdsucc equivalents) 5FdUrdsucc-anti-Ly-2.1 resulted in 85% tumor inhibition compared to mean tumor size of control mice. Irrelevant 5FdUrdsucc conjugates failed to inhibit tumor growth. Multiple doses of 5FdUrdsucc-I-1 conjugate produced 50% growth inhibition of the moderately differentiated tumor LIM1899. In contrast, the human colon carcinoma Colo 205 was relatively resistant to free 5FdUrdsucc and 5FdUrdsucc-250-30.6 conjugates.
authors.affiliation: Austin Research Institute, Austin Hospital, Heidelberg, Victoria, Australia.
authors.forename: K G
authors.initials: KG
authors.lastname: Krauer
authors.forename: I F
authors.initials: IF
authors.lastname: McKenzie
authors.forename: G A
authors.initials: GA
authors.lastname: Pietersz
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000378:metabolism / Q000628:therapy*; D004354:Drug Screening Assays, Antitumor; D005467:Floxuridine / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D000922:Immunotoxins / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D009368:Neoplasm Transplantation; D013945:Thymoma / Q000378:metabolism / Q000628:therapy*; D013953:Thymus Neoplasms / Q000378:metabolism / Q000628:therapy*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D005467:Floxuridine