Antitumor effect of 2'-deoxy-5-fluorouridine conjugates against a murine thymoma and colon carcinoma xenografts

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 a...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1992-01, Vol.52 (1), p.132-137
Main Authors: Krauer, K G, McKenzie, I F, Pietersz, G A
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - metabolism
Antibodies, Monoclonal - therapeutic use
Colonic Neoplasms - metabolism
Colonic Neoplasms - therapy
Drug Screening Assays, Antitumor
Floxuridine - metabolism
Floxuridine - therapeutic use
Humans
Immunotoxins - metabolism
Immunotoxins - therapeutic use
Mice
Neoplasm Transplantation
Thymoma - metabolism
Thymoma - therapy
Thymus Neoplasms - metabolism
Thymus Neoplasms - therapy
Tumor Cells, Cultured
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Summary: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.
ISSN:0008-5472