Antitumor activity of alkylesters of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) against murine lymphoma L5178Y resistant to 5-fluoro-2'-deoxyuridine.
A series of twenty six 5'-substituted FdUMP (5-fluoro-2'-deoxyuridine 5'-monophosphate) have been evaluated for their inhibitory effects on the proliferation of murine lymphoma L5178Y cells sensitive or resistant to FUdR (5-fluoro-2'-deoxyuridine). 5'-Octylphenylene-FdUMP was the most active among these active derivatives against the parent cell line (L5178Y/P). Several other FdUMP derivatives also proved as potent as FUdR in their antiproliferating activity on the L5178Y/P cell line. Activity of these derivatives was decreased considerably by a substituent with a long aliphatic chain and the introduction of acyl groups on the C-3' position. Eicosyl-FdUMP was found to show no or low cross-resistance on the L5178Y/FUdR subline which was about 19 000-fold resistant to FUdR compared with the parent cell line. This derivative might penetrate cell membrane in an intact form and be converted into FdUMP by a phosphodiesterase inside the cell, because an anabolic enzyme, deoxyuridine kinase, was defective in cells of the L5178Y/FUdR subline. The derivatives were promising as antitumor agents for the treatment of relapsed patients following 5-fluorouracil therapy.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003856:Deoxyuracil Nucleotides / Q000494:pharmacology*; D004351:Drug Resistance; D005467:Floxuridine / Q000378:metabolism / Q000494:pharmacology*; D005468:Fluorodeoxyuridylate / Q000494:pharmacology*; D008223:Lymphoma / Q000473:pathology*; D051379:Mice; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D003856:Deoxyuracil Nucleotides; D005467:Floxuridine; D005468:Fluorodeoxyuridylate