Thymidylate synthase inhibitors.
Thymidylate synthase (TS) is a critical enzyme for DNA replication and cell growth because it is the only de novo source of thymine nucleotide precursors for DNA synthesis. TS is the primary target of 5-fluorouracil (5-FU), which has been used for cancer treatment for more than 40 years. However, dissatisfaction with the overall activity of 5-FU against the major cancers, and the recognition that TS still remains an attractive target for anticancer drugs because of its central position in the pathway of DNA synthesis, led to a search for new inhibitors of TS structurally analogous to 5,10-methylenetetrahydrofolate, the second substrate of TS. TS inhibitory antifolates developed to date that are in various stages of clinical evaluation are ZD 1694 and ZD9331 (Astra-Zeneca, London, UK), (Eli Lilly, Indianapolis, IN), LY231514 (BW1843U89 (Glaxo-Wellcome, Research Triangle Park, NC), and AG337 and AG331 (Agouron, La Jolla, CA). Although each of these compounds has TS as its major intracellular site of action, they differ in propensity for polyglutamylation and for transport by the reduced folate carrier. LY231514 also has secondary target enzymes. As a result, each compound is likely to have a different spectrum of antitumor activity and toxicity. This review will summarize the development and properties of this new class of TS inhibitors.
Danenberg
P V
PV
Department of Biochemistry and Molecular Biology, USC/Norris Cancer Center, University of Southern California School of Medicine, Los Angeles, USA.
Malli
H
H
Swenson
S
S
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005492:Folic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005493:Folic Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D005971:Glutamates / Q000494:pharmacology / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D054833:Isoindoles; D000068437:Pemetrexed; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D005971:Glutamates; D007211:Indoles; D054833:Isoindoles; D011799:Quinazolines; D013876:Thiophenes; C094299:ZD 9331; D000068437:Pemetrexed; C079601:1843U89; D006147:Guanine; C031662:CB 3717; C087748:AG 331; D005492:Folic Acid; D013940:Thymidylate Synthase; C068874:raltitrexed; C099178:nolatrexed