Inhibition of thymidylate synthetase," The Journal of Biological Chemistry, vol.
Heidelberger, "Thymidylate synthetase: mechanism of inhibition by 5-fluoro-2,-deoxyuridylate," Biochemical and Biophysical Research Communications, vol.
CI might also favor the ability of cancer cells to acquire resistance to chemotherapics, such as the one related to imatinib mesylate, secondary to chromosome amplifications and duplications in cells with CI (Rajagopalan & Lengauer, 2004); and to 5-fluorouracyl, resulting from amplification of the thymidylate synthetase
gene in aneuploid cells (Wang et al., 2004).
Decreased expression of six RNA species was seen at various time points in all cell strains analyzed: plasminogen activator (PLAT), centromere protein F (CPF), replication factor C (RFC3), thymidylate synthetase (TYMS), a putative mitotic checkpoint kinase (BUB1), and a gene of unknown function (GenBank accession no.
The genes decreased included plasminogen activator (PLAT), centromere protein F (CPF), replication factor C (RFC3), thymidylate synthetase (TYMS), putative mitotic checkpoint kinase (BUB1), and a gene of unknown function (GenBank accession no.
Because the enzyme, thymidylate synthetase
, plays a crucial role in the DNA synthesis of rapidly growing cells, many anticancer agents are designed to block its activity, thereby inhibiting tumor growth.
The mode of action of this modality is by interfering with pyrimidine metabolism and converting to 5-fluro-2-deoxyuridine-5-phosphate (F-dump), which is potent inhibitor of thymidylate synthetase
, thus DNA synthesis is blocked.6,7
It also has an inhibitory effect on TGF-b-induced expression of the type I collagen gene in human fibroblasts.6 It interrupts both DNA and RNA synthesis at several levels, including the inhibition of thymidylate synthetase
and the production of toxic metabolites.7-10 Intralesional TAC causes inhibition of protein synthesis and fibroblast migration.