Info
🌱 來自: Pharmacogenomics
Drug targets
- 5,10-Methylenetetrahydrofolate reductase (MTHFR)
- Involved in metabolism of
- 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate,
- methyl donor for the methylation of DNA,
- homocysteine,
- & DNA synthesis
- Reduced MTHFR activity affects intracellular folate pools → ↑ tox in pts treated w/ antifolates
- Thymidylate synthase (TS)
- Essential enzyme in de novo synthesis of thymidylate, precursor of thymidine triphosphate, essential for DNA synthesis & repair
- TS gene promoter is polymorphic & has 2 (TSER2) or 3 (TSER3) 28-bp tandem repeat sequences
- In vitro studies show TS promoters w/ the TSER3 sequence generate 3× higher mRNA than those w/ the TSER2 sequence
- Inhibition of TS by FdUMP is 1 of the 1° mechanisms of action of 5-FU
- TS expression levels inversely correlate w/ the sensitivity of tumors to 5-FU; therefore, TSER2 homozygotes respond better to 5-FU than TSER3 homozygotes or heterozygotes (Devita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 10th ed. 2014; Annu Rev Med. 2015;66:65; Br J Haematol 2003;122(2):240)