Thymidylate synthase and drug resistance.
Thymidylate synthase is an important target for both fluorinated pyrimidines and for new folate analogues. Resistance to 5-fluorouracil (5FU) can be related to insufficient inhibition of thymidylate synthase. The 5FU-nucleotide FdUMP induces inhibition of thymidylate synthase which is enhanced and retained for longer in the presence of increased folate pools, for which leucovorin is a precursor. In a murine model system, 5FU treatment caused a 4-fold induction of thymidylate synthase levels which may have contributed to resistance. Addition of leucovorin to this treatment prevented this induction and increased the antitumour effect 2-3-fold. In the clinical setting, 5FU administration to patients resulted in approximately 50% inhibition of TS after 48 h. The combination with leucovorin resulted in a more pronounced inhibition after 48 h (approximately 70%). A significant relationship was observed with outcome of treatment; when thymidylate synthase levels were high and inhibition was low, no response was observed. A separate study showed that low thymidylate synthase levels appeared to be an independent prognostic factor for adjuvant therapy.
Peters
G J
GJ
Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands.
van der Wilt
C L
CL
van Triest
B
B
Codacci-Pisanelli
G
G
Johnston
P G
PG
van Groeningen
C J
CJ
Pinedo
H M
HM
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D003110:Colonic Neoplasms / Q000201:enzymology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D011379:Prognosis; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D013940:Thymidylate Synthase; D005472:Fluorouracil