THYMIDYLATE SYNTHASE AND DRUG-RESISTANCE

Thymidylate synthase is an important target, for both fluorinated pyri midines and for new folate analogues. Resistance to 5-fluorouracil (5F U) can be related to insufficient inhibition of thymidylate synthase. The 5FU-nucleotide FdUMP induces inhibition of thymidylate synthase wh ich is enhanced and retained for longer in the presence of increased f olate pools, for which leucovorin is a precursor. In a murine model sy stem, 5FU treatment caused a 4-fold induction of thymidylate synthase levels which may have contributed to resistance. Addition of leucovori n to this treatment prevented this induction and increased the antitum our effect 23-fold. In the clinical setting, 5FU administration to pat ients resulted in approximately 50% inhibition of TS after 48 h. The c ombination with leucovorin resulted in a more pronounced inhibition af ter 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 sho wed that low thymidylate synthase levels appeared to be an independent prognostic factor for adjuvant therapy.