Figure 2 Key steps in purine biosynthesis GMP guanine monophosphate Reprinted from Henry J R Mader M M Recent Advances in Antimetabolite Cancer Chemotherapies In Annual Reports in Medicinal Chemistry Doherty A M Ed Elsevier Oxford UK 2004 pp 161172 with p

be converted to tetrahydrofolate (THF) by DHFR, followed by further transformation back to N5,N10-CH2-THF through the action of SHMT.9 Therefore, inhibition of TS, DHFR, or SHMTwith an appropriate agent would interrupt the process of thymidine biosynthesis. Low thymidine levels cause defects in DNAthat in turn activate stress response elements, such as the Fas ligand/Fas death pathway leading to apoptosis.10 It has also been proposed that defects in this Fas-dependent apoptotic signaling pathway are one cause of cellular resistance to drugs.

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