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A high percentage of cells in S-phase is associated with a better clinical response to MTX ( TYMS , CPTS , and an MTX target enzyme, DHFR ( via AMPK activation ( In parallel with MTXs most well-known targets, several NAD+-dependent enzymes were inhibited by the antifolate in vitro : 2-oxoglutarate, isocitrate, malate, pyruvate, succinate, 6-phosphogluconate and glucose-6-phosphate dehydrogenases, glutamate-cysteine ligase, glutathione reductase, and glutathione peroxidase ( in vitro and in vivo , resulting in decreased levels of S-adenosylmethionine (SAM) (30), the main methyl donor of metabolism

10.1016/S0039-128X(99)00037-9 103 MortonR