The survival of an S-phase cell exposed to an antimetabolite depends on two variables that the learner can manipulate: drug concentration and exposure duration. At low concentration, thymidylate synthase inhibition is partial, dTTP falls only modestly, and replication slows without stalling; the cell may survive and resume cycling when the drug is removed. As concentration rises, the enzyme block becomes more complete, dTTP falls further, and the probability of replication fork stalling and collapse increases. Exposure duration matters because only a fraction of a tumor cell population is in S phase at any instant. A short exposure kills the cells currently in S phase; a longer exposure catches successive cohorts as they enter S phase from G1. The interaction is not simply additive: a high concentration for a short time may kill fewer cells than a moderate concentration maintained for a full cycle time, because the latter reaches every cell that will enter S phase during the exposure.
Normal tissues with a high growth fraction, such as bone marrow and gut epithelium, also feed cells into S phase and are therefore vulnerable to the same concentration-and-duration logic. The therapeutic window is the difference between the tumor's sensitivity and the normal tissue's sensitivity under the same exposure. Leucovorin rescue can widen that window for methotrexate by selectively restoring thymidylate synthesis in normal tissues, but it does not change the fundamental relationship between concentration, duration, and S-phase killing.