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Extensive studies on cellular fates of the DNA damage-inducing drug, methionine sulfoximine (MSX), have provided insight to pharmacokinetic limitations that contribute to its marginal clinical efficacy. However, the importance of T-cell depletion in MSX failure remains unresolved. Here, we show that in the presence of functional splenocytes, MSX-induced lethality of naive CD4+ T cells is two orders of magnitude greater than by previously described splenectomy or xanthurenic acid-induced depletion, consistent with the major role of spleen-derived T cells in drug-induced T-cell depletion. MSX-induced lethality was sustained with naive T cells, but treatment with an activator of T-cell effector mechanisms, anti-CD3 and anti-CD28 mAbs, led to substantial recovery of CD4+ T cells, implicating a pharmacodynamic limitation in MSX. Cytokine deprivation rapidly abolished the recovery from MSX, suggesting a strong role for cytokines in MSX clearance. Anti-IL-2 mAbs followed by withdrawal of IL-2, which is a survival factor for naive and memory T cells, restored the drug sensitivity, suggesting that effector T cells can be sensitized for death by depletion of high levels of IL-2.
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