Biochemical Modulation of Pyrimidine Pools for Enhancement of Antipyrimidine Cytotoxicity

Biochemical modulation in cancer therapy focuses on the improvement of the therapeutic index of a known anticancer drug (called the effector agent) through the pharmacologic manipulation of appropriate intracellular metabolic pathways by either an anti-metabolite or a metabolite (called the modulating agent) to produce either the selective enhancement of the antitumor effect or the selective protection of the host from the effector agent. For example, certain antipyrimidine effector agents must be activated intracellularly by anabolism to the fraudulent pyr imidine nucleotide analogues in order to exert cytotoxicity. Since these antipyrimidines must successfully compete at each step in their metabolic conversion with the normal pyrimidine counterparts, a modulating agent that selectively lowers the pools of the competing normal intracellular pyrimidines in the tumor can facilitate the targeting of the fraudulent pyrimidines to their effector sites, and thereby enhance their antitumor activity.