An overview of thymidine

Abstract

This review summarizes a body of information suggesting that proper metabolic modulation with certain metabolites can sensitize tumor cells to anti-metabolites, and others can de-sensitize (i.e. protect) normal cells from the toxicity of anti-metabolites. This new approach offers the possibility of increasing the selectivity of drug therapy, with the promise of a real advance in cancer chemotherapy. The metabolite thymidine (TdR), long used as a cell synchronizing agent, is known to exert this effect in vitro by metabolic modulation of a number of enzymes in the salvage pathway to DNA synthesis. Against this biochemical background, in vivo effects of TdR employed as an agent for cancer therapy are reviewed as follows: 1) TdR alone, and in combination with, 2) Methotrexate (MTX), or 3) 5-Fluorouracil (FU), or 4) Cytosine arabinoside (ara-C). TdR is shown in all instances either to protect against host toxicity (eg. MTX), or to potentiate the anti-tumor effect (eg. FU and ara-C). Findings are also presented that a sequential schedule of MTX prior to TdR prior to FU is important for the optimal therapeutic activity of these drugs. The biochemical basis for the MTX leads to FU augmentation is reportedly due to increased activation of FU by MTX (acting indirectely). On the basis of this biochemical insight, a completely different chemotherapeutic agent methyl-mercaptopurine raboside (MMPR) was substituted for MTX, resulting in a dramatic potentiation of anticancer activity. Metabolic modulation with still other metabolites (UR) and a hormone (testosterone) was demonstrated to protect from host toxicity due to certain anti-cancer agents without offsetting anti-tumor activity. The ability to prevent leukopenia by these means was particularly impressive. Clinical trials have been initiated with TdR alone, TdR + MTX, and TdR + FU; the available clinical data are summarized.