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An overview of thymidine

Daniel S. Martin MD, Robert L. Stolfi PhD, Robert C. Sawyer PhD, Rabindranath Nayak PhD, Sol Spiegelman PhD, Charles W. Young MD, Thomas Woodcock MD

Abstract

This review summarizes a body of information suggesting that proper metabolic modulation with certain metabolites can sensitize tumor cells to antimetabolites, and others can de-sensitize (i .e . protect) normal cells from the toxicity of antimetabolites. 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 → FU augmentation is reportedly due to increased activation of FU by MTX (acting indirectly). On the basis of this biochemical insight, a completely different chemotherapeutic agent methyl-mercaptopurine rihoside (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.

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Procduct Name CAS Molecular Formula Supplier Price
5-Fluorouracil 51-21-8 C4H3FN2O2 949 suppliers $5.00-$2492.67
Uridine 58-96-8 C9H12N2O6 835 suppliers $5.00-$35193.00
Thymidine 50-89-5 C10H14N2O5 743 suppliers $9.00-$1395.00
Methotrexate 59-05-2 C20H22N8O5 742 suppliers $8.00-$11728.00
Cytarabine 147-94-4 C9H13N3O5 710 suppliers $5.00-$1025.00
Testosterone 58-22-0 C19H28O2 470 suppliers $25.00-$623.00
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