Thymidine 5'-O-pivaloate. A prodrug derivative of thymidine with potential applications in high-dose methotrexate therapy.

Abstract Thymidine 5'- O -pivaloate was evaluated as a prodrug derivative of thymidine for possible use in the prevention of toxicity from high-dose 4-amino-4-deoxy- N 10 -methylpteroyl- l -glutamic acid (methotrex- ate, MTX) therapy. Plasma levels of free thymidine were higher and remained elevated for a longer period in animals receiving the ester than in animals receiving an equivalent amount of thymidine itself. The higher concentration time achieved with the ester was reflected in more extensive labeling of bone marrow and gut DNA, and resulted in increased survival of L 1210 leukemic mice treated with high-dose MTX. The rate of cleavage of the ester to free thymidine was significantly lower in human serum in vitro than in mouse serum.