Methotrexate and radiation

Abstract

INTRODUCTION Methotrexate is an anatlogue of aminopterin which was first used in the treatment of acute leukaemia in 1947. However, because of its better therapeutic index, the closely related amethopterin superseded aminopterin and was marketed as Methotrexate. Methotrexate is a folic .acid antagonist and its essential action is disruption of DNA synthesis. The conversion of deoxyuridine to thymidine requires tetrahydrofolic acid which is, during this process, oxidized to dihydrofolic acid. The kinetics of this system are dependent on the reconversion of dihydrofolic acid to the tetrahydro form by the enzyme folic acid reductase. It is at this site that Methotrexate exerts its action by electrostatic binding of the enzyme for which it has an affinity 100,000 times that of the substrate. Thus tlhe synthesis of thymidine and formation of DNA is prevented. Berenbaum’s diagram illustrates the action (Fig. l).’ Fortunately the addition of exogenous formyl tetrahydrofolic acid, folic acid or folinic acid (Leucovorin) bypasses this block and allows the continued production of thymidine-an effect which has been utilized to therapeutic advantage. In this way ‘Methotrexate probably affects both normal and malignant cells as DNA synthesis is attempted and kills cells in the S phase of the cell cycle thus causing a block at the GI-S transition. This results in synchronization of the cell population and the arrest of cells at a relatively radiosensitive stage (Fig. 2). Jacobson7 in his study of Methotrexate on the bone marrow also demonstrated an effect on mitosis in that although there was no change in prophase, metaphases were increased and anaphases and telophases decreased. Thus metaphase arrest is a histopathologically observable appearance of chromosome distribution within the cell nucleus which reflects the Methotrexate effect on the oomponent DNA.