[Mechanism of action of antineoplastic agents in the DNA synthesis of tumor cells]

Abstract

The overall process of DNA biosynthesis can be divided into two major steps, one consisting essentially of nucleotide synthesis from low-molecular-weight metabolites and the other of polymerization of the nucleotides to form the duplicated DNA. Some antineoplastic agents are structural analogues of bases or nucleosides of intermediate metabolites, and are converted to their ribotides by enzymes catalyzing nucleotide metabolism. With some of these agents, the resulting ribotides then act as inhibitors of nucleotide synthesis. With others the resulting ribotides are subjected to stepwise enzymatic reactions and are then incorporated into DNA during its synthesis, thus rendering it inactive. Some antineoplastic agents, on the other hand, affect the DNA chain apparently through intercalation in double-stranded DNA, binding to DNA or nuclear protein, or interstrand linkage, or else through activation of endonuclease or inhibition of topoisomerase. The former effects result in inhibition of DNA double-strand dissociation, while the latter result in double-stranded DNA scission and apurinic acid formation. Antineoplastic agents thus vary widely, with respect to both the processes of their activation and inactivation and their effects on DNA synthesis. Their mechanisms of action and effects also tend to differ among various types of tumor cells and host organs. Investigation of the action mechanisms of these agents and determination of their appropriate utilization will be required in order to achieve better results in cancer chemotherapy.