Antimetabolites

Cell Cycle

Antimetabolites are cytotoxic agents that inhibit the functioning of key enzymes involved in DNA synthesis, and can be incorporated into DNA and RNA to cause strand breaks or premature chain termination. These compounds are able to exert their lethal effect at a molecular level by displaying structural similarity to naturally occurring purines and pyrimidines. ^[3] More specifically, antimetabolites affect DNA synthesis by preventing purine or pyrimidine biosynthesis. There are four main categories of antimetabolites: (1) antifolates, (2) purine analogues, (3) pyrimidine analogues, and (4) sugar-modified analogues. ^[2]

Antifolates
While folic acid (vitamin B9 or folacin) is not biologically active, its importance to biological processes is centred upon its derivatives, such as tetrahydrofolate, that form following its conversion to dihydrofolic acid in the liver. Vitamin B9 is essential to a number of bodily functions including nucleotide biosynthesis to the remethylation of homocysteine. Folate is essential to DNA synthesis, DNA repair, DNA methylation, and to act as a cofactor where folate is utilized. Therefore, antifolates are effective at impairing the ability of cells to rapidly divide and grow.

Examples of antifolates include methotrexate (MTX). MTX competitively and irreversibly inhibits the enzyme DHFR that is instrumental to tetrahydrofolate synthesis from dihydrofolate. MTX inhibits the synthesis of DNA, RNA, thymidylates and proteins through this inhibitory effect which is observable during the S phase of the cell cycle.

Pemetrexed (Alimta), while chemically synonymous with folic acid, acts by inhibiting the enzymes TS, DHFR, and glycinamide ribonucleotide formyltransferase that are implicated in purine and pyrimidine synthesis. Thus, pemetrexed is similar to MTX as it also acts to prevent DNA and RNA formation. ^[3]

Purine analog
Mercaptopurine (6-MP) ribonucleotide is a purine analog that functions to inhibit purine nucleotide synthesis and metabolism. This process alters the synthesis and function of RNA and DNA. Mercaptopurine interferes with nucleotide interconversion and glycoprotein synthesis.^[3]

Pyrimidine analogues
Gemcitabine is a drug belonging to the pyrimidine analogues. Intracellular metabolism of this drug by nucleoside kinases produces the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides which are responsible for the cytotoxic effect of gemcitabine on DNA synthesis. The inhibitory effect of gemcitabine arises from the diphosphate analog binding irreversibly to the active site of ribonucleotide reductase (RNR), which is responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. As a result of the inability to replicate deoxyribonucleotides for DNA synthesis the cell undergoes apoptosis. Another mechanism of action of gemcitabine is to arrest cell growth as a result of the triphosphate analog substituting cytidine during DNA replication. The inability to add new nucleosides also results in apoptosis.

Similar to gemcitabine, 5-FU is an antimetabolite that arrests cells during the S phase. The compound blocks the methylation reaction of deoxyuridylic acid to thymidylic acid that causes thymine deficiency. As a result, the formation of RNA is inhibited and DNA synthesis is halted which causes cell death. 5-FU is effective at inhibiting growth of cells that are rapidly dividing and those that take up 5-FU readily. The prodrug formulae of 5-FU is capecitabine. It is easily absorbed in the gastrointestinal tract where a set of enzymatic conversions produces the active form 5-FU. The key enzyme that is responsible for converting capecitabine to 5-FU is thymidine phosphorylase; in some human carcinomas the enzyme is expressed in higher concentrations than in normal tissues. ^[3]

As a consequence of their ability to arrest cell growth and induce apoptosis, antimetabolites are an area of clinical relevance and research interest among scientists and oncologists for the synergistic effects these compounds can have with chemotherapy drugs.