24.03.3 Antimetabolites

Antimetabolites are compounds that are structurally similar to normal cellular components. They exert their cytotoxic effects by blocking or subverting the pathways of DNA synthesis. They fall into two main classes; the folate antagonists or antifolates which interfere with nucleotide synthesis and the purine and pyrimidine analogues which are incorporated into DNA and affect the cell cycle.

The most widely used antifolate is methotrexate which is used in the treatment of acute lymphocytic leukaemia, choriocarcinoma, Burkitt’s lymphoma, breast cancer as well as head and neck carcinomas. Methotrexate is an analogue of folic acid, a dietary compound which is a building block precursor for nucleotide (adenine, guanine, thymidine) and amino acid (methionine, serine) synthesis. Folic acid undergoes reduction to the tetrahydrofolate form via an enzymatic reaction catalysed by dihydrofolate reductase (DHFR) and it is this metabolite that undergoes subsequent reactions to form the essential nucleotides and amino acids. Methotrexate is an inhibitor of DHFR. This inhibition deprives the cell of tetrahydrofolate and subsequent metabolite production leading to depressed DNA, RNA and protein synthesis and ultimately cell death. Adverse reactions include renal, liver and pulmonary damage as well as the common adverse effects like nauseas, vomiting, diarrhoea and myelosuppression.

The other main class of antimetabolites are the purine and pyrimidine analogues which are inserted into DNA and subvert the cell cycle killing susceptible cells. Amongst the purine analogues are 6-mercaptopurine which is used in the maintenance of remission of acute lymphoblastic leukaemia. 6-mercaptopurine is converted to 6-thioinosinic acid (TIMP) which blocks the synthesis of cellular purines. Furthermore, TIMP itself can be incorporated into RNA making it non-functional. Bone marrow depression is the common adverse effect associated with 6-mercaptopurine although jaundice as a result of hepatotoxicity occurs in about one-third of patients. Anorexia, vomiting and diarrhoea have also been reported. A second purine analogue developed as an anticancer agent is 6-thioguanine which is used in the treatment of acute non-lymphocytic leukaemia (usually in conjunction with other cytotoxic drugs). This drug is converted to nucleotide di- and triphosphate forms which inhibit the synthesis of cellular DNA. Bone marrow suppression is the major adverse effect associated with this drug.

5-fluoruricil (5-Fu) is a pyrimidine analogue indicated for use against slowly growing solid tumours (such as colorectal, breast, ovarian) and in the treatment of superficial basal cell carcinomas. 5-Fu is converted to 5-FdUMP which competes with the precursor of dTMP, dUMP for thymidylate synthase enzyme. This competition results in a decrease in dTMP which affects tumour cell DNA synthesis. As well as the common adverse effects associated with anticancer drugs, 5-Fu can cause severe ulceration of the oral and gastrointestinal mucosa. Other pyrimidine analogues used as anticancer drugs are capecitabine (metastatic breast cancer, colorectal cancer), cytarabine (acute nonlymphocytic leaukamia) and gemcitabine (pancreatic cancer, non-small cell lung cancer).