Antimetabolites are structural analogues of naturally occurring compounds and function as fraudulent substances for vital biochemical reactions.

Folic Acid Analogues

Methotrexate (Amethopterin) is a folic acid antagonist that binds to dihydrofolate reductase, thus interfering with the synthesis of the active cofactor tetrahydrofolic acid, which is necessary for the synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. Methotrexate is used for the following types of cancer:

Acute lymphoid leukemia: During the initial phase, vincristine and prednisone are used. Methotrexate and mercaptopurine are used for maintenance therapy. In addition, methotrexate is given intrathecally, with or without radiotherapy, to prevent meningeal leukemia.

Diffuse histiocytic lymphoma: Cyclophosphamide, vincristine, methotrexate, and cytarabine (COMA).

Mycosis fungoides: Methotrexate.

Squamous cell, large-cell anaplastic, and adenocarcinoma: Doxorubicin and cyclophosphamide, or methotrexate.

Head and neck squamous cell: Qi-platinum and bleomycin, or methotrexate.

Choriocarcinoma: Methotrexate.

Tumor cells acquire resistance to methotrexate as the result of several factors, including the following:

• The deletion of a high-affinity, carrier-mediated transport system for reduced folates.

• An increase in the concentration of dihydrofolate reductase.

• The formation of a biochemically altered reductase with reduced affinity for methotrexate.

To overcome this resistance, higher doses of methotrexate need to be administered. The effects of methotrexate may be reversed by the administration of leucovorin, the reduced folate. This leucovorin “rescue” prevents or reduces the toxicity of methotrexate, which is expressed as mouth lesions (stomatitis), injury to the gastrointestinal epithelium (diarrhea), leukopenia, and thrombocytopenia.

Pyrimidine Analogs

Fluorouracil and fluorodeoxyuridine (floxuridine) inhibit pyrimidine nucleotide biosynthesis and interfere with the synthesis and actions of nucleic acids. To exert its effect, fluorouracil (5-FU) must first be converted to nucleotide derivatives such as 5-fluorodeoxyuridylate (5-FdUMP).

FdUMP inhibits thymidylate synthetase, and this in turn inhibits the essential formation of DTTP, one of the four precursors of DNA. In addition, 5-FU is sequentially converted to 5-FUTP, which becomes incorporated into RNA, thus inhibiting its processing and functioning.

Fluorouracil is used for the following types of cancer:

Breast carcinoma: Cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMP + P). The alternate drugs are doxorubicin and cyclophosphamide.

Colon carcinoma: Fluorouracil.

Gastric adenocarcinoma: Fluorouracil, doxorubicin (Adriamycin), and mitomycin (FAM), or fluorouracil and semustine.

Hepatocellular carcinoma: Fluorouracil alone or in combination with lomustine.

Pancreatic adenocarcinoma: Fluorouracil.

Resistance of 5-FU occurs as the result of one or a combination of the following factors:

• Deletion of uridine kinase

• Deletion of nucleoside phosphorylase

• Deletion of orotic acid phosphoribosyltransferase

• Increased thymidylate kinase

Because 5-FU is metabolized rapidly in the liver, it is administered intravenously and not orally. 5-FU causes myelosuppression and mucositis.

Deoxycytidine Analogs

Cytosine arabinoside (Cytarabine, Cytosar, and Ara-C) is an analog of deoxycytidine, differing only in its substitution of sugar arabinose for deoxyribose.

Cytosine arabinoside is used in the treatment of acute granulocytic leukemia. Doxorubicin; daunorubicin and cytarabine; cytarabine and thioguanine; or cytarabine, vincristine, and prednisone are the combinations of agents employed.

Resistance to cytosine arabinoside may stem from the following factors:

• The deletion of deoxycytidine kinase

• An increased intracellular pool of dCTP, a nucleotide that competes with Ara-CTP

• Increased cytidine deaminase activity, converting Ara-C to inactive Ara-U

The toxic effects of cytosine arabinoside are myelosuppression and injury to the gastrointestinal epithelium, which causes nausea, vomiting, and diarrhea.

Purine Antimetabolites

6-Mercaptopurine (6MP) and 6-thioguanine (6TG) are analogues of the purines hypoxanthine and guanine, which must be activated by nucleotide formation

ThiolMP and ThioGMP are feedback inhibitors of phosphoribosylpyrophosphate amidotransferase, which is the first and rate-limiting step in the synthesis of purine. In addition, these analogues inhibit the de novo biosynthesis of purine and block the conversion of inosinic acid to adenylic acid or guanylic acid. The triphosphate nucleotides are incorporated into DNA, and this results in delayed toxicity after several cell divisions. 6-Mercaptopurine is used in the treatment of acute lymphoid leukemia. Maintenance therapy makes use of both methotrexate and 6-mercaptopurine. Mercaptopurine is absorbed well from the gastrointestinal tract. It is metabolized through (1) methylation of the sulfhydryl group and subsequent oxidation and (2) conversion to 6-thiouric acid by the aid of xanthine oxidase, which is inhibited by allopurinol. Mercaptopurine may cause hyperuricemia. Its chief toxicities are hepatic damage and bone marrow depression.

Thioguanine is used in patients with acute granulocytic leukemia, usually in combination with cytosine arabinoside and daunorubicin.