Antimetabolites are chemotherapy drugs that are structurally related to normal metabolites found in the body. They act as a substrate in place of an actual metabolite that would be used in normal metabolism. As such, cell replication and growth is inhibited to stop proliferation of cancer cells. This occurs through substrate competition for enzyme-binding sites or incorporation directly into DNA or RNA. Antimetabolites are cell cycle–dependent and late G1/S phase-specific, with major effects on the processes involved in DNA replication.

The major classes of antimetabolites are pyrimidine and purine analogs, and antifolates. Pyrimidine analogs and purine analogs are structures that mimic DNA but are modified slightly by substitution of a hydrogen with a halogen or an oxygen with a sulfur or arabinose sugar with ribose/deoxyribose. The hypomethylating agents (HMAs) azacitidine and decitabine are cytosine analogs that target the enzyme DNA methyltransferase (DNMT) and are discussed in Chapter 7, Epigenetic Modulators. Antifolates target DNA enzymatic pathways that include dihydrofolate reductase and thymidylate synthase, which are involved in DNA synthesis, and are discussed in Chapter 4, Antimetabolites: Antifolates.

Figure 3-1

Ribonucleotide reductase is a critical enzyme in the intracellular metabolism of pyrimidines and purines. The enzyme is responsible for reducing ribose to deoxyribose and making deoxyribonucleotides for eventual incorporation into newly synthesized DNA. Inhibition of ribonucleotide reductase leads to decreased formation of deoxynucleotides with resultant cell cycle arrest in mid-to-late G1, impeding entry into S phase with consequent impairment of DNA replication and repair.

We will start our discussion of antimetabolites with hydroxyurea, a specific ribonucleotide reductase (RNR) inhibitor which exerts its major impact prior to DNA synthesis, then discuss the pyrimidine and purine analogs that directly impede DNA synthesis, and end with discussion of L-asparaginase, which has its major impact on protein synthesis and overall cellular metabolism and growth.

Deoxyribonucleotide triphosphates (dNTP) are required for DNA synthesis and de novo pathway for dNTP synthesis is through the reduction of the C2′-OH bond of ribonucleotides to deoxyribonucleotides.

Figure 3-2

Table 3-1

Table 3-2

Table 3-3

Figure 3-3

Figure 3-4

Table 3-4

This chapter addresses the clinical pharmacology of agents that target cells (both normal and malignant) that are in the early phases of cell cycle progression, namely G1 and S phases, and inhibit DNA synthesis and replication. These agents are mainstays of antileukemia therapies, particularly for the acute myeloid and lymphoblastic leukemias, and also for chronic lymphoid malignancies including lymphomas, hairy cell leukemia, and Waldenstrom’s macroglobulinemia.

• Antimetabolites are toxic to all cell types that are active in cell cycle and undergoing DNA synthesis. As such, normal oral and gastrointestinal mucosa, skin, and liver are susceptible to the cytotoxic effects of these drugs.
• Hydroxyurea, cytosine arabinoside, and 5-FU can induce a severe palmar-plantar erythrodysesthesia (hand -foot syndrome) associated with painful erythroderma and blistering. This syndrome is managed with drug discontinuation and steroids.
• All of the pyrimidine and purine analogs cross the blood–brain barrier and can cause both CNS and peripheral neuropathies.
• CNS toxicity associated with moderate- and high-dose cytarabine can be severe and irreversible. Cerebellar testing including a hand writing sample and finger-nose examination is mand atory prior to each moderate- or high-dose infusion and drug should be discontinued for any early signs of cerebellar dysfunction.

• BadeNA, LuC, PatzkeCL, et al. Optimizing pegylated asparaginase use: an institutional guideline for dosing, monitoring, and management. J Oncol Pharm Pract. 2019. doi: 10.1177/1078155219838316.
• ChabnerB, LongoD. Cancer Chemotherapy, Immunotherapy, and Biotherapy: Principles and Practice. 5th ed. Philadelphia, PA: Wolters Kluwer; 2011.
• ChesonBD, VenaDA, SorensenJM. Neurotoxicity of purine analogs: a review. J Clin Oncol. 1994; 12(10): 2216– 2228. doi: 10.1200/JCO.1994.12.10.2216.
• EmadiA, LawJY, StrovelET, et al. Asparaginase Erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed/refractory acute myeloid leukemia. Cancer Chemother Pharmacol. 2018; 81(1): 217– 222. doi: 10.1007/s00280-017-3459-6.
• Micromedex Healthcare Series[ intranet database]. Version 5.1. Greenwood Village, Colo: Thomson Micromedex.
• National Comprehensive Cancer Network. Prevention and treatment of cancer-related infections. Version 1.2019. https://www.nccn.org/professionals/. Accessed March 28, 2019.
• WeissRB, FreimanJ, KwederSL, DiehlLF, ByrdJC. Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia. J Clin Oncol. 1998; 16(5): 1885– 1889. doi: 10.1200/JCO.1998.16.5.1885.