Antimetabolite-Based Cancer Drugs

Antimetabolites are structurally related to normal cellular components. They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors by inhibiting their synthesis or by competing with them in DNA or RNA synthesis. The antimetabolites are a clinically important group of cancer drugs used in the treatment of a variety of solid tumors and hematologic malignancies. The widely used compounds include the antifolate, methotrexate (MTX), the pyrimidine analogues, 5-fluorouracil (5-FU) and cytosine arabinoside (ara-C, 1-ß-D-arabinofuranosylcytosine, cytarabine).

Table 17. Antimetabolite-Based Cancer Drugs

Table 17 illustrates the new generation of antimetabolite cancer drugs.

Alimta (Pemetrexed) is a novel antifolate, a class of drugs that targets the folic acid metabolic pathway, which effects availability of certain B complex vitamins.

Nelarabine is a novel water soluble prodrug of ara-G with T- cell selectivity. It is a nucleoside analogue that is rapidly converted to its corresponding arabinosylguanine nucleotide triphosphate (araGTP), resulting in inhibition of DNA synthesis and cytotoxity.

Tezacitabine (FMdC) interrupts DNA replication and is a next-generation nucleoside analogue, to treat cancer. Nucleoside analogues are a class of drugs that affect DNA synthesis.

Gemzar is a nucleoside analogue. It is a novel chemotherapeutic agent that mimics a natural building block of DNA. It disrupts the process of cell replication and works by interfering with the process by which cells divide and repair themselves, thus preventing the further growth of cancer cells and leading to cell death.

Clofarabine, purine nucleoside antimetablolite, is a nucleoside analog from the family of compounds which include the marketed drugs fludarabine, cladribine and gemcitabine and targets DNA and mitochondria. Clofarabine (a second generation, synthetic nucleoside) was designed to be potent, resistant to cellular inactivation, stable chemically and better tolerated than other nucleoside analogs. Clofarabine appears to have multiple mechanisms of action, including inhibition of both DNA polymerases and ribonucleotide reductase and the induction of apoptosis. Clofarabine has shown clinical activity in leukemias, and pharmacological activity in solid tumors.

Triapine is a small molecule that inhibits an enzyme, ribonucleotide reductase, necessary for the synthesis of DNA. Synthesis of DNA is necessary for cancer cells to replicate; therefore, inhibition of the ribonucleotide reductase enzyme prevents cancer cells from dividing in the body. Disruption of DNA synthesis in some cancer cells will also cause their death. DNA synthesis is involved in repairing damage to cancer cells that have been treated with many of the standard cancer chemotherapy agents, which work by damaging DNA. The ability of cancer cells to rapidly repair DNA damage is one reason that cancer cells become resistant to standard chemotherapy agents. Because Triapine inhibits DNA synthesis, it can inhibit DNA repair, and therefore it can be predicted to increase the anti-tumor effects of many of the common anti-cancer drugs, such as cisplatin, cyclophosphamide, and etoposide.

Decitabine is a chemotherapeutic agent that has been shown to have a broad spectrum of activity in several hematological malignancies as well as solid tumors. Decitabine belongs to a new class of drugs called hypomethylating agents, with a unique mechanism of action. Methylation is a process in which methyl (CH3) groups are added to DNA to inactivate or "silence" genes. Recent research demonstrates tumor suppressor genes and DNA repair genes are hypermethylated and silenced in a majority of cancers, typically at an early stage of the disease. Hypermethylation, then, is an early warning sign that may prove useful for early cancer detection and screening of cancer patients. Therapy that removes the methyl groups (by hypomethylation) may "switch on" natural defense mechanisms against cancerDecitabine is the most specific and potent hypomethylating agent so far tested in clinical trials.

Strictly speaking, alkylating agents and platinum-based cancer drug are not antimetabolite cancer drugs. They are described here, since their actions are closely related to antimetabolite agents. Alkylating agents, such as Carmustine, Cyclophosphamide, Ifosfamide, Iomustine, Mechlorethamine, and Streptozotocin, leads to cross-linkages among nucleotides in the DNA chains and facilitates DNA strand breakage. Compared to the standard available alkylating agents, Cloretazine has unique and advantageous features, which could lead to an enhanced spectrum, or improved antitumor activity.  For example, in addition to damaging DNA, Cloretazine also inhibits a key enzyme O⁶-alkylguanine-DNA alkyltransferase(AGT) involved in the repair of the DNA damage. Thus, it blocks a major mechanism of drug resistance common to several of the standard alkylating agents. Cloretazine also exhibited excellent penetration across the blood brain barrier, and a high degree of antitumor activity against intra-cranially implanted leukemia cells. The latter distinguishes Cloretazine from many anticancer agents that have difficulty penetrating into the brain, a site where primary tumors can occur and a common site of metastases for several other solid tumors. Oxaliplatin (Eloxatin) and Satraplatin is new generation of platinum-based cancer drug.