Antifolates are a group of compounds generally used to treat different forms of cancer. Deficiency in folic acid hinders the synthesis of DNA and division of cells which are processes that result to the malignant growth of tumors.

History

Antifolates are considered to be the oldest agents of antimetabolite class of anticancers and were amongst the first modern anticancer drugs. It was in 1947 that the first described antifolate was clinically used. It was the 2,4-diamino-pteroylglutamate (4-amino-folic acid; aminopterin; AMT) that resulted the very first remissions of leukemia in children. Soon after, AMT was superseded by its 10-methyl congener, methotrexate (MTX), based on toxicity considerations. At present, antifolates are used as antimetabolic chemotherapy in various forms of cancers like breast cancer, head and neck cancer, bladder cancer, acute lymphocytic leukemia, non-Hodgkin’s lymphoma, choriocarcinoma, and osteogenic sarcoma. Antifolates are used in treating non-cancerous type of diseases like malaria, bacterial infections, psoriasis, and rheumatoid arthritis Antifolates drugs are seen to act as cytotoxic drugs by interfering with one or more biosynthetic steps which involves folate coenzymes. In theory, a folate analogue may perform in one of numerous ways; like for instance, “by competing with folates for uptake into cells, by inhibiting the formation of folate coenzymes, or by inhibiting one or more reactions that are mediated by folate coenzymes (Kamen et al, 2000)”.

It was in 1940’s that the most important effects of folates on cellular metabolic processes were revealed which lead to a clinical investigation leading to the growth of the first folate antagonists. It was also found out by chief investigators that AMT or aminopterin, which is an antifolate can cause pediatric patients with severe leukemia to go into reduction. Thus, this chemotherapy which is in an antimetabolic form was initially used as antileukemic agents. However, in the field of research in cancer, using of antimetabolites as a type of chemotherapy was undeniably a most important advancement. Another giant success was made in the investigation of the antimetabolite drug which involved the use of methotrexate (MTX), another antifolate, which is known to be a derivative of aminopterin, and used on mice with the L1210 form of leukemia; due to its achievement and great efficacy with reduced toxicity in comparison with aminopterin, methotrexate became the primary antifolate. Moreover, the clinical usefulness of MTX and other folate antagonists, knowledge of the system of action and the pharmacology of these agents has resulted “additional dividends in terms of information on important principles of cancer chemotherapy and mechanisms of drug resistance of general applicability to all types of antineoplastic agents (Kamen et al, 2000).” Today, due to the numerous uses of MTX, it has been the most widely used and studied folate antagonist in the field of medical oncology.

How it works

The role of antifolate medicines is to produce an intracellular state of folic acid insufficiency in order to restrain enzymes that are dependent on folate which are on the folate metabolic pathway. These folate antagonists act as antitumor agents and were engineered to suppress the effects of folic acid and its derivatives on cellular processes.

MTX, which is a prototype antifol probably has been studied as thoroughly as any drug in use in clinical medicine as of the present time. MTX has been found to be very effective in neoplastic diseases like choriocarcinoma, clearly giving treatment to approximately half of the patients with this disease who use it. While MTX is efficient when used alone, it is usually used in combination with other antineoplastic medicines. The anticancer movement of antifolates can be improved if they are administered with drugs that restrain nucleoside transport by preventing neoplastic cells from recovering nucleoside precursors. Presently, MTX serves as the principle biochemical prototype for the clinical research of all new antifolates. Aside from MTX and AMT, original antifolates are still under clinical investigation and are being used in medicine include: thymidylate synthase (TS), serine hydroxymethyltransferase (SHMT), folyilpolyglutamyl synthetase (FPGS), g-glutamyl hydrolase (g-GH), glycinamide-ribonucleotide transformylase (GARTfase), leucovorin (LV), amino-imidazole-carboxamide-ribonucleotide transformylase (AICARTfase), 5-fluorouracil (5-FU), and folate transporters.

Metabolism

Metabolism of Folate is an important intracellular process, which without it cells cannot live on. Folates are vital to single-carbon metabolism within cells. The molecules which interacted with folates are also accountable for the growth and survival of cells. Antifolates are valuable in demonstrating the significance of folate metabolism to the survival of cells. Folate antagonists also hamper the metabolic pathway of folates at some level. “At the molecular level, the substrates along this pathway are forced to transform into tight-binding inhibitors of the enzyme DHFR, due to the structural difference of the antifolate; because instead of having a hydroxyl at the 4-position of the pteridine ring, antifolates have an amino group at this location, changing the way upon which the substrate binds to the enzyme’s active site. DHFR is the enzyme that is involved in this reaction, and is the one that sustains the manufacturing of tetrahydrofolates, the reduced forms of folate inside the cell. tetrahydrofolates become exhausted by the presence of antifolates, which actually use the tetrahydrofolates carrier route into the cell to take up the intracellular folates. Tetrahydrofolates play an important part in the configuration of the DNA molecule in the sense that it is the etrahydrofolates cofactors that donate a carbon atom in the enzymatic development of thymidylate and purine nucleotides, which are vital antecedents for the fusion of DNA. Thus, the intrusion of the fabrication of tetrahydrofolates by antifolates restrains the biosynthesis of necessary nucleotides for DNA synthesis. Some examples of tetrahydrofolates are: 10-formyltetrahydrofolate and 5, 10-methylenetetrahydrofolate, which both donates single carbon groups in the biosynthetic reaction that forms nucleotides. They turn out to be converted out of their biologically active, reduced form into dihydrofolate. DHFR, an enzyme necessary for them to be converted back into tetrahydrofolate. This means, when DHFR is reduced by the intervention of an antifolate, the quantity of intracellular folates is also lessened, which add greatly to the deterrence of the formation of nucleotide precursors essential for the synthesis of DNA. The hindrance of DNA production is ultimately leading directly to the death of cells causing the antitumor effect of the antifol.

In the case of mammalian cells, when the enzyme called folylpolyglutamate synthetase or FPGS adds around seven glutamate molecules to both folate and antifolate during polyglutamylation. Taking this process into account is important during the evaluation of the efficacy of the folate antagonists drugs because partially, it is what’s responsible for the period of the medicine’s stay within the cell. The reason for this is the polyglutamylation of the antifolate which adds additional negative charge to it, increasing its size, and finally decreasing the efflux of the drug as it becomes trapped within the cell, extending its total effect. In addition, antifolate polyglutamates are seen to be more effective as folate-dependant enzyme inhibitors than monoglutamated drugs. They are direct inhibitors of DHFR and are also able to effectively inhibit other folate-dependant enzymes such as glycinamide ribonucleotide (GAR), aminoimidazole carboxamide ribonucleotide (AICAR) transformylases, and thymidylate synthase (TS) because they bind to the enzyme with greater strength, the glutamates are slower to become detached from it than the antifolate is in its original form. When using antifolate drugs, the cell-cycle must be taken into consideration to ensure its maximum efficacy. Many of the same enzymes and proteins that are involved with folate metabolism fluctuate in accordance with the cell cycle. In fact, the folate-dependant enzymes, such as DHFR, increase during the S-phase of mitosis. Cells in the resting (G0) phase are less affected by the same amount of antifolate drug than are cells in other stages. Therefore, antifolates are most effective when there are relatively few cells, as in the G0 phase. Another important factor is that when using a folate antagonist, the synthesis of DNA in both normal and cancerous cells will be hindered. However, RNA and protein synthesis will still take place within the cell. If folates are not replenished, megaloblasts (giant cells), will form and cell death will then increase.

Adverse Reactions/Side Effects

While extensive research efforts in the area of antimetabolic chemotherapy are taking place, the antifolates currently being administered to patients, like MTX, must be used with a degree of caution. Recent studies have found that high concentrations of MTX in the blood plasma are correlated with toxicity. Taking relatively low doses of antifolates is more beneficial because absorption is increased with the lower doses. Studies have shown that increasing oral doses of MTX in particular, decreases overall absorption. However, absorption can be enhanced when taken on an empty stomach with pure water. Increasing of the doeses gives certain benefits like the increase of polyglutamate formation which leads to extended periods of DHFR inhibition.

Another precaution to take into consideration is using of other drugs alongside antifolates as there are serious interactions that can occur. Like for instance, a toxic effect is produced when antifolate is used in combination with an antibiotic. Using antifolates with non-steroidal, anti-inflammatory type of medicines (NSAIDs) can prove to be more serious because such a combination has the potential to lead to death. NSAIDs like naproxen and ketoprofen, should be used with extreme caution. Other common NSAID drugs like aspirin, phenylbutazone, salicylate, probenecid, and trimethoprim should also be monitored carefully during the use of antifolate drugs. Patients under the medication of antifolates should avoid drinking alcoholic drinks completely because it increases the risk of developing hepatic fibrosis and cirrhosis. However, it should be noted that there are also drugs which actually has the capacity to reduce antifolate toxicity, such as methylxanthines (e.g., caffeine and aminophylline).

Prolonged intake of folate antagonists can occasionally produce adverse effects. The most adversely affected by folate antagonists are the self-renewing tissues such as the bone marrow and epithelial cells. More tissues become affected as the dose increases. Patienst who are young can cope better than older ones because their youth could mean that their renal functions perform greater and better, resulting in quicker elimination of the drug from the body. Sometimes it is necessary to halt the administration of the antifolate, such as if it is causing mucositis, a serious symptom of gastrointestinal toxicity and/or if it causing symptoms of renal toxicity, such as renal impairment. Occasionally, the chronic use of antifolates causes hepatoxicity, although the validity of this is still under investigation. Other less common, but significant forms of toxicity that can be induced by antifolate drugs are neuro, pulmonary, and skin toxicity.

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