Cancer folic acid analogues

During the 1980s and 1990s the role of folic acid analogues, especially methotrexate (MTX) (422), in cancer chemotherapy has been intensively studied enzyme dihydrofolate reductase (DHFR) has been the primary target of this effort. The introduction of 10-ethyl-10-deazaaminopterin (10-EDAM) (423), piritrexim (PTX) (424) and trimetrexate (TMX) (425) into clinical trials attests to the continued interest in this field <87MI 718-06). 

In stark contrast, the second historically significant anti-cancer drug, methotrexate, originated from nutritional research. The observation that the vitamin folic acid stimulated prohferation of acute lymphoblastic leukemia (ALL) cells in children prompted synthesis of folate analogues. In the late 1940s methotrexate became the first drug to induce remissions in children with ALL [11]. 

The main folate antagonist is methotrexate, an analogue of folic acid. Methotrexate competitively inhibits dihydrofolate reductase, the enzyme responsible for the synthesis of purine and pyramidine from folic acid. Trimetrexate, a methotrexate analogue, is useful in treating methotrexate-resistant tumours. It is also used to treat Pneumocystis carinii infections. Methotrexate is usually given orally, but may also be given intravenously or intrathecally. In addition to its use in cancer therapy, it is used in the treatment of psoriasis. Methotrexate can cause an obstructive nephropathy due to its precipitation in the renal calyx. 

A search for antimetabolites, i.e. analogues of essential metabolites that might displace the latter in vital processes, was proposed as a rational approach to the discovery of antibacterial agents, but it has had little success other than the achievements in the folic acid field (Section 1.06.6). Substances that resemble the components of nucleic acids have, however, had considerable success in the chemotherapy of cancer and of some virus diseases and in the suppression of the immune response. They may act by becoming incorporated in false nucleic acids or by blocking the synthesis of nucleic acids, nucleotides, nucleosides or of the pyrimidine and purine bases cytosine (88), thymine (89 R = Me), adenine (90) and guanine (91 X = CH). The simplest antimetabolites are analogues of these bases. 

The formation of thymidylate is specifically blocked by certain analogues of folic acid and by derivatives of 5-fluorouracil these agents have an important use in the treatment of cancer in humans. 

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