Methotrexate,

Percutaneous Hver biopsy after each 1.5 g of total accumulated methotrexate dosage to detect hepatic fibrosis or cirrhosis not rehably predicted by semm aminotransferase tests are recommended (1,50). Concurrent use of NSAIDs may increase toxicity of methotrexate, although toxicity may be avoided if the dmgs are separated by 12 h. 

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-3] interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabohtes, interfering with complex metaboHc pathways in the cell, include methotrexate [59-05-2] 5-fluorouracil [51-21-8] and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxombicin [23214-92-8] h.a.ve been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

Folate antagonists (eg, methotrexate and certain antiepileptics) are used ia treatment for various diseases, but their adininistration can lead to a functional folate deficiency. Folate utilization can be impaired by a depletion of ziac (see Zinc compounds). In humans, the intestinal bmsh border folate conjugase is a ziac metaHoenzyme (72). One study iadicates that the substantial consumption of alcohol, when combiaed with an iaadequate iatake of folate and methionine, may iacrease the risk of colon cancer (73). Based on this study, it is recommended to avoid excess alcohol consumption and iacrease folate iatake to lower the risk of colon cancer. 

There are no hiUy effective therapeutic agents for the treatment of thederiasis. Chlorotetracycline (20) and oxytetracycline (3) have therapeutic activity duting the iacubation period. Pamaquiae (68) was reported to have a specific effect on the erythrocyctic forms. Other dmgs with limited efficacy are imidocarb (19) on T annulata halofugiaone (45) on both T annulata and T parva and the naphthoquiaones menoctone (76), parvaquone (88), and buparvaquone (89) on T parva. Methotrexate (90) has been found to be active in vitro (Table 9). 

The classification of these dmgs as antimetaboHtes stems from the mode of action as antagonists to the natural metaboHc processes leading to either DNA, RNA, or proteiu synthesis (13) (see Nucleic acids Proteins). They either inhibit function of a key en2yme involved in protein synthesis or are recmited into the cell division process as DNA synthesis terrninators. For example, methotrexate (8) is a foHc acid [59-30-3], antagonist and... 

The 1- and 3-deaza analogues (463a, 463b) of the DHFR-inhibitory antitumour drug methotrexate have also been investigated (71JOC2818). 

In view of the well-documented inhibition of dihydrofolate reductase by aminopterin (325), methotrexate (326) and related compounds it is generally accepted that this inhibitory effect constitutes the primary metabolic action of folate analogues and results in a block in the conversion of folate and dihydrofolate (DHF) to THF and its derivatives. As a consequence of this block, tissues become deficient in the THF derivatives, and this deficiency has many consequences similar to those resulting from nutritional folate deficiency. The crucial effect, however, is a depression of thymidylate synthesis with a consequent failure in DNA synthesis and arrest of cell division that has lethal results in rapidly proliferating tissues such as intestinal mucosa and bone marrow (B-69MI21604, B-69MI21605). 

In the treatment of human neoplastic diseases methotrexate has largely supplanted aminopterin in chemotherapy, due to the better therapeutic index of the former in experimental animals, although this superiority over (325) has not been conclusively demonstrated in man. 

Methotrexate — see Folic acid, 4-amino-4-deoxy-10-methyl-... 

Figure 3 (a) Structure of methotrexate and the structures of three model compounds that could... 

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