Methotrexate, selective toxicity

The active form of folate is the tetrahydro-derivative that is formed through reduction by dihydrofolate reductase. This enzymatic reaction (Figure 29.5) is inhibited by trimethoprim, leading to a decrease in the folate coenzymes for purine, pyrimidine, and amino acid synthesis. Bacterial reductase has a much stronger affinity for trimethoprim than does the mammalian enzyme, which accounts for the drug s selective toxicity. [Note Examples of other folate reductase inhibitors include pyrimethamine, which is used with sulfonamides in parasitic infections (see p. 353), and methotrexate, which is used in cancer chemotherapy (see p. 378).]... 

It is evident, therefore, that the 2,4-diaminopyrimidines, like pyrimethamine and trimethoprim, the dihydrotriazines like proguanil (in its active metabolite form), the 2,4-diaminopteridines, and methotrexate, inhibit dihydrofolate reductase. Their selective toxicity to plasmodia may be due to a combination of greater binding to the parasite enzyme and to their selective uptake by parasitised erythrocytes. However, a new antifolic mode of action has recently been proposed for compounds like tetrahydrohomopteroic acid [288], which may inhibit folate metabolism by an action on the feedback... 

Hydroxyurea inhibits cell synthesis in the S phase of the DNA cycle. It is used selectively in the treatment of psoriasis, especially in those with liver disease who would be at risk of adverse effects with other agents. However, it is less effective than methotrexate. The typical dose is 1 g/day, with a gradual increase to 2 g/day as needed and as tolerated. Adverse effects include bone marrow toxicity with leukopenia or thrombocytopenia, cutaneous reactions, leg ulcers, and megaloblastic anemia. 

It is not surprising then that, despite its effectiveness, methotrexate therapy is underscored by serious side-effects and problems which have prompted ongoing research programmes to attempt the preparation of new analogues possessing better tumour-cell selectivity, lower toxicity, better transport properties, and improved lipid solubility and membrane permeability. These efforts have resulted in the preparation of thousands of analogues in which virtually every major area of the molecule has been varied and evaluated. 

Further studies have validated this hypothesis, in part,4 and ultimately this inventive premise was borne out in clinical practice. As a result, 5-FU (5) was eventually approved for treatment of solid tumors, such as breast, colorectal, and gastric cancers. Marketed as Adrucil when administered intravenously, 5-FU can be used either as monotherapy or combination therapy with various cytotoxic drugs and biochemical modulators, such as leucovorin and methotrexate.5 Because 5-fluorouracil is not orally bioavailable, it must be administered by continuous infusion to optimize its efficacy due to its short half-life in plasma. In addition, 5-FU has poor selectivity toward tumors in vivo, and its distribution into tissues such as bone marrow, the gastrointestinal tract, the liver and skin causes high incidences of toxicity. In addition, in spite of its limited lipid solubility, 5-fluorouracil diffuses readily across the blood-brain barrier into cerebrospinal fluid and brain tissue.1,5... 

Drug interactions may potentiate methotrexate toxicity. For example nonsteroidal anti-inflammatory drugs can reduce renal clearance of methotrexate, resulting in toxic levels. Table 96-5 lists selected drugs that interact with, and increase toxicity of, methotrexate. 

Figure 6. Some common pharmaceuticals that inhibit enzymes. Methotrexate binds to the enzyme that normally uses dihyrofolate. This binding prevents the enzyme from binding dihydrofolate reductase and carrying out its function. Inhibition of these enzymes is toxic for virtually al I cells but has some selectivity for rapidly dividing cells. Warfarin binds to an enzyme site that is normally occupied by vitamin K. Again, with warfarin bound, liver enzymes that aid in synthesis of certain blood clotting proteins cannot function properly. As a resuitthe blood clotting proteins produced are defective and there is reduced ability to clot blood.

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