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Abstract

The three most widely studied and clinically useful folate antagonists are aminopterin, methotrexate (MTX, amethopterin), and 3′ ,5′-dichloro-MTX (Fig. 1). These compounds are all 4-amino analogs of folic acid and are powerful inhibitors of the enzyme dihydrofolate reductase (DHFR) (Fig. 2). The folate antagonists have extremely low inhibition constants (ca. 10−10 M) and they bind in a stoichiometric manner to dihydrofolate reductase at pH 6.0 (Werkheiser, 1961; Bertino et al., 1964). At a more alkaline pH, they bind less tightly and the binding is competitive with the substrate, dihydrofolate. This enzyme-inhibitor complex can be dissociated with regeneration of the enzyme and inhibitor by chromatography on DEAE-cellulose or hydroxylapatite, or by gel filtration at pH 9.0 in the presence of 0.15 M KC1 (Mathews and Huennekens, 1963; Bertino et al., 1964, 1965).

Keywords

Acute Myelocytic Leukemia Acute Leukemia Mycosis Fungoides Dihydrofolate Reductase Cytosine Arabinoside 
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© Springer-Verlag Berlin · Heidelberg 1975

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  • Joseph R. Bertino

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