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J Med Chem. 2003 Jul 3;46(14):2816-8.

Dihydrofolate reductase mutant with exceptional resistance to methotrexate but not to trimetrexate.

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Departments of Medicinal Chemistry and of Genetics and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA.


Two double (F31A/F34A, I60A/L67G) and one quadruple (F31A/F34A/I60A/L67G) mutant murine dihydrofolate reductases were constructed and evaluated for their ability to impart antifolate resistance. Both I60A/L67G and F31A/F34A/I60A/L67G were found to be unstable and devoid of catalytic activity. The K(i) values for F31A/F34A, methotrexate (MTX), bis-MTX, and PT-523 were found to be 10100-, 4410-, and 617-fold higher than the wild-type enzyme, respectively, but only 13.5-fold higher for trimetrexate (TMTX). These findings suggest that F31A/F34A could be used for gene therapy to render normal cells resistant to MTX but sensitive to TMTX.

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