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Limitations on the Therapeutic Effectiveness of the Folic Acid Antagonists¹

Department of Experimental Therapeutics, Roswell Park Memorial Institute, Buffalo, New York

Suspected causes of the limitations of the therapeutic effectiveness of the folic acid antagonists, amethopterin in particular, are presented. An hypothesis is elaborated, emphasizing the dynamic nature of the processes involved in drug intoxication. A variety of experimental and clinical chemotherapeutic regimens are reviewed in terms of this hypothesis, and modifications of both the tissue permeability and the stereochemistry of the anti-metabolites are discussed.

¹ This work was supported by grants (CA-02906 and CA-05298) from the National Cancer Institute, USPHS.