Cellular pharmacology of fluorinated pyrimidines in vivo in man

Fluorinated pyrimidines, particularly 5-fluorouracil (FUra), have been the subject of intense and almost continuous basic and clinical study since development in the late 1950's by Dr. Charles Heidelberger. Despite this intensive effort, the most important mechanisms by which FUra influences tumor growth in individual cancer patients and the therapeutically optimum method of administration of the drug alone and in combination with other drugs or ionizing radiation continue to be questions of interest. This article reviews aspects of the study of FUra pertinent to the thesis that for this drug as for other agents used to treat human cancers, data on intracellular concentrations of drug and metabolites as a function of dose, schedule of administration and time are needed for correlation with effects on tumor proliferation if a rational basis for individualization of therapy is to be achieved. A preliminary description of ongoing studies of the tissue concentrations of FUra and metabolites in human colorectal carcinoma and in adjacent normal bowel after rapid injection and after 24-hour infusion of radiolabelled pharmacologically active doses of FUra is included as one approach to learning more about the cellular pharmacology of fluorinated pyrimidines.