C. Myers, R. Diasio, H. Eliot
Sep 1, 1976
Citations
0
Influential Citations
92
Citations
Quality indicators
Journal
Cancer treatment reviews
Abstract
Summary There are four areas of current research interest in the fluoropyrimidines which may improve clinical utility of this class of drugs (Table 2) . First, there is the obvious need for comprehensive pharmacokinetic information in man not only on the parent drug, be it 5FU, FUdR or ftorafur, but also on all potentially active metabolites. Second, knowledge of the distribution of uridine kinase, phosphoribosyl transferase and thymidine kinase in human bone marrow, gastrointestinal mucosa and accessible tumors would help clarify which of these enzymes controls 5-FU activation. Third, the availability of techniques to determine FdUMP formation within the target tumor cell provides an opportunity for predictive pharmacologic testing which should be fully exploited, especially in the adjuvant situation where tumor tissue is available and severe drug toxicity unacceptable. Table 2 . Major areas of current interest 1. Adequate pharmacodynamic studies in man of parent drug and active metabolites. 2. Distribution ofuridine kinase, phosphoribosyl transferase and thymidine kinase in normal and malignant human tissues. 3. Predictive pharmacologic testing based on either direct measurement of FdUMP formation or levels of nucleotide synthetic enzymes in tumour samples. 4. Synthesis of additional analogs which share the lipid solubility of ftorafur and its reduced marrow toxicity, but which lack its neurotoxicity. Finally, the greater lipid solubility and lessened marrow toxicity of ftorafur represents an improvement over 5-FU which may be counterbalanced by new and potentially serious neurotoxicity. For this reason, attempts should be made to synthesize new analos which lack this neurotoxicity, but which preserve both the increased lipid solubility and detreased marrow toxicity.