Summation of Session II
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It has been apparent from this conference that the FUra-CF combination is of exceptional interest to investigators in all areas of cancer chemotherapy, from basic biochemistry to clinical studies. There are a number of reasons for this. First, the FUra-CF combination was proposed on the basis of rational a priori biochemical studies at the enzymological level, which revealed the role of CH2H4PteGlu in the mechanism of interaction between FdUMP and TS. Secondly, there is a multiplicity of biochemical pathways and reactions involved in the conversion of CF to the reduced folate cofactor form. This provides the opportunity for many more biochemical studies which in turn should give rise to more ideas for drug modulation. Thirdly, the basic concept seems to hold up across the board. In contrast to many modulation ideas which seem to work basically as conceived in vitro only to fizzle out when taken to in vivo systems, the effect of adding folates works in stabilizing the ternary complex in the test tube, it works to enhance the toxicity of the drugs in cell culture, and so far all indications are that the same biochemical mechanism is operative in human patients as well. This is encouraging in that it validates a concept of cancer drug pharmacology for which there was heretofore little precedent, namely, that finding out more about how drugs work will lead to more effective ways to use them.
KeywordsTernary Complex Thymidylate Synthetase Drug Modulation Exceptional Interest Fluorinated Pyrimidine
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