Folyl and antifolyl polyglutamates

The role of folylpolyglutamates in biosynthetic processes has gained increasing importance with the recognition that these compounds are not only the forms of folate co-factors that accumulate within cells, but, in addition, are the preferred substrates for folate dependent reactions in eukaryotic cells. More recently attention has turned to the potential importance of the polyglutamyl derivatives of methotrexate that have been detected in normal and malignant cells both in vitro and in vivo. The biochemical transformation of this important chemotherapeutic agent is of particular significance since polyglutamyl derivatives of methotrexate are not only potent inhibitors of the target enzyme, but have quite different cellular pharmacokinetics than the parent monoglutamate. Hence, nearly three and a half decades after 4-aminoantifolates were first applied clinically in the treatment of human neoplasms, we have begun to appreciate a new dimension in antifolate pharmacology which may have profound implications for our understanding of the mechanism of the cytotoxicity and selectivity of this class of agents. With the development of highly sensitive methodology for the rapid detection of folyl and antifolyl polyglutamates, it is now possible to define in depth the intracellular transformation of these agents and their role in determining antifolate action against normal and malignant cells. This information will very likely influence how regimens with methotrexate and related antifolates will be further developed and employed clinically. It is this evolving interest in the polyglutamylation of folates and antifolates that stimulated the first workshop on this subject held at the Airlie Foundation, in Airlie, Virginia May 2023, 1981. This book, which contains the papers presented at the Airlie meeting, provides a review of many aspects of the biochemistry of folyl and antifolylpolyglutamates by the major investigators in this field. The workshop encompasses a broad range of topics including synthesis and detection of these compounds, characteristics of the interactions between enzymes and olylpolyglutamates, and the biological importance of folylpolyglutamates under physiological and ophysiological conditions. The characteristics of folyl-poly-y-glutamate synthetases in bacteria, yeast and mammalian systems are described. Finally, formation of methotrexate polyglutamyl derivatives in mammalian cells is considered in detail, emphasizing the extent to which these metabolites are retained within cells and the ramification of their biosynthesis in terms of inhibition of folate dependent reactions and drug cytotoxicity.