Heterocyclic
para-aminobenzoate modifications of 2-desamino-2-methyl-5,8-dideazafolic
acid and a series of its N10-substituted analogs have produced a number of interesting compounds that have enabled a deeper understanding of the biochemical events required for activity in this class of
antimetabolite. There is a relationship that has become apparent between compound potency and both uptake via the
reduced-folate carrier and FPGS substrate activity. Rapid cellular uptake and metabolism of
polyglutamate forms that are approximately 100-fold more potent as inhibitors of TS can translate a modest TS inhibitor such as
ICI D1694 into a very potent inhibitor of cell growth (approximately 500- and approximately 10-fold more potent than
CB3717 or
ICI 198583, respectively). Polyglutamation may therefore act as an almost essential activation step and
ICI D1694 may be highly specific for
tumors expressing both the
reduced-folate carrier and FPGS. Polyglutamation of
folate analogs also leads to
drug retention which may play a major role in the pharmacodynamics of TS inhibition by
ICI D1694 in vivo. Current studies with 3H-ICI
D1694 are aimed at demonstrating metabolism to polyglutamates in
tumor cells. The serious toxic limitations of
CB3717, i.e., liver and kidney toxicities, are not seen with
ICI D1694 reflecting the good water solubility of the
drug compared with
CB3717. The toxicities observed in mice are however to hematological tissues and are due to its TS inhibitory effects. Thus
ICI D1694 may elicit toxicities in man more typical of an
antimetabolite than of
CB3717. The clinical evaluation of
ICI D1694 may further our understanding of the role that metabolism to polyglutamates may have in therapeutic activity.