Whole-body disposition and polyglutamate distribution of the GAR formyltransferase inhibitors LY309887 and lometrexol in mice: effect of low-folate diet

Abstract

The reduced hepatic retention and biochemical profile of LY309887 compared to lometrexol suggest that it may be less likely to produce delayed cumulative toxicity while still retaining antitumor activity. However, the increased hepatic accumulation observed in LFD mice emphasizes the importance of assessing and supplementing folate in cancer patients treated with this class of compounds.

Synthesis of (6R)- and (6S)-5,10-dideazatetrahydrofolate oligo-γ-glutamates: Kinetics of multiple glutamate ligations catalyzed by folylpoly-γ-glutamate synthetase

“…When an internal reference was not available (e.g. a 13 C NMR spectrum in D 2 O) the frequency of the solvent deuterium was utilized. ¹H NMR assignments of diastereotopic protons are noted as, e.g.…”

“…11 Rapid conversion to polyglutamate forms has also been observed with purified hFPGS 12 and in the mouse. 13 It is an excellent substrate for purified mammalian FPGS with kinetic constants similar to the best natural substrates, 10-formyltetrahydrofolate (10-formyl-H 4 PteGlu) and tetrahydrofolate (H 4 PteGlu). 8,10,14,15 The (6R)-and (6S)-diastereomers of DDAH 4 PteGlu 1 have K M values with human FPGS of 1.7 and 1.0 µM respectively.…”

New agents in cancer clinical trials

“…Newer versions of the agent do not require uptake by the folate receptor to enter the cell and hence are less likely to induce this side e ect. Modi®cations of folate diet have been shown to change the pharmacokinetics of these agents and thereby a ect their toxicity pro®le (Habeck et al, 1998).…”

Concentration-Dependent Processivity of Multiple Glutamate Ligations Catalyzed by Folylpoly-γ-glutamate Synthetase

“…FPGS has been found to convert DDAH 4 PteGlu 1 rapidly to polyglutamate forms in cell-free reactions (11), in cells (12), and in the mouse (13). Thus, the polyglutamate forms of DDAH 4 PteGlu 1 predominate within the cell and account for the cytotoxic action of the drug.…”

“…The ligation product would also need to remain bound during the binding of another molecule each of ATP and glutamate in preparation for the next turnover (e.g., Figure 2B). DDAH 4 PteGlu 1 , like the naturally occurring tetrahydrofolates, is rapidly converted to DDAH 4 PteGlu 5-6 in human cancer cells (12), murine liver (13), and with purified recombinant human cytosolic FPGS (11) with little accumulation of short chain polyglutamates. This evidence is suggestive of a processive mechanism for human FPGS, which is investigated in the current studies.…”