Mechanism of cytotoxicity of 5,10-dideazatetrahydrofolic acid in human ovarian carcinoma cells in vitro and modulation of the drug activity by folic or folinic acid

Abstract

Summary Inhibition of clonogenic potential by the glycinamideribonucleosyl transformylase inhibitor 5,10-dideazatetrahydrofolic acid (DDATHF, Lometrexol)

Role of membrane folate-binding protein in the cytotoxicity of 5,10-dideazatetrahydrofolic acid in human ovarian carcinoma cell lines in vitro

“…However, under those conditions, there was an increase in DDATHF cytotoxicity in both cell lines, suggesting that folic acid bound to FBP reduces the anti-tumour activity of the drug. These data are consistent with earlier observations that the presence of folic acid and folinic acid markedly reduce the cytotoxicity of DDATHF in vitro (Erba et al, 1994), and in vivo the toxicity was reversed and DDATHF anti-tumour activity retained only in animals that had received folic acid before DDATHF Grindey et al, 1992).…”

“…Aspects of the cellular pharmacology of DDATHF have been investigated in detail; it causes no detectable DNA breaks even after 48 h continuous exposure and its cytotoxic potential can be modulated by folic and folinic acid (Erba et al, 1994); DDATHF prevents the proliferation of tumour cells in vitro Beardsley et al, 1989;Moran et al, 1989;Erba et al, 1994) and in vivo (Beardsley et al, 1986;Shih et al, 1988;Alati et al, 1992;Grindley et al, 1992), and causes purine nucleotide depletion . Because of its chemical homology to folates, the drug is taken up by cells through physiological folate uptake mechanisms (reviewed in Antony, 1992).…”

Selective potentiation of lometrexol growth inhibition by dipyridamole through cell-specific inhibition of hypoxanthine salvage

“…Furthermore, Chan and Howell (1990) demonstrated the potentiation of methotrexate cytotoxicity in ovarian cancer cells by dipyridamole by inhibition of not only thymidine but also hypoxanthine uptake. Cells treated with lometrexol have reduced ATP and GTP pools; co-incubation with hypoxanthine both repletes these pools (Pizzorno et al, 1991) and abolishes the cytotoxic effect of lometrexol (Erba et al, 1994). Thus, dipyridamole should enhance lometrexol cytotoxicity by the inhibition of hypoxanthine uptake.…”

Crystal Structures of Human Bifunctional Enzyme Aminoimidazole-4-carboxamide Ribonucleotide Transformylase/IMP Cyclohydrolase in Complex with Potent Sulfonyl-containing Antifolates

“…Thus, folate-based inhibitors of GAR Tfase do not usually inhibit ATIC because of differential interactions within the two active sites (7). For example, 6R-dideazatetrahydrofolate (Lometrexol), potently inhibits GAR Tfase (nM) but not ATIC (M) (13,14).…”