Disease relevance of DDATHF

• Uptake of D1694, 1843U89, or DDATHF was 2.5-4.5-fold higher than MTX in these sarcoma cell lines [1].
• The two different schedules of administration for DDATHF, 4 and 8 hr prior to 5-FU, showed no differences in antitumor activity or toxicity [2].
• Lometrexol (5,10-dideazatetrahydrofolic acid; DDATHF), is a specific inhibitor of glycinamideribonucleosyl (GAR) transformylase with anti-tumour activity in murine and human carcinomas [3].

High impact information on DDATHF

• This inability of p53 to initiate a G(1) arrest after DDATHF treatment was mirrored by an independence of the cytotoxicity of DDATHF on p53 function [4].
• Cell cycle analyses of DDATHF-treated HL-60 cells demonstrated an initial block in early S phase by day 3 followed by an accumulation of cells in the G1 and G2 + M phases of the cell cycle [5].
• The novel tetrahydrofolate, 5,10-dideazatetrahydrofolic acid (DDATHF), was designed as an inhibitor of folate metabolism at a site other than dihydrofolate reductase [5].
• This possibility was confirmed by the finding that DDATHF caused a pronounced reduction in intracellular GTP and ATP levels within 2 h, with maximum decreases being observed by 24 h, a time interval which preceded the inhibition of cellular proliferation by this agent [5].
• 5,10-Dideazatetrahydrofolic acid (DDATHF) transport in CCRF-CEM and MA104 cell lines [6].

Chemical compound and disease context of DDATHF

• However, HX increased the protective effect of DDATHF from ICI D1694 toxicity, had no effect on the CB3717-DDATHF interaction, and reduced the protective effect of DDATHF on FdUrd toxicity [7].
• These data indicated that a deficiency in dietary folic acid in mice caused increased hepatic retention of radioactivity and sustained plasma concentrations of DDATHF which are probably responsible for the observed toxicity of DDATHF in mice [8].

Biological context of DDATHF

• However, in striking contrast to DDATHF, which is potently cytotoxic, 1 failed to inhibit tumor cell growth in culture at concentrations of up to 100 microM [9].
• Hydrogenation of both the 9,10 double bond and the pyrido ring of 9a and 9b (MeOH-0.1 N HCl, 3.5 atm, Pt) was followed by ester hydrolysis to give 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (11a) and the 5-methyl analogue 11b [10].
• Only on SKOV3 cells was DDATHF cytotoxicity the same regardless of the amount of folic acid in the medium (IC50 8 nM) [3].
• DDATHF blocked cells in the early-middle S-phases of the cell cycle, and there was a corresponding marked reduction in the rate of DNA synthesis after drug withdrawal [11].
• Mice were maintained on diets for 2 weeks prior to receiving a single i.v. 30 mg/kg dose of [14C]DDATHF (tissue distribution) or DDATHF (plasma pharmacokinetics) [8].

Anatomical context of DDATHF

• The cytotoxicity activity of DDATHF was evaluated in vitro in NIH/3T3 cells transfected with human alpha-folate-binding protein (FBP) complementary DNA to examine the role of the receptor [3].
• RESULTS/CONCLUSION: All the antifolates inhibited bone marrow proliferation in suspension cultures and all drugs except DDATHF inhibited colony formation by more mature progenitor cells (CFU-C) in clonogenic assays [12].
• Similar protection was not observed in KB cells, suggesting that KB mFBP was not functional in DDATHF transport [13].

Associations of DDATHF with other chemical compounds

• We conclude that carcinoma cells are killed equally well by DDATHF and related compounds whether or not the p53 pathway is intact and that the utility of GART inhibitors would not be limited to p53-negative tumors [4].
• The transport properties of DDATHF were also studied in a mutant cell line (CEM/MTX), resistant to MTX based on impaired drug transport [6].
• Compound 1 was found to be a good substrate for partially purified mouse liver folypolyglutamate synthetase (FPGS), with a Michaelis constant (Km = 15 microM) comparable to that reported for the reduced folate substrate (6S)-5,6,7,8-tetrahydropteroyl-L-glutamic acid and for (6R,6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamic acid (DDATHF) [9].
• Indeed this thiazole was over 4 times more active in the MCF-7 cell line than the clinically investigated compound 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) [14].
• In a medium containing 2.27 microM folic acid the DDATHF IC50 values were 50 nm on OVCAR3, 500 nM on SW626 and 1000 nM on IGROV1 [3].

Gene context of DDATHF

• Against two novel antifolates targetting enzymes other than DHFR, minor crossresistance was observed for ICI-198, 583, but full sensitivity was retained for DDATHF [15].
• HX prevented the fall in dATP levels caused by DDATHF addition to cells treated with TS inhibitors [7].
• 5,10-Dideazatetrahydrofolic acid (DDATHF) reduces de nova purine biosynthesis by inhibiting glycinamide ribonucleotide transformylase [7].
• Previous studies from our laboratory have shown that DDATHF is an effective inducer of the maturation of HL-60 promyelocytic leukemia [16].
• The relationship between guanine nucleotide pools and the induction of HL-60 differentiation by DDATHF was further supported by the finding that maturation and the depletion of intracellular GTP by DDATHF were not reversed by guanine nucleosides in HL-60 cells deficient in hypoxanthine-guanine phosphoribosyltransferase activity [17].

Analytical, diagnostic and therapeutic context of DDATHF

• Cell culture cytotoxicity studies of all of the above acyclic analogues of DDATHF against CCRF-CEM human lymphoblastic leukemic cells gave IC50s ranging from 0.042 greater than 48 microM [18].
• Bioanalysis of the investigational anti-tumour drug 5,10-dideaza-5,6,7,8-tetrahydrofolic acid by high-performance liquid chromatography with ultraviolet detection [19].
• A high-performance liquid chromatographic (HPLC) method with ultraviolet detection at 278 nm is presented for the determination of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid in plasma [19].

References