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Chemical Compound Review

Lometrexol     (2S)-2-[[4-[2-[(9R)-4-amino- 2-oxo-3,5,7...

Synonyms: Lometrexolum, DDATHF-B, CHEMBL34412, SureCN18530, T-64, ...
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Disease relevance of Lometrexol


High impact information on Lometrexol


Chemical compound and disease context of Lometrexol


Biological context of Lometrexol

  • The disposition of total lometrexol in plasma was best described by a biexponential model for data acquired up to 12 h after drug administration, although triexponential plasma pharmacokinetics were often found to give a more adequate description when data were available at later time intervals (24 h and greater) [9].
  • Moderate plasma protein binding of lometrexol was evident (78 +/- 3%) with an inverse linear relationship between fraction of unbound lometrexol and the concentration of serum albumin [9].
  • Longer time intervals between administration of lometrexol and start of rescue were then evaluated (part III), and in the last part of the study (part IV), the maximum tolerated dose of single intermittent doses of lometrexol with folinic acid given from day 7 to day 9 was established [10].
  • Moreover, compound 1 is a potent inhibitor of tumor cell proliferation (IC(50) = 16 nM, CCRF-CEM), which represents a 10-fold improvement over Lometrexol, a GAR Tfase inhibitor that has been in clinical trials [11].
  • A comparison of the efficacy and toxicity of lometrexol in C3H mammary tumor-bearing mice showed that in mice on LFD, lometrexol treatment produced a delayed toxicity with an LD50 of 0.1-0.3 mg/kg, a 3000-fold increase in lethality compared to SD mice [12].

Anatomical context of Lometrexol


Associations of Lometrexol with other chemical compounds


Gene context of Lometrexol

  • Using FPGS from two different species, Km values below 2 micromol/L and high relative first order rate constants, k' (Vmax/Km) of 6.4 and 13.7 compared with another substrate, lometrexol, were obtained [17].
  • They also suggest that the N10 position on the bridge region in both series of compounds, and probably for the pyridopyrimidine lometrexol, is not an important determinant [18].
  • Consistent with these changes in liver FPGS, mice injected i.v. with a single dose of lometrexol accumulated significantly more drug in liver and tumors of LFD animals compared to SD mice [12].
  • RESULTS: Cell populations treated for up to 96h with lometrexol or LY309887 did not replicate and maintained a cell cycle distribution with distinct G1, S and G2/M regions [19].

Analytical, diagnostic and therapeutic context of Lometrexol

  • Recent clinical trials with lometrexol [(6R)-5,10-dideazatetrahydrofolate] have revealed a level of toxicity in humans that was not predicted on the basis of previous in vivo preclinical studies [20].
  • The most promising preclinical features of lometrexol in animal models were its significant activity against a broad panel of solid tumors, the schedule dependency of its antitumor activity, and the availability of a rescue regimen with folinic or folic acid [10].
  • Lometrexol pharmacokinetics were also examined in seven patients who received 45 or 60 mg/m2 lometrexol as part of a separate study of the drug given with folinic acid rescue 5-7 days after treatment [9].
  • In two pancreatic human xenografts, LY309887 achieved greater efficacy than lometrexol [21].
  • A reversed-phase high-performance liquid chromatographic (HPLC) assay is described for the quantitative determination of lometrexol in biological samples; the assay is rapid, simple, specific, and highly sensitive [15].


  1. Failure of pretreatment with intravenous folic acid to alter the cumulative hematologic toxicity of lometrexol. Muggia, F.M., Synold, T.W., Newman, E.M., Jeffers, S., Leichman, L.P., Doroshow, J.H., Johnson, K., Groshen, S. J. Natl. Cancer Inst. (1996) [Pubmed]
  2. Dipyridamole potentiates antipurine antifolate activity in the presence of hypoxanthine in tumor cells but not in normal tissues in vitro. Marshman, E., Newell, D.R., Calvert, A.H., Dickinson, A.M., Patel, H.R., Campbell, F.C., Curtin, N.J. Clin. Cancer Res. (1998) [Pubmed]
  3. 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. Erba, E., Sen, S., Sessa, C., Vikhanskaya, F.L., D'Incalci, M. Br. J. Cancer (1994) [Pubmed]
  4. A novel class of monoglutamated antifolates exhibits tight-binding inhibition of human glycinamide ribonucleotide formyltransferase and potent activity against solid tumors. Habeck, L.L., Leitner, T.A., Shackelford, K.A., Gossett, L.S., Schultz, R.M., Andis, S.L., Shih, C., Grindey, G.B., Mendelsohn, L.G. Cancer Res. (1994) [Pubmed]
  5. The role of alpha-folate receptor-mediated transport in the antitumor activity of antifolate drugs. Theti, D.S., Jackman, A.L. Clin. Cancer Res. (2004) [Pubmed]
  6. The impact of p53 status on cellular sensitivity to antifolate drugs. Lu, X., Errington, J., Curtin, N.J., Lunec, J., Newell, D.R. Clin. Cancer Res. (2001) [Pubmed]
  7. Cellular but not plasma pharmacokinetics of lometrexol correlate with the occurrence of cumulative hematological toxicity. Synold, T.W., Newman, E.M., Carroll, M., Muggia, F.M., Groshen, S., Johnson, K., Doroshow, J.H. Clin. Cancer Res. (1998) [Pubmed]
  8. Selective potentiation of lometrexol growth inhibition by dipyridamole through cell-specific inhibition of hypoxanthine salvage. Turner, R.N., Aherne, G.W., Curtin, N.J. Br. J. Cancer (1997) [Pubmed]
  9. Clinical pharmacokinetics of the antipurine antifolate (6R)-5,10- dideaza-5,6,7,8-tetrahydrofolic acid (Lometrexol) administered with an oral folic acid supplement. Wedge, S.R., Laohavinij, S., Taylor, G.A., Boddy, A., Calvert, A.H., Newell, D.R. Clin. Cancer Res. (1995) [Pubmed]
  10. Phase I study of the antipurine antifolate lometrexol (DDATHF) with folinic acid rescue. Sessa, C., de Jong, J., D'Incalci, M., Hatty, S., Pagani, O., Cavalli, F. Clin. Cancer Res. (1996) [Pubmed]
  11. Rational design, synthesis, evaluation, and crystal structure of a potent inhibitor of human GAR Tfase: 10-(trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic acid. Zhang, Y., Desharnais, J., Marsilje, T.H., Li, C., Hedrick, M.P., Gooljarsingh, L.T., Tavassoli, A., Benkovic, S.J., Olson, A.J., Boger, D.L., Wilson, I.A. Biochemistry (2003) [Pubmed]
  12. The role of dietary folate in modulation of folate receptor expression, folylpolyglutamate synthetase activity and the efficacy and toxicity of lometrexol. Mendelsohn, L.G., Gates, S.B., Habeck, L.L., Shackelford, K.A., Worzalla, J., Shih, C., Grindey, G.B. Adv. Enzyme Regul. (1996) [Pubmed]
  13. Competitive particle concentration fluorescence immunoassay for measuring 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (lometrexol) in serum. Taber, L.D., O'Brien, P., Bowsher, R.R., Sportsman, J.R. Clin. Chem. (1991) [Pubmed]
  14. Dietary folate and folylpolyglutamate synthetase activity in normal and neoplastic murine tissues and human tumor xenografts. Gates, S.B., Worzalla, J.F., Shih, C., Grindey, G.B., Mendelsohn, L.G. Biochem. Pharmacol. (1996) [Pubmed]
  15. Specific and sensitive high-performance liquid chromatographic method with fluorescence detection for measurement of lometrexol and its polyglutamates in biologic samples. Muindi, J.R., Young, C.W., Shih, C. J. Chromatogr. (1993) [Pubmed]
  16. New antifolates in clinical development. Takimoto, C.H., Allegra, C.J. Oncology (Williston Park, N.Y.) (1995) [Pubmed]
  17. Enzyme inhibition, polyglutamation, and the effect of LY231514 (MTA) on purine biosynthesis. Mendelsohn, L.G., Shih, C., Chen, V.J., Habeck, L.L., Gates, S.B., Shackelford, K.A. Semin. Oncol. (1999) [Pubmed]
  18. Structural preferences among folate compounds and their analogues for ATPase-mediated efflux by inside-out plasma membrane vesicles derived from L1210 cells. Schlemmer, S.R., Sirotnak, F.M. Biochem. Pharmacol. (1995) [Pubmed]
  19. Cell cycle effects of antifolate antimetabolites: implications for cytotoxicity and cytostasis. Tonkinson, J.L., Marder, P., Andis, S.L., Schultz, R.M., Gossett, L.S., Shih, C., Mendelsohn, L.G. Cancer Chemother. Pharmacol. (1997) [Pubmed]
  20. Augmentation of the therapeutic activity of lometrexol -(6-R)5,10-dideazatetrahydrofolate- by oral folic acid. Alati, T., Worzalla, J.F., Shih, C., Bewley, J.R., Lewis, S., Moran, R.G., Grindey, G.B. Cancer Res. (1996) [Pubmed]
  21. Biochemistry and pharmacology of glycinamide ribonucleotide formyltransferase inhibitors: LY309887 and lometrexol. Mendelsohn, L.G., Shih, C., Schultz, R.M., Worzalla, J.F. Investigational new drugs. (1996) [Pubmed]
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