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Chemical Compound Review

AG-K-04502     5-methyl-6-[[(3,4,5- trimethoxyphenyl)amino...

Synonyms: CTK6J8809, ZINC00598852, AC1L1KO2
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Disease relevance of trimetrexate

 

High impact information on trimetrexate

 

Chemical compound and disease context of trimetrexate

 

Biological context of trimetrexate

  • Trimetrexate is extensively protein bound and is cleared primarily by hepatic metabolism, so it is not unreasonable to believe that alteration in protein binding of the drug or in metabolic capacity of the liver could produce enhanced toxic effects [12].
  • Trimetrexate, an investigational antifol, has been associated with marked variability in drug tolerance among patients [3].
  • Cells grown out of the pooled resistant colonies retained the same level of resistance to trimetrexate whether Bcl-2 was induced or repressed, consistent with the theory that Bcl-2 functions by facilitating gene amplification, rather than being the resistance mechanism per se [13].
  • Induction of Bcl-2 expression caused a temporary delay of apoptosis and resulted in roughly a 3-fold increase in the frequency of resistant colonies when cells were selected with trimetrexate [13].
  • The pharmacokinetics of trimetrexate were studied in 25 patients over the entire dose range [14].
 

Anatomical context of trimetrexate

 

Associations of trimetrexate with other chemical compounds

  • This report quantitates the effects of the commonly used antifolates as well as the classic antineoplastic antifolate methotrexate and a lipid-soluble analogue, trimetrexate, on the target enzyme, dihydrofolate reductase (DHFR), in the PC organisms [20].
  • As an inhibitor of this enzyme, trimetrexate was almost 600-fold (amount of antifolate required to inhibit catalytic reaction by 50%) and 750-fold (inhibition constant) more potent than pyrimethamine, the DHFR inhibitor currently used to treat toxoplasma infection [15].
  • In this study, mouse cells transfected to express a green fluorescent protein-DHFR fusion protein and subsequently exposed to the antifolate trimetrexate (TMTX) showed a specific and time-dependent increase in cellular levels of the fusion protein [21].
  • Sequence and schedule-dependent synergy of trimetrexate in combination with 5-fluorouracil in vitro and in mice [8].
  • These results have a corollary in an earlier study showing that the same concentrations of metoprine and trimetrexate could enhance the growth inhibition and cytotoxicity of the folate-based inhibitor of thymidylate synthase, 10-propargyl-5,8-dideazafolic acid (Galivan et al., Cancer Res., 47: 5256-5260, 1987) [22].
 

Gene context of trimetrexate

  • The DHFR-overproducing lines all had significant cross-resistance to both metoprine and trimetrexate; the two lines with defective MTX transport were not cross-resistant, and the CEM/MTX-R cells showed collateral sensitivity to these agents [23].
  • Expression of costimulatory molecules B7-1/B7-2 and Fas is increased on L1210 cells, but not L1210/DDP, in the presence of methotrexate or trimetrexate (TMTX) [24].
  • In cells resistant to MTX by virtue of both mechanisms, CCRF-CEM/R2, triazinate, and trimetrexate were partially cross-resistant [25].
  • However, the toxic effects of piritrexim and trimetrexate suggest that dihydrofolate reductase (DHFR) activity is essential for the parasite, most probably because of the role of this enzyme in the synthesis of thymidine nucleotides via thymidylate synthase [26].
  • Further analysis of sensitivity of the cells to trimetrexate (TMQ), which is not polyglutamated and does not require the reduced folate transporter, but is a potent inhibitor of human DHFR, revealed a modest decrease in sensitivity to TMQ (2.4- to 15-fold) [27].
 

Analytical, diagnostic and therapeutic context of trimetrexate

References

  1. Trimetrexate for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. Allegra, C.J., Chabner, B.A., Tuazon, C.U., Ogata-Arakaki, D., Baird, B., Drake, J.C., Simmons, J.T., Lack, E.E., Shelhamer, J.H., Balis, F. N. Engl. J. Med. (1987) [Pubmed]
  2. Understanding trimetrexate toxicity. Donehower, R.C. J. Natl. Cancer Inst. (1988) [Pubmed]
  3. Correlates of severe or life-threatening toxic effects from trimetrexate. Grem, J.L., Ellenberg, S.S., King, S.A., Shoemaker, D.D. J. Natl. Cancer Inst. (1988) [Pubmed]
  4. Phase II trial of trimetrexate in the treatment of recurrent childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study. Pappo, A., Dubowy, R., Ravindranath, Y., Alvarado, C., Rao, S., Whitehead, V.M., Vega, R., Kamen, B., Vietti, T. J. Natl. Cancer Inst. (1990) [Pubmed]
  5. Cross-resistance to the lipid-soluble antifolate trimetrexate in human carcinoma cells with the multidrug-resistant phenotype. Assaraf, Y.G., Molina, A., Schimke, R.T. J. Natl. Cancer Inst. (1989) [Pubmed]
  6. Phase I trial of trimetrexate glucuronate on a five-day bolus schedule: clinical pharmacology and pharmacodynamics. Grochow, L.B., Noe, D.A., Dole, G.B., Rowinsky, E.K., Ettinger, D.S., Graham, M.L., McGuire, W.P., Donehower, R.C. J. Natl. Cancer Inst. (1989) [Pubmed]
  7. Inability of leucovorin to rescue a naturally methotrexate-resistant human soft tissue sarcoma cell line from trimetrexate cytotoxicity. Li, W.W., Bertino, J.R. Cancer Res. (1992) [Pubmed]
  8. Sequence and schedule-dependent synergy of trimetrexate in combination with 5-fluorouracil in vitro and in mice. Elliott, W.L., Howard, C.T., Dykes, D.J., Leopold, W.R. Cancer Res. (1989) [Pubmed]
  9. Pharmacology and toxicity of a potent "nonclassical" 2,4-diamino quinazoline folate antagonist, trimetrexate, in normal dogs. Weir, E.C., Cashmore, A.R., Dreyer, R.N., Graham, M.L., Hsiao, N., Moroson, B.A., Sawicki, W.L., Bertino, J.R. Cancer Res. (1982) [Pubmed]
  10. Role of substrate depletion in the inhibition of thymidylate biosynthesis by the dihydrofolate reductase inhibitor trimetrexate in cultured hepatoma cells. Rhee, M.S., Balinska, M., Bunni, M., Priest, D.G., Maley, G.F., Maley, F., Galivan, J. Cancer Res. (1990) [Pubmed]
  11. Quantitation of folic acid enhancement of antifolate synergism. Gaumont, Y., Kisliuk, R.L., Parsons, J.C., Greco, W.R. Cancer Res. (1992) [Pubmed]
  12. Trimetrexate: predictors of severe or life-threatening toxic effects. Eisenhauer, E.A., Zee, B.C., Pater, J.L., Walsh, W.R. J. Natl. Cancer Inst. (1988) [Pubmed]
  13. Inhibition of apoptosis by overexpressing Bcl-2 enhances gene amplification by a mechanism independent of aphidicolin pretreatment. Yin, D.X., Schimke, R.T. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  14. Pediatric phase I trial and pharmacokinetic study of trimetrexate. Balis, F.M., Patel, R., Luks, E., Doherty, K.M., Holcenberg, J.S., Tan, C., Reaman, G.H., Belasco, J., Ettinger, L.J., Zimm, S. Cancer Res. (1987) [Pubmed]
  15. Potent in vitro and in vivo antitoxoplasma activity of the lipid-soluble antifolate trimetrexate. Allegra, C.J., Kovacs, J.A., Drake, J.C., Swan, J.C., Chabner, B.A., Masur, H. J. Clin. Invest. (1987) [Pubmed]
  16. A gene transfer strategy for making bone marrow cells resistant to trimetrexate. Spencer, H.T., Sleep, S.E., Rehg, J.E., Blakley, R.L., Sorrentino, B.P. Blood (1996) [Pubmed]
  17. Sensitization of hematopoietic stem and progenitor cells to trimetrexate using nucleoside transport inhibitors. Allay, J.A., Spencer, H.T., Wilkinson, S.L., Belt, J.A., Blakley, R.L., Sorrentino, B.P. Blood (1997) [Pubmed]
  18. Characterization of trimetrexate transport in human lymphoblastoid cells and development of impaired influx as a mechanism of resistance to lipophilic antifolates. Fry, D.W., Besserer, J.A. Cancer Res. (1988) [Pubmed]
  19. Trimetrexate in relapsed T-cell lymphoma with skin involvement. Sarris, A.H., Phan, A., Duvic, M., Romaguera, J., McLaughlin, P., Mesina, O., King, K., Medeiros, L.J., Rassidakis, G.Z., Samuels, B., Cabanillas, F. J. Clin. Oncol. (2002) [Pubmed]
  20. Activity of antifolates against Pneumocystis carinii dihydrofolate reductase and identification of a potent new agent. Allegra, C.J., Kovacs, J.A., Drake, J.C., Swan, J.C., Chabner, B.A., Masur, H. J. Exp. Med. (1987) [Pubmed]
  21. Cells exposed to antifolates show increased cellular levels of proteins fused to dihydrofolate reductase: a method to modulate gene expression. Mayer-Kuckuk, P., Banerjee, D., Malhotra, S., Doubrovin, M., Iwamoto, M., Akhurst, T., Balatoni, J., Bornmann, W., Finn, R., Larson, S., Fong, Y., Gelovani Tjuvajev, J., Blasberg, R., Bertino, J.R. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  22. Antifolate drug interactions: enhancement of growth inhibition due to the antipurine 5,10-dideazatetrahydrofolic acid by the lipophilic dihydrofolate reductase inhibitors metoprine and trimetrexate. Galivan, J., Nimec, Z., Rhee, M., Boschelli, D., Oronsky, A.L., Kerwar, S.S. Cancer Res. (1988) [Pubmed]
  23. Patterns of cross-resistance to the antifolate drugs trimetrexate, metoprine, homofolate, and CB3717 in human lymphoma and osteosarcoma cells resistant to methotrexate. Diddens, H., Niethammer, D., Jackson, R.C. Cancer Res. (1983) [Pubmed]
  24. Drug resistance results in alterations in expression of immune recognition molecules and failure to express Fas (CD95). Bhushan, A., Kupperman, J.L., Stone, J.E., Kimberly, P.J., Calman, N.S., Hacker, M.P., Birge, R.B., Tritton, T.R., Newell, M.K. Immunol. Cell Biol. (1998) [Pubmed]
  25. Cytotoxic effects of folate antagonists against methotrexate-resistant human leukemic lymphoblast CCRF-CEM cell lines. Mini, E., Moroson, B.A., Franco, C.T., Bertino, J.R. Cancer Res. (1985) [Pubmed]
  26. The toxicity of antifolates in Babesia bovis. Nott, S.E., Bagnara, A.S. Int. J. Parasitol. (1993) [Pubmed]
  27. Enzyme studies of methotrexate-resistant human leukemic cell (K562) subclones. Koizumi, S., Allegra, C.J. Leuk. Res. (1992) [Pubmed]
  28. Trimetrexate: a second generation folate antagonist in clinical trial. Lin, J.T., Bertino, J.R. J. Clin. Oncol. (1987) [Pubmed]
  29. Complete regression of large solid tumors using engineered drug-resistant hematopoietic cells and anti-CD137 immunotherapy. McMillin, D.W., Hewes, B., Gangadharan, B., Archer, D.R., Mittler, R.S., Spencer, H.T. Hum. Gene Ther. (2006) [Pubmed]
 
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