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Chemical Compound Review

Tomudex     (2S)-2-[[5-[methyl-[(2- methyl-4-oxo-1H...

Synonyms: Raltitrexed, SureCN7438, SureCN7439, ZD-16, ICI-D-1694, ...
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Disease relevance of ZD 1694


Psychiatry related information on ZD 1694

  • However, there may be disincentives within certain national health-care systems to the introduction of a more resource-efficient drug such as raltitrexed [6].
  • Toxicity associated with raltitrexed comprised grade 1/2 diarrhoea (31.6% of treatment cycles), nausea (12.4%) and vomiting (8.4%), with no grade 3/4 events; grade 1/2 alopecia (17.9%); grade 1 (only) stomatitis (2.3%) and grade 1/2/3 lethargy (70.3%, only 2.3% grade 3), anaemia (14.3%, only 0.3% grade 3) and neutropenia (3.3%, only 0.3% grade 3) [7].

High impact information on ZD 1694

  • Fluorouracil: active in ZD1694 (tomudex)-resistant cell lines with markedly elevated thymidylate synthase levels [8].
  • (c) Cell growth inhibition studies with MRP5 transfected HEK293 cells showed that MRP5 conferred high-level resistance (>160-fold) against the antifolates MTX, GW1843, and ZD1694 (raltitrexed) in short-term (4 hours) incubations with high drug concentrations; this resistance was proportional to the MRP5 level [9].
  • This suggests that STAT1 regulates expression of gene(s) involved in cell surface trafficking of Fas in response to CPT-11 or tomudex [10].
  • Camptothecin-resistant P388/CPT45 cells lacking Top1 are cross-resistant to FdUMP[10] as well as to FdUMP, FdU, and the thymidylate synthase inhibitor raltitrexed (Tomudex) [11].
  • PATIENTS AND METHODS: Eligible patients with histologically proven advanced MPM, not pretreated with chemotherapy, WHO performance status (PS) 0 to 2, and adequate hematological, renal, and hepatic function were randomly assigned to receive cisplatin 80 mg/m2 IV on day 1, alone (arm A) or combined with raltitrexed 3 mg/m2 (arm B) [12].

Chemical compound and disease context of ZD 1694


Biological context of ZD 1694


Anatomical context of ZD 1694


Associations of ZD 1694 with other chemical compounds


Gene context of ZD 1694

  • The changes in cell cycle regulatory proteins associated with growth inhibition and DNA damage by Tomudex are not p53 dependent [28].
  • Tomudex treatment resulted in the decrease in p27(kip1) expression, with an increase in cyclin E and cdk2 protein expression and kinase activities 24 h after a 2-h exposure [28].
  • The increased abundance of hypophosphorylated pRb and binding to transcription factor E2F-1 is consistent with ZD1694-induced cell growth inhibition in HCT-8 cells [29].
  • In this study, we have demonstrated the dose- and time-dependent induction of DNA fragmentation accompanied by elevation of p53 and WAF1 protein expression by ZD1694 [29].
  • Tomudex belongs to a class of compounds that use the reduced-folate carrier (RFC) for uptake into cells and which are excellent substrates for folylpolyglutamate synthetase (FPGS) [30].

Analytical, diagnostic and therapeutic context of ZD 1694

  • METHODS: Patients who responded or had stable disease after receiving 12 weeks of the regimens described by de Gramont and Lokich, or raltitrexed chemotherapy, were randomised to either intermittent (a break in chemotherapy, re-starting on the same drug on progression), or continuous chemotherapy until progression [31].
  • PATIENTS AND METHODS: From February 1991 to January 1993, 61 patients with a range of solid tumor received 161 courses of ZD1694 given as a single 15-minute intravenous infusion every 3 weeks, at escalating doses from 0.1 to 3.5 mg/m2 [24].
  • D-1694-treated cells detached from the dish within 1-2 days after a megaloblastosis, whereas DDATHF-treated cells remained adherent to the dishes for at least 10 days after treatment [32].
  • L1210 cells that were incubated for 4 h with 0.1 microM 3H-ICI D1694 accumulated approximately 1.5 microM intracellular 3H, and the high performance liquid chromatography analysis of the cell extracts demonstrated that 96% of the 3H was associated with the ICI D1694 polyglutamate fractions (principally glu4) [19].
  • In addition, Tomudex has an acceptable toxicity profile and a convenient dosing schedule (single intravenous injection every 3 weeks) and thus appears to offer real potential as a novel agent for the treatment of patients with advanced CRC [33].


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  9. The human multidrug resistance protein MRP5 transports folates and can mediate cellular resistance against antifolates. Wielinga, P., Hooijberg, J.H., Gunnarsdottir, S., Kathmann, I., Reid, G., Zelcer, N., van der Born, K., de Haas, M., van der Heijden, I., Kaspers, G., Wijnholds, J., Jansen, G., Peters, G., Borst, P. Cancer Res. (2005) [Pubmed]
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  11. A novel polypyrimidine antitumor agent FdUMP[10] induces thymineless death with topoisomerase I-DNA complexes. Liao, Z.Y., Sordet, O., Zhang, H.L., Kohlhagen, G., Antony, S., Gmeiner, W.H., Pommier, Y. Cancer Res. (2005) [Pubmed]
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  18. Overexpression of p21waf1 leads to increased inhibition of E2F-1 phosphorylation and sensitivity to anticancer drugs in retinoblastoma-negative human sarcoma cells. Li, W.W., Fan, J., Hochhauser, D., Bertino, J.R. Cancer Res. (1997) [Pubmed]
  19. ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study. Jackman, A.L., Taylor, G.A., Gibson, W., Kimbell, R., Brown, M., Calvert, A.H., Judson, I.R., Hughes, L.R. Cancer Res. (1991) [Pubmed]
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  21. Identification of 5-fluorouracil-inducible target genes using cDNA microarray profiling. Maxwell, P.J., Longley, D.B., Latif, T., Boyer, J., Allen, W., Lynch, M., McDermott, U., Harkin, D.P., Allegra, C.J., Johnston, P.G. Cancer Res. (2003) [Pubmed]
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  28. Cyclin E-cdk2 activation is associated with cell cycle arrest and inhibition of DNA replication induced by the thymidylate synthase inhibitor Tomudex. Yin, M.B., Guo, B., Panadero, A., Frank, C., Wrzosek, C., Slocum, H.K., Rustum, Y.M. Exp. Cell Res. (1999) [Pubmed]
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