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Chemical Compound Review

Vamidex     (2S)-2-[[4-[(2,7-dimethyl-4- oxo-1H...

Synonyms: Plevitrexed, CHEMBL126648, AG-K-40617, BGC9331, ZD-9331, ...
 
 
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Disease relevance of Plevitrexed

  • CONCLUSION: DLTs in this phase I study of oral ZD9331 were myelosuppression and skin toxicity [1].
  • Minor response (40% shrinkage of tumor) was observed in one patient with colorectal cancer treated at 12 mg/m(2)/d. CONCLUSION: The recommended dose for ZD9331 on this schedule is 25 mg/d. Neutropenia, thrombocytopenia, and rash were dose-limiting, and efficacy studies in colorectal cancer are indicated [2].
  • Interferon-gamma-induced sensitization of colon carcinomas to ZD9331 targets caspases, downstream of Fas, independent of mitochondrial signaling and the inhibitor of apoptosis survivin [3].
  • Since five of six patients treated at the ZD9331/docetaxel dose-level of 260/60 mg/m(2) had grade 4 neutropenia that was brief and uncomplicated in the first course, a rigorous exploration of higher dose levels was not undertaken [4].
  • These results suggest that, in pancreatic cancer, ZD9331 is equivalent to gemcitabine and may offer a promising alternative to current therapies [5].
 

High impact information on Plevitrexed

  • The ex vivo potency of several antifolates (MTX, trimetrexate [TMQ], GW1843U89, multitargeted antifolate [MTA], Raltitrexed, and ZD9331) was studied via in situ inhibition of thymidylate synthase (TS) [6].
  • The RFC-mediated thymidylate synthase inhibitor plevitrexed also increased uptake of [(125)I]dUrd in tumor (10-fold) but, in contrast, also caused increased incorporation in other normal tissues such as spleen and small bowel (4.5- and 4.6-fold, respectively) [7].
  • HCT116 wild-type (wt) and p53-/- cells underwent apoptosis and loss in clonogenic survival when exposed to ZD9331, whereas p21Cip1-/- cells were resistant [8].
  • Finally, the CDK inhibitor roscovitine potentiated the cytotoxic activity of ZD9331 in both wt and p21Cip1-/- cells, strongly suggesting a role for p21Cip1-dependent CDK inhibition in cytotoxicity induced by thymidylate synthase inhibition [8].
  • Cell cycle analyses revealed that HCT116 wt and p21Cip1 -/- cells accumulated in S phase within 24 h of ZD9331 exposure; however, wt cells exited S-phase more rapidly, where apoptosis occurred before mitosis, either in late S or G2 [8].
 

Chemical compound and disease context of Plevitrexed

 

Biological context of Plevitrexed

  • PURPOSE: To assess the toxicity profile and dose-limiting toxicities (DLTs), to determine the maximum-tolerated dose, and to study the pharmacokinetics of ZD9331 when administered orally to patients with advanced solid tumors [1].
  • To gain an understanding of the relationship between the pharmacokinetics of ZD9331 and antitumor activity perturbations in tumor, dTTP and dUMP concentrations were also determined [10].
  • ZD9331 exhibits potent growth inhibitory and cytotoxic activity; e.g., IC50 for the inhibition of human W1L2 lymphoblastoid cell line was 7 nM [11].
  • Up-regulation of TS protein showed a time-, dose-, and cell-type-specific response to treatment with ZD9331 [12].
  • However, reduction in the survivin:Fas ratio by transfection of survivin small interfering RNA and/or overexpression of Fas did not affect sensitivity of HT29 to ZD9331 +/- IFN-gamma [3].
 

Anatomical context of Plevitrexed

 

Associations of Plevitrexed with other chemical compounds

 

Gene context of Plevitrexed

  • Resistance to continuous exposure to ZD9331 was caused by a 14-fold increase in TS activity [17].
  • These results demonstrate that continuous exposure of the cells to ZD9331 leads not only to a decreased expression of RFC1 but also to TS gene amplification and overexpression [18].
  • The four ovarian and one colon cell line that were relatively more sensitive to ZD9331 expressed FPGS mRNA<or=median (p=0.061) [19].
  • Pharmacokinetic/pharmacodynamic study of ZD9331, a nonpolyglutamatable inhibitor of thymidylate synthase, in a murine model following two curative administration schedules [10].
  • However, IFN-gamma alone (but not ZD9331) up-regulated the expression of caspases -3, -4, -7, and -8, and in combination with ZD9331 demonstrated enhanced caspase activation and cleavage of poly(ADP-ribose) polymerase that was not prevented by overexpression of Bcl-2 [3].
 

Analytical, diagnostic and therapeutic context of Plevitrexed

References

  1. Phase I and pharmacologic study of oral ZD9331, a novel nonpolyglutamated thymidylate synthase inhibitor, in adult patients with solid tumors. de Jonge, M.J., Punt, C.J., Sparreboom, A., Planting, A.S., Peters, M.E., van De Schraaf, J., Jackman, A., Smith, R., de Mulder, P.H., Verweij, J. J. Clin. Oncol. (2002) [Pubmed]
  2. Phase I study of ZD9331 on short daily intravenous bolus infusion for 5 days every 3 weeks with fixed dosing recommendations. Goh, B.C., Ratain, M.J., Bertucci, D., Smith, R., Mani, S., Vogelzang, N.J., Schilsky, R.L., Hutchison, M., Smith, M., Averbuch, S., Douglass, E. J. Clin. Oncol. (2001) [Pubmed]
  3. Interferon-gamma-induced sensitization of colon carcinomas to ZD9331 targets caspases, downstream of Fas, independent of mitochondrial signaling and the inhibitor of apoptosis survivin. Geller, J., Petak, I., Szucs, K.S., Nagy, K., Tillman, D.M., Houghton, J.A. Clin. Cancer Res. (2003) [Pubmed]
  4. A phase I and pharmacokinetic study of the nonpolyglutamatable thymidylate synthase inhibitor ZD9331 plus docetaxel in patients with advanced solid malignancies. Schwartz, G.H., Jones, C.B., Garrison, M., Patnaik, A., Takimoto, C., McCreery, H., Skinner, M., Tolcher, A.W., Rowinsky, E.K. Investigational new drugs. (2004) [Pubmed]
  5. A phase II/III study comparing intravenous ZD9331 with gemcitabine in patients with pancreatic cancer. Smith, D., Gallagher, N. Eur. J. Cancer (2003) [Pubmed]
  6. Circumvention of methotrexate resistance in childhood leukemia subtypes by rationally designed antifolates. Rots, M.G., Pieters, R., Peters, G.J., van Zantwijk, C.H., Mauritz, R., Noordhuis, P., Willey, J.C., Hählen, K., Creutzig, U., Janka-Schaub, G., Kaspers, G.J., Veerman, A.J., Jansen, G. Blood (1999) [Pubmed]
  7. BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to alpha-folate receptor-overexpressing tumors. Gibbs, D.D., Theti, D.S., Wood, N., Green, M., Raynaud, F., Valenti, M., Forster, M.D., Mitchell, F., Bavetsias, V., Henderson, E., Jackman, A.L. Cancer Res. (2005) [Pubmed]
  8. P21Cip1 is a critical mediator of the cytotoxic action of thymidylate synthase inhibitors in colorectal carcinoma cells. Geller, J.I., Szekely-Szucs, K., Petak, I., Doyle, B., Houghton, J.A. Cancer Res. (2004) [Pubmed]
  9. Phase I trial of the antifolate ZD9331 in combination with cisplatin in patients with refractory solid malignancies. Bilenker, J.H., Stevenson, J.P., Flaherty, K.T., Algazy, K., McLaughlin, K., Haller, D.G., Giantonio, B.J., Koehler, M., Garcia-Vargas, J.E., O'Dwyer, P.J. Cancer Chemother. Pharmacol. (2004) [Pubmed]
  10. Pharmacokinetic/pharmacodynamic study of ZD9331, a nonpolyglutamatable inhibitor of thymidylate synthase, in a murine model following two curative administration schedules. Aherne, G.W., Hardcastle, A., Ward, E., Dobinson, D., Crompton, T., Valenti, M., Brunton, L., Jackman, A.L. Clin. Cancer Res. (2001) [Pubmed]
  11. Cellular pharmacology and in vivo activity of a new anticancer agent, ZD9331: a water-soluble, nonpolyglutamatable, quinazoline-based inhibitor of thymidylate synthase. Jackman, A.L., Kimbell, R., Aherne, G.W., Brunton, L., Jansen, G., Stephens, T.C., Smith, M.N., Wardleworth, J.M., Boyle, F.T. Clin. Cancer Res. (1997) [Pubmed]
  12. Comparison of thymidylate synthase (TS) protein up-regulation after exposure to TS inhibitors in normal and tumor cell lines and tissues. Welsh, S.J., Titley, J., Brunton, L., Valenti, M., Monaghan, P., Jackman, A.L., Aherne, G.W. Clin. Cancer Res. (2000) [Pubmed]
  13. 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]
  14. The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition. Webley, S.D., Welsh, S.J., Jackman, A.L., Aherne, G.W. Br. J. Cancer (2001) [Pubmed]
  15. Phase I trial of ZD9331, a nonpolyglutamatable thymidylate synthase inhibitor, given as a 5-day continuous infusion to patients with refractory solid malignancies. Rees, C., Beale, P., Trigo, J.M., Mitchell, F., Jackman, A., Smith, R., Douglass, E., Judson, I. Clin. Cancer Res. (2003) [Pubmed]
  16. Downstream molecular determinants of response to 5-fluorouracil and antifolate thymidylate synthase inhibitors. Van Triest, B., Pinedo, H.M., Giaccone, G., Peters, G.J. Ann. Oncol. (2000) [Pubmed]
  17. Multiple mechanisms of resistance to methotrexate and novel antifolates in human CCRF-CEM leukemia cells and their implications for folate homeostasis. Mauritz, R., Peters, G.J., Priest, D.G., Assaraf, Y.G., Drori, S., Kathmann, I., Noordhuis, P., Bunni, M.A., Rosowsky, A., Schornagel, J.H., Pinedo, H.M., Jansen, G. Biochem. Pharmacol. (2002) [Pubmed]
  18. Molecular characterization of human acute leukemia cell line resistant to ZD9331, a non-polyglutamatable thymidylate synthase inhibitor. Kobayashi, H., Takemura, Y., Miyachi, H. Cancer Chemother. Pharmacol. (1998) [Pubmed]
  19. A rationale for the clinical development of the thymidylate synthase inhibitor ZD9331 in ovarian and other solid tumours. Jackman, A.L., Melin, C.J., Kimbell, R., Brunton, L., Aherne, G.W., Theti, D.S., Walton, M. Biochim. Biophys. Acta (2002) [Pubmed]
  20. A phase II study to determine the efficacy and tolerability of intravenous ZD9331 in heavily pretreated patients with ovarian cancer. Rader, J.S., Clarke-Pearson, D., Moore, M., Carson, L., Holloway, R., Kao, M.S., Wiznitzer, I., Douglass, E.C. Gynecol. Oncol. (2003) [Pubmed]
  21. Phase II multicentre trial of ZD9331 monotherapy as first-line treatment for gastric cancer. Petruzelka, L. Anticancer Drugs (2003) [Pubmed]
 
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