The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
Chemical Compound Review

Caprelsa     N-(4-bromo-2-fluoro-phenyl)- 6-methoxy-7...

Synonyms: Zactima, Vandetanib, QCR-37, GNF-PF-2188, AC1MIWRU, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of Zactima

  • Our results support the view that targeting chemical kinase inhibitors such as ZD6474 to tissues with oncogenic forms of RET is a useful treatment strategy for RET-dependent carcinomas [1].
  • Importantly, ZD6474 showed high efficacy and very low toxicity [1].
  • ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma [1].
  • Once-daily oral administration of ZD6474 to growing rats for 14 days produced a dose-dependent increase in the femoro-tibial epiphyseal growth plate zone of hypertrophy, which is consistent with inhibition of VEGF signaling and angiogenesis in vivo [2].
  • Selective inhibition of VEGF signaling has been demonstrated in vivo in a growth factor-induced hypotension model in anesthetized rat: administration of ZD6474 (2.5 mg/kg, i.v.) reversed a hypotensive change induced by VEGF (by 63%) but did not significantly affect that induced by basic fibroblast growth factor [2].
  • Vandetanib suppressed phosphorylation of VEGFR-2 in HUVECs and EGFR in hepatoma cells and inhibited cell proliferation [3].
  • Given the toxicity profile, which includes prolongation of the QT interval and sudden death, only prescribers and pharmacies certified through the vandetanib Risk Evaluation Mitigation Strategy Program are able to prescribe and dispense vandetanib [4].

High impact information on Zactima


Chemical compound and disease context of Zactima


Biological context of Zactima


Anatomical context of Zactima

  • Histological analysis of Calu-6 tumors treated with 50 mg/kg/day ZD6474 for 24 days showed a significant reduction (>70%) in CD31 (endothelial cell) staining in nonnecrotic regions [2].
  • Daily oral treatment with ZD6474 (50 mg/kg), started on day 14 (after the establishment of micrometastases), significantly reduced the frequency of large (>3 mm) metastatic colonies (in the liver and lymph nodes) and osteolytic bone lesions [13].
  • RESULTS: ZD6474 causes a dose-dependent inhibition of EGFR phosphorylation in mouse NIH-EGFR fibroblasts and human MCF-10A ras breast cancer cells, two cell lines that overexpress the human EGFR [12].
  • ZD6474 (100 mg/kg/day, p.o., 2 weeks) significantly inhibited tumor growth (p < 0.05 vs. control) and reduced tumor dissemination into the peritoneal cavity (p < 0.05 vs. control) [14].
  • Analysis of putative ZD6474 metabolites in feces found four, with the N-demethyl-piperidinyl-ZD6474 metabolite being the most prominent but still accounting for less than 2% of the total amount of ZD6474 present [15].

Associations of Zactima with other chemical compounds

  • Here, we show that ZD6474, a low molecular weight tyrosine kinase inhibitor, blocks the enzymatic activity of RET-derived oncoproteins at a one-half maximal inhibitory concentration of 100 nM [11].
  • Substitution of valine 804 with the small amino- acid glycine renders the RET kinase even more susceptible to inhibition (ZD6474 IC(50): 20 nM) than the wild-type kinase [16].
  • We have recently demonstrated that the pyrazolopyrimidines PP1 and PP2 and the 4-anilinoquinazoline ZD6474 display a strong inhibitory activity (IC(50)< or =100 nM) towards constitutively active oncogenic RET kinases [16].
  • These include monoclonal antibodies, such as panitumumab and matuzumab; dual inhibitors of EGFR and vascular endothelial growth factor receptor, such as ZD6474 and AEE788; inhibitors of multiple EGFR family members, such as lapatinib; and irreversible inhibitors, such as canertinib and HKI272 [17].
  • In the other two trials, the efficacy of ZD6474 in combination with certain standard chemotherapy regimens is being compared with that of standard chemotherapy alone: one with carboplatin and paclitaxel in previously untreated patients, and the second with docetaxel in patients who progressed after platinum-containing therapy [18].
  • Tumor concentrations of vandetanib were increased by irinotecan in the concurrent schedule, possibly due to decreased tumor perfusion in this group [19].

Gene context of Zactima


Analytical, diagnostic and therapeutic context of Zactima

  • ZD6474 also restrained growth of much larger (0.9 cm(3) volume) Calu-6 lung tumor xenografts and induced profound regression in established PC-3 prostate tumors of 1.4 cm(3) volume [2].
  • A cooperative and long-lasting inhibition of tumor growth was obtained with ZD6474 in combination with concomitant radiotherapy [21].
  • Our present findings thus suggest that castration + ZD6474 could be a particularly effective way to treat prostate tumors [25].
  • After treatment with ZD6474 (100 mg/kg), CE-MRI failed to detect tumors in either prevention or therapeutic treatment regimens [26].
  • RESULTS: In comparison with orchiectomy, ZD6474 treatment produced greater tumor growth inhibition (P < 0.001), inducing complete cytostasis for the duration of dosing [27].


  1. ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma. Vidal, M., Wells, S., Ryan, A., Cagan, R. Cancer Res. (2005) [Pubmed]
  2. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Wedge, S.R., Ogilvie, D.J., Dukes, M., Kendrew, J., Chester, R., Jackson, J.A., Boffey, S.J., Valentine, P.J., Curwen, J.O., Musgrove, H.L., Graham, G.A., Hughes, G.D., Thomas, A.P., Stokes, E.S., Curry, B., Richmond, G.H., Wadsworth, P.F., Bigley, A.L., Hennequin, L.F. Cancer Res. (2002) [Pubmed]
  3. Vandetanib, an inhibitor of VEGF receptor-2 and EGF receptor, suppresses tumor development and improves prognosis of liver cancer in mice. Inoue, K., Torimura, T., Nakamura, T., Iwamoto, H., Masuda, H., Abe, M., Hashimoto, O., Koga, H., Ueno, T., Yano, H., Sata, M. Clin. Cancer Res. (2012) [Pubmed]
  4. Vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease: u.s. Food and drug administration drug approval summary. Thornton, K., Kim, G., Maher, V.E., Chattopadhyay, S., Tang, S., Moon, Y.J., Song, P., Marathe, A., Balakrishnan, S., Zhu, H., Garnett, C., Liu, Q., Booth, B., Gehrke, B., Dorsam, R., Verbois, L., Ghosh, D., Wilson, W., Duan, J., Sarker, H., Miksinski, S.P., Skarupa, L., Ibrahim, A., Justice, R., Murgo, A., Pazdur, R. Clin. Cancer Res. (2012) [Pubmed]
  5. Small in-frame deletion in the epidermal growth factor receptor as a target for ZD6474. Arao, T., Fukumoto, H., Takeda, M., Tamura, T., Saijo, N., Nishio, K. Cancer Res. (2004) [Pubmed]
  6. A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Miller, K.D., Trigo, J.M., Wheeler, C., Barge, A., Rowbottom, J., Sledge, G., Baselga, J. Clin. Cancer Res. (2005) [Pubmed]
  7. Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer. Bianco, C., Giovannetti, E., Ciardiello, F., Mey, V., Nannizzi, S., Tortora, G., Troiani, T., Pasqualetti, F., Eckhardt, G., de Liguoro, M., Ricciardi, S., Del Tacca, M., Raben, D., Cionini, L., Danesi, R. Clin. Cancer Res. (2006) [Pubmed]
  8. Prolonged exposure of colon cancer cells to the epidermal growth factor receptor inhibitor gefitinib (Iressa(TM)) and to the antiangiogenic agent ZD6474: Cytotoxic and biomolecular effects. Azzariti, A., Porcelli, L., Xu, J.M., Simone, G.M., Paradiso, A. World J. Gastroenterol. (2006) [Pubmed]
  9. Sequence-dependent inhibition of human colon cancer cell growth and of prosurvival pathways by oxaliplatin in combination with ZD6474 (Zactima), an inhibitor of VEGFR and EGFR tyrosine kinases. Troiani, T., Lockerbie, O., Morrow, M., Ciardiello, F., Eckhardt, S.G. Mol. Cancer Ther. (2006) [Pubmed]
  10. Baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from vandetanib in non-small cell lung cancer. Hanrahan, E.O., Ryan, A.J., Mann, H., Kennedy, S.J., Langmuir, P., Natale, R.B., Herbst, R.S., Johnson, B.E., Heymach, J.V. Clin. Cancer Res. (2009) [Pubmed]
  11. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Carlomagno, F., Vitagliano, D., Guida, T., Ciardiello, F., Tortora, G., Vecchio, G., Ryan, A.J., Fontanini, G., Fusco, A., Santoro, M. Cancer Res. (2002) [Pubmed]
  12. Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Ciardiello, F., Caputo, R., Damiano, V., Caputo, R., Troiani, T., Vitagliano, D., Carlomagno, F., Veneziani, B.M., Fontanini, G., Bianco, A.R., Tortora, G. Clin. Cancer Res. (2003) [Pubmed]
  13. Antitumor vascular strategy for controlling experimental metastatic spread of human small-cell lung cancer cells with ZD6474 in natural killer cell-depleted severe combined immunodeficient mice. Yano, S., Muguruma, H., Matsumori, Y., Goto, H., Nakataki, E., Edakuni, N., Tomimoto, H., Kakiuchi, S., Yamamoto, A., Uehara, H., Ryan, A., Sone, S. Clin. Cancer Res. (2005) [Pubmed]
  14. ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model. Arao, T., Yanagihara, K., Takigahira, M., Takeda, M., Koizumi, F., Shiratori, Y., Nishio, K. Int. J. Cancer (2006) [Pubmed]
  15. Tissue distribution and metabolism of the tyrosine kinase inhibitor ZD6474 (Zactima) in tumor-bearing nude mice following oral dosing. Gustafson, D.L., Bradshaw-Pierce, E.L., Merz, A.L., Zirrolli, J.A. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  16. Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Carlomagno, F., Guida, T., Anaganti, S., Vecchio, G., Fusco, A., Ryan, A.J., Billaud, M., Santoro, M. Oncogene (2004) [Pubmed]
  17. Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. Heymach, J.V., Nilsson, M., Blumenschein, G., Papadimitrakopoulou, V., Herbst, R. Clin. Cancer Res. (2006) [Pubmed]
  18. ZD6474--clinical experience to date. Heymach, J.V. Br. J. Cancer (2005) [Pubmed]
  19. Investigation of two dosing schedules of vandetanib (ZD6474), an inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling, in combination with irinotecan in a human colon cancer xenograft model. Troiani, T., Serkova, N.J., Gustafson, D.L., Henthorn, T.K., Lockerbie, O., Merz, A., Long, M., Morrow, M., Ciardiello, F., Eckhardt, S.G. Clin. Cancer Res. (2007) [Pubmed]
  20. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Ciardiello, F., Bianco, R., Caputo, R., Caputo, R., Damiano, V., Troiani, T., Melisi, D., De Vita, F., De Placido, S., Bianco, A.R., Tortora, G. Clin. Cancer Res. (2004) [Pubmed]
  21. Cooperative antitumor effect of multitargeted kinase inhibitor ZD6474 and ionizing radiation in glioblastoma. Damiano, V., Melisi, D., Bianco, C., Raben, D., Caputo, R., Fontanini, G., Bianco, R., Ryan, A., Bianco, A.R., De Placido, S., Ciardiello, F., Tortora, G. Clin. Cancer Res. (2005) [Pubmed]
  22. Anti-tumor activity of the combination of cetuximab, an anti-EGFR blocking monoclonal antibody and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases. Morelli, M.P., Cascone, T., Troiani, T., Tuccillo, C., Bianco, R., Normanno, N., Romano, M., Veneziani, B.M., Fontanini, G., Eckhardt, S.G., De Pacido, S., Tortora, G., Ciardiello, F. J. Cell. Physiol. (2006) [Pubmed]
  23. ZD6474, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, inhibits growth of experimental lung metastasis and production of malignant pleural effusions in a non-small cell lung cancer model. Matsumori, Y., Yano, S., Goto, H., Nakataki, E., Wedge, S.R., Ryan, A.J., Sone, S. Oncol. Res. (2006) [Pubmed]
  24. Vandetanib in patients with inoperable hepatocellular carcinoma: A phase II, randomized, double-blind, placebo-controlled study. Hsu, C., Yang, T.S., Huo, T.I., Hsieh, R.K., Yu, C.W., Hwang, W.S., Hsieh, T.Y., Huang, W.T., Chao, Y., Meng, R., Cheng, A.L. J. Hepatol. (2012) [Pubmed]
  25. Inhibitory effects of castration in an orthotopic model of androgen-independent prostate cancer can be mimicked and enhanced by angiogenesis inhibition. Hammarsten, P., Halin, S., Wikst??m, P., Henriksson, R., Rudolfsson, S.H., Bergh, A. Clin. Cancer Res. (2006) [Pubmed]
  26. Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Leenders, W.P., Küsters, B., Verrijp, K., Maass, C., Wesseling, P., Heerschap, A., Ruiter, D., Ryan, A., de Waal, R. Clin. Cancer Res. (2004) [Pubmed]
  27. Combination antiangiogenic and androgen deprivation therapy for prostate cancer: a promising therapeutic approach. Nicholson, B., Gulding, K., Conaway, M., Wedge, S.R., Theodorescu, D. Clin. Cancer Res. (2004) [Pubmed]
WikiGenes - Universities