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

• Here we show that, when fed orally, ZD6474 suppressed RET-mediated phenotypes within the context of this in vivo model [1].
• Recently, the low molecular weight tyrosine kinase inhibitor ZD6474 was found to block the enzymatic activity of RET-derived oncoproteins in cultured cell lines [1].
• No correlation was observed between the sensitivity to ZD6474 and the level of EGFR or VEGFR expression [5].
• Here, the ability of gefitinib and ZD6474 to inhibit tumor cell proliferation was examined directly in eight cancer cell lines in vitro, and a strong correlation was noted between the IC(50) values of gefitinib and ZD6474 (r = 0.79) [5].
• ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration [2].

Chemical compound and disease context of Zactima

• 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 [6].
• 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 [7].
• 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 [8].
• ZD6474 in combination with oxaliplatin has synergistic antiproliferative properties in human colorectal cancer cell lines in vitro when oxaliplatin is administered before ZD6474 [9].
• These analyses suggest that low baseline circulating VEGF may be predictive of PFS advantage in patients with advanced non-small cell lung cancer receiving vandetanib versus gefitinib or vandetanib + docetaxel versus docetaxel [10].

Biological context of Zactima

• ZD6474 inhibited the phosphorylation of the mutant EGFR by 10-fold compared with cells with wild-type EGFR [5].
• Thus, targeting RET oncogenes with ZD6474 might offer a potential treatment strategy for carcinomas sustaining oncogenic activation of RET [11].
• A dose-dependent supra-additive effect in growth inhibition and in apoptosis in vitro was observed by the combined treatment with ZD6474 and paclitaxel or docetaxel [12].
• RESULTS: In vitro, ZD6474 dose dependently inhibited cell growth, induced apoptosis, and synergistically enhanced the cytotoxic activity of gemcitabine and ionizing radiation [7].
• PCR analysis showed that ZD6474 increased the ratio between gene expression of deoxycytidine kinase and ribonucleotide reductase [7].

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

• When GEO growth was apparent after 4 weeks of treatment with EGFR inhibitors, mice were either re-treated with EGFR inhibitors or treated with ZD6474 [20].
• We have investigated the antitumor and antiangiogenic effect of ZD6474, an inhibitor of both VEGFR and EGFR signaling as a single agent and in combination with ionizing radiation [21].
• We investigated the activity of ZD6474 in combination with cetuximab, an anti-EGFR blocking monoclonal antibody, to determine the anti-tumor activity of EGFR blockade through the combined use of two agents targeting the receptor at different molecular sites in cancer cells and of VEGFR-2 blockade in endothelial cells [22].
• These results indicate that ZD6474, an inhibitor of VEGFR-2, may be useful in controlling the growth of established lung metastasis and pleural effusions by NSCLC [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 [23].
• Vandetanib induced a significant increase in circulating VEGF and decrease in circulating VEGFR levels [24].

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].

References