Abstract
The proangiogenic vascular endothelial growth factor-A (VEGF) is essential for the development of new tumor vessels. ZD6474 is a novel inhibitor of VEGF receptor-2 (VEGFR-2) tyrosine kinase activity, which also has additional activity against epidermal growth factor (EGF) receptor tyrosine kinase. The antitumor activity of different schedules of ZD6474 in a clinically relevant, metastasizing, murine renal cell carcinoma (RENCA) model was evaluated in this study. RENCA cells were inoculated into the left kidney of 24 mice (day 0). Daily ZD6474 (50 mg/kg p.o.) treatment was initiated 1 day or 10 days after tumor cell inoculation and continued until day 21. Following treatment, kidney weight and volume were assessed and blood vessel density determined by CD31 staining. Visible metastases in the lungs, spleen, and lymph nodes were quantified using a dissection microscope. In an additional study, animals were treated according to the same regimen and quantitative three-dimensional microvascular corrosion casting was performed to enable detailed assessment of the tumor vascular architecture. Therapy initiated on day 1 or day 10 resulted in a 79% and 59% reduction in primary tumor volume, a 79% and 60% reduction in the number of lung metastases, and a 58% and 59% reduction in vessel density of primary tumors compared with the control group, respectively. Corrosion casting proved a 5.4- and 3.2-fold lower vascular volume compared with untreated tumors, observations that paralleled with significant architectural alterations. In this RENCA model, ZD6474 was a highly active inhibitor of tumor angiogenesis, primary tumor growth and tumor metastasis.
Similar content being viewed by others
Abbreviations
- EGF:
-
epidermal growth factor
- EGFR:
-
EGF receptor
- i.p.:
-
intra-peritoneum
- KOH:
-
potassium hydroxide
- MEC:
-
microvascular endothelial cell
- p.o.:
-
per os
- PBS:
-
phosphate-buffered saline
- PECAM-1:
-
platelet/endothelial cell adhesion molecule-1
- SEM:
-
standard error of mean
- VEGF:
-
vascular endothelial growth factor-A
- VEGFR-2:
-
VEGF receptor-2
References
P Carmeliet (2003) ArticleTitleAngiogenesis in health and disease Nat Med 9 653–60 Occurrence Handle10.1038/nm0603-653 Occurrence Handle1:CAS:528:DC%2BD3sXktFOntbY%3D Occurrence Handle12778163
LM Ellis W Liu F Fan et al. (2001) ArticleTitleRole of angiogenesis inhibitors in cancer treatment Oncology (Huntingt) 15 39–46 Occurrence Handle1:STN:280:DC%2BD3MvltFGmtQ%3D%3D
J Drevs C Laus M Mendinger et al. (2002) ArticleTitleAntiangiogenesis: Current clinical data and future perspectives Onkologie 25 520–7 Occurrence Handle10.1159/000068622 Occurrence Handle1:STN:280:DC%2BD3s%2Fls1KltQ%3D%3D Occurrence Handle12566896
N Ferrara HP Gerber J LeCouter (2003) ArticleTitleThe biology of VEGF and its receptors Nat Med 9 669–76 Occurrence Handle1:CAS:528:DC%2BD3sXktFOnur4%3D Occurrence Handle12778165
RK Jain (2003) ArticleTitleMolecular regulation of vessel maturation Nat Med 9 685–93 Occurrence Handle10.1038/nm0603-685 Occurrence Handle1:CAS:528:DC%2BD3sXktFOnurw%3D Occurrence Handle12778167
SR Wedge DJ Ogilvie M Dukes et al. (2002) ArticleTitleZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration Cancer Res 62 4645–55 Occurrence Handle1:CAS:528:DC%2BD38XmsVShsL8%3D Occurrence Handle12183421
H Hurwitz L Fehrenbacher W Novotny et al. (2004) ArticleTitleBevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer N Engl J Med 350 2335–42 Occurrence Handle10.1056/NEJMoa032691 Occurrence Handle1:CAS:528:DC%2BD2cXks1Gjt74%3D Occurrence Handle15175435
F Ciardiello R Caputo V Damiano et al. (2003) ArticleTitleAntitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase Clin Cancer Res 9 1546–56 Occurrence Handle1:CAS:528:DC%2BD3sXislerur8%3D Occurrence Handle12684431
J Drevs R Muller-Driver C Wittig et al. (2002) ArticleTitlePTK787/ZK 222584, a specific vascular endothelial growth factor-receptor tyrosine kinase inhibitor, affects the anatomy of the tumor vascular bed and the functional vascular properties as detected by dynamic enhanced magnetic resonance imaging Cancer Res 62 4015–22 Occurrence Handle1:CAS:528:DC%2BD38XlsV2lsLg%3D Occurrence Handle12124335
T Takeuchi T Ueki Y Sasaki et al. (1997) ArticleTitleTh2-like response and antitumor effect of anti-interleukin-4 mAb in mice bearing renal cell carcinoma Cancer Immunol Immunother 43 375–81 Occurrence Handle10.1007/s002620050347 Occurrence Handle1:CAS:528:DyaK2sXisVeitrw%3D Occurrence Handle9067410
H Nishimatsu T Takeuchi T Ueki et al. (1999) ArticleTitleCD95 ligand expression enhances growth of murine renal cell carcinoma in vivo Cancer Immunol Immunother 48 56–61 Occurrence Handle10.1007/s002620050548 Occurrence Handle1:CAS:528:DyaK1MXjtlaksLw%3D Occurrence Handle10235489
W Malkusch MA Konerding B Klapthor J Bruch (1995) ArticleTitleA simple and accurate method for 3-D measurements in microcorrosion casts illustrated with tumour vascularization Anal Cell Pathol 9 69–81 Occurrence Handle1:STN:280:BymD38%2Fht1w%3D Occurrence Handle7577757
CJ Bruns G Kohl M Guba et al. (2003) ArticleTitleAnti-angiogenic and anti-tumor activity of a novel VEGFR-2 tyrosine kinase inhibitor ZD6474 in a metastatic human pancreatic tumor model Proc Am Assoc Cancer Res 44 604
F Ciardiello R Bianco R Caputo et al. (2004) ArticleTitleAntitumor 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 Clin Cancer Res 10 784–93 Occurrence Handle1:CAS:528:DC%2BD2cXovVKitw%3D%3D Occurrence Handle14760102
MA Konerding E Fait A Gaumann (2001) ArticleTitle3D microvascular architecture of pre-cancerous lesions and invasive carcinomas of the colon Br J Cancer 84 1354–62 Occurrence Handle10.1054/bjoc.2001.1809 Occurrence Handle1:STN:280:DC%2BD3M3msVWmuw%3D%3D Occurrence Handle11355947
MA Konerding W Malkusch B Klapthor et al. (1999) ArticleTitleEvidence for characteristic vascular patterns in solid tumours: quantitative studies using corrosion casts Br J Cancer 80 724–32 Occurrence Handle10.1038/sj.bjc.6690416 Occurrence Handle1:STN:280:DyaK1M3osleqtw%3D%3D Occurrence Handle10360650
Author information
Authors and Affiliations
Corresponding author
Additional information
Both authors have contributed equally to this work.
Rights and permissions
About this article
Cite this article
Drevs, J., Konerding, M., Wolloscheck, T. et al. The VEGF receptor tyrosine kinase inhibitor, ZD6474, inhibits angiogenesis and affects microvascular architecture within an orthotopically implanted renal cell carcinoma. Angiogenesis 7, 347–354 (2004). https://doi.org/10.1007/s10456-005-1394-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10456-005-1394-3