Skip to main content

Advertisement

SpringerLink
Log in

Angiozyme: A Novel angiogenesis inhibitor

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Several inhibitors of angiogenesis are being developed for the treatment of cancer. One dominant strategy involves disruption of the vascular endothelial growth factor (VEGF) pathway by inhibition of the receptors for VEGF. Inhibition of the VEGF receptor activity can be accomplished using catalytic RNA molecules known as ribozymes, which downregulate VEGF receptor function by specifically cleaving the mRNAs for the primary VEGF receptors, Flt-1 and KDR. Significant inhibition of angiogenesis using ribozymes against both receptors has been demonstrated. In animal tumor models, antitumor effects are most pronounced with the anti-Flt-1 ribozyme known as Angiozyme (Ribozyme Pharmaceuticals, Boulder, CO). Extensive preclinical studies have demonstrated no significant toxicities. Clinical trials of Angiozyme are currently in progress for patients with advanced malignancy. Preliminary results demonstrate Angiozyme to be well tolerated, without significant side effects. Several phase II trials are underway for patients with advanced malignancy to test therapeutic efficacy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971, 285:1182–1186.

    Article  PubMed  CAS  Google Scholar 

  2. Ohta Y, Tomita Y, Oda M, et al.: Tumor angiogenesis and recurrence in stage I non-small cell lung cancer. Ann Thorac Surg 1999, 68:1034–1038.

    Article  PubMed  CAS  Google Scholar 

  3. Linderholm B, Grankvist K, Wilking N, et al.: Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. J Clin Oncol 2000, 18:1423–1431. This clinical study demonstrates the importance of VEGF as an independent prognostic marker for node-positive breast cancer.

    PubMed  CAS  Google Scholar 

  4. Imoto H, Osaki T, Taga S, et al.: Vascular endothelial growth factor expression in non-small-cell lung cancer: prognostic significance in squamous cell carcinoma. J Thorac Cardiovasc Surg 1998, 115:1007–10014.

    Article  PubMed  CAS  Google Scholar 

  5. Jacobsen J, Rasmuson T, Grankvist K, et al.: Vascular endothelial growth factor as prognostic factor in renal cell carcinoma. J Urol 2000, 163:343–347.

    Article  PubMed  CAS  Google Scholar 

  6. Ferrara N, Alitalo K: Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 1999, 5:1359–1364. Concise review of the multiple roles for manipulation of the VEGF pathway in experimental therapeutics for many human diseases.

    Article  PubMed  CAS  Google Scholar 

  7. Antiangiogenesis Information [database online]. Bethesda, MD: National Cancer Institute; 2000. Available at http:// cancertrials.nci.nih.gov/news/angio/index.htm Updated summary of the ongoing clinical trials for angiogenesis inhibitors for cancer therapy, accessible via the Internet.

  8. Beckner ME: Factors promoting tumor angiogenesis. Cancer Invest 1999, 17:594–623. Excellent summary of the multiple factors interacting to influence the process of angiogenesis.

    Article  PubMed  CAS  Google Scholar 

  9. Pavco PA, Bouhana KS, Gallegos AM, et al.: Antitumor and antimetastatic activity of ribozymes targeting the messenger RNA of vascular endothelial growth factor receptors. Clin Cancer Res 2000, 6:2094–2103.

    PubMed  CAS  Google Scholar 

  10. Senger DR, Galli SJ, Dvorak AM, et al.: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983, 219:983–985.

    Article  PubMed  CAS  Google Scholar 

  11. Leung DW, Cachianes G, Kuang WJ, et al.: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989, 246:1306–1309.

    Article  PubMed  CAS  Google Scholar 

  12. Shibuya M: Role of VEGF-flt receptor system in normal and tumor angiogenesis. Adv Cancer Res 1995, 67:281–316.

    Article  PubMed  CAS  Google Scholar 

  13. Ellis LM, Takahashi Y, Liu W, Shaeen RM: Vascular endothelial growth factor in human colon cancer: biology and therapeutic implications. Oncologist 2000, 5(suppl 1):11–15.

    Article  PubMed  CAS  Google Scholar 

  14. Benjamin LE, Golijanin D, Itin A, et al.: Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 1999, 103:159–165.

    PubMed  CAS  Google Scholar 

  15. Jakeman LB, Winer J, Bennett GL, et al.: Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest 1992, 89:244–253.

    PubMed  CAS  Google Scholar 

  16. Neufeld G, Cohen T, Gebrinovtch S, Poltorak Z: Vascular endothelial growth factor (VEGF) and its receptors. Faseb J 1999, 13:9–22.

    PubMed  CAS  Google Scholar 

  17. Gabrilovich D, Ishida T, Oyama T, et al.: Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998, 92:4150–4166. This article highlights the potential importance of VEGF as an immunosuppressive agent in cancer biology.

    PubMed  CAS  Google Scholar 

  18. Speirs V, Atkin SL: Production of VEGF and expression of the VEGF receptors Flt-1 and KDR in primary cultures of epithelial and stromal cells derived from breast tumours. Br J Cancer 1999, 80:898–903.

    Article  PubMed  CAS  Google Scholar 

  19. Decaussin M, Sartelet H, Robert C, et al.: Expression of vascular endothelial growth factor (VEGF) and its two receptors (VEGF-R1-Flt1 and VEGF-R2-Flk1/KDR) in non-small cell lung carcinomas (NSCLCs): correlation with angiogenesis and survival. J Pathol 1999, 188:369–377.

    Article  PubMed  CAS  Google Scholar 

  20. Liu B, Earl HM, Baban D, et al.: Melanoma cell lines express VEGF receptor KDR and respond to exogenously added VEGF. Biochem Biophys Res Commun 1995, 217:721–727.

    Article  PubMed  CAS  Google Scholar 

  21. Shalaby F, Ho J, Standford WL, et al.: A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell 1997, 89:981–990.

    Article  PubMed  CAS  Google Scholar 

  22. Fong GH, Rossant J, Gertsenstein M, Breitman ML: Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995, 376:66–70.

    Article  PubMed  CAS  Google Scholar 

  23. Barleon B, Siemeister G, Martiny-Baron G, et al.: Vascular endothelial growth factor up-regulates its receptor fms-like tyrosine kinase 1 (FLT-1) and a soluble variant of FLT-1 in human vascular endothelial cells. Cancer Res 1997, 57:5421–5425.

    PubMed  CAS  Google Scholar 

  24. Kim KJ, Winer J, Armanini M, et al.: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993, 362:841–844.

    Article  PubMed  CAS  Google Scholar 

  25. Zhang HT, Craft P, Scott PA, et al.: Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells. J Natl Cancer Inst 1995, 87:213–219.

    Article  PubMed  CAS  Google Scholar 

  26. Zaug AJ, Been MD, Cech TR: The Tetrahymena ribzyme acts like an RNA restriction endonuclease. Nature 1986, 324:429–433.

    Article  PubMed  CAS  Google Scholar 

  27. Baer M, Altman S: A catalytic RNA and its gene from Salmonella typhimurium. Science 1985, 228:998–1002.

    Article  Google Scholar 

  28. Usman U, Stinchcomb D: Design, synthesis and function of therapeutic hammerhead ribozymes. In Nucleic Acids and Molecular Biology. Edited by Eckstein R, Lilley D. Berlin: Springer-Verlag; 1996:243–264.

    Google Scholar 

  29. Usman N, Beigelman L, McSwiggen JA: Hammerhead ribozyme engineering. Curr Opin Struct Biol 1996, 6:527–533.

    Article  PubMed  CAS  Google Scholar 

  30. Fell PL, Hudson A, Reynolds MA, et al.: Cellular uptake properties of a 2′-amino/2′-O-methyl-modified chimeric hammerhead ribozyme targeted to the epidermal growth factor receptor mRNA. Antisense Nucleic Acid Drug Dev 1997, 7:319–326.

    PubMed  CAS  Google Scholar 

  31. Parry TJ, Cushman C, Gallegos AM, et al.: Bioactivity of anti-angiogenic ribozymes targeting Flt-1 and KDR mRNA. Nucleic Acids Res 1999, 27:2569–2577.

    Article  PubMed  CAS  Google Scholar 

  32. Sandberg JA, Bouhana KS, Gallegos AM, et al.: Pharmacokinetics of an antiangiogenic ribozyme (ANGIOZYME) in the mouse. Antisense Nucleic Acid Drug Dev 1999, 9:271–277.

    PubMed  CAS  Google Scholar 

  33. Parker VP, Sandberg JA, Smith J, et al.: Phase I and pharmacokinetic studies of Angiozyme, a synthetic ribozyme targeting the VEGF receptor Flt-1 [abstract]. Proc ASCO 2000, 19:703a.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology and Oncology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, T-40, 44195, Cleveland, OH, USA

    David E. Weng MD, PhD

  2. Ribozyme Pharmaceuticals, Inc., 2950 Wilderness Place, 80301, Boulder, CO, USA

    Nassim Usman PhD

Authors
  1. David E. Weng MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nassim Usman PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weng, D.E., Usman, N. Angiozyme: A Novel angiogenesis inhibitor. Curr Oncol Rep 3, 141–146 (2001). https://doi.org/10.1007/s11912-001-0014-7

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-001-0014-7

Keywords

Search

Navigation