Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Intracarotid delivery of oncolytic HSV vector G47Δ to metastatic breast cancer in the brain

Gene Therapy volume 12, pages 647–654 (2005)Cite this article

Abstract

Delivery of viral vectors to tumors in the brain is a challenge, especially via systemic administration, which is key to targeting the invasive margins of malignant glioma and the multiple foci of metastatic disease. Like for other cancer therapeutics, the blood–brain barrier or even the blood–tumor barrier significantly limits delivery and efficacy. Blood–brain barrier disruption (BBBD) is one strategy for transiting the cerebrovasculature. G47Δ is a third-generation oncolytic replication-competent herpes simplex virus (HSV) vector, containing deletions of the γ34.5 and α47 genes and an inactivating LacZ insertion in UL39 (ICP6). Intracarotid artery delivery of G47Δ after BBBD with 25% mannitol significantly extended the life of nude mice bearing intracerebral human MDA-MB-435 breast tumors, whereas, G47Δ injection contralateral to the tumor, in the absence of mannitol or mannitol alone had no effect on survival. G47Δ replication was extensive after BBBD, as visualized by X-gal staining. Staining of peripheral organs, lung and liver, was minimal and not altered by BBBD. This is the first demonstration of intracarotid arterial delivery of oncolytic HSV vectors and antitumor efficacy in a mouse model and opens the door to the use of mouse syngenic tumor models and transgenic/knockout animals.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Kirn D, Martuza RL, Zwiebel J . Replication-selective virotherapy for cancer: biological principles, risk management and future directions. Nat Med 2001; 7: 781–787.

    Article  CAS  PubMed  Google Scholar 

  2. Varghese S, Rabkin SD . Oncolytic herpes simplex virus vectors for cancer virotherapy. Cancer Gene Ther 2002; 9: 967–978.

    Article  CAS  PubMed  Google Scholar 

  3. Markert JM et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Therapy 2000; 7: 867–874.

    Article  CAS  PubMed  Google Scholar 

  4. Chou J, Kern ER, Whitley RJ, Roizman B . Mapping of herpes simplex virus-1 neurovirulence to gamma 34.5, a gene nonessential for growth in culture. Science 1990; 250: 1262–1266.

    Article  CAS  PubMed  Google Scholar 

  5. Mineta T et al. Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nat Med 1995; 1: 938–943.

    Article  CAS  PubMed  Google Scholar 

  6. Todo T, Martuza RL, Rabkin SD, Johnson PA . Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing. Proc Natl Acad Sci USA 2001; 98: 6396–6401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mohr I, Gluzman Y . A herpesvirus genetic element which affects translation in the absence of the viral GADD34 function. EMBO J 1996; 15: 4759–4766.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. York IA et al. A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8+ T lymphocytes. Cell 1994; 77: 525–535.

    Article  CAS  PubMed  Google Scholar 

  9. Tsukada Y, Fouad A, Pickren JW, Lane WW . Central nervous system metastasis from breast carcinoma. Autopsy Study Cancer 1983; 52: 2349–2354.

    CAS  PubMed  Google Scholar 

  10. Posner JB, Chernick NL . Intracranial metastases from systemic cancer. Adv Neurol 1987; 19: 579–592.

    Google Scholar 

  11. Sorensen JB, Hansen HH, Hansen M, Dombernowsky P . Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol 1988; 6: 1474–1480.

    Article  CAS  PubMed  Google Scholar 

  12. Lee YT . Breast carcinoma: pattern of metastasis at autopsy. J Surg Oncol 1983; 23: 175–180.

    Article  CAS  PubMed  Google Scholar 

  13. Schouten LJ, Rutten J, Huveneers HA, Twijnstra A . Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 2002; 94: 2698–2705.

    Article  PubMed  Google Scholar 

  14. Crivellari D et al. High incidence of central nervous system involvement in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel. Ann Oncol 2001; 12: 353–356.

    Article  CAS  PubMed  Google Scholar 

  15. Bendell JC et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 2003; 97: 2972–2977.

    Article  PubMed  Google Scholar 

  16. Toda M, Rabkin SD, Martuza RL . Treatment of human breast cancer in a brain metastatic model by G207, a replication-competent multimutated herpes simplex virus 1. Hum Gene Ther 1998; 9: 2177–2185.

    Article  CAS  PubMed  Google Scholar 

  17. Mahmoud-Ahmed AS et al. Results of whole brain radiotherapy in patients with brain metastases from breast cancer: a retrospective study. Int J Radiat Oncol Biol Phys 2002; 54: 810–817.

    Article  PubMed  Google Scholar 

  18. Lang FF, Sawaya R . Surgical treatment of metastatic brain tumors. Semin Surg Oncol 1998; 14: 53–63.

    Article  CAS  PubMed  Google Scholar 

  19. Lagerwaard FJ et al. Identification of prognostic factors in patients with brain metastases: a review of 1292 patients. Int J Radiat Oncol Biol Phys 1999; 43: 795–803.

    Article  CAS  PubMed  Google Scholar 

  20. De Boer AG, Breimer DD . The blood–brain barrier: clinical implications for drug delivery to the brain. J R Coll Physicians Lond 1994; 28: 502–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Pardridge WM . Drug and gene delivery to the brain: the vascular route. Neuron 2002; 36: 555–558.

    Article  CAS  PubMed  Google Scholar 

  22. Rapoport SI . Osmotic opening of the blood–brain barrier: principles, mechanism, and therapeutic applications. Cell Mol Neurobiol 2000; 20: 217–230.

    Article  CAS  PubMed  Google Scholar 

  23. Black KL . Biochemical opening of the blood–brain barrier. Adv Drug Del Rev 1995; 15: 37–52.

    Article  CAS  Google Scholar 

  24. Doolittle ND et al. Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood–brain barrier for the treatment of patients with malignant brain tumors. Cancer 2000; 88: 637–647.

    Article  CAS  PubMed  Google Scholar 

  25. Prados MD et al. A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. Neuro-oncol 2003; 5: 96–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kroll RA et al. Improving drug delivery to intracerebral tumor and surrounding brain in a rodent model: a comparison of osmotic versus bradykinin modification of the blood–brain and/or blood–tumor barriers. Neurosurgery 1998; 43: 879–886; discussion 886–879.

    Article  CAS  PubMed  Google Scholar 

  27. Nilaver G et al. Delivery of herpesvirus and adenovirus to nude rat intracerebral tumors after osmotic blood–brain barrier disruption. Proc Natl Acad Sci USA 1995; 92: 9829–9833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rainov NG et al. Selective uptake of viral and monocrystalline particles delivered intra-arterially to experimental brain neoplasms. Hum Gene Ther 1995; 6: 1543–1552.

    Article  CAS  PubMed  Google Scholar 

  29. Rapoport SI, Fredericks WR, Ohno K, Pettigrew KD . Quantitative aspects of reversible osmotic opening of the blood–brain barrier. Am J Physiol 1980; 238: R421–R431.

    CAS  PubMed  Google Scholar 

  30. Liu R, Rabkin SD . Oncolytic herpes simplex virus vectors for the treatment of human breast cancer. Chin Med J 2005, in press.

  31. Davies DC . Blood–brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 2002; 200: 639–646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Roberts HC, Roberts TP, Brasch RC, Dillon WP . Quantitative measurement of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced MR imaging: correlation with histologic grade. AJNR Am J Neuroradiol 2000; 21: 891–899.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Lu S, Ahn D, Johnson G, Cha S . Peritumoral diffusion tensor imaging of high-grade gliomas and metastatic brain tumors. AJNR Am J Neuroradiol 2003; 24: 937–941.

    PubMed  PubMed Central  Google Scholar 

  34. Neuwelt EA . Mechanisms of disease: the blood–brain barrier. Neurosurgery 2004; 54: 131–140; discussion 141–132.

    Article  PubMed  Google Scholar 

  35. Green NK, Seymour LW . Adenoviral vectors: systemic delivery and tumor targeting. Cancer Gene Ther 2002; 9: 1036–1042.

    Article  CAS  PubMed  Google Scholar 

  36. Wakimoto H, Johnson PR, Knipe DM, Chiocca EA . Effects of innate immunity on herpes simplex virus and its ability to kill tumor cells. Gene Therapy 2003; 10: 983–990.

    Article  CAS  PubMed  Google Scholar 

  37. Fredericks WR, Rapoport SI . Reversible osmotic opening of the blood–brain barrier in mice. Stroke 1988; 19: 266–268.

    Article  CAS  PubMed  Google Scholar 

  38. Wiranowska M, Wilson TC, Bencze KS, Prockop LD . A mouse model for the study of blood–brain barrier permeability. J Neurosci Methods 1988; 26: 105–109.

    Article  CAS  PubMed  Google Scholar 

  39. Murakami H et al. Comparison of blood–brain barrier permeability in mice and rats using in situ brain perfusion technique. Am J Physiol Heart Circ Physiol 2000; 279: H1022–H1028.

    Article  CAS  PubMed  Google Scholar 

  40. Schellingerhout D, Rainov NG, Breakefield XO, Weissleder R . Quantitation of HSV mass distribution in a rodent brain tumor model. Gene Therapy 2000; 7: 1648–1655.

    Article  CAS  PubMed  Google Scholar 

  41. Neuwelt EA, Pagel MA, Dix RD . Delivery of ultraviolet-inactivated 35S-herpesvirus across an osmotically modified blood–brain barrier. J Neurosurg 1991; 74: 475–479.

    Article  CAS  PubMed  Google Scholar 

  42. Rainov NG, Kramm CM . Vector delivery methods and targeting strategies for gene therapy of brain tumors. Curr Gene Ther 2001; 1: 367–383.

    Article  CAS  PubMed  Google Scholar 

  43. Sundaresan P, Hunter WD, Martuza RL, Rabkin SD . Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation in mice. J Virol 2000; 74: 3832–3841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wakimoto H et al. The complement response against an oncolytic virus is species-specific in its activation pathways. Mol Ther 2002; 5: 275–282.

    Article  CAS  PubMed  Google Scholar 

  45. Ikeda K et al. Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses. Nat Med 1999; 5: 881–887.

    Article  CAS  PubMed  Google Scholar 

  46. Bergman I et al. Comparison of in vitro antibody-targeted cytotoxicity using mouse, rat and human effectors. Cancer Immunol Immunother 2000; 49: 259–266.

    Article  CAS  PubMed  Google Scholar 

  47. Szalai AJ et al. The Arthus reaction in rodents: species-specific requirement of complement. J Immunol 2000; 164: 463–468.

    Article  CAS  PubMed  Google Scholar 

  48. Yazaki T, Manz HJ, Rabkin SD, Martuza RL . Treatment of human malignant meningiomas by G207, a replication-competent multimutated herpes simplex virus 1. Cancer Res 1995; 55: 4752–4756.

    CAS  PubMed  Google Scholar 

  49. Advani SJ et al. Replication-competent, nonneuroinvasive genetically engineered herpes virus is highly effective in the treatment of therapy-resistant experimental human tumors. Cancer Res 1999; 59: 2055–2058.

    CAS  PubMed  Google Scholar 

  50. Todo T et al. Viral shedding and biodistribution of G207, a multimutated, conditionally replicating herpes simplex virus type 1, after intracerebral inoculation in aotus. Mol Ther 2000; 2: 588–595.

    Article  CAS  PubMed  Google Scholar 

  51. Cailleau R, Olive M, Crucigar QV . Long term human breast carcinoma cell lines of metastatic origin: preliminary characterization. In vitro 1978; 14: 911–915.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr George Perides (Beth Israel Deaconess Medical Center, Boston, MA, USA) for instruction in intracarotid injections in the mouse and Drs Ed Neuwelt and Leslie Muldoon (Oregon Health Sciences University, Portland, OR, USA) for technical advice on osmotic disruption of the blood–brain barrier. Purified G47Δ was kindly provided by MediGene Inc. (San Diego, CA, USA). This work was supported in part by a grant from the US Army Medical Research Materiel Command (DAMD17-99-1-9202 to SDR).

Author information

Author notes

  1. R Liu

    Present address: The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China

Authors and Affiliations

  1. Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Charlestown, MA, USA

    R Liu, R L Martuza & S D Rabkin

  2. Harvard Medical School, Boston, MA, USA

    R L Martuza & S D Rabkin

Authors
  1. R Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R L Martuza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S D Rabkin
    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

Liu, R., Martuza, R. & Rabkin, S. Intracarotid delivery of oncolytic HSV vector G47Δ to metastatic breast cancer in the brain. Gene Ther 12, 647–654 (2005). https://doi.org/10.1038/sj.gt.3302445

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302445

Keywords

This article is cited by

Search

Advanced search

Quick links