Despite recent advances in both surgery and chemoradiotherapy, mortality rates for advanced cancer remain high. There is a pressing need for novel therapeutic strategies; one option is systemic oncolytic viral therapy. Intravenous administration affords the opportunity to treat both the primary tumour and any metastatic deposits simultaneously. Data from clinical trials have shown that oncolytic viruses can be systemically delivered safely with limited toxicity but the results are equivocal in terms of efficacy, particularly when delivered with adjuvant chemotherapy. A key reason for this is the rapid clearance of the viruses from the circulation before they reach their targets. This phenomenon is mainly mediated through neutralising antibodies, complement activation, antiviral cytokines, and tissue-resident macrophages, as well as nonspecific uptake by other tissues such as the lung, liver and spleen, and suboptimal viral escape from the vascular compartment. A range of methods have been reported in the literature, which are designed to overcome these hurdles in preclinical models. In this paper, the potential advantages of, and obstacles to, successful systemic delivery of oncolytic viruses are discussed. The next stage of development will be the commencement of clinical trials combining these novel approaches for overcoming the barriers with systemically delivered oncolytic viruses. 1. Introduction Cancer remains a major health problem and is the 5th leading cause of death worldwide [1]. There have been many advances in the last few decades both in surgical care and chemoradiotherapy regimes. Certainly this has contributed to improved survival rates for commonly occurring cancers. However, relapse and disease progression are still all too common occurrences in modern medical practice. A variety of novel adjuvant therapies have been developed over the last decade, and oncolytic viruses have been particularly promising members of this cohort. Oncolytic viruses came to medical prominence in the 19th century when coincidental viral infections were observed to cause regression of some forms of haematological malignancies. Rabies inoculation was also demonstrated to regress a patient’s advanced cervical carcinoma [2]. A succession of studies in the 1950s and 60s were unable to establish oncolytic viral therapy as a viable anti-cancer modality. As a result, the field remained a medical curiosity until the advent of genetic engineering in the late 1980s. In the last decade, there have been rapid advancements in the oncolytic viral therapy field. Naturally
References
[1]
W. H. Organisation, “Disease and injury country estimates,” 2008, http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html.
[2]
E. Kelly and S. J. Russell, “History of oncolytic viruses: genesis to genetic engineering,” Molecular Therapy, vol. 15, no. 4, pp. 651–659, 2007.
[3]
H. H. Wong, N. R. Lemoine, and Y. Wang, “Oncolytic viruses for cancer therapy: overcoming the obstacles,” Viruses, vol. 2, no. 1, pp. 78–106, 2010.
[4]
G. C. Katsafanas and B. Moss, “Vaccinia virus intermediate stage transcription is complemented by Ras-GTPase-activating protein SH3 domain-binding protein (G3BP) and cytoplasmic activation/proliferation-associated protein (p137) individually or as a heterodimer,” Journal of Biological Chemistry, vol. 279, no. 50, pp. 52210–52217, 2004.
[5]
H. Yang, S. K. Kim, M. Kim et al., “Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction,” Journal of Clinical Investigation, vol. 115, no. 2, pp. 379–387, 2005.
[6]
C. C. O'Shea, L. Johnson, B. Bagus et al., “Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity,” Cancer Cell, vol. 6, no. 6, pp. 611–623, 2004.
[7]
M. A. Mac Cheever, “Twelve immunotherapy drugs that could cure cancers,” Immunological Reviews, vol. 222, no. 1, pp. 357–368, 2008.
[8]
F. R. Khuri, J. Nemunaitis, I. Ganly et al., “A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer,” Nature Medicine, vol. 6, no. 8, pp. 879–885, 2000.
[9]
J. R. Hecht, R. Bedford, J. L. Abbruzzese et al., “A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma,” Clinical Cancer Research, vol. 9, no. 2, pp. 555–561, 2003.
[10]
J. Nemunaitis, C. Cunningham, A. Buchanan et al., “Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity,” Gene Therapy, vol. 8, no. 10, pp. 746–759, 2001.
[11]
T. Reid, E. Galanis, J. Abbruzzese et al., “Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial,” Gene Therapy, vol. 8, no. 21, pp. 1618–1626, 2001.
[12]
T. Reid, E. Galanis, J. Abbruzzese et al., “Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints,” Cancer Research, vol. 62, no. 21, pp. 6070–6079, 2002.
[13]
T. R. Reid, S. Freeman, L. Post, F. McCormick, and D. Y. Sze, “Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin,” Cancer Gene Therapy, vol. 12, no. 8, pp. 673–681, 2005.
[14]
E. J. Small, M. A. Carducci, J. M. Burke et al., “A phase I trial of intravenous CG7870, a replication-selective, prostate-specific antigen-targeted oncolytic adenovirus, for the treatment of hormone-refractory, metastatic prostate cancer,” Molecular Therapy, vol. 14, no. 1, pp. 107–117, 2006.
[15]
A. L. Pecora, N. Rizvi, G. I. Cohen et al., “Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers,” Journal of Clinical Oncology, vol. 20, no. 9, pp. 2251–2266, 2002.
[16]
S. A. Laurie, J. C. Bell, H. L. Atkins et al., “A phase 1 clinical study of intravenous administration of PV701, an oncolytic virus, using two-step desensitization,” Clinical Cancer Research, vol. 12, no. 8, pp. 2555–2562, 2006.
[17]
A. I. Freeman, Z. Zakay-Rones, J. M. Gomori et al., “Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme,” Molecular Therapy, vol. 13, no. 1, pp. 221–228, 2006.
[18]
S. J. Hotte, R. M. Lorence, H. W. Hirte et al., “An optimized clinical regimen for the oncolytic virus PV701,” Clinical Cancer Research, vol. 13, no. 3, pp. 977–985, 2007.
[19]
N. Kemeny, K. Brown, A. Covey et al., “Phase I, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver,” Human Gene Therapy, vol. 17, no. 12, pp. 1214–1224, 2006.
[20]
Y. Fong, T. Kim, A. Bhargava et al., “A herpes oncolytic virus can be delivered via the vasculature to produce biologic changes in human colorectal cancer,” Molecular Therapy, vol. 17, no. 2, pp. 389–394, 2009.
[21]
S. K. Geevarghese, D. A. Geller, H. A. De Haan et al., “Phase I/II study of oncolytic herpes simplex virus NV1020 in patients with extensively pretreated refractory colorectal cancer metastatic to the liver,” Human Gene Therapy, vol. 21, no. 9, pp. 1119–1128, 2010.
[22]
C. J. Breitbach, J. Burke, D. Jonker et al., “Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans,” Nature, vol. 477, no. 7362, pp. 99–102, 2011.
[23]
L. Vidal, H. S. Pandha, T. A. Yap et al., “A phase I study of intravenous oncolytic reovirus type 3 dearing in patients with advanced cancer,” Clinical Cancer Research, vol. 14, no. 21, pp. 7127–7137, 2008.
[24]
J. Nemunaitis, I. Ganly, F. Khuri et al., “Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: a phase II trial,” Cancer Research, vol. 60, no. 22, pp. 6359–6366, 2000.
[25]
E. V. Shashkova, K. Doronin, J. S. Senac, and M. A. Barry, “Macrophage depletion combined with anticoagulant therapy increases therapeutic window of systemic treatment with oncolytic adenovirus,” Cancer Research, vol. 68, no. 14, pp. 5896–5904, 2008.
[26]
G. Y. Minuk, R. W. Paul, and P. W. K. Lee, “The prevalence of antibodies to Reovirus type 3 in adults with idiopathic cholestatic liver disease,” Journal of Medical Virology, vol. 16, no. 1, pp. 55–60, 1985.
[27]
J. H. Tai, J. V. Williams, K. M. Edwards, P. F. Wright, J. E. Crowe, and T. S. Dermody, “Prevalence of reovirus-specific antibodies in young children in Nashville, Tennessee,” Journal of Infectious Diseases, vol. 191, no. 8, pp. 1221–1224, 2005.
[28]
C. L. White, K. R. Twigger, L. Vidal et al., “Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing type 3) during a phase I clinical trial,” Gene Therapy, vol. 15, no. 12, pp. 911–920, 2008.
[29]
Y. Chen, D. C. Yu, D. Charlton, and D. R. Henderson, “Pre-existent adenovirus antibody inhibits systemic toxicity and antitumor activity of CN706 in the nude mouse LNCaP xenograft model: Implications and proposals for human therapy,” Human Gene Therapy, vol. 11, no. 11, pp. 1553–1567, 2000.
[30]
V. Tsai, D. E. Johnson, A. Rahman et al., “Impact of human neutralizing antibodies on antitumor efficacy of an oncolytic adenovirus in a murine model,” Clinical Cancer Research, vol. 10, no. 21, pp. 7199–7206, 2004.
[31]
Z. Zhang, J. Krimmel, Z. Zhang, Z. Hu, and P. Seth, “Systemic delivery of a novel liver-detargeted oncolytic adenovirus causes reduced liver toxicity but maintains the antitumor response in a breast cancer bone metastasis model,” Human Gene Therapy, vol. 22, no. 9, pp. 1137–1142, 2011.
[32]
K. Flanagan, R. T. Glover, H. H？rig, W. Yang, and H. L. Kaufman, “Local delivery of recombinant vaccinia virus expressing secondary lymphoid chemokine (SLC) results in a CD4 T-cell dependent antitumor response,” Vaccine, vol. 22, no. 21-22, pp. 2894–2903, 2004.
[33]
Y. Ichihashi, “Extracellular enveloped vaccinia virus escapes neutralization,” Virology, vol. 217, no. 2, pp. 478–485, 1996.
[34]
M. Law, R. Hollinshead, and G. L. Smith, “Antibody-sensitive and antibody-resistant cell-to-cell spread by vaccinia virus: Role of the A33R protein in antibody-resistant spread,” Journal of General Virology, vol. 83, no. 1, pp. 209–222, 2002.
[35]
G. L. Smith, J. A. Symons, A. Khanna, A. Vanderplasschen, and A. Alcamí, “Vaccinia virus immune evasion,” Immunological Reviews, vol. 159, pp. 137–154, 1997.
[36]
A. Vanderplasschen, E. Mathew, M. Hollinshead, R. B. Sim, and G. L. Smith, “Extracellular enveloped vaccinia virus is resistant to complement because of incorporation of host complement control proteins into its envelope,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 13, pp. 7544–7549, 1998.
[37]
D. H. Kirn, Y. Wang, W. Liang, C. H. Contag, and S. H. Thorne, “Enhancing poxvirus oncolytic effects through increased spread and immune evasion,” Cancer Research, vol. 68, no. 7, pp. 2071–2075, 2008.
[38]
P. Yotnda, B. Savoldo, N. Charlet-Berguerand, C. Rooney, and M. Brenner, “Targeted delivery of adenoviral vectors by cytotoxic T cells,” Blood, vol. 104, no. 8, pp. 2272–2280, 2004.
[39]
E. J. Ilett, M. Bárcena, F. Errington-Mais et al., “Internalization of oncolytic reovirus by human dendritic cell carriers protects the virus from neutralization,” Clinical Cancer Research, vol. 17, no. 9, pp. 2767–2776, 2011.
[40]
E. J. Ilett, R. J. Prestwich, T. Kottke et al., “Dendritic cells and T cells deliver oncolytic reovirus for tumour killing despite pre-existing anti-viral immunity,” Gene Therapy, vol. 16, no. 5, pp. 689–699, 2009.
[41]
S. H. Thorne, R. S. Negrin, and C. H. Contag, “Synergistic antitumor effects of immune cell-viral biotherapy,” Science, vol. 311, no. 5768, pp. 1780–1784, 2006.
[42]
I. D. Iankov, B. Blechacz, C. Liu et al., “Infected cell carriers: a new strategy for systemic delivery of oncolytic measles viruses in cancer virotherapy,” Molecular Therapy, vol. 15, no. 1, pp. 114–122, 2007.
[43]
T. Hakkarainen, M. Sarkioja, P. Lehenkari et al., “Human mesenchymal stem cells lack tumor tropism but enhance the antitumor activity of oncolytic adenoviruses in orthotopic lung and breast tumors,” Human Gene Therapy, vol. 18, no. 7, pp. 627–641, 2007.
[44]
S. Komarova, Y. Kawakami, M. A. Stoff-Khalili, D. T. Curiel, and L. Pereboeva, “Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses,” Molecular Cancer Therapeutics, vol. 5, no. 3, pp. 755–766, 2006.
[45]
A. M. Sonabend, I. V. Ulasov, M. A. Tyler, A. A. Rivera, J. M. Mathis, and M. S. Lesniak, “Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma,” Stem Cells, vol. 26, no. 3, pp. 831–841, 2008.
[46]
C. Pfirschke and V. Schirrmacher, “Cross-infection of tumor cells by contact with T lymphocytes loaded with Newcastle disease virus,” International Journal of Oncology, vol. 34, no. 4, pp. 951–962, 2009.
[47]
J. Qiao, T. Kottke, C. Willmon et al., “Purging metastases in lymphoid organs using a combination of antigen-nonspecific adoptive T cell therapy, oncolytic virotherapy and immunotherapy,” Nature Medicine, vol. 14, no. 1, pp. 37–44, 2008.
[48]
G. Coukos, A. Makrigiannakis, E. H. Kang et al., “Use of carrier cells to deliver a replication-selective herpes simplex virus-1 mutant for the intraperitoneal therapy of epithelial ovarian cancer,” Clinical Cancer Research, vol. 5, no. 6, pp. 1523–1537, 1999.
[49]
A. Munguia, T. Ota, T. Miest, and S. J. Russell, “Cell carriers to deliver oncolytic viruses to sites of myeloma tumor growth,” Gene Therapy, vol. 15, no. 10, pp. 797–806, 2008.
[50]
Z. Raykov, G. Balboni, M. Aprahamian, and J. Rommelaere, “Carrier cell-mediated delivery of oncolytic parvoviruses for targeting metastases,” International Journal of Cancer, vol. 109, no. 5, pp. 742–749, 2004.
[51]
P. Yotnda, A. R. Davis, M. J. Hicks, N. S. Templeton, and M. K. Benner, “Liposomal enhancement of the antitumor activity of conditionally replication-competent adenoviral plasmids,” Molecular Therapy, vol. 9, no. 4, pp. 489–495, 2004.
[52]
A. Fontanellas, S. Hervás-Stubbs, I. Mauleón et al., “Intensive pharmacological immunosuppression allows for repetitive liver gene transfer with recombinant adenovirus in nonhuman primates,” Molecular Therapy, vol. 18, no. 4, pp. 754–765, 2010.
[53]
J. Qiao, H. Wang, T. Kottke et al., “Cyclophosphamide facilitates antitumor efficacy against subcutaneous tumors following intravenous delivery of reovirus,” Clinical Cancer Research, vol. 14, no. 1, pp. 259–269, 2008.
[54]
N. M. Girgis, B. C. DeHaven, X. Fan, K. M. Viner, M. Shamim, and S. N. Isaacs, “Cell surface expression of the vaccinia virus complement control protein is mediated by interaction with the viral A56 protein and protects infected cells from complement attack,” Journal of Virology, vol. 82, no. 9, pp. 4205–4214, 2008.
[55]
G. J. Kotwal, S. N. Isaacs, R. McKenzie, M. M. Frank, and B. Moss, “Inhibition of the complement cascade by the major secretory protein of vaccinia virus,” Science, vol. 250, no. 4982, pp. 827–830, 1990.
[56]
A. Sahu, S. N. Isaacs, A. M. Soulika, and J. D. Lambris, “Interaction of vaccinia virus complement control protein with human complement proteins: factor I-mediated degradation of C3b to iC3b1 inactivates the alternative complement pathway,” Journal of Immunology, vol. 160, no. 11, pp. 5596–5604, 1998.
[57]
A. H. J. Kim, I. D. Dimitriou, M. C. H. Holland et al., “Complement C5a receptor is essential for the optimal generation of antiviral CD8+ T cell responses,” Journal of Immunology, vol. 173, no. 4, pp. 2524–2529, 2004.
[58]
M. Kopf, B. Abel, A. Gallimore, M. Carroll, and M. F. Bachmann, “Complement component C3 promotes T-cell priming and lung migration to control acute influenza virus infection,” Nature Medicine, vol. 8, no. 4, pp. 373–378, 2002.
[59]
A. F. Ochsenbein, D. D. Pinschewer, B. Odermatt, M. C. Carroll, H. Hengartner, and R. M. Zinkernagel, “Protective T cell-independent antiviral antibody responses are dependent on complement,” Journal of Experimental Medicine, vol. 190, no. 8, pp. 1165–1174, 1999.
[60]
M. Suresh, H. Molina, M. S. Salvato, D. Mastellos, J. D. Lambris, and M. Sandor, “Complement component 3 is required for optimal expansion of CD8 T cells during a systemic viral infection,” Journal of Immunology, vol. 170, no. 2, pp. 788–794, 2003.
[61]
A. Verschoor, M. A. Brockman, M. Gadjeva, D. M. Knipe, and M. C. Carroll, “Myeloid C3 determines induction of humoral responses to peripheral herpes simplex virus infection,” Journal of Immunology, vol. 171, no. 10, pp. 5363–5371, 2003.
[62]
A. Verschoor, M. A. Brockman, D. M. Knipe, and M. C. Carroll, “Cutting edge: myeloid complement C3 enhances the humoral response to peripheral viral infection,” Journal of Immunology, vol. 167, no. 5, pp. 2446–2451, 2001.
[63]
N. M. Girgis, B. C. DeHaven, Y. Xiao, E. Alexander, K. M. Viner, and S. N. Isaacs, “The vaccinia virus complement control protein modulates adaptive immune responses during infection,” Journal of Virology, vol. 85, no. 6, pp. 2547–2556, 2011.
[64]
S. B. Pushpakumar, G. Perez-Abadia, C. Soni et al., “Enhancing complement control on endothelial barrier reduces renal post-ischemia dysfunction,” Journal of Surgical Research, vol. 170, no. 2, pp. e263–e270, 2011.
[65]
J. M. Lubinski, H. M. Lazear, S. Awasthi, F. Wang, and H. M. Friedman, “The herpes simplex virus 1 IgG Fc receptor blocks antibody-mediated complement activation and antibody-dependent cellular cytotoxicity in vivo,” Journal of Virology, vol. 85, no. 7, pp. 3239–3249, 2011.
[66]
L. M. Hook, J. M. Lubinski, M. Jiang, M. K. Pangburn, and H. M. Friedman, “Herpes simplex virus type 1 and 2 glycoprotein C prevents complement-mediated neutralization induced by natural immunoglobulin M antibody,” Journal of Virology, vol. 80, no. 8, pp. 4038–4046, 2006.
[67]
J. Tian, Z. Xu, J. S. Smith, S. E. Hofherr, M. A. Barry, and A. P. Byrnes, “Adenovirus activates complement by distinctly different mechanisms in vitro and in vivo: indirect complement activation by virions in vivo,” Journal of Virology, vol. 83, no. 11, pp. 5648–5658, 2009.
[68]
J. Gandhi, S. M. Cashman, and R. Kumar-Singh, “Soluble CD59 expressed from an adenovirus in vivo is a potent inhibitor of complement deposition on murine liver vascular endothelium,” PLoS One, vol. 6, no. 6, article e21621, 2011.
[69]
R. E. Randall and S. Goodbourn, “Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures,” Journal of General Virology, vol. 89, no. 1, pp. 1–47, 2008.
[70]
S. V. Kotenko, G. Gallagher, V. V. Baurin et al., “IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex,” Nature Immunology, vol. 4, no. 1, pp. 69–77, 2003.
[71]
D. B. Stetson and R. Medzhitov, “Type I interferons in host defense,” Immunity, vol. 25, no. 3, pp. 373–381, 2006.
[72]
C. E. Samuel, “Antiviral actions of interferons,” Clinical Microbiology Reviews, vol. 14, no. 4, pp. 778–809, 2001.
[73]
A. Le Bon and D. F. Tough, “Links between innate and adaptive immunity via type I interferon,” Current Opinion in Immunology, vol. 14, no. 4, pp. 432–436, 2002.
[74]
A. Alcami and G. L. Smith, “Vaccinia, cowpox, and camelpox viruses encode soluble gamma interferon receptors with novel broad species specificity,” Journal of Virology, vol. 69, no. 8, pp. 4633–4639, 1995.
[75]
I. Haralambieva, I. Iankov, K. Hasegawa, M. Harvey, S. J. Russell, and K. W. Peng, “Engineering oncolytic measles virus to circumvent the intracellular innate immune response,” Molecular Therapy, vol. 15, no. 3, pp. 588–597, 2007.
[76]
K. Mossman, C. Upton, R. M. L. Buller, and G. McFadden, “Species specificity of ectromelia virus and vaccinia virus interferon-γ binding proteins,” Virology, vol. 208, no. 2, pp. 762–769, 1995.
[77]
A. U. Ahmed, C. E. Rolle, M. A. Tyler et al., “Bone marrow mesenchymal stem cells loaded with an oncolytic adenovirus suppress the anti-adenoviral immune response in the cotton rat model,” Molecular Therapy, vol. 18, no. 10, pp. 1846–1856, 2010.
[78]
T. L. A. Nguyên, H. Abdelbary, M. Arguello et al., “Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 39, pp. 14981–14986, 2008.
[79]
A. Otsuki, A. Patel, K. Kasai et al., “Histone deacetylase inhibitors augment antitumor efficacy of herpes-based oncolytic viruses,” Molecular Therapy, vol. 16, no. 9, pp. 1546–1555, 2008.
[80]
R. Alemany, K. Suzuki, and D. T. Curiel, “Blood clearance rates of adenovirus type 5 in mice,” Journal of General Virology, vol. 81, no. 11, pp. 2605–2609, 2000.
[81]
R. C. Carlisle, Y. Di, A. M. Cerny et al., “Human erythrocytes bind and inactivate type 5 adenovirus by presenting Coxsackie virus-adenovirus receptor and complement receptor 1,” Blood, vol. 113, no. 9, pp. 1909–1918, 2009.
[82]
M. Lyons, D. Onion, N. K. Green et al., “Adenovirus type 5 interactions with human blood cells may compromise systemic delivery,” Molecular Therapy, vol. 14, no. 1, pp. 118–128, 2006.
[83]
M. Aghi, S. D. Rabkin, and R. L. Martuza, “Angiogenic response caused by oncolytic herpes simplex virus-induced reduced thrombospondin expression can be prevented by specific viral mutations or by administering a thrombospondin-derived peptide,” Cancer Research, vol. 67, no. 2, pp. 440–444, 2007.
[84]
R. K. Jain, A. V. Finn, F. D. Kolodgie, H. K. Gold, and R. Virmani, “Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization,” Nature Clinical Practice Cardiovascular Medicine, vol. 4, no. 9, pp. 491–502, 2007.
[85]
K. Kurozumi, J. Hardcastle, R. Thakur et al., “Effect of tumor microenvironment modulation on the efficacy of oncolytic virus therapy,” Journal of the National Cancer Institute, vol. 99, no. 23, pp. 1768–1781, 2007.
[86]
K. Nakamura, J. Sasajima, Y. Mizukami et al., “Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro-angiogenic cells,” PloS One, vol. 5, no. 1, article e8824, 2010.
[87]
C. Rolny, M. Mazzone, S. Tugues et al., “HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF,” Cancer Cell, vol. 19, no. 1, pp. 31–44, 2011.
[88]
B. B. Goldberg, J. B. Liu, and F. Forsberg, “Ultrasound contrast agents: a review,” Ultrasound in Medicine and Biology, vol. 20, no. 4, pp. 319–333, 1994.
[89]
I. V. Larina, B. M. Evers, and R. O. Esenaliev, “Optimal drug and gene delivery in cancer cells by ultrasound-induced cavitation,” Anticancer Research, vol. 25, no. 1, pp. 149–156, 2005.
[90]
A. Lawrie, A. F. Brisken, S. E. Francis, D. C. Cumberland, D. C. Crossman, and C. M. Newman, “Microbubble-enhanced ultrasound for vascular gene delivery,” Gene Therapy, vol. 7, no. 23, pp. 2023–2027, 2000.
[91]
K. Y. Ng and Y. Liu, “Therapeutic ultrasound: Its application in drug delivery,” Medicinal Research Reviews, vol. 22, no. 2, pp. 204–223, 2002.
[92]
W. G. Pitt, G. Husseini, and B. J. Staples, “Ultrasonic drug delivery—a general review,” Expert Opinion on Drug Delivery, vol. 1, no. 1, pp. 37–56, 2004.
[93]
A. Greco, A. Di Benedetto, C. M. Howard et al., “Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach,” Molecular Therapy, vol. 18, no. 2, pp. 296–306, 2010.
[94]
C. M. Howard, F. Forsberg, C. Minimo, J. B. Liu, D. A. Merton, and P. P. Claudio, “Ultrasound guided site specific gene delivery system using adenoviral vectors and commercial ultrasound contrast agents,” Journal of Cellular Physiology, vol. 209, no. 2, pp. 413–421, 2006.
[95]
N. Araki, M. T. Johnson, and J. A. Swanson, “A role for phosphoinositide 3-kinase in the completion of macropinocytosis and phagocytosis by macrophages,” Journal of Cell Biology, vol. 135, no. 5, pp. 1249–1260, 1996.
[96]
D. Cox, B. M. Dale, M. Kashiwada, C. D. Helgason, and S. Greenberg, “A regulatory role for Src homology 2 domain-containing inositol 5′-phosphatase (SHIP) in phagocytosis mediated by Fcγ receptors and complement receptor 3 (αMβ2; CD11b/CD18),” Journal of Experimental Medicine, vol. 193, no. 1, pp. 61–71, 2001.
[97]
D. Cox, C. C. Tseng, G. Bjekic, and S. Greenberg, “A requirement for phosphatidylinositol 3-kinase in pseudopod extension,” Journal of Biological Chemistry, vol. 274, no. 3, pp. 1240–1247, 1999.
[98]
T. H. Sulahian, A. Imrich, G. Deloid, A. R. Winkler, and L. Kobzik, “Signaling pathways required for macrophage scavenger receptor-mediated phagocytosis: analysis by scanning cytometry,” Respiratory Research, vol. 9, p. 59, 2008.
[99]
S. Wee, D. Wiederschain, S. M. Maira et al., “PTEN-deficient cancers depend on PIK3CB,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 35, pp. 13057–13062, 2008.
