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.

  • Original Article
  • Published:

Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver

Cancer Gene Therapy volume 14, pages 139–150 (2007)Cite this article

Abstract

We administered an adenoviral vector, Onyx-015, into the hepatic artery of patients with metastatic colorectal cancer involving the liver. Thirty-five patients enrolled in this multi-institutional phase I/II trial received up to eight arterial infusions of up to 2 × 1012 viral particles. Hepatic toxicity was the primary dose-limiting toxicity observed in preclinical models. However, nearly 200 infusions of this adenoviral vector were administered directly into the hepatic artery without significant toxicity. Therefore, we undertook this analysis to determine the impact of repeated adenoviral exposure on hepatic function. Seventeen patients were treated at our institution, providing a detailed data set on the changes in hepatic function following repeated exposure to adenovirus. No changes in hepatic function occurred with the first treatment of Onyx-015 among these patients. Transient increases in transaminase levels occurred in one patient starting with the second infusion and transient increases in bilirubin was observed in two patients starting with the fifth treatment. These changes occurred too early to be explained by viral-mediated lysis of hepatocytes. In addition, viremia was observed starting 3–5 days after the viral infusion in half of the patient, but was not associated with hepatic toxicity. To further understand the basis for the minimal hepatic toxicity of adenoviral vectors, we evaluated the replication of adenovirus in primary hepatocytes and tumor cells in culture and the expression of the coxsackie-adenoviral receptor (CAR) in normal liver and colon cancer metastatic to the liver. We found that adenovirus replicates poorly in primary hepatocytes but replicates efficiently in tumors including tumors derived from hepatocytes. In addition, we found that CAR is localized at junctions between hepatocytes and is inaccessible to hepatic blood flow. CAR is not expressed on tumor vasculature but is expressed on tumor cells. Spatial restriction of CAR to the intercellular space in normal liver and diminished replication of adenovirus in hepatocytes may explain the minimal toxicity observed following repeated hepatic artery infusions with Onyx-015.

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
Figure 7

Similar content being viewed by others

References

  1. Rougier P, Bugat R, Douillard JY, Culine S, Suc E, Brunet P et al. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 1997; 15: 251–260.

    Article  CAS  PubMed  Google Scholar 

  2. Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22: 229–237.

    Article  CAS  PubMed  Google Scholar 

  3. de Gramont A, Tournigand C, Louvet C, Maindrault-Goebel F, Andre T . First-line therapy for advanced colorectal cancer. Curr Oncol Rep 2005; 7: 167–172.

    Article  CAS  PubMed  Google Scholar 

  4. McCormick F . Cancer-specific viruses and the development of ONYX-015. Cancer Biol Ther 2003; 2: S157–S160.

    Article  CAS  PubMed  Google Scholar 

  5. Kirn DH, McCormick F . Replicating viruses as selective cancer therapeutics. Mol Med Today 1996; 2: 519–527.

    Article  CAS  PubMed  Google Scholar 

  6. Heise C, Sampson-Johannes A, Williams A, McCormick F, Von Hoff DD, Kirn DH . ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nat Med 1997; 3: 639–645.

    Article  CAS  PubMed  Google Scholar 

  7. McCormick F . Interactions between adenovirus proteins and the p53 pathway: the development of ONYX-015. Semin Cancer Biol 2000; 10: 453–459.

    Article  CAS  PubMed  Google Scholar 

  8. Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996; 274: 373–376.

    Article  CAS  PubMed  Google Scholar 

  9. Harada JN, Berk AJ . p53-Independent and -dependent requirements for E1B-55K in adenovirus type 5 replication. J Virol 1999; 73: 5333–5344.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Kirn D . Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned? Gene Therapy 2001; 8: 89–98.

    Article  CAS  PubMed  Google Scholar 

  11. McCormick F . ONYX-015 selectivity and the p14ARF pathway. Oncogene 2000; 19: 6670–6672.

    Article  CAS  PubMed  Google Scholar 

  12. Reid T, Galanis E, Abbruzzese J, Sze D, Wein LM, Andrews J et al. Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints. Cancer Res 2002; 62: 6070–6079.

    CAS  PubMed  Google Scholar 

  13. Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, Romel L 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. Nat Med 2000; 6: 879–885.

    Article  CAS  PubMed  Google Scholar 

  14. Morley S, MacDonald G, Kirn D, Kaye S, Brown R, Soutar D . The dl1520 virus is found preferentially in tumor tissue after direct intratumoral injection in oral carcinoma. Clin Cancer Res 2004; 10: 4357–4362.

    Article  CAS  PubMed  Google Scholar 

  15. Ganly I, Kirn D, Eckhardt G, Rodriguez GI, Soutar DS, Otto R et al. A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res 2000; 6: 798–806.

    CAS  PubMed  Google Scholar 

  16. Reid T, Galanis E, Abbruzzese J, Sze D, Andrews J, Romel L 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 2001; 8: 1618–1626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Reid TR, Freeman S, Post L, McCormick F, Sze DY . Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin. Cancer Gene Ther 2005; 12: 673–681.

    Article  CAS  PubMed  Google Scholar 

  18. Falcone A, Allegrini G, Lencioni M, Pfanner E, Brunetti I, Cianci C et al. Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: a phase II study. Cancer Chemother Pharmacol 1999; 44: 159–163.

    Article  CAS  PubMed  Google Scholar 

  19. Falcone A, Cianci C, Pfanner E, Bertuccelli M, Brunetti I, Muttini MP et al. Continuous-infusion 5-fluorouracil in metastatic colorectal cancer patients pretreated with bolus 5-fluorouracil: clinical evidence of incomplete cross-resistance. Ann Oncol 1994; 5: 291.

    Article  CAS  PubMed  Google Scholar 

  20. Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 1998; 352: 1407–1412.

    Article  CAS  PubMed  Google Scholar 

  21. Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003; 21: 2059–2069.

    Article  CAS  PubMed  Google Scholar 

  22. Mori A, Bertoglio S, Guglielmi A, Aschele C, Bolli E, Tixi L et al. Activity of continuous-infusion 5-fluorouracil in patients with advanced colorectal cancer clinically resistant to bolus 5-fluorouracil. Cancer Chemother Pharmacol 1993; 33: 179–180.

    Article  CAS  PubMed  Google Scholar 

  23. Sze DY, Freeman SM, Slonim SM, Samuels SL, Andrews JC, Hicks M et al. Becker Young Investigator Award: intraarterial adenovirus for metastatic gastrointestinal cancer: activity, radiographic response, and survival. J Vasc Interv Radiol 2003; 14: 279–290.

    Article  PubMed  Google Scholar 

  24. Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 2003; 80: 148–158.

    Article  CAS  PubMed  Google Scholar 

  25. Worgall S, Wolff G, Falck-Pedersen E, Crystal RG . Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration. Hum Gene Ther 1997; 8: 37–44.

    Article  CAS  PubMed  Google Scholar 

  26. Duncan SJ, Gordon FC, Gregory DW, McPhie JL, Postlethwaite R, White R et al. Infection of mouse liver by human adenovirus type 5. J Gen Virol 1978; 40: 45–61.

    Article  CAS  PubMed  Google Scholar 

  27. Bao JJ, Zhang WW, Kuo MT . Adenoviral delivery of recombinant DNA into transgenic mice bearing hepatocellular carcinomas. Hum Gene Ther 1996; 7: 355–365.

    Article  CAS  PubMed  Google Scholar 

  28. Tollefson AE, Ryerse JS, Scaria A, Hermiston TW, Wold WS . The E3-11.6-kDa adenovirus death protein (ADP) is required for efficient cell death: characterization of cells infected with adp mutants. Virology 1996; 220: 152–162.

    Article  CAS  PubMed  Google Scholar 

  29. Doronin K, Toth K, Kuppuswamy M, Krajcsi P, Tollefson AE, Wold WS . Overexpression of the ADP (E3-11.6 K) protein increases cell lysis and spread of adenovirus. Virology 2003; 305: 378–387.

    Article  CAS  PubMed  Google Scholar 

  30. Tollefson AE, Scaria A, Ying B, Wold WS . Mutations within the ADP (E3-11.6 K) protein alter processing and localization of ADP and the kinetics of cell lysis of adenovirus-infected cells. J Virol 2003; 77: 7764–7778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lichtenstein DL, Toth K, Doronin K, Tollefson AE, Wold WS . Functions and mechanisms of action of the adenovirus E3 proteins. Int Rev Immunol 2004; 23: 75–111.

    Article  CAS  PubMed  Google Scholar 

  32. Wold WS, Gooding LR . Adenovirus region E3 proteins that prevent cytolysis by cytotoxic T cells and tumor necrosis factor. Mol Biol Med 1989; 6: 433–452.

    CAS  PubMed  Google Scholar 

  33. Gooding LR, Sofola IO, Tollefson AE, Duerksen-Hughes P, Wold WS . The adenovirus E3-14.7 K protein is a general inhibitor of tumor necrosis factor-mediated cytolysis. J Immunol 1990; 145: 3080–3086.

    CAS  PubMed  Google Scholar 

  34. Gooding LR, Aquino L, Duerksen-Hughes PJ, Day D, Horton TM, Yei SP et al. The E1B 19 000-molecular-weight protein of group C adenoviruses prevents tumor necrosis factor cytolysis of human cells but not of mouse cells. J Virol 1991; 65: 3083–3094.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wold WS . Adenovirus genes that modulate the sensitivity of virus-infected cells to lysis by TNF. J Cell Biochem 1993; 53: 329–335.

    Article  CAS  PubMed  Google Scholar 

  36. Tollefson AE, Toth K, Doronin K, Kuppuswamy M, Doronina OA, Lichtenstein DL et al. Inhibition of TRAIL-induced apoptosis and forced internalization of TRAIL receptor 1 by adenovirus proteins. J Virol 2001; 75: 8875–8887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Christ M, Louis B, Stoeckel F, Dieterle A, Grave L, Dreyer D et al. Modulation of the inflammatory properties and hepatotoxicity of recombinant adenovirus vectors by the viral E4 gene products. Hum Gene Ther 2000; 11: 415–427.

    Article  CAS  PubMed  Google Scholar 

  38. Anders M, Hansen R, Ding RX, Rauen KA, Bissell MJ, Korn WM . Disruption of 3D tissue integrity facilitates adenovirus infection by deregulating the coxsackievirus and adenovirus receptor. Proc Natl Acad Sci USA 2003; 100: 1943–1948.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Johnston DE . Special considerations in interpreting liver function tests. Am Fam Physician 1999; 59: 2223–2230.

    CAS  PubMed  Google Scholar 

  40. Costelli P, Aoki P, Zingaro B, Carbo N, Reffo P, Lopez-Soriano FJ et al. Mice lacking TNFalpha receptors 1 and 2 are resistant to death and fulminant liver injury induced by agonistic anti-Fas antibody. Cell Death Differ 2003; 10: 997–1004.

    Article  CAS  PubMed  Google Scholar 

  41. Hoek JB, Pastorino JG . Ethanol, oxidative stress, and cytokine-induced liver cell injury. Alcohol 2002; 27: 63–68.

    Article  CAS  PubMed  Google Scholar 

  42. Iimuro Y, Gallucci RM, Luster MI, Kono H, Thurman RG . Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology 1997; 26: 1530–1537.

    Article  CAS  PubMed  Google Scholar 

  43. Orange JS, Salazar-Mather TP, Opal SM, Biron CA . Mechanisms for virus-induced liver disease: tumor necrosis factor-mediated pathology independent of natural killer and T cells during murine cytomegalovirus infection. J Virol 1997; 71: 9248–9258.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Simeonova PP, Gallucci RM, Hulderman T, Wilson R, Kommineni C, Rao M et al. The role of tumor necrosis factor-alpha in liver toxicity, inflammation, and fibrosis induced by carbon tetrachloride. Toxicol Appl Pharmacol 2001; 177: 112–120.

    Article  CAS  PubMed  Google Scholar 

  45. Sheron N, Lau J, Daniels H, Goka J, Eddleston A, Alexander GJ et al. Increased production of tumour necrosis factor alpha in chronic hepatitis B virus infection. J Hepatol 1991; 12: 241–245.

    Article  CAS  PubMed  Google Scholar 

  46. Mookerjee RP, Sen S, Davies NA, Hodges SJ, Williams R, Jalan R . Tumour necrosis factor alpha is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis. Gut 2003; 52: 1182–1187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cohen CJ, Shieh JT, Pickles RJ, Okegawa T, Hsieh JT, Bergelson JM . The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction. Proc Natl Acad Sci USA 2001; 98: 15191–15196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Heise CC, Williams AM, Xue S, Propst M, Kirn DH . Intravenous administration of ONYX-015, a selectively replicating adenovirus, induces antitumoral efficacy. Cancer Res 1999; 59: 2623–2628.

    CAS  PubMed  Google Scholar 

  49. Reid T, Warren R, Kirn D . Intravascular adenoviral agents in cancer patients: lessons from clinical trials. Cancer Gene Ther 2002; 9: 979–986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Palo Alto Veteran's Administration Health Care System and Stanford University, Stanford, CA, USA

    T Au, S Thorne, D Sze & T R Reid

  2. University of California, San Francisco, CA, USA

    W M Korn

  3. Oxford University, Jennerex Biotherapeutics, San Francisco, CA, USA

    D Kirn

Authors
  1. T Au
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Thorne
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W M Korn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Sze
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Kirn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T R Reid
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T R Reid.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Au, T., Thorne, S., Korn, W. et al. Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver. Cancer Gene Ther 14, 139–150 (2007). https://doi.org/10.1038/sj.cgt.7700988

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700988

Keywords

This article is cited by

Search

Advanced search

Quick links