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Assessment of growth inhibition and morphological changes in in vitro and in vivo hepatocellular carcinoma models post treatment with dl1520 adenovirus

Abstract

Background and aims: E1B-deleted virus dl1520 (ONYX-015) has been previously used in clinical trials mainly for treatment of head and neck tumors, and has been shown to have beneficial effects independent of p53 status. The main aim of this investigation was to carry out a preclinical study for assessment of the use of dl1520 in in vitro and in vivo hepatocellular carcinoma (HCC) models with various p53 status (deleted, mutant, and wild type), and study the ultrastructural changes in the carcinoma cells during and following treatment with dl1520. Methods: dl1520 (ONYX-015) virus was used for treatment of three HCC cell lines in culture, then for treatment of developed xenografts in SCID mice. The effects of dl1520 on HCC cell growth and accompanied morphological changes were assessed by various techniques including transmission electron microscopy. dl1520 infection was confirmed using polymerase chain reaction and immunolabeling at transmission electron microscopy level. Results: dl1520 was effective in killing cells and inhibiting HCC cell growth both in vitro and in vivo. The cell killing was at higher levels in cells possessing abnormal p53. Survival rates in SCID mice treated with dl1520 were statistically significantly higher in HCC tumors with deleted and mutant p53, than in tumors with wild-type p53. Conclusions: The findings in this study suggest that dl1520 could be safely and effectively used for treatment of HCC dependent on the p53 status of the cells in vivo. Characteristic morphological changes that took place in the dl1520-treated HCC cells/tumors were distinct at transmission electron microscopy level and are the first of their kind to be reported.

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References

  1. Lotze MT, Flickinger JC, Carr B . In Hepatobiliar neoplasms Anonymous Cancer: Principles and Practice of Oncology Philadelphia, PA: Lippincott 1993 883–914

    Google Scholar 

  2. Fong Y, Blumgart LH . Hepatic colorectal metastases: current status of surgical therapy Oncology 1998 12: 1489–1498

    CAS  PubMed  Google Scholar 

  3. Sherlock S, Dooley J . Diseases of the Liver and Biliary System Oxford, UK: Blackwell Scientific 1993

    Google Scholar 

  4. Nagashima I, Hamada C, Naruse K . Surgical resection for small hepatocellular carcinoma Surgery 1996 119: 40–45

    Article  CAS  PubMed  Google Scholar 

  5. Barker DD, Berk AJ . Adenovirus proteins from both E1B reading frames are required for the transformation of rodent cells by viral infection and DNA transfection Virology 1987 156: 107–121

    Article  CAS  PubMed  Google Scholar 

  6. Bischoff JR . An adenovirus mutant that replicates selectively in p53-deficient human tumour cells Science 1996 274: 373–376

    Article  CAS  PubMed  Google Scholar 

  7. Rothmann T, Hengstermann A, Whitaker NJ et al. Replication of ONYX-015, a potential anticancer adenovirus, is independent of p53 status in tumour cells J Virol 1998 72: 9470–9478

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Goodrum FD, Ornelles DA . p53 status does not determine outcome of E1B 55-kilodalton mutant adenovirus lytic infection J Virol 1998 72: 9479–9490

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Hay JG, Shapiro N, Sauthoff H et al. Targeting the replication of adenoviral gene therapy vectors to lung cancer cells: the importance of the adenoviral E1b-55kD gene Hum Gene Ther 1999 10: 579–590

    Article  CAS  PubMed  Google Scholar 

  10. Heise C, Sampson-Johannes A, Williams A, McCormick F, Von Hoff DD, Kirn D . ONYX-015, an E1B gene-attenuated adenovirus, causes tumour-specific cytolysis and antitumoural efficacy that can be augmented by standard chemotherapeutic agents Nat Med 1997 3: 639–644

    Article  CAS  PubMed  Google Scholar 

  11. Harada JN, Berk AJ . p53-independent and -dependent requirements for E1B-55K in adenovirus type 5 replication J Virol 1999 72: 5333–5344

    Google Scholar 

  12. Vollmer CM, Ribas A, Butterfield LH et al. p53 selective and nonselective replication of an E1B-deleted adenovirus in hepatocellular carcinoma Cancer Res 1999 59: 4369–4374

    CAS  PubMed  Google Scholar 

  13. Kirn D, Hermiston T, McCormick F . ONYX-015: clinical data are encouraging Nat Med 1998 4: 1341–1342

    Article  CAS  PubMed  Google Scholar 

  14. Ganly I, Kirn D, Eckhardt G 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 

  15. Heise C, Williams A, Xue S et al. Intravenous administration of ONYX-015, a selectively replicating adenovirus, induces antitumoral efficacy Cancer Res 1999 59: 2623–2628

    CAS  PubMed  Google Scholar 

  16. Habib NA, Sarraf CE, Mitry RR et al. E1B-deleted adenovirus (dl1520) gene therapy for patients with primary and secondary liver tumours Hum Gene Ther 2001 12: 219–226

    Article  CAS  PubMed  Google Scholar 

  17. Reid T, Galanis E, Abbruzzese J 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 Ther 2001 8: 1618–1626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lane DP . Killing tumour cells with viruses — a question of specificity Nat Med 1998 4: 1012–1013

    Article  CAS  PubMed  Google Scholar 

  19. Lowe SW . Progress of the smart bomb cancer virus Nat Med 1997 4: 1012–1013

    Google Scholar 

  20. Sambrook J, Fritsch EF, Maniatis T . Molecular Cloning: A Laboratory Manual New York: Cold Spring Harbour Laboratory 1989

    Google Scholar 

  21. Mitry RR, Sarraf CE, Havlik R et al. Detection of adenovirus and initiation of apoptosis in hepatocellular carcinoma cells after Ad-p53 treatment Hepatology 2000 885–889

  22. Yang CT, You L, Uematsu K, Yeh CC, McCormick F, Jablons DM . p14(ARF) modulates the cytolytic effect of ONYX-015 in mesothelioma cells with wild-type p53 Cancer Res 2001 61: 5959–5963

    CAS  PubMed  Google Scholar 

  23. Wyllie AH . Cell death is a new classification separating apoptosis from necrosis In: Browen ID, Lockshin RA, eds Cell Death in Biology and Pathology New York: Chapman & Hall 1981 9–29

    Chapter  Google Scholar 

  24. Alison MR, Sarraf CE . Apoptosis as a gene-directed program of cell death In: Bittar ED, Bittar N, eds Principles of Medical Biology Stamford, CT: JAI Press 1998 1–55

    Google Scholar 

  25. Greber UF, Willetts M, Webster P . Stepwise dismantling of adenovirus 2 during entry into cells Cell 1993 75: 477–486

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Professor Arnold Berk, University of Southern California, Los Angeles, for kindly providing the dl1520 adenovirus, the Pedersen Family Charitable Foundation for vital financial support, and VE Emons, Department of Histopathology, Imperial College School of Medicine, for preparing tissues for electron microscopy.

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Correspondence to Nagy A Habib.

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Habib, N., Mitry, R., Sarraf, C. et al. Assessment of growth inhibition and morphological changes in in vitro and in vivo hepatocellular carcinoma models post treatment with dl1520 adenovirus. Cancer Gene Ther 9, 414–420 (2002). https://doi.org/10.1038/sj.cgt.7700455

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