CardioVascular and Interventional Radiology

, Volume 41, Issue 1, pp 153–162 | Cite as

Hepatic Intra-arterial Delivery of a “Trojan-horses” Gene Therapy: A Pilot Study on Rabbit VX2 Hepatic Tumor Model

  • Olivier Pellerin
  • Ikram Amara
  • Marc Sapoval
  • Tchao Méachi
  • Carole Déan
  • Philippe Beaune
  • Isabelle de Waziers
Laboratory Investigation
First Online:
Received:
Accepted:

Abstract

Purpose

Gene-directed enzyme prodrug therapy (GDEPT) is a “Trojan-horses” suicide gene therapy that consists of tumor-targeted gene delivery (vectorized by mesenchymal stem cells MSCs) encoding an enzyme that converts a harmless prodrug into cytotoxic metabolites in situ. Then, cytotoxic metabolites passively diffuse in the neighboring tumor cells and kill them (bystander effect). The goal of our study was to assess the feasibility and efficacy of intra-arterial administration of MSCs transduced with an optimized gene (MSC-CYP2B6TM-RED) followed by intravenous administration of cyclophosphamide (CPA) into the VX2 rabbit liver tumor.

Materials and Methods

Nine rabbits with a VX2 liver tumor were randomly assigned into three groups: Control group A (one rabbit) free of any treatment; Control group B (two rabbits) receiving intravenous injection of cyclophosphamide at day 3 and CPA at day 14; and Group C (six rabbits) receiving the GDEPT treatment, consisting of successive intra-arterial injection of transduced-MSCs at days 0 (n = 6) and 11 (n = 3), followed by injection of CPA at days 3 (n = 6) and 14 (n = 3). The tumor response was assessed by ultrasound scan every 7 days and histopathological analysis at sacrifice (D25).

Results

There was a significant difference in the tumor volume between control groups (A + B) and group C at D7: 38/19 cm3 (p = 0.024); D11: 51/20 cm3 (p = 0.024), and D25: 121/37 cm3 (p = 0.048). Tumor necrosis was significantly greater and metastatic spread was lower for rabbits who received GDEPT (78% of total tumor surface) than for control animals (A + B) (22% of total tumor surface (p = 0.006).

Conclusion

Intra-arterial delivery of transduced-MSCs is feasible and, after CPA injection, resulted in 78% tumor necrosis (p = 0.006) and less metastasis in a VX2 liver tumor model.

Keywords

Gene-directed enzyme prodrug therapy Intra-arterial delivery Liver cancer Rabbit VX2 
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Notes

Acknowledgements

This work has been selected by the CIRSE 2017 Scientific Programme Committee and the CVIR Editorial Board, and cordially invited to send a complete manuscript for publication in the official journal of CIRSE, the CardioVascular and Interventional Radiology (CVIR). This work was supported by SATT Ile de France and the Ligue Nationale contre le Cancer, comités d’Ile de France. Ikrame Amara was a graduate student funded by the Cancéropole Ile-de-France. Baxter freely provided Cyclophosphamid. We acknowledge Julien Namur, Florentina Pascale from Archimmed SARL for their advice and help in the present work, and Dr. Jean Bénard PharmD, Ph.D, for his comments and editing.

Compliance with Ethical Standards

Conflict of interest

This work was supported by SATT Ile de France and the Ligue Nationale contre le Cancer, comités d’Ile de France. Baxter freely provided Cyclophosphamid. Second author was a graduate student funded by the Cancéropole Ile-de-France. Sixth and seventh authors are the inventor of patent PCT/EP2012/058219, US-2014-0127180A1.

References

  1. 1.
    Amara I, Pramil E, Senamaud-Beaufort C, et al. Engineered mesenchymal stem cells as vectors in a suicide gene therapy against preclinical murine models for solid tumors. J Controll Release. 2016;239:82–91.CrossRefGoogle Scholar
  2. 2.
    Amara I, Touati W, Beaune P, de Waziers I. Mesenchymal stem cells as cellular vehicles for prodrug gene therapy against tumors. Biochimie. 2014;105:4–11.CrossRefPubMedGoogle Scholar
  3. 3.
    Atencio IA, Grace M, Bordens R, et al. Biological activities of a recombinant adenovirus p53 (SCH 58500) administered by hepatic arterial infusion in a Phase 1 colorectal cancer trial. Cancer Gene Ther. 2006;13(2):169–81.CrossRefPubMedGoogle Scholar
  4. 4.
    Ayash LJ, Wright JE, Tretyakov O, et al. Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response. J Clin Oncol. 1992;10(6):995–1000.CrossRefPubMedGoogle Scholar
  5. 5.
    Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology. 2016;150(4):835–53.CrossRefPubMedGoogle Scholar
  6. 6.
    Cantore M, Fiorentini G, Zamagni D, Muttini MP, Mambrini A, Rabbi C. Molecular therapy: clinical applications. Intra-arterial adenoviruses administration. J Exp Clin Cancer Res. 2003;22(4 Suppl):47–9.PubMedGoogle Scholar
  7. 7.
    Chen CS, Lin JT, Goss KA, He YA, Halpert JR, Waxman DJ. Activation of the anticancer prodrugs cyclophosphamide and ifosfamide: identification of cytochrome P450 2B enzymes and site-specific mutants with improved enzyme kinetics. Mol Pharmacol. 2004;65(5):1278–85.CrossRefPubMedGoogle Scholar
  8. 8.
    Culver KW, Ram Z, Wallbridge S, Ishii H, Oldfield EH, Blaese RM. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science. 1992;256(5063):1550–2.CrossRefPubMedGoogle Scholar
  9. 9.
    de Baere T, Arai Y, Lencioni R, et al. Treatment of liver tumors with lipiodol TACE: technical recommendations from experts opinion. Cardiovasc Intervent Radiol. 2016;39(3):334–43.CrossRefPubMedGoogle Scholar
  10. 10.
    De Waziers I, Touati W, Diry M, Flinois JP, Dansette P, Beaune P Mutant cytochrome p450 2b6 proteins and uses thereof. Google Patents. 2014.Google Scholar
  11. 11.
    Fujii T, Le Du F, Xiao L, et al. Effectiveness of an adjuvant chemotherapy regimen for early-stage breast cancer: a systematic review and network meta-analysis. JAMA Oncol. 2015;1(9):1311–8.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Greco O, Dachs GU. Gene directed enzyme/prodrug therapy of cancer: historical appraisal and future prospectives. J Cell Physiol. 2001;187(1):22–36.CrossRefPubMedGoogle Scholar
  13. 13.
    Kim YI, Chung JW, Park JH, Han JK, Hong JW, Chung H. Intraarterial gene delivery in rabbit hepatic tumors: transfection with nonviral vector by using iodized oil emulsion. Radiology. 2006;240(3):771–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Lee KH, Liapi E, Buijs M, et al. Considerations for implantation site of VX2 carcinoma into rabbit liver. J Vasc Interv Radiol JVIR. 2009;20(1):113–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Nguyen TA, Tychopoulos M, Bichat F, et al. Improvement of cyclophosphamide activation by CYP2B6 mutants: from in silico to ex vivo. Mol Pharmacol. 2008;73(4):1122–33.CrossRefPubMedGoogle Scholar
  16. 16.
    Pan JG, Zhou X, Luo R, Han RF. The adeno-associated virus-mediated HSV-TK/GCV suicide system: a potential strategy for the treatment of bladder carcinoma. Med Oncol. 2012;29(3):1938–47.CrossRefPubMedGoogle Scholar
  17. 17.
    Pascale F, Ghegediban SH, Bonneau M, et al. Modified model of VX2 tumor overexpressing vascular endothelial growth factor. J Vasc Interv Radiol JVIR. 2012;23(6):809–17.CrossRefPubMedGoogle Scholar
  18. 18.
    Reid T, Galanis E, Abbruzzese J, et al. Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints. Can Res. 2002;62(21):6070–9.Google Scholar
  19. 19.
    Reid T, Warren R, Kirn D. Intravascular adenoviral agents in cancer patients: lessons from clinical trials. Cancer Gene Ther. 2002;9(12):979–86.CrossRefPubMedGoogle Scholar
  20. 20.
    Romieu-Mourez R, Francois M, Boivin MN, Stagg J, Galipeau J. Regulation of MHC class II expression and antigen processing in murine and human mesenchymal stromal cells by IFN-gamma, TGF-beta, and cell density. J Immunol. 2007;179(3):1549–58.CrossRefPubMedGoogle Scholar
  21. 21.
    Suckow MA, Stevens KA, Wilson RP. The laboratory rabbit, guinea pig, hamster, and other rodents. Cambridge: Academic Press; 2012.Google Scholar
  22. 22.
    Sze DY, Freeman SM, Slonim SM, et al. Dr. Gary J. Becker Young Investigator Award: intraarterial adenovirus for metastatic gastrointestinal cancer: activity, radiographic response, and survival. J Vasc Interv Radiol JVIR. 2003;14(3):279–90.CrossRefPubMedGoogle Scholar
  23. 23.
    Tan SL, Ahmad TS, Selvaratnam L, Kamarul T. Isolation, characterization and the multi-lineage differentiation potential of rabbit bone marrow-derived mesenchymal stem cells. J Anat. 2013;222(4):437–50.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Touati W, Tran T, Seguin J, et al. A suicide gene therapy combining the improvement of cyclophosphamide tumor cytotoxicity and the development of an anti-tumor immune response. Curr Gene Ther. 2014;14(3):236–46.CrossRefPubMedGoogle Scholar
  25. 25.
    Wu H, Exner AA, Shi H, Bear J, Haaga JR. Dynamic evolutionary changes in blood flow measured by MDCT in a hepatic VX2 tumor implant over an extended 28-day growth period: time-density curve analysis. Acad Radiol. 2009;16(12):1483–92.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2017

Authors and Affiliations

  1. 1.INSERM URM-S 970ParisFrance
  2. 2.Université Paris Descartes, Sorbonne Paris CitéParisFrance
  3. 3.Department of Interventional RadiologyHôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de ParisParisFrance
  4. 4.INSERM, UMR-S 1147ParisFrance
  5. 5.Department of PathologyHôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de ParisParisFrance
  6. 6.Department of BiochimistryHôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de ParisParisFrance

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