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Drug–virus interaction: effect of administration of recombinant adenoviruses on the pharmacokinetics of docetaxel in a rat model

Cancer Gene Therapy volume 16, pages 405–414 (2009)Cite this article

Abstract

Modern cancer therapy combines recombinant viruses with traditional chemotherapeutic agents that are metabolized by hepatic cytochrome P450 3A4 (CYP3A4). A single dose of recombinant adenovirus (Ad) expressing β-galactosidase (AdlacZ) significantly alters CYP3A2, the correlate of CYP3A4, in rats for 14 days. Recombinant adenovirus expressing human p53 (Adp53) also suppresses CYP3A2. Plasma clearance of docetaxel (DTX) in animals given AdlacZ (3.38±0.22 l h−1 kg−1) was significantly lower than that of those given DTX alone (7.35±1.22 l h−1 kg−1, P⩽0.05). Area under the plasma concentration-time curve of DTX in rats given AdlacZ (2987.37±197.97 ng ml−1 h−1) was significantly greater than those given drug alone (1496.14±281.62 ng ml−1 h−1, P⩽0.05). Both viruses prolonged DTX half-life (t1/2). Ad infection may cause significant variability in the pharmacokinetics and pharmacodynamics of anti-cancer agents and should be considered when designing therapeutic regimens for patients with viral infection and those enrolled in clinical trials using recombinant viruses.

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References

  1. Ritter T, Lehmann M, Volk HD . Improvements in gene therapy: averting the immune response to adenoviral vectors. BioDrugs 2002; 16: 3–10.

    Article  CAS  PubMed  Google Scholar 

  2. Cao H, Koehler DR, Hu J . Adenoviral vectors for gene replacement therapy. Viral Immunol 2004; 17: 327–333.

    Article  CAS  PubMed  Google Scholar 

  3. Vattemi E, Claudio PP . Adenoviral gene therapy in head and neck cancer. Drug News Perspect 2006; 19: 329–337.

    Article  CAS  PubMed  Google Scholar 

  4. Peng Z . Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther 2005; 16: 1016–1027.

    Article  CAS  PubMed  Google Scholar 

  5. Gurnani M, Lipari P, Dell J, Shi B, Nielsen LL . Adenovirus-mediated p53 gene therapy has greater efficacy when combined with chemotherapy against human head and neck, ovarian, prostate, and breast cancer. Cancer Chemother Pharmacol 1999; 44: 143–151.

    Article  CAS  PubMed  Google Scholar 

  6. Nemunaitis J, Swisher SG, Timmons T, Connors D, Mack M, Doerksen L et al. Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer. J Clin Oncol 2000; 18: 609–622.

    Article  CAS  PubMed  Google Scholar 

  7. Inoue A, Narumi K, Matsubara N, Sugawara S, Saijo Y, Satoh K et al. Administration of wild-type p53 adenoviral vector synergistically enhances the cytotoxicity of anti-cancer drugs in human lung cancer cells irrespective of the status of p53 gene. Cancer Lett 2000; 157: 105–112.

    Article  CAS  PubMed  Google Scholar 

  8. Yoo GH, Piechocki MP, Oliver J, Lonardo F, Zumstein L, Lin HS et al. Enhancement of Ad-p53 therapy with docetaxel in head and neck cancer. Laryngoscope 2004; 114: 1871–1879.

    Article  CAS  PubMed  Google Scholar 

  9. Cristofanilli M, Krishnamurthy S, Guerra L, Broglio K, Arun B, Booser DJ et al. A nonreplicating adenoviral vector that contains the wild-type p53 transgene combined with chemotherapy for primary breast cancer: safety, efficacy, and biologic activity of a novel gene-therapy approach. Cancer 2006; 107: 935–944.

    Article  CAS  PubMed  Google Scholar 

  10. Clarke SJ, Rivory LP . Clinical pharmacokinetics of docetaxel. Clin Pharmacokinet 1999; 36: 99–114.

    Article  CAS  PubMed  Google Scholar 

  11. Marre F, Sanderink GJ, de Sousa G, Gaillard C, Martinet M, Rahmani R . Hepatic biotransformation of docetaxel (Taxotere) in vitro: involvement of the CYP3A subfamily in humans. Cancer Res 1996; 56: 1296–1302.

    CAS  PubMed  Google Scholar 

  12. Fujita K . Cytochrome P450 and anticancer drugs. Curr Drug Metab 2006; 7: 23–37.

    Article  CAS  PubMed  Google Scholar 

  13. Callahan SM, Ming X, Lu SK, Brunner LJ, Croyle MA . Considerations for use of recombinant adenoviral vectors: dose effect on hepatic cytochromes P450. J Pharmacol Exp Ther 2005; 312: 492–501.

    Article  CAS  PubMed  Google Scholar 

  14. Callahan SM, Boquet MP, Ming X, Brunner LJ, Croyle MA . Impact of transgene expression on drug metabolism following systemic adenoviral vector administration. J Gene Med 2006; 8: 566–576.

    Article  CAS  PubMed  Google Scholar 

  15. Fujitaka K, Oguri T, Isobe T, Fujiwara Y, Kohno N . Induction of cytochrome P450 3A4 by docetaxel in peripheral mononuclear cells and its expression in lung cancer. Cancer Chemother Pharmacol 2001; 48: 42–46.

    Article  CAS  PubMed  Google Scholar 

  16. Nallani SC, Goodwin B, Buckley AR, Buckley DJ, Desai PB . Differences in the induction of cytochrome P450 3A4 by taxane anticancer drugs, docetaxel and paclitaxel, assessed employing primary human hepatocytes. Cancer Chemother Pharmacol 2004; 54: 219–229.

    Article  CAS  PubMed  Google Scholar 

  17. Kruyt FA, Curiel DT . Toward a new generation of conditionally replicating adenoviruses: pairing tumor selectivity with maximal oncolysis. Hum Gene Ther 2002; 13: 485–495.

    Article  CAS  PubMed  Google Scholar 

  18. Gabrilovich DI . INGN 201 (Advexin): adenoviral p53 gene therapy for cancer. Expert Opin Biol Ther 2006; 6: 823–832.

    Article  CAS  PubMed  Google Scholar 

  19. Scripture CD, Figg WD . Drug interactions in cancer therapy. Nat Rev Cancer 2006; 6: 546–558.

    Article  CAS  PubMed  Google Scholar 

  20. Goh BC, Lee SC, Wang LZ, Fan L, Guo JY, Lamba J et al. Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. J Clin Oncol 2002; 20: 3683–3690.

    Article  CAS  PubMed  Google Scholar 

  21. Alexandre J, Rey E, Girre V, Grabar S, Tran A, Montheil V et al. Relationship between cytochrome 3A activity, inflammatory status and the risk of docetaxel-induced febrile neutropenia: a prospective study. Ann Oncol 2007; 18: 168–172.

    Article  CAS  PubMed  Google Scholar 

  22. Nallani SC, Genter MB, Desai PB . Increased activity of CYP3A enzyme in primary cultures of rat hepatocytes treated with docetaxel: comparative evaluation with paclitaxel. Cancer Chemother Pharmacol 2001; 48: 115–122.

    Article  CAS  PubMed  Google Scholar 

  23. Wang Y, Hu JK, Krol A, Li YP, Li CY, Yuan F . Systemic dissemination of viral vectors during intratumoral injection. Mol Cancer Ther 2003; 2: 1233–1242.

    CAS  PubMed  Google Scholar 

  24. Wang Y, Yang Z, Liu S, Kon T, Krol A, Li CY et al. Characterisation of systemic dissemination of nonreplicating adenoviral vectors from tumours in local gene delivery. Br J Cancer 2005; 92: 1414–1420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pavek P, Dvorak Z . Xenobiotic-induced transcriptional regulation of xenobiotic metabolizing enzymes of the cytochrome P450 superfamily in human extrahepatic tissues. Curr Drug Metab 2008; 9: 129–143.

    Article  CAS  PubMed  Google Scholar 

  26. Martinez C, Garcia-Martin E, Pizarro RM, Garcia-Gamito FJ, Agundez JA . Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy. Br J Cancer 2002; 87: 681–686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. DeLoia JA, Zamboni WC, Jones JM, Strychor S, Kelley JL, Gallion HH . Expression and activity of taxane-metabolizing enzymes in ovarian tumors. Gynecol Oncol 2008; 108: 355–360.

    Article  CAS  PubMed  Google Scholar 

  28. Zamboni WC, Strychor S, Joseph E, Parise RA, Egorin MJ, Eiseman JL . Tumor, tissue, and plasma pharmacokinetic studies and antitumor response studies of docetaxel in combination with 9-nitrocamptothecin in mice bearing SKOV-3 human ovarian xenografts. Cancer Chemother Pharmacol 2008; 62: 417–426.

    Article  CAS  PubMed  Google Scholar 

  29. Vigant F, Descamps D, Jullienne B, Esselin S, Connault E, Opolon P et al. Substitution of hexon hypervariable region 5 of adenovirus serotype 5 abrogates blood factor binding and limits gene transfer to liver. Mol Ther 2008; 16: 1474–1480.

    Article  CAS  PubMed  Google Scholar 

  30. Waddington SN, McVey JH, Bhella D, Parker AL, Barker K, Atoda H et al. Adenovirus serotype 5 hexon mediates liver gene transfer. Cell 2008; 132: 397–409.

    Article  CAS  PubMed  Google Scholar 

  31. Li Y, Okegawa T, Lombardi DP, Frenkel EP, Hsieh JT . Enhanced transgene expression in androgen independent prostate cancer gene therapy by taxane chemotherapeutic agents. J Urol 2002; 167: 339–346.

    Article  CAS  PubMed  Google Scholar 

  32. Yu W, Fang H . Clinical trials with oncolytic adenovirus in China. Curr Cancer Drug Targets 2007; 7: 141–148.

    Article  PubMed  Google Scholar 

  33. Rodgers T, Rowland M . Mechanistic approaches to volume of distribution predictions: understanding the processes. Pharm Res 2007; 24: 918–933.

    Article  CAS  PubMed  Google Scholar 

  34. Baker SD, Sparreboom A, Verweij J . Clinical pharmacokinetics of docetaxel : recent developments. Clin Pharmacokinet 2006; 45: 235–252.

    Article  CAS  PubMed  Google Scholar 

  35. Won KA, Baumann H . The cytokine response element of the rat alpha 1-acid glycoprotein gene is a complex of several interacting regulatory sequences. Mol Cell Biol 1990; 10: 3965–3978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Smith JS, Tian J, Lozier JN, Byrnes AP . Severe pulmonary pathology after intravenous administration of vectors in cirrhotic rats. Mol Ther 2004; 9: 932–941.

    Article  CAS  PubMed  Google Scholar 

  37. Le HT, Boquet MP, Clark EA, Callahan SM, Croyle MA . Renal pathophysiology after systemic administration of recombinant adenovirus: changes in renal cytochromes P450 based on vector dose. Hum Gene Ther 2006; 17: 1095–1111.

    Article  CAS  PubMed  Google Scholar 

  38. Imaoka S, Hashizume T, Funae Y . Localization of rat cytochrome P450 in various tissues and comparison of arachidonic acid metabolism by rat P450 with that by human P450 orthologs. Drug Metab Pharmacokinet 2005; 20: 478–484.

    Article  CAS  PubMed  Google Scholar 

  39. Aitken AE, Richardson TA, Morgan ET . Regulation of drug-metabolizing enzymes and transporters in inflammation. Annu Rev Pharmacol Toxicol 2006; 46: 123–149.

    Article  CAS  PubMed  Google Scholar 

  40. Renton KW . Regulation of drug metabolism and disposition during inflammation and infection. Expert Opin Drug Metab Toxicol 2005; 1: 629–640.

    Article  CAS  PubMed  Google Scholar 

  41. Ozer J, Ratner M, Shaw M, Bailey W, Schomaker S . The current state of serum biomarkers of hepatotoxicity. Toxicology 2008; 245: 194–205.

    Article  CAS  PubMed  Google Scholar 

  42. Amacher DE . Serum transaminase elevations as indicators of hepatic injury following the administration of drugs. Regul Toxicol Pharmacol 1998; 27: 119–130.

    Article  CAS  PubMed  Google Scholar 

  43. Callahan SM, Wonganan P, Croyle MA . Molecular and Macromolecular Alterations of Recombinant Adenoviral Vectors Do Not Resolve Changes in Hepatic Drug Metabolism During Infection. Virol J 2008; 5: 111.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Schaller M, Hogaboam CM, Lukacs N, Kunkel SL . Respiratory viral infections drive chemokine expression and exacerbate the asthmatic response. J Allergy Clin Immunol 2006; 118: 295–302; quiz 303–294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Seemungal TA, Wedzicha JA . Viral infections in obstructive airway diseases. Curr Opin Pulm Med 2003; 9: 111–116.

    Article  PubMed  Google Scholar 

  46. Shirali GS, Ni J, Chinnock RE, Johnston JK, Rosenthal GL, Bowles NE et al. Association of viral genome with graft loss in children after cardiac transplantation. N Engl J Med 2001; 344: 1498–1503.

    Article  CAS  PubMed  Google Scholar 

  47. Maizel Jr JV, White DO, Scharff MD . The polypeptides of adenovirus. I. Evidence for multiple protein components in the virion and a comparison of types 2, 7A, and 12. Virology 1968; 36: 115–125.

    Article  CAS  PubMed  Google Scholar 

  48. Boquet MP, Wonganan P, Dekker JD, Croyle MA . Impact of Route of Systemic Administration of Adenovirus on Virus-Mediated Toxicity: Focus on Mortality, Virus Distribution, and Drug Metabolism. J Pharmacol Toxicol Methods 2008; 58: 222–232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Coon MJ, van der Hoeven TA, Dahl SB, Haugen DA . Two forms of liver microsomal cytochrome P-450, P-450lm2 and P-450LM4 (rabbit liver). Methods Enzymol 1978; 52: 109–117.

    Article  CAS  PubMed  Google Scholar 

  50. van der Hoeven T . Assay of Hepatic Microsomal Testosterone Hydroxylases by High-Performance Liquid Chromatography. Anal Biochem 1984; 138: 57–65.

    Article  CAS  PubMed  Google Scholar 

  51. Yang Y, Raper SE, Cohn JA, Engelhardt JF, Wilson JM . An approach for treating the hepatobiliary disease of cystic fibrosis by somatic gene transfer. Proc Natl Acad Sci USA 1993; 90: 4601–4605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ahn WS, Bae SM, Lee JM, Namkoong SE, Yoo JY, Seo YS et al. Anti-cancer effect of adenovirus p53 on human cervical cancer cell growth in vitro and in vivo. Int J Gynecol Cancer 2004; 14: 322–332.

    Article  CAS  PubMed  Google Scholar 

  53. Parise RA, Ramanathan RK, Zamboni WC, Egorin MJ . Sensitive liquid chromatography-mass spectrometry assay for quantitation of docetaxel and paclitaxel in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 783: 231–236.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Blake Roessler at the University of Michigan for kindly providing the Adp53 construct and Tim Madden at the MD Anderson Cancer Center (Houston, TX) for assistance with analysis of DTX in plasma samples. We also thank Michael Boquet and Courtney Clemens for expert technical assistance. This study was supported by research Grant R21GM69870 from the National Institutes of Health (MAC).

Author contributions: PW conducted the experiments, analyzed data and wrote the manuscript; WCZ, and SS performed docetaxel assays; JDD performed real-time PCR analysis; MAC designed and supervised the project and wrote the manuscript.

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Authors and Affiliations

  1. Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA

    P Wonganan & M A Croyle

  2. Division of Pharmacotherapy and Experimental Therapeutics School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA

    W C Zamboni

  3. Molecular Therapeutics Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    S Strychor

  4. Institute of Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, USA

    J D Dekker & M A Croyle

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  1. P Wonganan
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Correspondence to M A Croyle.

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Wonganan, P., Zamboni, W., Strychor, S. et al. Drug–virus interaction: effect of administration of recombinant adenoviruses on the pharmacokinetics of docetaxel in a rat model. Cancer Gene Ther 16, 405–414 (2009). https://doi.org/10.1038/cgt.2008.99

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