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Intranasal Administration of Perillyl Alcohol Activates Peripheral and Bronchus-Associated Immune System In Vivo

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Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Perillyl alcohol (POH) presents antitumoral activity but clinical application is hampered by adverse effects following oral administration. This work aimed to verify the cytotoxic effect of intranasal POH administration in the histology of lung, liver, brain; the cellularity and function of peripheral and bronchoalveolar-associated immune system. C57 adult mice received 1-min inhalation with POH, vehicle 70 % ethanol or saline buffer, once (84 μg/day) or twice (164 μg/day) during five consecutive days, and were killed 72 h after treatment. Spleen, cervical and mesenteric lymph nodes were removed for 3H-thymidine proliferation assay, leukocyte cellularity and flow cytometry analysis. Peripheral blood and bronchoalveolar lavage cells were collected to assess cellularity and immunoglobulin (IgA, IgM) levels. Intranasal POH did not alter body weight or liver, brain and lung morphology, but increased splenocyte and cervical lymph node cell proliferation, and IgM production without altering peripheral lymphocyte subsets. Treatment also increased the percentage of alveolar macrophages (83 %) and IgA-producing lymphocytes (15 %), a pattern characteristic of activated bronchoalveolar innate immune system. Intranasal administration of POH activated peripheral immune system and innate immunity of bronchus-associated lymphoid tissue, thus suggesting a possible role for POH as a chemotherapeutic drug also in pathological processes affecting the lung.

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References

  • Azzoli CG, Miller VA, Ng KK et al (2003) A phase I trial of perillyl alcohol in patients with advanced solid tumors. Cancer Chemother Pharmacol 51:493–498

    CAS  PubMed  Google Scholar 

  • Bailey HH, Wilding G, Tutsch KD et al (2004) A phase I trial of perillyl alcohol administered four times daily for 14 days out of 28 days. Cancer Chemother Pharmacol 54:368–376

    Article  CAS  PubMed  Google Scholar 

  • Banks WA, Morley JE, Niehoff ML et al (2009) Delivery of testosterone to the brain by intranasal administration: comparison to intravenous testosterone. J Drug Target 17:91–97

    Article  CAS  PubMed  Google Scholar 

  • Belanger JT (1998) Perillyl alcohol: applications in oncology. Altern Med Rev 3:448–457

    CAS  PubMed  Google Scholar 

  • Caruso G, Caffo M, Alafaci C et al (2011) Could nanoparticle systems have a role in the treatment of cerebral gliomas? Nanomedicine 7:744–752

    CAS  PubMed  Google Scholar 

  • Chaudhary SC, Alam MS, Siddiqui MS et al (2009) Perillyl alcohol attenuates Ras-ERK signaling to inhibit murine skin inflammation and tumorigenesis. Chem Biol Interact 179:145–153

    Article  CAS  PubMed  Google Scholar 

  • Cho H-Y, Wang W, Jhaveri N et al (2012) Perillyl alcohol for the treatment of temozolomide-resistant gliomas. Mol Cancer Ther 11:2462–2472

    Article  CAS  PubMed  Google Scholar 

  • Crowell PL, Ren Z, Lin S et al (1994) Structure-activity relationships among monoterpene inhibitors of protein isoprenylation and cell proliferation. Biochem Pharmacol 47:1405–1415

    Article  CAS  PubMed  Google Scholar 

  • da Fonseca CO, Linden R, Futuro D et al (2008a) Ras pathway activation in gliomas: a strategic target for intranasal administration of perillyl alcohol. Arch Immunol Ther Exp 56:267–276

    Article  Google Scholar 

  • da Fonseca CO, Schwartsmann G, Fischer J et al (2008b) Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas. Surg Neurol 70:259–266

    Article  PubMed  Google Scholar 

  • da Fonseca CO, Simao M, Lins IR et al (2011a) Efficacy of monoterpene perillyl alcohol upon survival rate of patients with recurrent glioblastoma. J Cancer Res Clin Oncol 137:287–293

    Article  PubMed  Google Scholar 

  • da Fonseca CO, Teixeira RM, Ramina R et al (2011b) Case of advanced recurrent glioblastoma successfully treated with monoterpene perillyl alcohol by intranasal administration. J Cancer Ther 2:16–21

    Article  Google Scholar 

  • Das CB, Mahlingam SM, Panda L et al (2010) Design and synthesis of potential new apoptosis agents: hybrid compounds containing perillyl alcohol and new constrained retinoids. Tetrahedron Lett 51:1462–1466

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dhuria SV, Hanson LR, Frey WH (2010) Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci 99:1654–1673

    CAS  PubMed  Google Scholar 

  • Haag JD, Lindstrom MJ, Gould MN (1992) Limonene-induced regression of mammary carcinomas. Cancer Res 52:4021–4026

    CAS  PubMed  Google Scholar 

  • Hohl RJ, Lewis K (1995) Differential effects of monoterpenes and lovastatin on RAS processing. J Biol Chem 270:17508–17512

    Article  CAS  PubMed  Google Scholar 

  • Holstein SA, Hohl RJ (2003) Monoterpene regulation of Ras and Ras-related protein expression. J Lipid Res 44:1209–1215

    Article  CAS  PubMed  Google Scholar 

  • Hudes GR, Szarka CE, Adams A et al (2000) Phase I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patients with refractory solid malignancies. Clin Cancer Res 6:3071–3080

    CAS  PubMed  Google Scholar 

  • Loutrari H, Hatziapostolou M, Skouridou V et al (2004) Perillyl alcohol is an angiogenesis inhibitor. J Pharmacol Exp Ther 311:568–575

    Article  CAS  PubMed  Google Scholar 

  • Rajesh D, Stenzel RA, Howard SP (2003) Perillyl alcohol as a radio-/chemosensitizer in malignant glioma. J Biol Chem 278:35968–35978

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported in part by grants from Rio de Janeiro Research Foundation (FAPERJ grants E-26/111.263/2010; E-26/110.758/2011) and National Research Council (CNPq grants 401943/2010-0 and 481059/2011-3).

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The authors declare that they have no conflict of interest.

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Correspondence to Thereza Quirico-Santos.

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M. D’Alincourt Salazar and R. F. da Silva contributed equally to this work.

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D’Alincourt Salazar, M., da Silva, R.F., Da Fonseca, C.O. et al. Intranasal Administration of Perillyl Alcohol Activates Peripheral and Bronchus-Associated Immune System In Vivo. Arch. Immunol. Ther. Exp. 62, 59–66 (2014). https://doi.org/10.1007/s00005-013-0262-x

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  • DOI: https://doi.org/10.1007/s00005-013-0262-x

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