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Effects of nefazodone on the development of experimentally induced tumors in stressed rodents

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Abstract

Rationale

Anxiety and depression are commonly encountered in patients with cancer and constitute risk and prognostic factors for the disease. Although previous findings do not support an overall association between the use of antidepressants and higher prevalence of cancer, results for serotonin uptake inhibitors are not entirely reassuring.

Objectives

We evaluated the effects of nefazodone, a serotonin and norepinephrine (NE) reuptake inhibitor and 5-HT2A receptor antagonist antidepressant, on the appearance of breast cancer induced by mammary tumor virus (MTV) in mice, and on the development of lung metastases in rats injected intravenously with Walker 256 (W-256) carcinosarcoma cells.

Methods

Female C3H/He mice carrying the MTV were monitored for mammary tumor incidence and latent periods while being treated with a daily intraperitoneal injection with placebo or nefazodone. Rats were administered 104 W-256 cells, exposed to a chronic auditory stressor for 8 days, and then killed to evaluate metastatic nodules in the lungs.

Results

Although all of the mice were potential candidates for MTV-induced breast cancer, those treated with nefazodone were partially protected against adverse effects of stress induced by the daily administration of placebo on both parameters. Relative to placebo, nefazodone reduced the stress-induced increase in the number and percentage area of metastases in the frontal section through pulmonary hilus and increased the survival periods of rats given W-256 cells and exposed to a chronic auditory stressor.

Conclusions

Our results provide evidence of the beneficial effects of nefazodone against the adverse effects of stress on tumor development and metastaticity in rodents, but did not show significant effects in unstressed rodents.

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References

  • Abdul M, Anezinis PE, Logothetis CJ, Hoosein NM (1994) Growth inhibition of human prostatic carcinoma cell lines by serotonin antagonists. Anticancer Res 14:1215–1220

    CAS  PubMed  Google Scholar 

  • Ader R, Felten D, Cohen N (1990) Interactions between the brain and the immune system. Annu Rev Pharmacol Toxicol 30:561–602

    Article  CAS  PubMed  Google Scholar 

  • Bendele RA, Adams ER, Hoffman WP, Gries CL, Morton DM (1992) Carcinogenicity studies of fluoxetine hydrochloride in rats and mice. Cancer Res 52:6931–6935

    CAS  PubMed  Google Scholar 

  • Ben-Eliyahu S, Yirmiya R, Shavit Y, Liebeskind JC (1990) Stress-induced suppression of natural killer cell cytotoxicity in the rat: a naltrexone-insensitive paradigm. Behav Neurosci 104:235–238

    Article  CAS  PubMed  Google Scholar 

  • Benschop RJ, Jacobs R, Sommer B, Schurmeyer TH, Raab JR, Schmidt RE, Schedlowski M (1996) Modulation of the immunologic response to acute stress in humans by beta-blockade or benzodiazepines. FASEB J 10:517–524

    CAS  PubMed  Google Scholar 

  • Biondi M, Kotzalidis D (1990) Human psychoneuroimmunology today. J Clin Lab Anal 4:22–38

    CAS  PubMed  Google Scholar 

  • Blalock JE (1990) Molecular mechanisms of bidirectional communication between the immune and neuroendocrine systems. Int J Neurosci 51:363–364

    CAS  PubMed  Google Scholar 

  • Blalock JE, Bost KL, Smith EM (1985) Neuroendocrine peptide hormones and their receptors in the immune system. Production, processing and action. J Neuroimmunol 10:31–40

    Article  CAS  PubMed  Google Scholar 

  • Brandes LJ, Cheang M (1993). Response to antidepressants and cancer: cause for concern? J Clin Psychopharmacol 13:458

    PubMed  Google Scholar 

  • Cattaneo MG, Fesce R, Vicentini LM (1995) Mitogenic effect of serotonin in human small cell lung carcinoma cells via both 5-HT1A and 5-HT1D receptors. Eur J Pharmacol 291:209–211

    Article  CAS  PubMed  Google Scholar 

  • Cotterchio M, Kreiger N, Darlington G, Steingart A (2000) Antidepressant medication use and breast cancer risk. Am J Epidemiol 151:951–957

    CAS  PubMed  Google Scholar 

  • Covelli V, Munno I, Decandia P, Altamura M, Cannuscio B, Maffione AB, Jirillo E (1991) Effects of benzodiazepines on the immune system. Acta Neurol 13:418–423

    CAS  Google Scholar 

  • Crowson AN, Magro CM (1995) Antidepressant therapy. A possible cause of atypical cutaneous lymphoid hyperplasia. Arch Dermatol 131:925–929

    Article  CAS  PubMed  Google Scholar 

  • Dalton SO, Johansen C, Mellemkjaer L, Sorensen HT, McLaughlin JK, Olsen J, Olsen JH (2000) Antidepressant medications and risk for cancer. Antidepressant medications and risk for cancer. Epidemiology 11:171–176

    Article  CAS  PubMed  Google Scholar 

  • Davis R, Whittington R, Bryson HM (1997) Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression. Drugs 53:608–636

    CAS  PubMed  Google Scholar 

  • Eskandari F, Sternberg EM (2002) Neural-immune interactions in health and disease. Ann N Y Acad Sci 966:20–27

    CAS  PubMed  Google Scholar 

  • Freire-Garabal M, Núñez MJ, Balboa JL, Suárez JA, Belmonte A (1991) Effects of alprazolam on the development of MTV-induced mammary tumors in female mice under stress. Cancer Lett 62:185–189

    Article  Google Scholar 

  • Freire-Garabal M, Núñez MJ, Balboa JL, Fernández-Rial JC, Vallejo LG, González JG, Rey-Méndez M (1993) Effects of alprazolam on cellular immune response to surgical stress in mice. Cancer Lett 73:155–160

    Article  CAS  PubMed  Google Scholar 

  • Freire-Garabal M, Núñez MJ, Pereiro D, Riveiro P, Losada C, Fernández-Rial JC, García-Iglesias E, Prizmic J, Mayán JM, Rey-Méndez M (1998) Effects of fluoxetine on the development of lung metastases induced by operative stress in rats. Life Sci 63:31–38

    Article  Google Scholar 

  • Freire-Garabal M, Varela M, Riveiro P, Balboa J, Liñares D, Mañá P, Mayán JM, Rey-Méndez M, Núñez MJ (2000) Effects of nefazodone on the immune system. Eur Neuropsychopharmacol 10:255–264

    Article  CAS  PubMed  Google Scholar 

  • Fride E, Skolnick P, Arora PK (1990) Immunoenhancing effects of alprazolam in mice. Life Sci 47:2409–2420

    Article  CAS  PubMed  Google Scholar 

  • Hattori T, Hamai Y, Ikeda H, Harada T, Ikeda T (1978) Enhancing effect of thoracotomy on tumor growth in rats. Gann 69:401–406

    CAS  PubMed  Google Scholar 

  • Irwin M, Hauger RL, Britton K (1993) Benzodiazepines antagonize central corticotropin releasing hormone-induced suppression of natural killer cell activity. Brain Res 631:114–118

    Article  CAS  PubMed  Google Scholar 

  • Justice A (1985) Review of the effects of stress on cancer in laboratory animals: importance of time of stress application and type of tumor. Psychol Bull 98:108–138

    Article  CAS  PubMed  Google Scholar 

  • Keller SE, Schleifer SJ, Camerino MA, Falini JA, Halperin J, Stein M (1984) Stress-induced suppression of antibody production and PFCs in the rat. Psychosom Med 46:286–293

    Google Scholar 

  • Kelly JP, Rosenberg L, Palmer JR, Rao RS, Strom BL, Stolley PD, Zauber AG, Shapiro S (1999) Risk of breast cancer according to use of antidepressants, phenothiazines, and antihistamines. Am J Epidemiol 150:861–868

    CAS  PubMed  Google Scholar 

  • Matheson GK, Knowles A, Guthrie D, Gage D, Weinzapfel D, Blackbourne J (1997) Actions of serotonergic agents on hypothalamic-pituitary-adrenal axis activity in the rat. Gen Pharmacol 29:823–828

    CAS  PubMed  Google Scholar 

  • Mathews J (1995) Concern over Prozac-induced tumor growth may dwindle following FDA study. J Natl Cancer Inst 87:1285–1287

    CAS  PubMed  Google Scholar 

  • Medina D, DeOne KB (1970) Carcinogen-induced mammary tumors from preneoplastic nodule outgrowths in BALB-c mice. Cancer Res 30:1055–1059

    CAS  PubMed  Google Scholar 

  • Monjan AA, Collector MI (1977) Stress-induced modulation of the immune response. Science 15:307–308

    Google Scholar 

  • Murphy JM, Monson RR, Olivier DC, Sobol AM, Leighton AH (1987) Affective disorders and mortality. A general population study. Arch Gen Psychiatry 44:473–480

    CAS  PubMed  Google Scholar 

  • Pellegrino TC, Bayer BM (1998) Modulation of immune cell function following fluoxetine administration in rats. Pharmacol Biochem Behav 59:151–157

    Article  CAS  PubMed  Google Scholar 

  • Riley V (1975) Mouse mammary tumors: alteration of incidence as apparent function of stress. Science 189:465–467

    CAS  PubMed  Google Scholar 

  • Riley V (1981) Psychoneuroendocrine influences on immunocompetence and neoplasia. Science 212:1100–1109

    CAS  PubMed  Google Scholar 

  • Sanders VM, Straub RH (2002) Norepinephrine, the beta-adrenergic receptor, and immunity. Brain Behav Immun 16:290–332

    Article  CAS  PubMed  Google Scholar 

  • Schlumpf M, Parmar R, Butikofer EE, Inderbitzin S, Salili AR, Schreiber AA, Ramseier HR, van Loveren H, Lichtensteiger W (1995) Delayed developmental neuro- and immunotoxicity of benzodiazepines. Arch Toxicol Suppl 17:261–287

    CAS  PubMed  Google Scholar 

  • Shekelle RB, Raynor WJ, Ostfeld AM, Garron DC, Bieliauskas LA, Liu SC, Maliza C, Paul O (1981) Psychological depression and 17-year risk of death from cancer. Psychosom Med 43:117–125

    CAS  PubMed  Google Scholar 

  • Steplewski Z, Goldman PR, Ehya H, Poropatich C, Smith JM (1985) Effects of restraint stress on inoculated tumor growth and immune response in rats. Cancer Res 45:5128–5130

    CAS  PubMed  Google Scholar 

  • Storch DD (1996) Do antidepressants promote tumor growth? Am J Psychiatry 153:446

    CAS  Google Scholar 

  • Stucker O, Laemmel E, Teisseire B, Vicaut E (1997) Specific response of mouse tumor-feeding arterioles to stimulation by 5-HT1 agonists. Int J Radiat Oncol Biol Phys 37:1125–1131

    Article  CAS  PubMed  Google Scholar 

  • Surman OS (1993) Possible immunological effects of psychotropic medication. Psychosomatics 34:139–143

    CAS  PubMed  Google Scholar 

  • Van den Brenk HAS, Stone MG, Kelly H, Sharpington C (1976) Lowering of innate resistance of the lungs to the growth of blood-borne cancer cells in states of topical and systemic stress. Br J Cancer 33:60–78

    PubMed  Google Scholar 

  • Wallace WA, Balsitis M, Harrison BJ (2001) Male breast neoplasia in association with selective serotonin re-uptake inhibitor therapy: a report of three cases. Eur J Surg Oncol 27:429–431

    Article  CAS  PubMed  Google Scholar 

  • Walsh AE, Cowen PJ (1994) Attenuation of the prolactin-stimulating and hyperthermic effects of nefazodone after subacute treatment. J Clin Psychopharmacol 14:268–273

    CAS  PubMed  Google Scholar 

  • Weigent DA, Blalock JE (1990) Immunoreactive growth hormone releasing hormone production by rat leukocytes. J Neuroimmunol 29:1–13

    Article  CAS  PubMed  Google Scholar 

  • Zavala F (1997) Benzodiazepines, anxiety and immunity. Pharmacol Ther 75:199–216

    CAS  PubMed  Google Scholar 

Download references

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Authors and Affiliations

  1. Neuroimmunology Laboratory, Department of Pharmacology, School of Medicine, C/San Francisco, s/n. Santiago de Compostela, A Coruna, 15782, Spain

    Manuel Freire-Garabal, Manuel Rey-Méndez, Luis A. García-Vallejo, José Balboa, José M. Suárez, Elena Rodrigo, Julio Brenlla & María J. Núñez

Authors
  1. Manuel Freire-Garabal
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  2. Manuel Rey-Méndez
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  3. Luis A. García-Vallejo
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  4. José Balboa
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  5. José M. Suárez
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  6. Elena Rodrigo
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  7. Julio Brenlla
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  8. María J. Núñez
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Correspondence to Manuel Freire-Garabal.

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Freire-Garabal, M., Rey-Méndez, M., García-Vallejo, L.A. et al. Effects of nefazodone on the development of experimentally induced tumors in stressed rodents. Psychopharmacology 176, 233–238 (2004). https://doi.org/10.1007/s00213-004-1909-4

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  • DOI: https://doi.org/10.1007/s00213-004-1909-4

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