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Megalin genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin

The Pharmacogenomics Journal volume 8, pages 23–28 (2008)Cite this article

Abstract

Ototoxicity and nephrotoxicity are dose-limiting side effects of cisplatin. Megalin, a member of the low-density lipoprotein receptor family, is highly expressed in renal proximal tubular cells and marginal cells of the stria vascularis of the inner ear – tissues, which accumulate high levels of platinum–DNA adducts. On the assumption that the mechanisms of cisplatin-induced nephro- and ototoxicity involve megalin we analyzed the incidence of the non-synonymous single nucleotide polymorphisms (SNP) rs2075252 and rs4668123 in 25 patients who developed a distinct hearing loss during cisplatin therapy and in 25 patients without hearing impairment after cisplatin therapy. We found no association between cisplatin-induced ototoxicity and any allele of rs4668123 but observed a higher frequency of the A-allele of rs2075252 in the group with hearing impairment than in the group with normal hearing after cisplatin therapy (0.32 versus 0.14) (χ2=5.83, P<0.02; odds ratio: 3.45; 95% confidence interval: 1.11–11.2) indicating that SNPs at the megalin gene might impact the individual susceptibility against cisplatin-induced ototoxicity.

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References

  1. Brock PR, Bellman SC, Yeomans EC, Pinkerton CR, Pritchard J . Cisplatin ototoxicity in children: a practical grading system. Med Pediatr Oncol 1991; 19: 295–300.

    Article  CAS  PubMed  Google Scholar 

  2. Laurell G, Jungnelius U . High-dose cisplatin treatment: hearing loss and plasma concentrations. Laryngoscope 1990; 100: 724–734.

    Article  CAS  PubMed  Google Scholar 

  3. Weatherly RA, Owens JJ, Catlin FI, Mahoney DH . cis-platinum ototoxicity in children. Laryngoscope 1991; 101: 917–924.

    Article  CAS  PubMed  Google Scholar 

  4. Blakley BW, Gupta AK, Myers SF, Schwan S . Risk factors for ototoxicity due to cisplatin. Arch Otolaryngol Head Neck Surg 1994; 120: 541–546.

    Article  CAS  PubMed  Google Scholar 

  5. McHaney VA, Thibadoux G, Hayes FA, Green AA . Hearing loss in children receiving cisplatin chemotherapy. J Pediatr 1983; 102: 314–317.

    Article  CAS  PubMed  Google Scholar 

  6. Schaefer SD, Post JD, Close LG, Wright CG . Ototoxicity of low- and moderate-dose cisplatin. Cancer 1985; 56: 1934–1939.

    Article  CAS  PubMed  Google Scholar 

  7. Lanvers-Kaminsky C, Krefeld B, Dinnesen AG, Deuster D, Seifert E, Wurthwein G et al. Continuous or repeated prolonged cisplatin infusions in children: a prospective study on ototoxicity, platinum concentrations, and standard serum parameters. Pediatr Blood Cancer 2006; 47: 183–193.

    Article  CAS  PubMed  Google Scholar 

  8. Boulikas T, Vougiouka M . Cisplatin and platinum drugs at the molecular level (Review). Oncol Rep 2003; 10: 1663–1682.

    CAS  PubMed  Google Scholar 

  9. Schellens JH, Ma J, Planting AS, van der Burg ME, van Meerten E, de Boer-Dennert M et al. Relationship between the exposure to cisplatin, DNA-adduct formation in leucocytes and tumour response in patients with solid tumours. Br J Cancer 1996; 73: 1569–1575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Thomas JP, Lautermann J, Liedert B, Seiler F, Thomale J . High accumulation of platinum-DNA adducts in strial marginal cells of the cochlea is an early event in cisplatin but not carboplatin ototoxicity. Mol Pharmacol 2006; Mar: 28.

    Google Scholar 

  11. Schweitzer VG, Rarey KE, Dolan DF, Abrams G, Litterst CJ, Sheridan C . Ototoxicity of cisplatin vs. platinum analogs CBDCA (JM-8) and CHIP (JM-9). Otolaryngol Head Neck Surg 1986; 94: 458–470.

    Article  CAS  PubMed  Google Scholar 

  12. Schweitzer VG . Cisplatin-induced ototoxicity: the effect of pigmentation and inhibitory agents. Laryngoscope 1993; 103: 1–52.

    CAS  PubMed  Google Scholar 

  13. Schmitz C, Hilpert J, Jacobsen C, Boensch C, Christensen EI, Luft FC et al. Megalin deficiency offers protection from renal aminoglycoside accumulation. J Biol Chem 2002; 277: 618–622.

    Article  CAS  PubMed  Google Scholar 

  14. Schmidt CM, Bartholomaus E, Deuster D, Heinecke A, Dinnesen AG . The ‘Muenster classification’ of high frequency hearing loss following cisplatin chemotherapy. HNO 2006: 26 (Epub ahead of print).

  15. Mizuta K, Saito A, Watanabe T, Nagura M, Arakawa M, Shimizu F et al. Ultrastructural localization of megalin in the rat cochlear duct. Hear Res 1999; 129: 83–91.

    Article  CAS  PubMed  Google Scholar 

  16. Li Y, Womer RB, Silber JH . Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose. Eur J Cancer 2004; 40: 2445–2451.

    Article  CAS  PubMed  Google Scholar 

  17. Livak KJ, Flood SJ, Marmaro J, Giusti W, Deetz K . Oligonucleotides with fluorescent dyes at opposite ends provide a quenched probe system useful for detecting PCR product and nucleic acid hybridization. PCR Methods Appl 1995; 4: 357–362.

    Article  CAS  PubMed  Google Scholar 

  18. de Kok JB, Wiegerinck ET, Giesendorf BA, Swinkels DW . Rapid genotyping of single nucleotide polymorphisms using novel minor groove binding DNA oligonucleotides (MGB probes). Hum Mutat 2002; 19: 554–559.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The data presented in this article fulfill the requirements for the medical doctoral thesis of LR at the University of Muenster, Germany.

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Author notes

  1. L Riedemann and C Lanvers: Both these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, University Children's Hospital, Muenster, Germany

    L Riedemann, C Lanvers, J Boos & H Jürgens

  2. Department of Phoniatrics and Pediatric Audiology, University Hospital of Muenster, Muenster, Germany

    D Deuster, U Peters & A am Zehnhoff-Dinnesen

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  1. L Riedemann
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  2. C Lanvers
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  3. D Deuster
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  4. U Peters
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  5. J Boos
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  6. H Jürgens
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  7. A am Zehnhoff-Dinnesen
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Correspondence to A am Zehnhoff-Dinnesen.

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Riedemann, L., Lanvers, C., Deuster, D. et al. Megalin genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin. Pharmacogenomics J 8, 23–28 (2008). https://doi.org/10.1038/sj.tpj.6500455

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