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Mitomycin C induces multidrug resistance in glaucoma surgery

  • Glaucoma
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Background

Despite the adjuvant use of mitomycin C during trabeculectomy, failures still occur. We investigated whether cultured human Tenon fibroblasts exposed to low-dose mitomycin C developed a multidrug resistance phenotype in vitro, and whether mitomycin C treatment during previous filtration surgery induces P-glycoprotein expression in vivo.

Methods

Cultured human Tenon fibroblasts treated with low-dose 0.01 nM mitomycin C for 2 weeks were subsequently treated with 0.1 to 100 μM mitomycin C in the absence or presence of 4 μM verapamil, and allowed to recover for 24 hours. Low-dose mitomycin C-treated fibroblasts were analysed for P-glycoprotein expression using flow cytometry, immunoblotting, and RT-PCR for mdr-1 mRNA. In addition, fibroblasts were treated with low dose 0.1 nM 5-fluorouracil for 2 weeks and analysed for P-glycoprotein expression using flow cytometry. Expression of P-glycoprotein was analysed in surgically removed Tenon tissue (n = 30) using immunohistochemistry. Of the 30 patients, 20 had a previous trabeculectomy, of which nine had previous adjuvant therapy with mitomycin C during trabeculectomy.

Results

Partial resistance to mitomycin C after low-dose mitomycin C pre-treatment was significantly neutralised by the addition of verapamil. Low-dose mitomycin C up-regulated P-glycoprotein expression, but not mdr-1 mRNA expression. 5-Fluorouracil did not induce P-glycoprotein expression. P-glycoprotein expression was detected in all nine patients exposed to mitomycin C during previous trabeculectomies. Only six of 21 specimens from patients not previously exposed to mitomycin C showed faint P-glycoprotein expression.

Conclusion

The induction of P-glycoprotein by mitomycin C could explain some failures that occur after repeated use of mitomycin C during trabeculectomy. The concomitant use of verapamil or the use of 5-fluorouracil alone could increase the success rate of repeat trabeculectomies.

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Acknowledgements

The authors thank Beatrix Martiny and Claudia Gavranic for their expert technical assistance. This study was supported by grants from the German Research Foundation (DFG Es 82/5-3), the Köln Fortune program, and the Centre for Molecular Medicine, Cologne (ZMMK).

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Author notes

  1. Johannes M. Esser & Peter J. Esser

    Present address: Department of Ophthalmology, St. Elisabeth Hospital, 50935, Cologne, Germany

Authors and Affiliations

  1. Centre of Ophthalmology, University of Cologne, 50931, Cologne, Germany

    Arno Hueber, Johannes M. Esser, Norbert Kociok, Gerhard Welsandt, Christoph Lüke, Sigrid Roters & Peter J. Esser

  2. Centre of Ophthalmology, University of Cologne, Joseph-Stelzmann-Strasse 9, 50931, Cologne, Germany

    Arno Hueber

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  1. Arno Hueber
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Correspondence to Arno Hueber.

Additional information

The authors have no commercial or proprietary interests in any products or companies.The authors have full control of all primary data, and they agree to allow Graefe’s Archive for Clinical and Experimental Ophthalmology to review their data if requested.The trial was registered at ClinicalTrials.gov with the reference number NCT00449631.

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Hueber, A., Esser, J.M., Kociok, N. et al. Mitomycin C induces multidrug resistance in glaucoma surgery. Graefes Arch Clin Exp Ophthalmol 246, 297–304 (2008). https://doi.org/10.1007/s00417-007-0695-1

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  • DOI: https://doi.org/10.1007/s00417-007-0695-1

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