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Mitomycin C induces multidrug resistance in glaucoma surgery

  • Arno HueberEmail author
  • Johannes M. Esser
  • Norbert Kociok
  • Gerhard Welsandt
  • Christoph Lüke
  • Sigrid Roters
  • Peter J. Esser
Glaucoma

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.

Keywords

Glaucoma surgery Conjunctiva Cell culture Antiproliferative effects Multidrug resistance 

Notes

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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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Arno Hueber
    • 1
    • 2
    Email author
  • Johannes M. Esser
    • 1
    • 3
  • Norbert Kociok
    • 1
  • Gerhard Welsandt
    • 1
  • Christoph Lüke
    • 1
  • Sigrid Roters
    • 1
  • Peter J. Esser
    • 1
    • 3
  1. 1.Centre of OphthalmologyUniversity of CologneCologneGermany
  2. 2.Centre of OphthalmologyUniversity of CologneCologneGermany
  3. 3.Department of OphthalmologySt. Elisabeth HospitalCologneGermany

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