Dear Editor

We have read with interest the manuscript “Multidrug resistant proteins: P-glycoprotein and lung resistance protein expression in retinoblastoma” by Krishnakumar S, Mallikarjuna K, Desai N, et al [1]. We have studied 18 children with retinoblastoma using immunohistochemical detection of P-glycoprotein by the mouse monoclonal antibody HYB-241 in frozen section tumor samples. Like Krishnakumar et al, we found limited expression of P-glycoprotein in retinoblastoma cells since only four of the 18 samples were positive. However, 6 of 18 samples had P-glycoprotein positivity in tumor-associated endothelial cells. Contrarily to Krishnakumar S et al, we had the opportunity of evaluating children that received prior therapy with drugs that can be affected by P-glycoprotein and no obvious difference in its expression was evident. Only one of the three tumor samples coming from patients who had been exposed to P-glycoprotein mediated chemotherapeutic agents (vincristine and/or etoposide) were positive in retinoblastoma cells. In addition of the 6 cases in which P-glycoprotein was detected in tumor-associated endothelial cells, only one of them came from a patient who had been exposed to P-glycoprotein mediated chemotherapeutic agents (etoposide). Also, one patient whose tumor and tumor-associated endothelium were negative had endothelial cells in the optic nerve that were positive. The patient had not been exposed to P-glycoprotein mediated chemotherapy.

There is little information regarding its expression in normal eye blood vessels, but P-glycoprotein expression has been detected in the normal human retinal pigment epithelium and post laminar optic nerve [2] and it is absent in the permeable microvessels of the choroid and the ciliary process [3]. P-Glycoprotein expression in endothelial cells of newly formed capillaries induced by tumors has also been described [4]. Its prognostic relevance in retinoblastoma is unknown, and it cannot be determined form our data, since all of these eyes were already enucleated and no patient suffered an extraocular relapse.

The potential role of P-glycoprotein in tumor-associated endothelium creating a blood-tumor barrier is uncertain. Our results suggest that if cyclosporine is indeed improving the efficacy of chemotherapy, it may be acting by improving its delivery through P-glycoprotein expressing tumor- associated endothelial cells or through altering pharmacokinetics of chemotherapeutic drugs, rather than exclusively acting to reverse drug resistance at the level of the tumor cell.

Our data do not support the hypothesis that cyclosporine will be a useful adjunct to chemotherapy for the treatment of retinoblastoma via competitive inhibition of P-glycoprotein in tumor cells.

Disclosure There is no financial interest of the authors with any of the drugs and devices mentioned.

References

(1) Krishnakumar S, Mallikarjuna K, Desai N, et al. Multidrug resistant proteins: P-glycoprotein and lung resistance protein expression in retinoblastoma. Br J Ophthalmol 2004;88:1521-1526.

(2) Kennedy B, Mangini N. P Glycoprotein expression in human retinal pigment epithelium. Mol Vis 2002, 8, 422-430.

(3) Hofman P, Hoyng P, vander Werf F, Vrensen G, Schlingemann R. Lack of blood-brain barrier properties in microvessels of the prelaminar optic nerve head. Invest Ophthalmol Vis Sci 2001, 42, 895-901.

(4) Camassei FD, Arancia G, Cianfriglia M, et al: Nephroblastoma: multidrug resistance P-glycoprotein expression in tumor cells and intratumoral capillary endothelial cells. Am J Clin Pathol 2002, 117 (3), 484-90.