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Multidrug Resistance Protein (MRP) Expression in Retinoblastoma Correlates with the Rare Failure of Chemotherapy despite Cyclosporine for Reversal of P-Glycoprotein¹

Divisions of Hematology/Oncology, Immunology & Cancer Research, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8 Canada [H. S. L. C., G. H.]; Departments of Pediatrics [H. S. L. C., G. H.], Ophthalmology [Y. L., B. L. G.], and Molecular and Medical Genetics [B. L. G.], University of Toronto, Toronto, Ontario, M5S 1A8 Canada; British Columbia Cancer Agency, University of British Columbia, 601 West 10th Avenue, Vancouver, British Columbia, V5Z IL3 Canada [V. L.]; Cancer Research Laboratories, Queen's University, Botterell Hall, Kingston, Ontario, K7L 3N6 Canada [D. R. H., S. P. C. C., R. G. D.]; and Department of Pathology, Arizona Health Science Center, College of Medicine, University of Arizona, Tucson, Arizona 85724 [T. M. G.]

Failure of chemotherapy associated with expression of the multidrug resistance protein p170 frequently occurs in retinoblastoma (RB). Despite using cyclosporine, which inhibits p170 and improves our chemotherapy results, rare failures occur. In nonmetastatic primarily enucleated RBs, we show expression of p170 in 3 of 18 samples and expression of multidrug resistance protein (MRP), the second protein associated with resistance to chemotherapy, in 1 of 18 samples. All three RBs that failed chemotherapy without cyclosporine expressed MRP with p170. All three RBs that were enucleated immediately when chemotherapy failed despite the addition of cyclosporine expressed only MRP. One RB enucleated 2 years after failing chemotherapy with cyclosporine, despite radiation and salvage chemotherapy, expressed both p170 and MRP. Two metastatic RBs that expressed both p170 and MRP at diagnosis and at recurrence failed chemotherapy without cyclosporine, whereas one metastatic RB that expressed neither protein was cured by chemotherapy without cyclosporine. MRP may result in failure of chemotherapy despite the elimination of p170-expressing clones by cyclosporine.

¹ Supported by grants from the National Cancer Institute of Canada (to H. S. L. C., V. L., B. L. G., R. G. D., and S. P. C. C.); Medical Research Council of Canada (to H. S. L. C., S. P. C. C., R. G. D., V. L., and B. L. G)0; Elsa U. Pardee Foundation (to H. S. L. C.); Sandoz Canada, Inc., Hospital for Sick Children Pediatric Consultants and Research Institute, Atkinson Charitable Foundation (to H. S. L. C.); Canadian Genetic Diseases Network; Retinoblastoma Family Association; and Royal Arch Masons of Canada (to B. L. G.); and by NIH USPHS Grant CA37130 (to V. L.) and National Cancer Institute Grants CA32102 and CA17094 (to T. M. G.). S. P. C. C. is a Senior Scientist of the Ontario Cancer Treatment and Research Foundation. R. G. D. is the Stauffer Research Professor of Queen's University. B. L. G. is a Distinguished Scientist of the Medical Research Council of Canada.

² To whom requests for reprints should be addressed. Phone: (416) 813-5872; Fax: (416) 813-5327.

Received 2/17/97. Accepted 4/30/97.

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