Circumvention of Breast Cancer Resistance Protein (BCRP)-mediated Resistance to Camptothecins in Vitro Using Non-Substrate Drugs or the BCRP Inhibitor GF120918

Circumvention of Breast Cancer Resistance Protein (BCRP)-mediated Resistance to Camptothecins in Vitro Using Non-Substrate Drugs or the BCRP Inhibitor GF1209181

Divisions of Experimental Therapy [M. M., M. A. v. G., R. C. A. M. v. W., L. A. d. J., D. P., J. H. M. S.] and Medical Oncology [J. H. B., J. H. M. S.], The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Daiichi Pharmaceutical Co. Ltd., Tokyo 134-8630, Japan [A. T.]; and BioNumerik Pharmaceuticals, Inc., San Antonio, Texas 78229 [F. H. H.]

Abstract

This study was aimed at characterizing the role of BCRP/MXR/ABCP (BCRP) in resistance of the human ovarian tumor cell lines T8 and MX3 to camptothecins more extensively and investigating whether resistance can be reversed by inhibiting BCRP by GF120918. Camptothecins studied were topotecan, CPT-11, and its active metabolite SN-38, 9-aminocamptothecin, and the novel experimental camptothecins NX211, DX8951f, and BNP1350. Notably, DX8951f and BNP1350 appeared to be very poor substrates for BCRP, with much lower resistance factors observed both in T8 and MX3 cells than observed for the other camptothecins tested. In the presence of a nontoxic dose level of GF120918, the intracellular accumulation of topotecan in the T8 and MX3 cells was completely restored to the intracellular levels observed in the sensitive IGROV1 parental cell line. This resulted in almost complete reversal of drug resistance to topotecan and to most of the other topoisomerase I drugs tested in the T8 cell line and to complete reversal in the MX3 cells. However, coincubation of DX8951f or BNP1350 with GF120918 did not affect the cytotoxicity of either of these drugs significantly. From the combined data, we conclude that the affinities of topoisomerase I drugs for BCRP are, in decreasing order: SN-38 > topotecan > 9-aminocamptothecin ∼ CPT-11 > NX211 > DX8951f > BNP1350. Furthermore, GF120918 appears to be a potent reversal agent of BCRP-mediated resistance to camptothecins, with almost complete reversal noted at 100 nm. Potential BCRP-mediated resistance to topoisomerase I inhibitors can also be avoided by using the BCRP-insensitive drugs DX8951f or BNP1350. This observation may have important clinical implications for future development of novel camptothecins.

Footnotes

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵1 Supported by Grants NKI 95-1059 and NKI 99-2060 from the Dutch Cancer Society.
↵2 To whom request for reprints should be addressed, at the Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Phone: 31-20-5122569; Fax: 31-20-5122050; E-mail: JHM{at}nki.nl
↵3 The abbreviations used are: topo I, topoisomerase I; TPT, topotecan; P-gp, P-glycoprotein; BCRP, breast cancer resistance protein; 9-AC, 9-aminocamptothecin; CPT-11, irinotecan; MRP, multidrug resistance-associated protein; SRB, sulforhodamine B; Rf, resistance factor; FTC, fumitremorgin C.
- Accepted November 1, 1900.
- Received June 28, 1900.
- Revision received October 31, 1900.