MDR1 causes resistance to the antitumour drug miltefosine

Miltefosine (hexadecylphosphocholine) is used for topical treatment of brea st cancers. It has been shown previously that a high percentage of breast c arcinomas express MDR1 or MRP. We investigated the sensitivity of MDR1-expr essing cells to treatment with miltefosine. We show that cells overexpressi ng MDR1 (NCI/ADR-RES, KB-8-5, KB-C1, CCRF/VCR1000, CCRF/ADR5000) were less sensitive to miltefosine treatment when compared to the sensitive parental cell lines. HeLa cells transfected with MDR1 exhibited resistance to the co mpound, indicating that expression of this gene is sufficient to reduce the sensitivity to miltefosine. The resistance of MDR1-expressing cells to mil tefosine was less pronounced than that to adriamycin or vinblastine. Expres sion of MDR2 did not correlate with the resistance to miltefosine. As shown by a fluorescence quenching assay using MIANS-labelled P-glycoprotein (PGP ), miltefosine bound to PGP with a K-d of approximately 7 muM and inhibited PGP-ATPase activity with an IC50 of approximately 35 muM Verapamil was not able to reverse the resistance to miltefosine. Concentrations of miltefosi ne up to approximately 60 muM stimulated, whereas higher concentrations inh ibited the transport of [H-3]-colchicine with an IC50 of approximately 297 muM. Binding studies indicated that miltefosine seems to interact with the transmembrane domain and not the cytosolic nucleotide-binding domain of PGP . These data indicate that expression of MDR1 may reduce the response to mi ltefosine in patients and that this compound interacts with PGP in a manner different from a number of other substrates. (C) 2001 Cancer Research Camp aign.