Doxorubicin-peptide conjugates overcome multidrug resistance

A well-known mechanism leading to the emergence of multidrug-resistant tumo r cells is the overexpression of P-glycoprotein (P-gp), which is capable of lowering intracellular drug concentrations. To overcome this problem, we t ested the capability of two peptide vectors that are able to cross cellular membranes to deliver doxorubicin in P-gp-expressing cells. The antitumor e ffect of peptide-conjugated doxorubicin was tested in human erythroleukemic (K562/ADR) resistant cells. The conjugate showed potent dose-dependent inh ibition of cell growth against K562/ADR cells as compared with doxorubicin alone. Doxorubicin exhibited IC50 concentrations of 65 muM in the resistant cells, whereas vectorized doxorubicin was more effective with IC50 concent rations of 3 muM. After treatment of the resistant cells with verapamil, th e intracellular levels of doxorubicin were markedly increased and consequen t cytotoxicity was improved. In contrast, treatment of resistant cells with verapamil did not cause any further enhancement in the cell uptake nor in the cytotoxic effect of the conjugated doxorubicin, indicating that the con jugate bypasses the P-gp. Finally, we show by the in situ brain perfusion m ethod in P-gp-deficient and competent mice that vectorized doxorubicin bypa sses the P-gp present at the luminal site of the blood-brain barrier. These results indicate that vectorization of doxorubicin with peptide vectors is effective in overcoming multidrug resistance. [(C) 2001 Lippincott William s & Wilkins.].