IMMUNE-RESPONSE AGAINST THE MURINE MDRI PROTEIN-INDUCED BY VACCINATION WITH SYNTHETIC LIPOPEPTIDES IN LIPOSOMES

Intrinsically, or after exposure to chemotherapeutic drugs, many cance r cells overexpress a class of high molecular weight membrane glycopro teins associated with the multidrug resistance (mdr) of these cells. T his report describes an immunization protocol eliciting autoantibodies specific to extracellular epitopes of the murine mdr 1 P-glycoprotein (Pgp). Synthetic peptides with the sequences of extracellular loops o f murine Pgp were covalently coupled with four palmitic acid moieties per peptide molecule. These ''lipopeptides'' were reconstituted in the bilayer of liposomes containing lipid A and used to immunize mice. An tibodies against the lipopeptides corresponding to loop 2 and 4 were e licited in sera of immunized mice. They reacted specifically with extr acellular epitopes of the naturally occurring murine Pgp. After intera ction with resistant cancer cells, the antibodies induced an average 5 0% increase in cellular accumulation of doxorubicin and Bodipy-verapam il. In the presence of these antibodies the resistance of L1210 mdr ce lls was reduced from an LD(50) of 4 x 10(-5) M to 5 x 10(-7) M doxorub icin. (C) 1995 Academic Press, Inc.