Tosi P F, Radu D, Nicolau C
Center for Blood Research Laboratories, Boston, MA 02135, USA.
Biochem Biophys Res Commun. 1995 Jul 17;212(2):494-500. doi: 10.1006/bbrc.1995.1997.
Intrinsically, or after exposure to chemotherapeutic drugs, many cancer cells overexpress a class of high molecular weight membrane glycoproteins associated with the multidrug resistance (mdr) of these cells. This 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 of 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. Antibodies against the lipopeptides corresponding to loop 2 and 4 were elicited in sera of immunized mice. They reacted specifically with extracellular epitopes of the naturally occurring murine Pgp. After interaction with resistant cancer cells, the antibodies induced an average 50% increase in cellular accumulation of doxorubicin and Bodipy-verapamil. In the presence of these antibodies the resistance of L1210 mdr cells was reduced from an LD50 of 4 x 10(-5) M to 5 x 10(-7) M doxorubicin.
本质上，或者在接触化疗药物后，许多癌细胞会过度表达一类与这些细胞的多药耐药性（mdr）相关的高分子量膜糖蛋白。本报告描述了一种免疫方案，该方案可引发针对小鼠mdr 1 P - 糖蛋白（Pgp）细胞外表位的自身抗体。具有小鼠Pgp细胞外环序列的合成肽与每个肽分子四个棕榈酸部分共价偶联。这些“脂肽”在含有脂多糖A的脂质体双层中重构，并用于免疫小鼠。在免疫小鼠的血清中引发了针对对应于环2和环4的脂肽的抗体。它们与天然存在的小鼠Pgp的细胞外表位特异性反应。与耐药癌细胞相互作用后，这些抗体使阿霉素和Bodipy - 维拉帕米的细胞积累平均增加50％。在这些抗体存在的情况下，L1210 mdr细胞对阿霉素的耐药性从LD50为4×10（-5）M降低到5×10（-7）M。
