COMPLEMENT ACTIVATION BY CREMOPHOR EL AS A POSSIBLE CONTRIBUTOR TO HYPERSENSITIVITY TO PACLITAXEL - AN IN-VITRO STUDY

Background: Cancer patients treated with the anticancer drug, paclitax el (Taxol) often experience mild to severe hypersensitivity reactions, It is not known how these reactions are induced and whether the induc er is paclitaxel or its vehicle (i.e., Cremophor EL in 50% ethanol), M olecules present in Cremophor EL are similar in structure to certain n onionic block copolymers that activate complement proteins (i.e., prot eins involved in various immune processes), To explore the role of com plement in the observed hypersensitivity reactions, we studied the eff ects of paclitaxel and Cremophor EL plus ethanol on human complement i n vitro. Methods: Serum specimens from healthy individuals and cancer patients were incubated with paclitaxel or with relevant control compo unds (Cremophor EL with ethanol, ethanol only, docetaxel, and cyclospo rine), and markers of complement activation (SC5b-9 and Bb) were measu red by enzyme-linked immunosorbent assay, Similar incubations were per formed in the presence of inhibitors of complement activation (i.e., E GTA/Mg2+ and soluble complement receptor type 1 [sCR1]), Results: Pacl itaxel in Cremophor EL plus ethanol caused increased formation of SC5b -9 in serum specimens from 10 of 10 healthy control subjects and from five of 10 cancer patients, Experiments with one or more individual se ra indicated the above effect was due to Cremophor EL plus ethanol, th at increased formation of Bb also occurred, that the drug-induced rise in SC5b-9 was inhibited by sCR1, and that EGTA/Mg2+ partially inhibit ed SC5b-9 formation and stimulated Bb formation, Implication: The role of complement activation in hypersensitivity reactions associated wit h administration of paclitaxel in Cremophor EL plus ethanol should be studied in vivo.