REVERSAL OF C1300 MURINE NEUROBLASTOMA MULTIDRUG-RESISTANCE BY CREMOPHOREL, A SOLVENT FOR CYCLOSPORINE-A

We previously developed a homoharringtonine resistant C-1300 neuroblas toma cell line with cross-resistance to adriamycin and increased level s of p-glycoprotein, and showed that drug resistance could be reversed in this cell line by cyclosporin A. The present study shows that crem ophor EL, a parenteral vehicle for cyclosporin A, can also completely reverse this multidrug resistance in a clonogenic assay system. Cremop hor EL incubated with resistant cells for up to six days did not. redu ce levels of p-glycoprotein. Intracellular homoharringtonine analysis using HPLC revealed increased drug accumulation in resistant cells tre ated with cremophor EL. The increased drug level was not due to blocki ng of drug efflux commonly seen in other multidrug resistant models. T he data suggest that resistance modulation with cyclosporin A should b e interpreted with caution when cremophor EL is a solvent. Our work su ggests cremophor EL, a relatively nontoxic. lipophylic solvent, may ha ve a direct effect on membrane permeability, although other mechanisms cannot be ruled out.