Reversal of C1300 murine neuroblastoma multidrug resistance by cremophorEL, a solvent for cyclosporin A.
We previously developed a homoharringtonine resistant C-1300 neuroblastoma cell line with cross-resistance to adriamycin and increased levels of p-glycoprotein, and showed that drug resistance could be reversed in this cell line by cyclosporin A. The present study shows that cremophor EL, a parenteral vehicle for cyclosporin A, can also completely reverse this multidrug resistance in a clonogenic assay system. Cremophor EL incubated with resistant cells for up to six days did not reduce levels of p-glycoprotein. Intracellular homoharringtonine analysis using HPLC revealed increased drug accumulation in resistant cells treated with cremophor EL. The increased drug level was not due to blocking of drug efflux commonly seen in other multidrug resistant models. The data suggest that resistance modulation with cyclosporin A should be interpreted with caution when cremophor EL is a solvent. Our work suggests cremophor EL, a relatively nontoxic lipophylic solvent, may have a direct effect on membrane permeability, although other mechanisms cannot be ruled out.
Chervinsky
D S
DS
Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, New York 14263.
Brecher
M L
ML
Baker
R M
RM
Hoelcle
M J
MJ
Tebbi
C K
CK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002999:Clone Cells; D016572:Cyclosporine; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006248:Harringtonines / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077863:Homoharringtonine; D007424:Intracellular Fluid / Q000378:metabolism; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014677:Pharmaceutical Vehicles; D012997:Solvents; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006248:Harringtonines; D014677:Pharmaceutical Vehicles; D012997:Solvents; C000515:cremophor EL; D000077863:Homoharringtonine; D004317:Doxorubicin; D016572:Cyclosporine; D005990:Glycerol