The effect of hyperthermia in combination with melphalan on drug-sensitive and drug-resistant CHO cells in vitro.
The effect of temperature on the cytotoxicity of melphalan in a pleiotropic drug-resistant mutant CHO cell line (CHR C5) and in its drug-sensitive parent (Aux B1) was studied in vitro using a clonogenic assay. The cytotoxicity of melphalan was significantly enhanced at elevated but non-lethal temperatures (39-41 degrees C) and hyperthermia potentiated the effect of melphalan in the lethal temperature range (43-44 degrees C) in both cell lines. The effect of temperature on membrane permeability to melphalan was studied to determine whether the increase in cytotoxicity was associated with increased intracellular drug levels. The uptake of 14C-labelled melphalan during 5 min increased with increasing temperature. Drug efflux, however, also increased at elevated temperatures. Intracellular drug levels at equilibrium were increased at elevated temperatures but the magnitude of this effect was small in comparison with the much larger increases in cytotoxicity.
Bates
D A
DA
Department de Chimie, Université du Québec, Montréal, Canada.
Mackillop
W J
WJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D003131:Combined Modality Therapy; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006979:Hyperthermia, Induced; D008558:Melphalan / Q000493:pharmacokinetics / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D013696:Temperature; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D008558:Melphalan