Hyperthermic potentiation of BCNU toxicity in BCNU-resistant human glioma cells.
Experimental evidence indicating potentiation of the cytotoxic effect of drugs at high temperatures suggests that the utilization of drug-heat combinations for gliomas of the brain might be therapeutically useful. Hyperthermia may increase the cytotoxicity of a particular drug in areas of low drug concentration/time and in cell populations resistant to the drug. We report in vitro experiments with a BCNU resistant, U-373MG, and a BCNU sensitive, U-87MG, human derived glioma cell lines under hyperthermic conditions. Temperatures equal or above 42 degrees C potentiate BCNU cell kill in both lines. The thermo-sensitizer lidocaine increases thermal cell kill but only minimally with concentrations corresponding to therapeutic plasma lidocaine levels. Within our experimental conditions, the best strategy to overcome BCNU resistance involved a combination of heat, BCNU and cis-DDP. BCNU resistant cells have no cross resistance to cis-DDP and the combination of BCNU and cis-DDP is synergistic. At modest hyperthermic conditions (42 degrees C) 99.4% BCNU resistant cells are killed by a combination of BCNU and cis-DDP at drug concentrations identical to plasma concentrations after standard IV doses. Clinical protocols using heat and drug may need to incorporate two or more drugs for optimal effects.
University of Ottawa, Ottawa Civic Hospital, Canada.
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Da Silva
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Feeley
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Raaphorst
D002330:Carmustine / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005910:Glioma; D006358:Hot Temperature; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D008012:Lidocaine; D002330:Carmustine