The mechanism and overcoming of resistance in ACNU-resistant sublines of C6 and 9L rat glioma.

In order to study the mechanism of the resistance to chemotherapeutic agents, especially ACNU [1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride), two variant cell lines (C6/ACNU and 9L/ACNU) resistant to ACNU were selected in vivo from rat C6 and 9L glioma, respectively. Uptake and efflux of ACNU in these resistant cells were studied with Ethylene[14C]ACNU. The result indicated that the resistance exhibited by both sublines were due to both the reduced uptake of the drug and the increased efflux. The study of the effects of oxidative phosphorylation inhibitor, DNP (2,4-dinitrophenol), on the uptake and retention of ACNU suggested that there is an active outward transport mechanism for ACNU in both glioma sublines and that enhanced activity of this efflux mechanism renders cells highly resistant to the cytotoxic action of ACNU. In an attempt to clarify the more detailed biochemical mechanisms of this active efflux system, we surveyed various membrane-modifying agents which potentiate the sensitivity of these resistant cells to ACNU. Among a number of membrane-modifying agents, reserpine was found to retain ACNU in the resistant cells and to enhance the action of ACNU on these resistant cell lines. It may be concluded that drugs such as reserpine may overcome a mechanism of ACNU resistance.