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Altered Cytotoxicity of (2-Chloroethyl)-3-sarcosinamide-1-nitrosourea in Human Glioma Cell Lines SK-MG-1 and SKI-1 Correlates with Differential Transport Kinetics¹

Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2

Resistance to (2-chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU), an experimental anticancer compound, was investigated in the chloroethylnitrosourea-sensitive Mer^- SK-MG-1 and -resistant Mer^- SKI-1 human glioma cell lines. The transport of [³H]SarCNU was examined in suspension. The uptake of [³H]SarCNU was found to be temperature dependent in SK-MG-1 and SKI-1, but less so in SKI-1. At 37°C, uptake of 50 µM [³H]SarCNU was linear up to 4 s in both cell lines, with uptake being significantly faster in SK-MG-1 than in SKI-1 under initial rate conditions. There was no significant difference in the rate of influx at 22°C between both cell lines. Equilibrium was approached after 1 min at 22 and 37°C. At 37°C, steady state accumulation of SarCNU at 30 min was reduced significantly (35%) in SKI-1 cells compared with SK-MG-1 cells, although accumulation was similar at 22°C. In SK-MG-1 cells, up-take of [³H]SarCNU at 37°C was found to be saturable, but uptake in SKI-1 cells was not saturable over a 1000-fold range of concentrations. Analysis of efflux in cells preloaded with 50 µM [³H]SarCNU revealed that the rate of efflux was equivalent in both cell lines but that the efflux rate was more rapid at 37°C compared with 22°C. Metabolism of SarCNU at 37°C was not different in either cell line after a 60-min incubation, as determiend by thin layer chromatography. SKI-1 cells, compared with SK-MG-1 cells, were 3-fold more resistant to SarCNU at 37°C but only 2-fold more resistant at 22°C, a temperature at which SarCNU accumulation was similar in both cell lines. The 2-fold resistance at 22°C was similar to that of 1,3-bis(2-chloroethyl)-1-nitrosourea at 37 and 22°C. These findings indicate that increased cytotoxicity in SK-MG-1 cells is associated with a greater accumulation of SarCNU via an epinephrine-sensitive carrier that is not detectable in SKI-1 cells. However, part of the chloroethylnitrosourea resistance in SKI-1 cells is not secondary to decreased accumulation.

¹ This work was supported by NIH Grant NS22230.

² To whom requests for reprints should be addressed, at Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote Ste. Catherine Road., Montreal, Quebec, Canada, H3T 1E2.

Received 9/17/93. Accepted 1/18/94.

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