Abstract
Trifluoperazine (TFP) is effective in modulating DNA damage/repair in doxorubicin (DOX) treated cells. In the present study we have characterised the resistance phenotype of parental sensitive L1210 mouse leukaemia cells (L1210/S) adapted to grow in the presence of 0.017 microns DOX+5 microM TFP (L1210/DT). Although with prolonged exposure, 0.017 microM DOX alone produced < 35% cell kill in L1210/S cells, similar cytotoxicity was achieved at 0.43 microM DOX in L1210/S cells selected in the presence of 0.017 microM DOX+5 microM TFP. L1210/DT cells were > 30-fold resistant to DOX following a 3 h drug exposure in a soft agar colony assay. In contrast, DOX sensitivity in cells adapted to grow in 5 microM TFP alone was comparable to L1210/S cells. Resistance to other inhibitors of topoisomerase II in L1210/DT cells was > 30-fold to etoposide and > 6-fold to amsacrine. The levels of the 170 kDa and 180 kDa isoforms of topoisomerase II in an immunoblot were comparable between the L1210/S and L1210/DT cells. Cross resistance to vincristine in the L1210/DT cells was accompanied by the overexpression of plasma membrane P-glycoprotein. Although a 1.5-2-fold decrease in accumulation of etoposide and DOX was observed in the L1210/DT cells, drug levels for equivalent DNA damage in the alkaline elution assay were > 5-fold higher in the L1210/DT versus L1210/S cells. No abrogation in the modulating effects of TFP on DOX, VP-16 or amsacrine induced cytotoxicity was apparent in the L1210/DT cells. Results suggest that: (a) TFP in combination with low concentrations DOX can induce the selection of cells with the multidrug resistant phenotype; and (b) characteristics of cells selected for resistance to DOX or DOX plus TFP are comparable.
Highlights
Vs pulse exposure to DOX plus TFP is significantly more cytotoxic than DOX alone in both wild-type or resistant tumour cells (Ganapathi et al, 1984)
Based on a periodic determination of the cytotoxic effects of DOX in a soft-agar colony assay, the L1210/DT cells were stably resistant in the absence of DOX plus TFP for at least 3 months (200 doublings) during in vitro culture
Based on the IC50, following 3 h drug treatment the L12IO/DT cells were 30-fold resistant to DOX and VP-16, 6-fold resistant to m-AMSA and completely resistant to VCR (
Summary
Vs pulse exposure to DOX plus TFP is significantly more cytotoxic than DOX alone in both wild-type or resistant tumour cells (Ganapathi et al, 1984). Since the use of MDR modulating agents in initial treatment regimens to prevent emergence of drug resistance has been suggested (Salmon et al, 1991), we have pharmacologically and biochemically characterised L1210 mouse leukaemia cells selected for resistance to a combination of DOX plus TFP. Results from this study suggest that while mechanisms of resistance are qualitatively similar to that observed with cells selected for resistance to DOX alone, minimally cytotoxic concentrations of DOX alone in combination with non-cytotoxic levels of TFP can induce the selection of > 30-fold DOX-resistant cells with the MDR phenotype
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