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Characterization of acquired resistance to cis-diamminedichloroplatinum(II) in mouse leukemia cell lines
Abstract:
We have established in vivo cisplatin-resistant mouse leukemia cell lines, L-1210/DDP and P388/DDP, in order to elucidate the mechanism of acquired resistance to cisplatin. Resistance indices were 22 and 14, respectively, when the cells were exposed to cisplatin for 48 h. Uptake of cisplatin by both resistant lines was significantly reduced, compared with values for the respective parent lines (17% for L-1210/DDP and 27% for P388/DDP, at 100 microM for 1 h). While glutathione contents in the resistant cells were 1.7-1.9 times higher than those in the sensitive ones, their reduction by preincubation with buthionine sulfoximine did not influence the sensitivity of the cells to cisplatin. In addition, the resistant lines did not show lower sensitivity to CdCl2 than the respective sensitive ones, suggesting that intracellular SH groups might contribute little to the mechanism of cisplatin resistance in these cells. Postincubation with DNA repair inhibitors, caffeine and aphidicolon, did not selectively enhance the sensitivity of the resistant cells to cisplatin. These results suggested that reduced drug uptake would be a primary mechanism of cisplatin resistance in L-1210/DDP and P388/DDP. Cross-resistance patterns to platinum complexes were quite different between L-1210/DDP and P388/DDP. Colon 26/DDP, another cisplatin-resistant mouse tumor showed a different pattern from those observed with L-1210/DDP and P388/DDP. In the development of new platinum complexes we should use plural resistant lines for examining cross-resistance patterns to candidate platinum complexes.
Insights
Acquired cisplatin resistance in mouse leukemia involves reduced drug uptake, not glutathione or DNA repair. Developing new platinum drugs requires testing against multiple resistant cell lines to understand cross-resistance patterns.
Area of Science:
- Pharmacology
- Cancer Biology
- Drug Resistance Mechanisms
Background:
- Cisplatin is a vital chemotherapy drug.
- Understanding acquired cisplatin resistance is crucial for improving cancer treatment outcomes.
- Established cisplatin-resistant mouse leukemia cell lines (L-1210/DDP and P388/DDP) are valuable tools for mechanistic studies.
Purpose of the Study:
- To elucidate the primary mechanisms underlying acquired cisplatin resistance in established mouse leukemia cell lines.
- To investigate the roles of drug uptake, glutathione levels, and DNA repair in cisplatin resistance.
- To analyze cross-resistance patterns among different platinum-resistant cell lines for future drug development.
Main Methods:
- In vivo establishment of cisplatin-resistant L-1210/DDP and P388/DDP cell lines.
- Quantification of cisplatin uptake in sensitive and resistant cell lines.
- Assessment of glutathione content and the effect of buthionine sulfoximine.
- Evaluation of sensitivity to CdCl2 and DNA repair inhibitors (caffeine, aphidicolon).
- Analysis of cross-resistance patterns with other platinum complexes and cell lines.
Main Results:
- Resistant cell lines (L-1210/DDP, P388/DDP) exhibited significantly reduced cisplatin uptake compared to parent lines.
- Elevated glutathione levels in resistant cells did not correlate with increased cisplatin sensitivity upon inhibition.
- Intracellular SH groups and DNA repair mechanisms appeared to play minor roles in the observed resistance.
- Cross-resistance patterns varied significantly between L-1210/DDP, P388/DDP, and Colon 26/DDP cell lines.
Conclusions:
- Reduced cisplatin uptake is identified as a primary mechanism of acquired resistance in L-1210/DDP and P388/DDP cells.
- The distinct cross-resistance profiles highlight the heterogeneity of platinum resistance.
- Multiple resistant cell lines are essential for evaluating the efficacy of novel platinum-based anticancer agents.