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The reversal of multidrug resistance in multicellular tumor spheroids by SDZ PSC 833
P H Ehrlich1, Z A Moustafa, A E Archinal-Mattheis
1Oncology Research Program, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
Abstract:
Multidrug resistance (MDR) is a major impediment to the effective treatment of cancer. We have used multicellular tumor spheroids (MTS) as a model to investigate whether MDR can be reversed in a three dimensional structure. MTS are tightly associated aggregates of tumor cells that exhibit many of the properties of solid tumors. A human MDR breast carcinoma cell line was selected by exposure to taxol under monolayer conditions. The sensitive (parental) and drug-resistant phenotypes were retained when the cells were grown as MTS. Thus, the three dimensional conditions in this novel model system did not affect the MDR phenotype. SDZ PSC 833 is an efficient MDR reversing agent as determined under monolayer conditions and is currently being evaluated in clinical trials. Resistance to taxol and doxorubicin of the MDR cells grown as MTS was almost completely reversed by SDZ PSC 833. Our results suggest that SDZ PSC 833 has the potential to reverse the MDR phenotype in solid tumors.
Insights
Multidrug resistance (MDR) in cancer can be reversed using SDZ PSC 833. This agent effectively overcomes taxol and doxorubicin resistance in a novel 3D multicellular tumor spheroid model, showing potential for solid tumor treatment.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Multidrug resistance (MDR) significantly hinders effective cancer chemotherapy.
- Multicellular tumor spheroids (MTS) serve as a 3D model mimicking solid tumor properties.
Purpose of the Study:
- To investigate the reversal of MDR in a 3D tumor model.
- To evaluate the efficacy of SDZ PSC 833 in reversing MDR in MTS.
Main Methods:
- Established a human MDR breast carcinoma cell line resistant to taxol.
- Cultured sensitive and resistant cells as MTS to maintain phenotypes.
- Assessed the MDR-reversing effect of SDZ PSC 833 on taxol and doxorubicin resistance in MTS.
Main Results:
- The MDR phenotype was retained in cells grown as MTS.
- SDZ PSC 833 demonstrated significant MDR reversal in the MTS model.
- Resistance to both taxol and doxorubicin was nearly completely reversed by SDZ PSC 833.
Conclusions:
- SDZ PSC 833 is effective in reversing MDR in a 3D tumor model.
- The findings suggest SDZ PSC 833's potential for clinical application in treating solid tumors with MDR.