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The slow cell death response when screening chemotherapeutic agents
Joseph Blois1, Adam Smith, Lee Josephson
1The Center for Translational Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Cancer Chemotherapy and Pharmacology
|January 4, 2011
Summary
The sulforhodamine B (SRB) assay does not accurately reflect true cell death, especially with slow-acting chemotherapy. Sustained low doses may be more effective for maximizing tumor cell death than maximum tolerated dose strategies.
Area of Science:
- Cell biology
- Pharmacology
- Cancer research
Background:
- The sulforhodamine B (SRB) assay is a common method for assessing "cytotoxicity" in drug screening.
- However, its correlation with actual cell death, particularly apoptosis and necrosis, is not well-established.
Purpose of the Study:
- To investigate the relationship between direct cell death measurements and the SRB assay's results.
- To compare cell death kinetics with SRB assay outcomes across various cell lines and chemotherapeutic agents.
Main Methods:
- Eight adherent cell lines and four agents were used, creating 32 agent/cell combinations.
- Cell death was determined by flow cytometry measuring annexin V and vital fluorochrome binding.
- The SRB assay was used to determine IC50 values and final cell mass.
Main Results:
- Cell death kinetics varied, with 5/32 showing fast death, 17/32 slow death, and 10/32 no death, despite positive SRB assay results in all cases.
- Slow cell death involved a progressive increase in apoptotic and necrotic cells over at least 72 hours post-treatment.
- The SRB assay results did not correlate with annexin V and/or fluorochrome binding, indicating true cell death.
Conclusions:
- The SRB assay is an unreliable surrogate for measuring true cell death, especially in cases of slow cell death.
- Sustained exposure to chemotherapeutic agents at concentrations slightly above the SRB IC50 can maximize cell kill.
- For solid tumors, a strategy of sustained low-dose chemotherapy may be more effective than maximum tolerated dose approaches for maximizing tumor cell death.
