Measuring cytotoxicity: a new perspective on LC50.

BACKGROUND Cytotoxicity in cell culture is typically expressed as LC50 the concentration of a given agent which is lethal to 50% of the cells. This number is dependent on the incubation time with the agent. Previously, a two-term exponential model has been proposed to describe cell growth after a cytotoxic event: y(t) = k, * exp(-d(1)*t) + k2 * exp(d(2)*t). A dose-response relationship was observed between the parameter k2 in this formula and the concentration of the cytotoxic agent etoposide, in high-grade glioma cells was independent of incubation time. MATERIALS AND METHODS In order to test if the model can be applied more generally, DAOY medulloblastoma cells treated with MS275, a histone deacetylase inhibitor, were used. RESULTS The observed data fit the model well. CONCLUSION The concentration at which k2 is reduced by 50% is called KC50. It provides a far better description of the cytotoxicity of an agent in a specific cell line than the traditional LC50.

[1]  C. Lau,et al.  Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC , 2005, Molecular Cancer Therapeutics.

[2]  J. Pavillon,et al.  Mortality and LC50 values for several stages of the marine copepod Tigriopus brevicornis (Müller) exposed to the metals arsenic and cadmium and the pesticides atrazine, carbofuran, dichlorvos, and malathion. , 1998, Ecotoxicology and environmental safety.

[3]  S. Bates,et al.  MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors. , 2002, Cancer research.

[4]  R. Egeler,et al.  Chemosensitivity of glioma cells in vitro: a meta analysis , 1999, Journal of Cancer Research and Clinical Oncology.

[5]  H. Galla,et al.  Long recovery times improve the detection of cellular resistance in vitro , 1998, Journal of Cancer Research and Clinical Oncology.

[6]  R N Hill,et al.  Comparison of the up-and-down, conventional LD50, and fixed-dose acute toxicity procedures. , 1995, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[7]  Laird Ak.  Dynamics of Tumour Growth: Comparison of Growth Rates and Extrapolation of Growth Curve to One Cell , 1965 .

[8]  J. Murray,et al.  Virtual and real brain tumors: using mathematical modeling to quantify glioma growth and invasion , 2003, Journal of the Neurological Sciences.

[9]  John William Trevan,et al.  The Error of Determination of Toxicity. , 1927 .

[10]  N. Draper,et al.  Applied Regression Analysis , 1967 .

[11]  Ming Zhang,et al.  Predicting tumor cell repopulation after response: mathematical modeling of cancer cell growth. , 2006, Anticancer research.

[12]  N. Draper,et al.  Applied Regression Analysis , 1966 .

[13]  P. Bader,et al.  Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells. , 2006, International journal of oncology.

[14]  W R Greco,et al.  Modeling of the time-dependency of in vitro drug cytotoxicity and resistance. , 1998, Cancer research.

[15]  L. Appelman,et al.  Alternative acute inhalation toxicity testing by determination of the concentration-time-mortality relationship: experimental comparison with standard LC50 testing. , 1992, Regulatory toxicology and pharmacology : RTP.