Methods for predicting cardiac toxicity

Abstract

Methods are disclosed for determining whether organ toxicity, particularly cardiotoxicity, will occur in a patient selected for treatment with various kinase inhibitors, such as tyrosine kinase inhibitors, more particularly erbB inhibitors such as Herceptin. In addition, methods are disclosed for determining whether a potential drug is likely to produce a cardiotoxic effect. The methods involve analyzing lipid levels or the expression fatty acid oxidation enzymes, pAMP activated protein kinase, glucose uptake, to determine whether a fatty acid oxidation disorder is present. The identification of a fatty acid oxidation disorder can be used as a predictor of toxicity, especially cardiac toxicity, and as an indication that organ function should be carefully monitored if a drug such as a tyrosine kinase inhibitor is administered. Methods are also disclosed for protecting organs from metabolic stress and for the treatment of cells, such as adipocytes, to reduce their lipid content.

1 . An in-vitro method for determining drug-induced cell toxicity, the method comprising: identifying whether a cell oxidizes fatty acids in response to treatment with a drug, wherein the drug is determined to be toxic to the cell where the cell is identified to not oxidize fatty acids in response to treatment with the drug or wherein the drug is determined to not be toxic to the cell where the cell is identified to oxidize fatty acids in response to treatment with the drug. 
     
     
         2 . The method of  claim 1 , wherein the toxicity is cardiotoxicity. 
     
     
         3 . The method of  claim 1 , wherein the cell is a cardiomyocyte. 
     
     
         4 . The method of  claim 1 , wherein the drug is an anti-cancer agent. 
     
     
         5 . The method of  claim 1 , wherein the anti-cancer agent is a tyrosine kinase inhibitor. 
     
     
         6 . An in-vitro method for determining drug-induced cell toxicity, the method comprising:
 a.) contacting a cell with a drug; and   b.) assaying the cell for fatty acid oxidation,   
       wherein the drug is determined to be toxic where the cell does not oxidize fatty acids in response to contact with the drug or wherein the drug is determined to not be toxic where the cell oxidizes fatty acids in response to contact with the drug. 
     
     
         7 . The method of  claim 1 , wherein the toxicity is cardiotoxicity. 
     
     
         8 . The method of  claim 1 , wherein the cell is a cardiomyocyte. 
     
     
         9 . The method of  claim 1 , wherein the drug is an anti-cancer agent. 
     
     
         10 . The method of  claim 1 , wherein the anti-cancer agent is a tyrosine kinase inhibitor. 
     
     
         11 . An in-vitro method for determining drug-induced cell toxicity, the method comprising:
 assaying the cell for a fatty acid oxidation disorder, wherein the drug is determined to be toxic where the cell has a fatty acid oxidation disorder.   
     
     
         12 . The method of  claim 1 , wherein the toxicity is cardiotoxicity. 
     
     
         13 . The method of  claim 1 , wherein the cell is a cardiomyocyte. 
     
     
         14 . The method of  claim 1 , wherein the drug is an anti-cancer agent. 
     
     
         15 . The method of  claim 1 , wherein the anti-cancer agent is a tyrosine kinase inhibitor. 
     
     
         16 . An in-vitro method for determining drug-induced cell toxicity, the method comprising:
 a.) obtaining a cell from a subject selected for treatment with the drug;   b.) assaying the cell for a fatty acid oxidation disorder; and   c.) determining whether a fatty acid oxidation disorder exists in a cell,   
       wherein the presence of a fatty acid oxidation disorder predicts that the drug will be toxic and 
       wherein the absence of a fatty acid oxidation disorder predicts that the drug will not be toxic. 
     
     
         17 . The method of  claim 1 , wherein the toxicity is cardiotoxicity. 
     
     
         18 . The method of  claim 1 , wherein the cell is a cardiomyocyte. 
     
     
         19 . The method of  claim 1 , wherein the drug is an anti-cancer agent. 
     
     
         20 . The method of  claim 1 , wherein the anti-cancer agent is a tyrosine kinase inhibitor.