On Respiratory Impairment in Cancer Cells 337 



diminution in oxygen consumption or a loss in the ability to convert glucose and 

 fatty acids to CCK 



Warburg suggests in the present paper that perhaps the respiratory impair- 

 ment may involve an inability to couple oxidation with phosphorylation. Here 

 again, the available evidence does not support such a concept. Effects of inhibitors 

 such as fluoride ion or dinitrophenol are similar in neoplastic and nonneoplastic 

 tissues 8 and data of other investigators ( 6 = p- 321 ) have given no indication that oxida- 

 tive phosphorylation occurs in tumor mitochondria in a manner different from 

 that in their noncancerous counterparts. 



Another pertinent illustration of the inadequacy of the Warburg concept is that 

 it fails to consider that a large part of the respiration of Cancer cells may be due to 

 fatty acid oxidation. Although it seems fairly certain now that animal tissues 

 generally, including the neoplastic, use fatty acids as a metabolic fuel, nowhere in 

 Warburg's writings is there any consideration of the possible role played by fatty 

 acids in the respiration of cells. 



Another weakness of the Warburg hypothesis is that it does not fit in with what 

 we have learned in recent years of chemical mechanisms of glycolysis and respira- 

 tion. Again, Warburg states, "We need to know no more of respiration and fer- 

 mentation here than that they are energy-producing reactions . . ." ( 3 > p- 309 ). This 

 attitude may have been justified 25 years ago when little was known of their chemi- 

 cal nature. At present we recognize that they are not "independent metabolic 

 processes" but are intimately related. To assume that respiration and glycolysis 

 are separately activated, alternate means of cellular energy production, it is indeed 

 necessary to ignore all that has been learned of their chemical mechanisms. 



According to our present conceptions, the major pathway of oxidation of glu- 

 cose to carbon dioxide in most animal cells, whether normal or neoplastic, in- 

 volves its conversion to pyruvic acid by way of the Embden-Meyerhof process, 

 oxidative decarboxylation of pyruvic acid to acetyl coenzyme A, and condensation 

 of the latter with oxaloacetic acid to enter the citric acid cycle. Down to the pyruvic 

 acid stage, respiration and fermentation follow a common pathway. The extent 

 to which pyruvic acid, a common intermediary in both respiration and glycolysis, 

 competes for electrons held by the pyridine nucleotides with those factors that 

 transport electrons to oxygen — namely, the flavoproteins and cytochromes — should 

 be a crucial factor in determining the degree of aerobic glycolysis. 



If there is a disturbance in respiration that leads to an accumulation of lactic 

 acid, it can occur only at or beyond the pyruvic acid stage and must be due either 

 to some aberration in carbon transport through the citric acid cycle or to some 

 "bottleneck" in electron transport. Many enzymatic and isotope tracer studies 

 have fully established that the citric acid cycle operates in tumors <ß> pp- 311 ff). 

 Although cytochromes are reportedly low in tumors ( 9 >pp- 404ff) 5 as are also someof 

 the B vitamins invclved in electron transport ( 9 > p- 408 ), the generally unimpaired oxy- 

 gen consumption already referred to clearly indicates that electrons reach oxygen 

 about as readily in tumors as in other tissues. Thus, the available evidence indi- 

 cates to me that high glycolysis occurs, despite quantitatively and qualitatively 

 normal occurrence of carbon and electron transport. This can mean only that 



22 Warburg, Zellphysiologie 



