O. Warburg,249 starting from the observation that a number of tumors possessed a high rate of glycolysis (see Figs. 1 and 14; see also Baldwin,22 and Dixon and Webb 88), meaning an unusual ability to produce lactic acid from glucose, even in presence of oxygen (low Pasteur effect), concluded that anaerobic and aerobic fermentation (the latter increasing with the 'virulence' of the tumor cells) provided the main source of energy in form of ATP etc. for malignant tissues. He assumed that this developed from a 'faulty' or 'impaired' respiration, that is aerobic energy producing reactions within the cell involving the Krebs cycle combined with oxidative phosphorylation (see Figs. 1 and 14). Warburg also indicated that the damage to the respiratory system which might be caused by an inability to couple oxidation with phosphorylation was due to initial local anoxia and that the principal distinction between neoplastic and normalcells rested on a preponderance of fermentation over oxidation in the former. All this implies, of course, that significant quantitative differences in the activity of enzymes participating in these metabolic processes must exist.

Fig. 1. Cellular metabolism: metabolic pathways, cycles, substrates and products.

A number of arguments for and against these generalizing statements, emerging from Warburg's "trail blazing experiments," as Greenstein called them, have been put forward and will continue to be put forward for a long time. Considering first the 'pros,' it is agreed that one of the carriers participating in oxidative phosphorylation, namely cytochrome c is low in some tumors110 and that respiration rates (Qo2), measured in presence of added substrates, increased to a much higher degree in normal tissue slices than in those derived from tumors.110 It might be said therefore that the respiratory activity of neoplastic material is a maximal one, while normal cells have ample reserves. When glycolysis rates are measured simultaneously with respiratory rates in presence of glucose and serum in a manometric test, Burk and Schade69 claimed that malignant cells will cause a steady and notable increase in pressure with time, while normal and unimpaired body cells produce a negative or zero change in pressure during the same period. Others have supported the Warburg concept, although in nearly each case the question as to whether the 'faulty' respiration was the true cause of malignancy has not been answered. Quastel 204 studied the incorporation of amino acids such as glycine or phenylalanine into the proteins of embryonic, normal and tumor cells. Generally speaking this incorporation reflects protein synthesis, which is dependent on the energy in form of ATP, etc. produced by glycolysis and respiration (see Fig. 1). He came to the conclusion that there existed real differences in metabolic efficiencies between the three types of cells, in that a number of normal tissues with relatively high glycolytic rates (e.g. kidney medulla, retina) had little or no anaerobic efficiencies for amino acid incorporation, whereas embryonic and tumor tissue did. On the other hand embryonic and neoplastic cells differed in their relative metabolic activities: in both, malonate greatly inhibited respiration and amino acid incorporation but only with the tumor cells could this effect be almost reversed by the addition of glucose.

Over the years a number of points have been raised against the general validity of the Warburg concept, with Weinhouse 260 as the most outspoken antagonist and with Potter199 attempting to keep in a literal sense an equilibrium between the two schools of thought and introducing the expression of "respiratory enzyme balance" in place of "impairment." Weinhouse, not denying the existence of high glycolysis rates of some tumors, stressed the quantitative normality with respect to their respiratory efficiency (i.e. carbon-, phosphate- and hydrogen- transfer), starting with glucose and finishing with CO2, water and about 36-40 molecules of energy storing ATP. He with Bloch-Frankenthal39 also argued that the unusually pronounced glycolysis of Ehrlich ascites cells (used in Warburg's own experiments 25°) might be due to the easy accessibility of glucose to these freely suspended cells, the specific metabolism not being limited by the intracellular availability of glucose.

On several occasions Potter 197,198,199 underlined quite rightly the fact that, as a series of substrates and products, intermediary metabolites can follow alternative pathways. Apart from the Meyer hof-Embden route from glucose to lactic acid, glucose once phos phorylated may enter the so called hexose monophosphate or pentose shunt (see Dickens,81 Racker 206) which, while unlikely to contribute to energy storage, produces pentoses for the synthesis of nucleic acid and certain nucleotidic coenzymes, DPN and TPN. If this pathway is of importance in tumors, and Sahasrabudhe 221 has recently speculated in a positive manner about this possibility, then the original Warburg hypothesis has to amalgamate this. As it will be mentioned below, certain tumors are deficient in pyridine nucleotides; this, as Sahasrabudhe has pointed out, may be due to the increased demand in the malignant cell for adenylic derivatives which are preferentially utilised as building material of nucleic acids and not as moieties of coenzymes, essential among other hydrogen transferring agents in the process of oxidative phosphorylation. It is therefore not improbable that such proposals may help to resolve the contradictions of the fermentation respiration concept of cancer.