On Respiratory Impairment in Cancer Cells 



343 



the ratio of the absolute magnitude of aerobic glycolysis to the absolute magnitude 

 of respiration for any given conditions of experimental arrangement 17 . 



It is hoped that this simple test may prove useful or definitive in studies of many 

 tissues or cells of questionable malignancy — for example, in tissue cultures of 

 originally normal cells that are undergoing or have undergone carcinogenesis, as 

 well as numerous in vivo instances. In any event, the proposed test is a post facto 

 epitomization of three decades of experimental protocols in the literature that are 

 in harmony with the concepts recapitulated in this communication on respiratory 

 impairment in "THE metabolism of THE Cancer cell." 



References and Notes 



1 Warburg, O., Biochem. Z. 142 (1923), 317; Metabo- 

 lism of Tumors, translated by F. Dickens (Constable, 

 London, 1930); Science 123 (1956), 309; Science, this 

 issue. 



2 Various words expressing "impaired" respiration have 

 been employed by various writers, all, however, to 

 much the same gross end result, semantics aside: 

 damaged, destroyed, defective, diminished, disturbed, 

 eliminated, harmed, inadequate, inhibited, injured, 

 insufficient, limited, restrained, uncoupled, weakened, 

 eingeschränkt, entkoppelt, gehemmt, geschädigt, in- 

 suffizient, unzureichend, vergiftet, vermindert, zer- 

 stört, zugrunde gegangen, and zurückgegangen. In any 

 event, the irreversible respiratory limitation referred 

 to in Cancer cells is always partial, never total; other- 

 wise, their life and continued growth would totally 

 cease, so far as is known. 



3 Kidd, J. G., Winzler, R. J., Burk, D., Cancer Re- 

 search 4 (1944), 457. 



4 Weinhouse, S., Advances in Cancer Research 3 (1955), 

 239; Science, this issue. 



5 Weinhouse, s., Antimetabolites and Cancer (AAAS, 

 Washington, D.C, 1955), p. 1; Cancer Research 11 

 (1951), 585, 845. 



6 Weinhouse's frequently reiterated Statement that this 

 view held by him has now come to be held also by 

 Warburg is categorically incorrect, as simple inspec- 

 tion of the two recent articles by the latter in Science ( 1 ) 

 will suffice to show, in addition to many others that 

 date back to 1924. Questioned directly regarding the 

 accuracy of this footnote, Warburg has provided writ- 

 ten, emphatic confirmation (July 1956). 



7 Burk, D., Cold Spring Harbor Symposia on Quant. 

 Bio!. 7 (1939), 437, 441. 



8 Krebs, H. A., Metabolism and Function (Elsevier, 

 Amsterdam, 1950), p. 249. 



9 Adolph, E. F., Science 109 (1949), 579. 



10 It is important to note that the Qo, values for the 

 mouse tumors of Crabtree and Murphy and Hawkins 

 (1925 — 29), selected by Weinhouse from Burk's tables 

 and averaging — 13.9 for ten types, are, in fact, excep- 

 tionally high when compared with most values for 

 mouse tumors obtained during the last 25 years by 

 others using improved manometric methods. In the 

 vvork of Dickens and Simer in 1930 — 31 (also cited in 

 Burk's tables) the Qo. values for the five mouse tumor 

 types reported on averaged only — 7.1 ! Three of these 

 types (sarcoma 37S, tar Carcinoma 2146, and spindle- 

 cell tar tumor 173) had an average Qo, of — 5.6, com- 

 pared with — 16.6 for the same tumor strains as meas- 

 ured by Crabtree and used by Weinhouse. Thus, 



12 



13 



even the unadjusted average tumor Qo, value employed 

 by Weinhouse ( — 11.8) is, as the result of unwarranted 

 bias in selection and incomplete utilization of available 

 data, much too high. 

 1 1 Weinhouse's confusion is infectious, although mainly 

 among investigators who do not themselves perform 

 laboratory experiments on Cancer metabolism. One 

 may read, for example, "We hear about THE metab- 

 olism of THE cancer cell. Unfortunately, no such 

 phenomenon has been established. ... As Dr. Wein- 

 house said at the opening of the Symposium, the criti- 

 cal difference between metabolism in malignant tissues 

 and in normal tissues does not appear to reside in the 

 major ways in which they handle carbohydrate metabo- 

 lism." [Antimetabolites and Cancer (AAAS, Washing- 

 ton, D.C, 1955, pp. 305, 308)]. Such Statements could 

 scarcely be more incorrect or uninformed. They set the 

 clock back and encourage the empirical approach to 

 the problem of Cancer by a sheer and vicarious denial 

 of available fundamental Information. 

 Lewis, G. N., The Anatomy of Science (Yale Univ. 

 Press, New Haven, Conn., 1926), p. 171. 

 In paragraphs 4, 5, and 6 of his note in this issue of 

 Science, Weinhouse asks or raises several questions 

 that have been asked, discussed, and answered many 

 times in the literature of Cancer. 



14 The mechanism of the cancer respiratory impairment 

 may indeed often involve lowered content of a parti- 

 cular respiratory enzyme, but this is not a necessary 

 general requirement, since internal cellular arrange- 

 ment and chemical or structural restraint of other cor- 

 related enzymes are, as in so many living phenomena, 

 often of more decisive importance. Thus, certain 

 ascites Cancer cells have been found [B. Chance and 

 L. N. Castor, Science 116 (1952), 200] to have un- 

 usually high contents of cy tochrome c ; but even in such 

 ascites cells, the paraphenylenediamine and succinate 

 oxidative responses are characteristically low or zero 

 (1, p. 314); this is clearly indicative of respiratory res- 

 traint in spite of abnormally high absoute content of 

 cytochrome c (compare 4, pp. 295 — 6). Oxidation- 

 reduction potential restraints may well be involved 

 here, as well as low contents of cytochrome b or 

 DPNH demonstrated. 



15 Newton, L, Opticks (W. and J. Innys, London, ed. 2, 

 1718), pp. 344, 351. 



Presented orally at the 1956 meeting of American Asso- 

 ciation for Cancer Research. [Proc. 2, 98 (Natl. Inst, of 

 Health Information Release, 13 Apr.)]. 

 A description of these quantitative potentialities and 

 other qualitative aspects is in preparation. 



16 



17 



