542 5. QUINONES 



not an effective route at the dosage used.* Jolles and Laws (1954) thought 

 the improvement in patients given menadiol-diP might be due to an in- 

 creased tolerance to the X-irradiation, but their work with animals did not 

 support this view, no constant effect being observed. 



The mechanism by which quinones interfere with tumor cell mitosis and 

 growth is probably the same as that involved in the inhibition of normal 

 cells, such as fibroblasts, but some workers have assumed qualitative differ- 

 ences. Powell (1944, 1951) thought that cancer cells have a modified cy- 

 toskeletal structure, fibrils associated with mitosis being disarticulated. 

 Substances such as the quinones which link together these fibrils and thus 

 stabilize the malignant cells in a more normal arrangement were believed 

 to slow division. However, such a hypothesis has no experimental basis, 

 none of his work had any bearing on this concept, and the substances chosen 

 as antimitotic agents (e. g., 9,10-AQ and 9,10-PAQ) certainly seem to be 

 unlikely candidates for fibril-linkers (in fact, it is doubtful if they react 

 readily with SH groups). Menadione or menadiol-diP has no cross-linking 

 ability, and we have seen that Mitchell, Friedmann, and others have pro- 

 vided evidence that if reaction with SH groups is involved at all, it must be 

 the low molecular weight thiols rather than the protein components of the 

 cells. It is tempting to entertain the hypothesis in view of the great potency 

 of some of these compounds that a very specific structure or process is at- 

 tacked, this being solely associated with mitosis. The inactivation of some 

 component of the centriole, for example, might produce a failure in spindle 

 function and chromosomal movements. In any case, there is no evidence 

 for a qualitatively different action on tumor cells, nor is there reason to 

 believe that quinones selectively suppress neoplastic growth. It is possible, 

 as Holzer (1956) has suggested, that the high glycolytic activity of tumor 

 cells makes them more susceptible than normal cells to substances which 

 depress glycolysis, and it is true that certain carcinostatic agents potently 

 inhibit glycolysis, but there is certainly no reason to believe that the anti- 

 mitotic quinones affect glycolysis at all in concentrations blocking cell 

 division. 



* There has been much discussion, and rightly so, during the past few years of 

 the usual lack of critical evaluation in the clinical testing of drugs, but few seem to 

 have realized that one must examine reports of negative results just as sceptically 

 as those of favorable results. There are several instances in which obviously active 

 drugs have been proved to be ineffective by inadequate techniques. If an investiga- 

 tion is designed to demonstrate the incorrectness of someone's previous work or to 

 prove the inadequacy of some therapeutic procedure, some attempt should be made 

 to reproduce the previous work with respect to doses and routes of administration, 

 which was not done in the case cited. It must furthermore be remembered that ex- 

 periments with a single dose and route of administration provide information only on 

 the effectiveness under these conditions, even though the work was done very thorough- 

 ly and evaluated by adequate criteria. 



