EFFECTS ON NEOPLASTIC CELLS 539 



are taken up. Takizawa in a series of reports in 1940-1941 (see Hartwell, 

 1951) claimed that the application of p-benzoquinone, 1,4-naphthoquinone, 

 and phenanthraqiiinone in benzene at concentrations usually of 5-12 mM 

 to the skin of mice often results in papillomas, a certain fraction of these 

 becoming malignant as epitheliomas. The appearance of these tumors is 

 preceded by depilation and increased keratinization, with some local ne- 

 crosis of the epithelium (Takizawa, 1940). Chloro-p-benzoquinone, thymo- 

 quinone, and 1,2-naphthoquinone are inactive. jj-Benzohydroquinone and 

 chloranil given daily. for 40 days subcutaneously or intravenously to rabbits 

 do not produce tumors (Hartwell, 1951). Gwynn and Salaman (1953) 

 found that 1,4-naphthoquinone and menadione cause epidermal hyper- 

 plasia when applied at 33 mM in acetone to mouse skin, but 1,2-naphtho- 

 quinone and j9-benzoquinone do not. 9,10-Dimethyl-l,2-benzanthracene, 

 which alone causes benign papillomas, was applied simultaneously, and 

 none of the quinones altered the frequency of tumor induction. Tiedemann 

 (1953) painted mouse skin with 92 mM 2>-benzoquinone in benzene and 

 with benzene alone; in both cases there is depilation, epidermal necrosis, 

 inflammation, and the production of papillomas, but no carcinomas, thus 

 casting some doubt on the carcinogenicity of p-benzoquinone. It is still 

 undecided if such quinones can produce tumors, but in any event they 

 must be of rather low potency. The inhalation of p-benzoquinone vapor 

 for 1 hr 6 times a week by mice leads to an 8% incidence of lung carcinoma 

 (Kanisawa and Ide, 1959), but whether this is a specific or nonspecific 

 effect is unknown. 



It has been suggested that certain carcinogens are oxidized to the active 

 forms (Potter, 1942; Kensler et al., 1942 a, b), these products possibly 

 reacting with and inhibiting SH enzymes and NAD-linked systems. p-Di- 

 methylaminoazobenzene is carcinogenic and its oxidative products are quite 

 potent inhibitors of succinate oxidase and pyruvate decarboxylase, and this 

 was discussed with regard to the shifting of metabolism from aerobic to 

 anaerobic dominance. One factor determining which enzymes are attacked 

 within the cells would be the degree of saturation of the enzymes with 

 substrate or coenzyme; thus it was postulated that 3-phosphoglyceraldehyde 

 dehydrogenase may not be as readily inhibited as succinate oxidase because 

 it was assumed to be saturated with substrate under most conditions. Al- 

 though this can be a factor modifying the rate of enzyme inhibition, there 

 is a question as to its importance, since some inhibitors, such as iodoacetate, 

 seem to attack the 3-phosphoglyceraldehyde dehydrogenase preferentially. 

 It has also been suggested at times that p-benzoquinone may be the actual 

 carcinogenic substance produced from a variety of carcinogens, but there 

 is no evidence for this at present. 



Several reports have demonstrated some selective inhibition of tumor 

 growth by various quinones administered to tumor-bearing animals. Sub- 



