Cellular inhibition and the origin of cancer, with special reference to the mode of action of the carcinogenic hydrocarbons

Sections I and II:Intraperitoneal administration of a number of carcinogenic hydrocarbons, including 1:2:5:6- dibenz- :anthracene, 5:6 -clopenteno -1:2- benzanthracene, and 3:4- benzpyrene, produced considerable inhibition in the rate of growth of the Jensen and Walker tumours. On the other hand, a series of related non -carcinogenic compounds (anthracene, phenanthrene, 1:2- cyclopentenophenanthrene, dodecahydro -l:2 -benz- :anthracene, pyrene, fluoranthene, triphenylene, dehydronorcholene, perylene, 1:9- benzanthrone and diphenylene oxide) gave no inhibition of tumour growth when tested under the same conditions. Of the synthetic oestrogens 1-keto- 1:2:3:4 -tetrahydro- :phenanthrene and 9:10- dihydroxy- 9:10- di- n- propyl9:10- dihydro- 1:2:5:6- dibenzanthracene, the latter proved to be moderately inhibitory and the former quite inactive. Inhibitory activity was also shown to a variable extent by chrysene and by 1:2 -benz- :anthracene and certain of its derivatives (3 -, 4- and 7- methyl -), the carcinogenicity of which is either very feeble or nil.In comparative experiments on body -growth, x- radiation, lead and colchicine were found to produce a temporary interference which was followed by recovery to the normal growth-rate, with or without compensation. Although the carcinogenic hydrocarbons must be regarded as toxic substances, their growth- inhibiting action is apparently independent of toxicity in any non -specific sense, since manifest poisons evoke an entirely different response.The inhibition produced by the carcinogenic compounds was extremely prolonged, even after a single injection. This feature is discussed in relation to the rate of excretion of such substances. It was further noted that l:2:5:6- dibenzanthracene produced a diminution of both male and female fertility accompanied, in certain cases, by histological changes in the gonads.There is thus a correlation in compounds of this type between carcinogenicity and growthinhibitory power. It is suggested that the mode of action of these substances is indirect, and that they operate by producing a prolonged retardation of the growth of normal cells, which eventually react by a process of discontinuous variation to give a new cell race with a greatly increased fission rate.Section III:Attention is drawn to the striking multiplicity of carcinogenic agents, which, although they are sufficiently diverse as to have no physical or chemical features in common, nevertheless produce identical end -results in cells exposed to their action. Similar examples are quoted from other fields and the basis of biological non -specificity is examined. Arguing from the general biology of variation, it is suggested, in the special case of tumour -producing agents, that these operate by producing interference with certain normal functions of the cell, and particularly with growth, in such a way as to induce variation in the characters affected. The detailed evidence in support of this view derives from a certain degree of parallelism between optimal growth- inhibiting power and tumour- producing capacity which is shown by radioactive agents and the carcinogenic hydrocarbons. In a discussion of the biological nature of this cellular change, emphasis is concentrated on its irreversibility. A summary is given of the known biochemical effects of tumour -producing agents, including a reference to the possible significance of ischaemia in tumour induction. The conception of somatic cell variation in general, and of cellular inhibition in particular as its cause, is discussed in relation (1) to the salient features of the natural history of cancer and (2) to the theories of Virchow and Cohnheim, to allied genetic theories, to Warburg's hypothesis, and to the various infective hypotheses of tumour causation