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Earlier experiments carried out with the liver carcinogen p-dimefhylaminoazobenzene ( D A B ) have been repeated with another liver carcinogen, diethylnitrosamine ( D E N ) .Nine different experiments were perfbrmed, using 84 male Wistar rats. The results were the reverse of those obtained with DAB. With the latter, a protein-poor diet or a simultaneous administration of reserpine accelerates the process of cancerization, while addition to the carcinogen of certain phenolic ketones or of o,p'-dichlorodiphenyldichloroethane ( 0 ,~' -D D D ) inhibits it. With DEN, neither variations in the diet nor reserpine have any marked effect on the cancerization process, while the phenolic ketones and o,p'-D D D accelerate it.DAB is far more toxic to the hepatocytes, whereas DEN is more toxic to the cells of the connective-vascular system of the liver.As is the case with DAB, the carcinomas produced by DEN have their origin in biliary stem-cells, the different histological types of the tumours merely representing varying degrees of cellular differentiation.

Various 8-substituted cAMP analogues were converted into the corresponding N6,O2'-dibutyryl, N6-monobutyryl, or O2'-monobutyryl derivatives and the parent compounds as well as the new derivatives were tested for TSH-like stimulation of the thyroid function in mice in vivo by means of the McKenzie bioassay. It was found that a pronounced stimulatory effect on the thyroid secretion can be produced by certain cyclic nucleotides. The most potent compounds, 8H2N-cAMP, 8MeS-cAMP, and 8N3-cAMP at 15-30 mg/kg iv, showed an activity approximately one order of magnitude higher than that of cAMP and comparable to the action of 0.6-1.0 mU of TSH per mouse iv. Radioimmunological determination of thyroxine levels in the serum confirmed these results. Serum T4 levels in mice injected, for instance, with 8MeS-cAMP (30 mg/kg) rose from 4.85 +/- 0.25 to 6.32 +/- 0.41 mug/100 ml in 1 h, the net increase in T4 being comparable to that produced by TSH (1 mU/mouse) under identical experimental conditions. Introduction of one or two butyryl groups (in the N6 and/or O2' position) significantly increased or decreased the biological activity, dependent on the parent compound, but no direct correlation between biological activity and degree of butyrylation was apparent. The effect of these compounds on the thyroid seems to be specific for cyclic nucleotides because 8MeS-5'AMP which resembles 8MeS-cAMP but lacks the cyclic phosphate structure is inactive in the McKenzie bioassay and in the T4 radioimmunoassay.

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