The interesting research of Berenblum has brought an important contribution not only for the largely debated role of urethane as carcinogen, but also for the problem of carcinogenesis in general. The fact that croton oil, applied to the skin, induces the appearance of malignant tumors in animals previously fed with urethane, concords largely with the concept of plural changes taking place in carcinogenesis. The analysis of the influence exerted by carbamic acid upon amino acids would place the intervention of this agent at the first members of the biological realm. It can thus be seen that the bond between the amino acid group and the carboxyl and amine groups of carbamic acid occur in a way similar to that which occurs between two amino acids with the big difference that in the first case it would result in the appearance of the CNCN formation. (Fig. 277) As mentioned above, this CNCN formation represents the group which charcterizes the first biological entity. The place of this CNCN group, not at the end of the molecule opposed to the carboxyl as in the alkaline amino acids, but as corresponding to the bond which results in polymers, represents the anomaly, which according to the work hypothesis we advance, would correspond to the first cancerous entity. The fact that the carcinogenie activity of urethane takes place at the lowest levels of organization, explains the necessity that a certain time separates its intervention from that of croton oil, which would act only at the higher levels, probably inducing the passage from noninvasive to invasive phase. This time is necessary for the first cancerous changes to build up the series of cancerous hierarchic entities since the cocarcinogcn, croton oil, would act only in those more evoluted cancerous entities. In experiments in course, the passage of the noninvasive urethane induced carcinogenesis entities into invasive cancer, is successfully induced by preparations of unsaponifiable fractions.

The bond between the carbamic acid and an amino acid group

Fig. 277. The bond between the carbamic acid and an amino acid group leads to the formation of the NCNC group.