The problem of carcinogenesis appears in a new light when cancer is considered under the concepts presented above. Classically, the experimental induction of cancer is judged successful only if the result is a tumor in the invasive phase, that is, with abnormal cells invading normal surrounding tissues. This is considered to correspond to a fundamental specific change which transforms the normal cells into cancerous ones. The entire disease is held to stem from the relationship between these abnormal cells and the organism. (290, 291, 303) To these simple views of the abnormality, we have proposed another one.

In our view cancer represents a hierarchically organized condition. Its invasive form is only one phase in a long series of changes which transforms successive hierarchic entities into cancerous entities. Carcinogenesis, thus, is not simply a change of a normal cell into a cancerous one but a step by step progressive hierarchic development. A cell is cancerous only if it has a cancerous nucleus just as a nucleus is cancerous only if it is formed by cancerous chromosomes which, in turn, are cancerous if they have cancerous genes. With the same reasoning, it is possible to go far down in the organization, below genes even to nucleo proteins or still lower to histones or even alkaline amino acids, to find that the first changes, which can be considered to be specific for cancer, take place at the bottom of the organization of the biological realm. In other words, a cell becomes cancerous after specific cancerous changes have occurred in all the hierarchically inferior entities that compose it. Thus, a successful experimentally induced cancer, i.e., one that is already in the invasive phase, means that changes would have affected the entire series of hierarchic entities, including the cells, whose participation results in the invasive character. Seen under this aspect, carcinogenesis no longer can be accepted as a simple process occurring in the cells, but must be regarded as a succession of organized processes.

This becomes still more interesting when it is realized that changes in the constituents at the lowest levels of the organization can occur on a statistical basis, that is, independently of the direct intervention of external agents. As these changes have to be developed for many successive hierarchic entities, it takes a certain time for them to be realized. This would explain why most cancers appear after a certain age. Cells with cancerous nuclei, i.e., in the noninvasive phase, frequently are present, in older people, in many organs without producing clinical manifestations. Conceptually, in order for an agent to be considered a successful carcinogen, it must act upon these noninvasive entities to such an extent as to change them into invasive ones. It can thus act upon entities which have already progressed, by themselves, far enough in the hierarchic development of a cancerous process and have arrived at the noninvasive phase without any manifestation. The excessive length of time necessary, even for the most active agents, to induce invasive cancer would suggest, however, that more than a simple passage from an already existing noninvasive cancer into an invasive one is involved. A plurality of changes must be induced, some or all at levels below the cell.

We are inclined to favor this last hypothesis which obliges us to consider that a carcinogen induces changes at different levels of the organization. It is supported by a series of facts. In addition to having the capacity to induce invasive tumors, carcinogenic agents also induce precancerous lesions which correspond to cancerous entities below the invasive phase. Cells with abnormal nuclei or with only abnormal chromosomes are almost constantly seen in induced carcinogenesis. Even agents which produce a high proportion of invasive cancer consistently induce such changes at lower levels as well. For carcinogens which induce a low proportion of invasive cancers, the effects often appear to stop at lower levels. Such activity at subnuclear levels of the organization is seen in the capacity of most of the carcinogens to induce mutations and monstrosities.

In the concept of hierarchic organization, mutations are considered to result from changes taking place at the gene level, with lower levels left unaffected. Monstrosities result from changes at the chromosome level. Comparison of carcinogenesis with mutations and monstrosities has led us to consider that cancerous changes begin at levels much below those involved in mutations and monstrosities, possibly at the nucleo protein level or, even below. The complex cancerous condition to which the invasive form corresponds can thus be seen to be the result of a series of anomalies which have taken place at different levels below the tissular. Carcinogenesis at the invasive phase is conditioned by the existence of changes at all the lower hierarchic levels. While they can appear as the result of the development of the organization, conceivably these changes can be hastened or even induced by the carcinogens.

The concept of multiple changes in carcinogenesis has caused us to search for multiple factors in carcinogens themselves. The possibility that such factors might be found was suggested by the existence of so called co carcinogenic agents. These are substances without carcinogenic activity of their own but capable of inducing such activity in cases in which some carcinogens are administered in doses too small to induce invasive cancers by themselves. This peculiar intervention of co carcinogens can be explained through the multiple factors in carcinogenesis.

It can be conceived that the factors present in a carcinogen do not have equal activity. The differences appear evident when the carcinogen is administered in very small amounts. While some factors still have sufficient potency in these small amounts to accomplish their part in the complex process of carcinogenesis, others are quantitatively insufficient and do not induce changes. The total effect is an incomplete set of changes. Under these circumstances the addition of a co carcinogen can replace the action of the quantitatively inadequate factors, and consequently complete the plural action necessary to produce an invasive cancer. Because any one co carcinogen can replace only certain factors, co carcinogen activity has a certain specificity.

With the hypothesis of multiple actions in the same carcinogen, the next step was to try to recognize them. A study, identifying different active energetic centers in the structures of carcinogens, has substantiated the hypothesis.

We attempted, as a first step to systematize the analysis of such energetic centers in carcinogens. A short resume of this study is presented here.

Energetic Factors

A well known and generally accepted concept tries to correlate carcinogenic activity with the presence of one energetic factor, identified as a "condensation of electrons," at certain regions of a molecule and revealed by the physicomathematical approach offered by Pulman and Dawdel.

Studies of the role of electron distribution in carcinogenesis were started by Otto Schmidt (43), which showed that an electron density exceeding 0.44e/a^2 in the meso region of the molecule appears necessary to confer carcinogenic properties. This concept was partially modified and amplified by Pulman, Dawdel and their co workers (44) who have shown, by quantum analysis of various carcinogens, that the density of the w electrons is increased in certain preferred regions of the molecules, the K regions. They showed that, when electron densities exceed 1.292e at these regions, the substances have carcinogenic properties. Figure 95 shows such a K region.

The regions K in carcinogenic molecules

9:10 Dimethyl

1:2:7:8 Dibenzanthracene

Fig. 95. The regions K in carcinogenic molecules.

From our point of view, a tentatively interesting aspect of this condensation of π electrons lies in two facts: the presence in some carcinogen molecules of more than one such K region, and the presence of different values for these K regions in different molecules. It would be the presence of more than one K region in the same molecule which would result in intervention in more than one process and thus contribute to plural activity.

Further analyses, however, suggested that the condensation of π electrons in K regions would represent only one of the factors that would induce activity in these agents. We have identified another energetic factor in the presence of two atoms having the same electrical sign and being bound together within the molecule.