Speculations on the effects of abnormal trace metals or chelating agents on the nucleic acids lead to the conclusion that both structure and function of the genetic material may be altered. This aberration may be manifested in the formation of cancer.

From the data reported in the literature, one can speculate that the subunits are first made within the cells and there joined together, end on end, by some framework involving cations. From the size of the subunits, it would appear that more than a single ion is necessary for the binding; a matrix may be formed. Magnesium, because of its greater abundance, seems the dominant element in the connecting lattice. If trace elements are present at a ratio of 1:100 with magnesium, the picture would then be as in XCVII.

(XCVII)

The metals may be chelated to terminal phosphoric acid units (XCVIII) and also bound to water, which itself has a definite crystalline-like pattern in certain biological materials.

A further function of coordinate covalently bound cations may be to bind, in addition to hydrogen bonds, two strands of DNA together. This can be pictured as in XCIX.

(XCVIII)

Abnormal metals may alter both processes. We may assume that there is a constant making and breaking of fibril rods which, once broken, are reformed in the normal way with normal metal distributions and normal molecular unit lengths. In the presence, however, of an unusual concentration of abnormal metals, occasionally a new unit incorporating the abnormal metal may result. If sufficient of these new groups are formed, they may be reproduced, and new information will now be carried on by the carrier of genetic information. Secondary changes will be refleeted in the template mechanisms, and new associated proteins will be formed. The new kinds of cells will have their own rates of growth and destruction. The abnormally short-lived cells should cause no harm; those with a longer life span, or those multiplying at a greater rate than can be destroyed by normal enzyme systems, may result in what is called cancer.

Chelating agents can help form aberrations by removing the cations which function to hold subunits together, or bind two DNA strands, or aid in keeping the conformation of the nucleic acids. New equilibrations are possible between nucleic acid units, chelating agents, and normal or abnormal trace elements. Note that most cancer chemotherapeutic agents are chelating agents, and many are mutagenic agents. Chelating agents like diepoxybutane and bipyridyl produce chromated aberrations in lateral roots of Vicia faba. The chelating agent isonico-tinic acid hydrazide changes nucleic acid in tumor tissue. These actions may be caused by a binding of the cations; or these agents may indeed bind to the nucleic acids via the metals. In fact the well-known anticancer antimetabolite 6-mercaptopurine may not be an antimetabolite at all; it may not be incorporated in nucleic acids but could conceivably bind to RNA by combining with a metal associated with this nucleic acid.

This can perhaps explain why many diverse agents have similar action on tumors. As mentioned previously, most anticancer agents are chelating agents, and many therefore have mechanisms of action similar to 6MP.

Speculations concerning metals as a bridge between nucleic acids and anti-cancer agents may be extended to carcinogenic agents. Cyclopentadiene forms a strong complex with iron, and ferrocene is a well defined organic compound. It exists as a sandwich-compound. One atom of iron is complexed between two layers of the organic molecule, cyclopentadiene. The structure is now accepted as seen in C. It is better illustrated in three dimensions (CI).

Many unsaturated compounds, aliphatic ethylene, acetylene or aromatic benzene form complexes with transition element ions. Chromium dibenzene is now known. Biphenyl also forms these Pi-complex compounds. The addition of two more carbons to biphenyl results in the phenanthrene nucleus, a unit common to all carcinogenic hydrocarbons. It seems logical that these, too, could form Pi-complexes with transition elements (CII). This study should be done.

Extrapolating these ideas to the nucleic acid folding in carcinogenic hydrocarbons, we could postulate that a complex can be formed between hydrocarbon (HC), metal M, and nucleic acids (NA). This HC-M-NA would depend upon the two strands of DNA's forming an angular shaped molecule. If we draw either the pair guanine and cytosine or adenine and thymine, a structure not unlike phenanthrene is obtained (CIII).

Can we not then assume that the HC is held to the NA by an M? The complex would look as it is seen in CIV.

(CIV)

Of necessity the HC would also have to be angular, or in other words be a derivative of phenanthrene, to be carcinogenic. It may be by this means that the electron-donating properties of the hydrocarbons are manifested. The charge transfer complex may involve the donating of electrons from the hydrocarbon to the nucleic acids via a transition metal ion.

The azo dyes which resemble HC carcinogens should also fit this pattern, as should the styryls (CV), all of which may prove to be carcinogenic. Even the aromatic amines like 2-naphthyl-amine may be considered angular molecules after metabolic alteration to the 1-hydroxy-2-amino naphthalene, the chelating agent. If angularity is essential, the 2-amino-3-hydroxy naphthalene would not be carcinogenic albeit a chelating agent. These relationships should be studied.

If subunits of nucleic acids are held together by Pi-bonds only, metals and carcinogenic agents should be able to distort or disrupt these bonds.