This same rule would explain the distribution of potassium, another element of the same series. Potassium is the principal anti D cation for the cellular compartment, as it is one of the principal constituents of the earth's crust, the environment in which the nuclei developed. Excess of potassium in the cell results in a cellular A offbalance with consequent active proliferation. Potassium in excess appears thus to be the cellular growth inducing factor and its role in cancer has to be considered especially at the cellular level. Through the induced growth, the excess of cellular potassium would thus represent the factor immediately responsible for the invasive phase.

Following the rule of distribution of elements between the levels and compartments, an excess of cellular potassium will result in low blood potassium. This permits us to associate excess of cellular potassium and hypokalemia in cancer with active cellular proliferation. The opposite occurs in the state of shock and in offbalance D. The amount of potassium decreases in the cells. Consequently, the element accumulates and is retained in excessive amounts in the compartment immediately above the cells, the metazoic. Teleologically speaking, while the excess of sodium in the intestines and the excess of potassium in blood could be eliminated easily by means available to the organism, they are kept in high amounts in these superior compartments as reserves, disposable when and if the abnormality disappears and they can be used properly again. We have seen how this same mechanism explains the excessive amounts of copper in the blood in cancer patients.

This redistribution between compartments explains another fact about potassium. An excess of potassium is found in cancer cells: the greater the degree of malignancy, the greater the excess of the element. Along with the cellular excess, the amount of potassium in the blood drops to low values, even below 4 mEq. The low blood value cannot be related to lack of potassium, since quantities of the elements are eliminated in the urine. It has to be considered as a kind of defense through the higher level to an excessive amount of the element at its proper level. This relationship has led to the comparative study of the potassium content of red cells and serum as a means of obtaining indications concerning the intervention of this metal at its proper cellular level. The changes in the potassium content of red blood cells are considered to parallel those occurring in the cells in general. It is not the ratio between these values which is of interest, but each value by itself. Low amounts in red cells and in serum correspond to a quantitative deficiency; high amounts in both, to an excess of the metal; low amounts in cells and high in serum indicate a metabolic anomaly corresponding to a depletion of potassium in the cells as seen in offbalance D; while a high amount in cells and with low values in the serum indicate a cellular offbalance of the type A.

Administration of sodium and potassium as therapeutic aids has to be guided by these findings. Isotonic saline appears to be adequate as a replacement product but it is useless to administer it only because hyponatremia exists, except if this hyponatremia results from a quantitative insufficiency, as in excessive perspiration. The problem to be considered is how to restore the normal bond for the cation at its proper level. Often, what is needed is chloride ions for sodium, not more sodium. Similarly, with hyperkalemia, if it exists in cases of type D offbalance, it is not the hyperkalemia which has to be directly attacked; efforts must be made to have potassium again normally fixed in its own cellular compartment. The use of glucose, insulin and ACTH seems to accomplish this for potassium. While administration of potassium in cases of cancer with hypokalemia possibly produces some immediate subjective improvement, it is constantly followed by an exacerbation of tumor growth as long as it does not correspond to a quantitative deficiency. In cases where this potassium quantitative deficiency can be eliminated as the cause of hypokalemia, beneficial results are obtained through administration of agents such as magnesium sulfate or calcium salts.

Searching for a cation that might compete with potassium and sodium, we first chose ammonium. Theoretically, it seemed to be a likely choice since it penetrates into the cell and nucleus with ease. In the pharmacology of ammonium, the missing link is the factor or factors—the substances and conditions—which determine the role of this cation in the nuclear compartment. Ammonium proved valueless because it was taken up by the liver and transformed into urea. Therefore, we resorted to the use of another monovalent cation of the same homotropic 1A series but with a higher atomic weight, rubidium. This cation is very similar to ammonium ion. Rubidium and ammonium, in nitrates, sulfates and especially in double sulfates of aluminum or magnesium, are isomorphic. We tried rubidium salts in animals and found them to have a very low degree of toxicity.

In order to study its influence upon sodium and water retention in lesions in which fatty acids predominate, we administered 1-2 cc. of a 5% rubidium chloride solution in water, two or three times daily. In several cases, this caused diuresis and significant reduction in edema. With the idea of having rubidium act at the nuclear levels, we considered the use of rubidium compounds with anions that seem to intervene at these levels. Rubidium nucleinate was prepared and 1-2 cc. of a 10% solution in water administered to subjects two to three times daily. Although these studies are not yet sufficiently advanced to permit any conclusions to be drawn, it seems that the rubidium salts may be useful in cases of intractable edema related to a local condition.

These studies of the distribution of cations at different levels of organization appear to be extremely important if we want to reach cellular and especially nuclear levels with cations, particularly as radio active isotopes. We tried to go still further and utilize heavier cations. Experiments with cesium salts seem to present more difficulties, at least for the present, because of the insolubility resulting from the high atomic weight of this element.

In the VI B series, we know little about chromium. Molybdenum appears to be an active agent. The influence exerted by molybdenum is neutralized by the action of methionine, with its active thiol group. Excess of molybdenum found in some pastures induces a deficiency in copper and calcium in animals followed by osteomalacy and bone fractures, just as it induces low fertility. (174) The antagonism between these elements is shown by the inhibitory effect of ammonium molybdate upon oxidase activity of ceruloplasmin, the form in which copper is bound to protein in blood serum. (175)

The anti D effect of molybdenum is especially marked in microbes, in which it induces morphological and tinctorial changes. Bac. anthracis treated with ammonium molybdate shows a cocciform change and abnormally intensive Gram positive staining.