Iron, a member of the VIII series and an anti D agent belonging also to the cellular level, is of special interest. Its form of activity as cytochrome oxidase or hemoglobin has facilitated the understanding of its intervention. We could thus relate the high or low amount of the red cells in hemoglobin which corresponds to the amount of iron ions to the respective offbalance. Hypochromia corresponds to a type D offbalance and hyperchromia to a type A. These patterns, which were first recognized through clinical investigations are in accord with the anti D character of iron at the cellular level where it belongs. The existence of offbalances of A and D types in cancer explains the high and low values of Fe in the immediately higher level, the blood serum. Fever, as we have noted, corresponds to an off balance of type A at the metazoic compartment. The fact that serum iron is low during fever would indicate increased iron activity at the cellular level, which accords with its A inducing role. We administered iron compounds to cancer patients with hypochromic anemia to correct the anemia and also because of iron's anti D effect which might act antagonistically on sulfhydryl groups. In several cases, with very high sulfhydryl index values, ferrous sulfate has been administered in doses as large as several grams daily. In addition to producing an increase in hemoglobin and color index, ferrous sulfate in large doses has been observed to have another effect in some cases, reducing pain of an alkaline pattern. The salutary effect upon pain was noted more often with reduced iron than with ferrous sulfate. No other influence upon systemic changes was observed.

In tumors, iron produced an increase in rate of growth as expected. This peculiar effect of iron administration could be clearly seen in a case of lymphatic leukemia.

B.V., 4 years old, came under our care with the diagnosis of subacute lymphatic leukemia. He had a count of 145,000 leucocytes, of which 96% were lymphoblasts. Butanol administered in small doses reduced the number of leucocytes considerably, even after a few days of treatment. After two weeks, the count was below 5,000 leucocytes, with the proportion of lymphoblasts decreased to 6%. A count of 3,200 leucocytes made us discontinue the administration of butanol. In three weeks the count rose progressively to previous values. Butanol was again administered and again the blood count showed the same marked decrease in leucocytes.

All through this "remission," intensive hypochromic anemia persisted and led us to administer ferrous sulfate in addition to butanol. Within a few days after iron was added, the white cell count increased to 110,000 leucocytes/cmm., and the proportion of lymphoblasts rose to 90%. When the iron was stopped and butanol continued alone, the leucocyte count fell again, to 8,000/cmm. Iron was again administered and the total white count rose a second time in three days, from 8,000 to 80,000, with 96% lymphoblasts. When the iron was discontinued, the count again fell back within a week to between 6,000 and 7,000, this time with less than 30% lymphoblasts. This continued for another two weeks, when iron therapy was instituted for the third time, the count went up again to 38,000 within a single day. When butanol was administered alone, it went back to 5,600 in another five days. The boy died a few weeks later in acute shock during a blood transfusion.

While generalizations cannot be made from these findings, it could be definitely established in this particular case that the administration of iron was followed by a marked increase in the number of leucocytes and in the proportion of lymphoblasts. We saw this repeated, although not so spectacularly, in another case of lymphatic leukemia.

In several cancer patients who received iron in large doses over a prolonged period of time, tumor growth seemed to be stimulated. In animal experiments, tumor transplants grew only slightly faster in animals fed iron than in controls. Mice and rats used in these studies received approximately 0.05 gm. daily of reduced iron per 100 grams of body weight, mixed in powdered Purina chow, or were given a corresponding amount of ferrous sulfate in drinking water. Iron was added to the diet of the animals two or three weeks before tumor transplant, and was fed after transplant. Tumor growth was slightly enhanced and survival time shortened.

Similar studies were carried out using nickel and zinc alone or mixtures of them with iron. The metals reduced by hydrogen were obtained and a powder preparation was incorporated in powdered Purina chow in amounts calculated to provide approximately 0.05 gr. metal/100 gr. of body weight daily. Significant changes occurred in the evolution of Walker tumor transplants in rats receiving 0.05 gr. daily of zinc or nickel/100 gr. of body weight. In most experiments, two different results were noted. Tumor growth was retarded in a significant proportion in one group of animals, with the tumor disappearing in some cases. In another group with the same Walker tumors, tumor growth was stimulated. It is interesting to note that retardation occurred only in tumors with a necrotic, ulcerative character, while stimulation was noted in those with white masses. The correlation of necrotic and ulcerative tumors to an offbalance of type D and of massive non ulcerated white ones to offbalance of type A explains this paradoxical result. This would confirm the anti D or A inducing character of these metals.