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The Role of Sodium, Potassium, Calcium, and Magnesium 1N Cancer: a Review

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The Role of Sodium, Potassium, Calcium, and Magnesium 1N Cancer: a Review THE ROLE OF SODIUM, POTASSIUM, CALCIUM, AND MAGNESIUM 1N CANCER: A REVIEW M. J. SHEAR (From the Ofice of Cancer Inveeligationa, U. S. Public Health Service, Harvard Medicd School) r. INTRODUCTION Among the many angles from which the cancer problem has been attacked is the study of the r81e of inorganic substances. A large number of the chemical elements, starting with aluminum and on through the alphabet to zinc, have been considered as possibly playing a part in tumor growth, and importance has been ascribed to some of them. Commou constituents of living tissue, as well as substances which are found in the body in very small amoynts, or not at all, are among those alleged to have significance in cancer. It is possible that some inorganic substance which is present in the body only in traces may ultimately be found to be of impor- tance in malignant disease ; on the other hand, investigations have also been directed towards determining whether one, or more, of the fixed bases which constitute so large a fraction of the total min- eral content of normal living matter plays a determining r61e in tumor growth. A voluminous literature abounds in reports assert- ing that the fixed bases of the body, i.e. sodium, potassium, calcium, and magnesium, exert a significant influence on neoplasms. A re- tarding effect on tumor growth has frequently been ascribed to calcium and to magnesium, while an accelerating effect has been ascribed to potassium and to sodium. Importance has also been attached to the ratio of one base to another, especially to the po- tassium : calcium ratio. Around this phase of the problem a large literature has grown up. Much of the work is comparatively recent. The first papers in this field appeared a quarter of a century ago, but most of the contributions have been published during the past decade. Since no comprehensive review of this subject exists,' the literature has been critically surveyed and the material assembled in a convenient form. Studies designed to throw light upon the part played by these four elements in cancer cover a wide variety of approaches and 1 Of the brief r6sum6s and partial reviews, the more rwent aro those of Lieber (1924), Kahn (1925), Bishop (1930), and Mankin (1932). 924 SODIUM, POTASSIUM, CALOIUX AND MAGNESIUM IN OANOER 925 deal with many aspects of the tumor problem. Thus, analyses have been reported for tumors and for the blood of tumor-bearing individuals. Attempts have been made to influence susceptibility to tumors and to affect tumor growth by treatment with salts of these metals. The substances have been administered in various ways: by mouth, by injection, by inclusion in the diet, and by im- mersion of tumors in salt solutions prior to inoculation. In addition to such direct attacks upon the problem, there have been a number of indirect approaches. For example, it has bee11 asserted that the calcium ion concentration of the blood is de- creased in cancer, and several investigators have administered parathyroid hormone in an attempt to increase this concentration. Vitamin D, which exerts an important effect upon calcium me- tabolism, has also been given to tumor-bearing animals. Furthermore, it is possible that these four bases may be in- volved in cancer metabolism in ways that have in the past received but little recognition. Sfagnesium, for example, is an activator of enqmes involved in carbohydrate metabolism, as von Euler (1931) recently pointed out. Warburg (1933) is of the opinion that in- organic salts may exert an important influence on living tissues “indirectly, through their influence on the oxidative reactions. ” Much study has been devoted to cell respiration and carbohydrate metabolism in cancer, but relatively little is known about the effect of the common bases on these processes in malignant disease. Critical sifting of the published experimental data reveals that our present knowledge of the part played by sodium, potassium, calcium, and magnesium in cancer is incomplete and unsatisfac- tory. A study of the literature leaves one with the impression that sodium is of no especial significance, that potassium may have a stimulating effect, and that calcium appears to have a retarding effect on tumor growth. No substantial evidence is found for the oft-repeated assertion that magnesium has a beneficial effect in cancer. These are the indications furnished by the existing evi- dence. They are not, however, convincingly established concln- sions, of which there are but few. Apart from its academic interest, this problem has a direct bearing on clinical practice. For example, one school has been holding magnesium deficiency responsible for cancer and accord- ingly has strongly recommended administration of magnesium salts not only in treatment but also in prophylaxis, while the re- sults of other investigations indicate that magnesium may actually stimulate tumor growth instead of retarding it. Similarly, an- other school accepts the thesis that a deficiency of calcium ions is responsible for tumor growth and recommends administration of parathyroid hormone therapeutically and prophylactically, while 926 M. J. SHEAR other work indicates that administration of parathyroid hormone stimulates tumor growth. In this survey the numerous contributions to the literature have been correlated and evaluated with a view to determining which of the conflicting conclusions rest on the soundest basis, and to ascer- taining which direction further investigations may profitably take. 11. TUMORANALYSES Sodium, Potassium, Calcium, and Magnesium Contents: The analyses of Beebe (190445) and of Clowes and Frisbie (1905) laid the groundwork of our present knowledge of the inorganic compo- sition of tumor tissue. In Beebe’s pioneer contribution it was re- ported that fresh, vigorously growing human tumors were richer in potassium and poorer in calcium than degenerating tumors. Clowes and Frisbie reported similar results for mouse tumors. Beebe analyzed the tumors for sodium, potassium, and calcium and gave the data in terms of the dry weight of the tissues. The amount of magnesium found was so small that quantitative deter- minations could not be made. Calcium was precipitated as oxalate and weighed as the oxide. The sodium and potassium were weighed together as sulfates ; the potassium was then precipitated as the chloroplatinate, and the sodium obtained by difference. Thus, the sodium content waa not obtained by direct analysis, but by’ calculation. In preparing the tumors for analysis, the tissues were ashed at dull red heat. Only 8 malignant tumors were analyzed by Beebe, and these tu- mors (human) were of various types. Clowes and Frisbie analyzed 100 mouse tumors, all adenocar- oinomas (Jensen). In a systematic investigation they correlated the characteristics of this tumor with the potassium, sodium, and calcium contents. Magnesium was never found in appreciable quantities. They found that “the amounts of potassium and cal- cium are subject to most remarkable variations ; rapidly growing, large tumors showing a marked tendency to a high potassium and low calcium content, whilst the reverse is to be observed in the case of slow-growing tumors. This is so marked that in certain cases of very early tumors potassium only is to be recognized, whilst in the majority of old, necrotic tumors calcium only is present. It will be seen, furthermore, that a steady fall from a high percentage of potassium in the younger to practically none in the older tu- mors is accompanied by a corresponding increase from no calcium in the younger, to a high percentage of calcium in the older, ne- crotic tumors. ”’ No mention wag made as to the analytical methods employed: neither was it stated whether the tissues were prepared for analysis SODIUM, POTASSIUM, CALCIUM AND MAGNESIUM IN CANCER 927 by incineration or by digestion with oxidizing solutions. The data were given in terms of the original wet tissue and since no values for the H,O content were reported, the results cannot be recalcu- lated on the dry basis. Sixteen years elapsed before the next important contribution, that of Waterman (1921), appeared. The work of Beebe and of Clowes and Frisbie had stimulated a number of investigators to study the rSle of potassium and of calcium in cancer, and for the most part subsequent students accepted the results of Beebe and of Clowes and Frisbie quite uncritically. Thus Neuberg (1911), in his review, stated that Beebe had carried out an exhaustive in- vestigation on the mineral content of human tumors. As a matter of fact, Beebe’s work was far from being exhaustive: indeed, he himself had said: “It is impossible from so few experiments to draw definite conclusions as to the function of these metals. .9, Waterman felt that it was desirable to study this problem anew in order to confirm, if possible, these results which had been so un- critically accepted. He therefore proceeded to analyze carefully a series of about 30 assorted tumors of man, dog, rat, and fowl. Analyses were made for sodium, potassium, and calcium; the data were given in terms of dry weight of tissue. In order to avoid the loss of potassium which may occur during the ashing of tissues, Waterman destroyed the organic material ac- oording to one of the 80-called “wet-ashing” methods, i.e. by diges- tion with nitric and sulfuric acids. Although it has been recog- nized for some time that dry ashing may result in serious losses of certain inorganic constituents, this point has not been taken into consideration in many investigations on the composition of tissues. As regards the accurate determination of potassium, Waterman stated that there was no method available which was above criti- cism. He used both the standard chloroplatinate method and the then new cobalti-nitrite method of Kramer and Tisdall (1921~). Sodium he tried to determine directly as pyroantimonate, using the method of Kramer and Tisdall (1921b),which had ‘ust been de- vised.
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