Some chemical aspects of cancer research - Journal of Chemical

SOME CHEMICAL ASPECTS OF CANCER RESEARCH*,t ELLICEMCDONALD. CANCER RESEARCH LABORATORIES, UNIYERSITT OB PENNSYLVANIA,

PHILADELPHIA. PENNSYLVANIA

Cancer is the most important problem of our time because of the great death rate and the enormous increase of incidence within the last twenty-five years. There i s great need for research to discover nem facts about the disease for its prevention and cure. The problem should be attacked from the consideration of the chemistry of vital systems, in which the cell, the smallest particle capable of sustaining lqe, i s the unit. A model concept of such a biological system may be set u p infour components: (1)nucleus, (2) protoplasm, (3) cell membrane, and (4) enerirunment. Each of these phases i s of importance in the heterogmow vital system. The cancer cell has been s h m to h a w a different set of chemical reactions (metabolism) from normal cells. There is a defect in ths oxidative. processes and a larger production of lactic acid. The degradation of glycogen (the sole source of cell energy) to lactic acid apparently follows a different path in cancer. The nature of the injury to the oxidative processes of the cell i s the most sign6caut fact of present-day cancer research. The repair of this injury and the production of a more oxidizing potential than the limiting oxidation-reduction potential necessary to cell division, gives hope of transforming the cancer cell back to a normal chemical metabolism. A chemical cure of cancer seems, therefore, only a matter of time, trouble, and intelligent effort.

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Cancer is the most important hum& problem of our time: first, because it kills more people than any other single distase (heart disease which is higher in the mortality records is a combination of heart, kidney, high blood pressure and other diseases) ; second, because it has increased so greatly in incidence in recent times. In 50 American cities with a total population of 30 million, there has been a 58.2 per cent. increase in cancer deaths in 25 years. In the state of Pennsylvania, there has been a 62 per cent. increase in the same time. In Australia, in a decade, there bas been an increase of 40.5 per cent. in deaths from this disease. Not only has the mortality rate for cancer increased, but the rate of increase is becoming greater. In the statistical bulletin of the Metropolitan Life Insurance Company, which gives the mortality records of their policyholders for the first nine months of 1931, is the following statement, "The mortality record for cancer is the most unfavorable item to date (Oct., 1931) in the health record of 1931. We know of no explanation for the marked rise in the cancer death rate. It is true that, over a long period of years, an * Lecture delivered before the Chemical Society of Washington (Local Section of t h e A. C. S.), Washington, D. C., November 12, 1931. t In the preparation of this manuscript the author is indebted for assistance and criticism to the chemists in ow laboratories, particularly Doctors Fosbinder, Bancroft, and Schraeder and also to Dr. E. 0.Kraemer, Consultant to the Cancer Research. 820

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upward trend has been obsemed in the mortality from cancer, but no such decided rise (6.4 per cent.) has been obsemed in any one previous year." I n 1930, the mortality rate for white women was 117 per 100,000 of population and, if the future increase be calculated upon the past increase, in sixty years, the mortality rate for this class will be 192 per 100,000 of population and, in 100 years, cancer will take a stupendous toll of death in adult white women. Such a result is so contrary t o human experience, that we can only believe that something will intemene to prevent it. Cancer is a more important problem than war, pestilence, or famine. I n the United States, approximately 130,000 people dieannually from cancer. An estimate of mortality in the war years was made in Canada as an example of a small self-contained population of European stock. I n the four years of a war, unequaled for its losses and in a country which suffered war casualties about proportionally with the rest of the British army, the deaths a t home of men and women from cancer in those four war years were almost exactly equal t o the army casualties from war senrice. I n England in 1928, more than 12 per cent. of all deaths were from cancer. The casualties of cancer were as great as the casualties of war. We fight a losing battle every year with cancer and receive casualties equal t o those of a devastating war. Something must be done about i t and that something must be in the nature of the discovery of new facts about the disease for its prevention and cure. Yet such is the lack of proportionate perspqctive, that vast sums are being spent upon armament for human destruction and very little for the consemation of man. These may be felt even by those of us who are not pacifists and who have worn the uniform in the last great outburst of human destruction. The cost of one cruiser would maintain all the cancer research institutes in this country, not for one year nor for ten years, but for a hundred years. Surely, here is a war whose casualties are worthy of the enlistment of the interest of the American people. If man power makes might, conservation of man makes mighty; the salvage of this great human waste, as a selfprotective and preparedness measure, is an intelligent effort. Those who die from cancer are a t the height of their experience and powers. It is quite conceivable that the salvage of one single man, who might by his intelligence devise a new weapon, could alter the course of a war and bring victory where defeat loomed on the horizon. With the present great outburst of scientific discovery, such an event might be more than likely. The discovery of a cure of cancer would be a magnificent gesture and gain the friendship and applause of the whole world, and victory in such a war would belong to all mankind. Cancer is a problem in applied science which needs only time, money, and intelligent effort to solve.

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The disease is a subject to warrant careful consideration and organized effort, for it touches the life of a great number of people. What has been done about it? A devoted group of medical men in a number of countries has studied the disease in man and in animals for many years, with the result that the treatment of cancer has improved in two directions-improved surgical treatment and treatment by radiation (X-rays and radium). Better surgical methods, improved technic, and earlier diagnoses gain better results than the old results which were nil. But surgery is only applicable to such cancerous growths as are easy of access, which do not involve a vital organ or have not produced additional subgrowths called metastases. In other words, if the cancer can be completely cut out, surgery is of use; if it cannot, surgery had better not be attempted. Yet in the best clinics and under the best auspices, 75 per cent. of kncers are not suitable for surgical treatment because extension of the disease has already occurred. Since 1910, we have been concerned with elaboration of detail in the use of radiation, with improving methods of application and perfecting apparatus. So that now with surgery, aided by radiation under the very best auspices, about one-third of all cancer cases, as they come, can be cured. In this country, under the disorganized methods, it is very difficultto estimate the total number of cures of cancer; but, after several years of collection of opinions and statistics, the total proportion of cures in cancer is estimated at less than 10 per cent. and more than 5 per cent. of all cases treated, as , organized care is not complete. In fifty years of antiseptic surgery and $I twenty years of development of radiation treatment, we have been able to develop only two methods of treatment for cancer, neither of which gives anything like satisfactory results, but we use them because they are the only ones available. Yet these two methods, surgery and radiation, are a t the present time the only responsive measures for the treatment of cancer, and this is obviously a confession of failure. Yet why should it be so' Life is a very definite reaction which occurs and recurs according to definite constancy, and cancer is only a problem in the reproduction of a life history of cells, for cancer is a problem in cell division. A disease, such as cancer, is not a thing but a state, a deviation from normality. The cells, after our youthful growing period, have ceased to grow with arrival a t adult age, or certain inhibitions to growth have occurred. In cancer, which is generally a disease of the later half of life, certain cells have lost their inhibitions to growth and renew their power of division into a multiplicity of cells, almost always beginning in a local area. These cells are carried to distant parts of the body and maintain there the characteristics of the original cells, including their power of division and multiplication. Death occurs from extension of these cells as a growth to some vital organ, impairing its functions, to a general extension of the

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growth, producing such poisons as to alter the functions of the blood and other parts of the human organism, or by creating such obstruction, or lowered resistance, so that a terminal and fatal bacterial infection results. The disease is a cellular disease so that the cell, the smallest particle capable of sustaining life, is our unit, as the atom is the unit of the physicist and the molecule of the chemist. All life forms are colloid in character and we have to do with a heterogeneous system, elaborated into a polyphasic organization and with definite structural arrangement. The chemical complexity of the cell would be baffling were it not that there are phenomena which are common to all cells. Nature a t some stage in her complexity reiuvenates her simplicity. The atom, the unit of the physicist, by structural associations,forms the molecule which is equally satisfying to the chemist. The molecules form the cell where there is again renewal of the simplicity. The cell, in the study of cancer, is the unit and has a definite arrangement or organization. It is possible to create a model for thought exactly as the physicists create a model of the atom. In cancer research, it is possible to take as a construct, or a fixed model for thought, the cell with the component parts of its system. The cell consists of (1) the nucleus (normally with a pH FIGURE 1.-MODELCONSTRUCTED FOR of about 7.5), (2) the protoplasm (norC~NSIDERATION OF CELLACTION mally with a pH of about 6.6), (3) (1) Nucleus with a pH about 7.5; the cell membrane, and (4) the envi(2) protoplasm of cell with pH about 6.6; (3) semi-permeable cell memronment, which is the blood (with a brane; and (4) environment or hlood normal pH of 7.38 and more alkaline plasma with a normal pH of 7.38. in cancer) and tissue iuices. (See accompanying diagram.) The environment must be considered, for the cell and its environment are one. All energy forms, and the cell is an energy adapter, are brought to the cell and enter the cell through the environmental phase. In consideration of alteration in cellular reactions, the environmental phase is of the greatest importance because alterations in this phase determined the reactions of the cell, and, through this phase must go any influence, excepting radiation, which wL11 prevent the cell division or cure cancer. Part of the mistakes in the study of cancer in the past have been the consideration of the cell alone, as studied through the microscope in dead and stained preparations. In this, the most important phase in determining cell activity, the environment, was not considered.

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Our unit system may therefore be thought to consist of four distinct portions: (1) nucleus, (2) protoplasm, (3) semi-permeable cell membrane, and (4) the environment from which the cell receives its energy-producing materials and through which the products of reaction are removed. The protoplasm is an intimate association of salts, carbohydrates, fats, and proteins, many of which are specific to a high degree and which are partly contained in true solution and partly in a poly-dispersoid state. In the continual exchange of materials and energy, the processes of oxidation-reduction are of outstanding importance. If we deny a cell oxygen, it either gradually ceases to function and dies or, like yeast, it adopts some form of anaaobic breakdown in place of oxidation; if anaaobic breakdown fails, the cell then perishes. Life is an oxidation-reduction rhythm dependent upon oxidation-reduction potential that decides which one of two systems will oxidize the other. Since the process involves a transfer of electrons from oxidant to reductant, we may, by an adaptation of the Nernst formula, arrive a t the following equation: RT (Red.) E h = E . - - In nF

(Ox.)

where Eh is the voltage with respect to the hydrogen electrode as 0; E, is the normal electrode potential; Red. and Ox. the concentrations of the reductant and oxidant, respectively; T , the absolute temperature and R, the gas constant. It is important to reqgnize that this treatment applies to only perfectly reversible processes and herein lies the difficulty of applying it to vital systems whose processes are not generally reversible. However, many biological oxidations which are apparently irreversible proceed by a number of stages, some of which are truly reversible. The oxidation-reduction potential decides in which direction the reversible reaction will proceed, but the rate is determined mainly bythe oxidative catalysts whose influence must therefore be a most essential factor in the problem. In these cell oxidation-reduction processes, there are living catalysts which are known as the "dehydrogenases" or "dehydrases." Their function is to activate molecules so that they act either as hydrogen donators or hydrogen acceptors, depending upon the nature of the molecule and the conditions of reaction. The so-called inorganic ferments, or heavy metal catalysts, also play a great r81e in vital oxidation-reduction processes. In the living cell are other chemical substances for reversible oxidation-reduction systems, the most important of these being the sulfur compounds of the type RSH $ RSSR, the former being the reduced form. In this class are the cystine-cysteine and the glutathione-reduced glutathione systems, and in addition as oxidation-reduction systems, the fatty acids and carbohydrates.

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There is no doubt, in life processes, that a steady dynamic state exists which is not chemical equilibrium, but which may be conveniently spoken of as biological equilibrium, and through which energy may be liberated. The normal processes of the living cell are brought about by a continuous energy interchange which is dependent upon the physical, chemical, and colloidal state of the cell constituents and which, in its explanation, must be correlated with the fixed model of the cell with its four-component systems of (1) nucleus, surrounded by (2) protoplasm, enclosed by (3) cell membrane, and existing in (4) environment. The influence of conditions of biological equilibrium on the effect of catalysts (or, as the biologists call them, enzymes) is produced mainly through the environing medium which, in the case of the cancer cell, is the blood. It is significant that, in cancer, the blood, or (4) environment of our fixed model, has been found, by us, to be abnormally alkaline, averaging pH 7.44, where normal blood plasma is pH 7.38. The oxidation-reduction intensity (rH) which is analogous to the intensity of acidity or pH, is of enormous importance to these vital oxidation-reduction systems. The rH is a negative logarithm of the hydrogen pressure in equilibrium with the oxidation-reduction system in question. In simple systems, rH is a function of pH and Needham and Needham (1) have shown that it holds similarly for living cells, that rH is a function of pH. Our only and main interest in pH is that i t gives some measure of rH and is an easy and exact measurement cafiable of statistical estimation. The ideal is rH measurement; the means are pH measurement. There is, therefore, to be considered (always remembering our fixed model with its four-component system) a scheme as follows: Factors Influenci

Vital Cell System

Cololrsls (Eneymcs, d c . )

Condilion of Biological Equilibrium

Glycolytic enzyme Ceenzyrne Fe in the hemin form, and Cu Glutathime-reduced glutathione Cystine-cysteine Dehydrogenases, including: (1) heat-labilecatalysts acting on the substrate; (2) intermediate reversible H and 0 acceptors; and (3) heat-labile oxidants sensitive to CN

pH rH Ionic concentration of inorganic substances Glucose concentration Aggregation and dispersion of the colloid Buffer systems Phosphates Carbonates Proteins my. Fe-red. Fe RSH-RSSK

1

This scheme somewhat inadequately classifies the various factors which influence cell life into two great divisions-gross chemical action and catalytic activation and, as such, is applicable to the consideration of the forces influencing the metabolism of the vital activity of the cancer cell.

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In these biological oxidations, respiration is a central life process, supporting the complicated organization of the cell. The respiration yields energy for doing work and these work-producing chemical processes not only possess a large store of available free energy, but also put it at the disposal of the cell. This fact postulates a definite order and organization of the chemical process. The amount of respiration necessary to cell division, as in cancer, is many times that of mere maintenance. Shearer (2) found an eighty-fold increase during the first minutes after fertilization. For the measurement of the metabolic process of cells, manometric methods are almost exclusively employed. These are more convenient than chemical methods. The most important metabolic processes are reactions like the lactic acid formation from carbohydrates, which may be made to result in the liberation of a gas. By means of suitable apparatus and technic, the kinetics and quantitative relations may he easily studied. With the application of these methods and the use of the Barcroft manometer, 0. Warhurg (3), the latest Nobel prize winner for medicine, studied the metabolism of thin slices of cancerous and other tissues and, so doing, revolutionized modern thought and experimentation in cancer research. These researches, combined with those of 0. Meyerhof (4) on the carbohydrates and metabolism of isolated muscle, established that the utilization of oxygen by muscle takes place normally, not during the act of contraction, but rather during the periods of 'relaxation and rest. The processes of contraction are accompanied by the brreakdown of glycogen into lactic acid, whereas, in the recovery period, the oxidation involves a two-fold action, the burning of one part of sugar, or the lactic acid equivalent, to carbon dioxide and water, while three to six times the amount of lactic acid is built back or resynthesized to glycogen. The immediate source of the energy for contraction comes by an anaerobic reaction, while the recovery from contraction is accomplished by an aerobic chain of reactions which ends in the salvage of a large part of the carbohydrate which has been split during the anaerobic phase of the contraction period. One phase, the anoxidative, concerns itself with the breakdown of carbohydrate into lactic acid; the other process, the oxidative, concerns itself with the complete oxidation of a part of the carbohydrate and the recovery of another part from the fermentative breakdown. Following experiments upon yeast, it was found that these two metabolic processes, the anoxidative and fermentative splitting and the oxidative salvage of the split carbohydrate were characteristics of animal tissue cells other than muscle and especially of growing cells. When cancer cells were studied by Warbnrg (5) and his associates; these cells revealed the remarkable fact that they had an excessively high rate of fermentation, causing a vastly greater amount of sugar to be split

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to lactic acid than is the case in normal cells, and they had, on the other hand, a greatly diminished power of utilizing oxygen. Cancer cells could live and continue to split sugar in a nutrient solution where the pressure of oxygen had been reduced to '/laa,aoo volume per cent. They utilized the oxygen in full amount independently of the partial pressure of the gas. The high rate at which tumor cells are capable of splitting dextrose to lactic acid is shown by the fact that in vitro they can produce an amount of lactic acid equal to ten per cent. per hour of their own weight. The degree of glycolysis is a function of pH, the more alkaline the environing medium within physiologic limits, the greater the splitting of the sugar, which means a larger energy turnover and a greater functional capacity. These facts in regard to the greater lactic acid production and different metabolism of the cancer cells have been confirmed by a number of others, particularly Murphy (6),Waterman (7), and Baker, Dickens, and Gallimore (8). The latter found the following: (I) in agreement with Warburg, there is a marked difference in the anaerobic metabolism of glucose in normal and malignant tissue; (2) tumor tissues were found to produce 5-10 times as much lactic acid as normal tissues under the same conditions; (3) the amount of lactic acid produced was nearly equal to the glucose destroyed; (4) the addition of insulin or thyroxine produced no demonstrable effect upon the glucose metabolism. Mellanby and Harrison (9) have recently published some observations on the carbohydrate metabolism of cancer tissue, which, if confirmed, show that, not only is the oxidative mechanism deficipnt, but the formation of lactic acid from glycogen or glucose does not follow the path ordinarily taken in the case of normal tissue, for the above authors found the glucose 6-phosphate (Robison's ester) is not utilized by cancer cells. The significance of this and many other facts cannot well be realized without resorting to a consideration of the possible intermediate mechanism involved in the formation of lactic acid. The course of this reaction is dependent upon the presence of enzymes (catalysts) which are in turn affected by conditions of biological equilibrium. For example, F. G. Hopkins (10) has shown that glutathione (GSH) promotes the oxidation of certain unsaturated fatty acids, the 0 being transferred to the unsaturated linkage of the fatty acid, while the original SH unsaturated groups are reconstituted. At pH 7.4-7.6, the system, GSH fatty acid, behaves differently; here the oxygen uptake is equal to the amount required to oxidize the SH. The SH group is no longer an oxygen carrier, but becomes represented by A02 B -+A 0 BO where A is an auto-oxidator and B an acceptor. On the acid side of pH 7.4, the protein SH is oxidized and the total 0 amounts to ten times the 0 equivalent of the SH; a t pH 7.4-7.6 the uptake amounts to only sufficientto oxidize the SH. This is significant of the influence of conditions of biological equilibrium on

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the effectof catalysts (or, as the biologists call them, enzymes). It is also significant that, in cancer, the blood or (4) environment of our fixed model has been found by us to be considerably more alkaline or averaging pH 7.44, where normal blood plasma is pH 7.38. It is also significant that the higher the pH within physiologic limits the greater the glycolysis (9). Processes of Cellular Metabolism Showing Degradation of Glycogen to Lactic Acid

I I

LACTIC Acrn CH3CHOHCOOH

The scheme given above for the formation of lactic acid from glycogen is not without foundation and it is the logical present working hypothesis to explain some of the experimental facts of cancer metabolism. Robison's ester and hexose diphosphoric ester have been isolated from muscle after addition of sodium fluoride which checks the glycolysis and causes the accumulation of these esters. In a similar manner by poisoning glyoxalase, the enzyme which converts methyl glyoxal into lactic acid, Neuberg has isolated methyl glyoxal from many animal cells and tissues.

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These researches add additional evidence to the correctness of such a scheme of glycogen degradation as outlined. Lohmann (11) has shown that these reactions are influenced by catalysis and that a number of enzymes are involved in the hydrolysis of glycogen in successive stages to form trisaccharides and finally glucose or an active modification. The latter statement is qualified to include "active" glucose, as it is necessary to introduce this concept in order to explain certain puzzling observations in the mechanism of carbohydrate metabolism. The existence of "active" glucose in the blood stream has not yet been satisfactorily demonstrated experimentally, yet one must come back to the hypothesis; i t seems to play an important r81e. From a purely chemical point of view, the possibility of the existence of an active form of glucose is easily reconciled with presentlday structural formulas of the sugars. The normal form of glucose with which we are familiar, has the so-called Pyranose ring s t r u c t u r e t h a t is, a (1-5) oxygen ring structure. It is assumed that under certain conditions an active furanose, or ( 1 4 ) ring structure is formed. In this form the glucose is believed to be more active. The furanose ( 1 4 ) form of glucose has not been isolated. However, Fischer, in 1914, isolated a so-called "gamma" methyl glucoside having the ( 1 4 ) structure. He showed that this glucoside was much more reactive toward permanganate oxidation and toward acetone than the corresponding normal (1-5) a or 0 methyl glucosides were. By analogy one sees that the "gamma" form of glucose would be more reactive than the normal form. It is quite possible, therefore, that under biological conditions, a ring shift occurs, to give the more active furanose ( 1 4 ) type of sugar. Levene and his co-workers have shown that hexonic acids which may be obtained by oxidation of hexoses, also form oxygen rings (lactones) of varying length depending on the conditions employed. They have shown that the ( 1 4 ) lactones are more reactive than the (1-5) lactones. They conclude from this that the activity of the sugars themselves also may depend on the nature of the oxygen ring they possess and that one ring form easily passes over into another under appropriate conditions. Armstrong and Hilditch have shown that normal glucose dissolved in water is practically unaffected by permanganate. However, when the solution is previously treated with dilute HCI, reduction a t once sets in. They ascribe this to the conversion of normal glucose to an active form under the influence of the acid. It is known that dilute HCl favors the ring shift to the active ( 1 4 ) position in the synthesis of gamma methyl glucoside from glucose and methyl alcohol. Bernhauer and Wolff have shown that gamma methyl glucoside (1-4) yields 2.5 times as much lactic acid as normal a or 0 methyl glucoside (1-5) when heated with calcium oxide. This shows the favoring influence

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of the (1-4) ring on the split into 3-carbon chains. Ort has recently made some potential measurements on glucose solutions by means of oxidationreduction methods. He found that glucose solutions contain an active constituent to the extent of 1 part in 260,000. This active constituent is more readily oxidized than normal glucose. The recent investigations of Hibbert (12) on the polymerization of fructose to complex polysaccharides would be analogous to the condensation of active glucose to glycogen. The high rate of sugar metabolism in the body and the ease with which glucose is converted into glycogen and glycogen to lactic acid and other products point to the existence of an active form of glucose. Different sugars ferment a t different velocities, yet the intermediate and final products are the same. It is difficult to see how sugars of different structure can pass through the same intermediates to the same final products, unless one assumes that they first are converted into a form common to all, that is the "active" form. Lactic acid is formed more rapidly from glycogen than from free glucose by the muscle enzyme system, so it appears that the glucose split from glycogen exists in a more reactive state than the free glucose. The action of insulin in decreasing sugar in diabetics may be explained by assuming that it acts by converting the normal form into the active form which is then oxidized or utilized more readily in the body. In the enzymic synthesis of sucrose, Oparin and Kurssonow (13) have applied the newer knowledge of the structure of sugar with marked success. The sucrose molecule contains a pyranose (1-5) ring structure (glucose residue) and a furanose (2-5) ring structure (fructose residue). When cleavage of the sucrose takes place, glucose and inactive fructose are obtained, removing one of the products of the reaction, i. e., the fructose in the furanose form, or a ring shift from the (2-5) to the (2-6) position has taken place. Through the synthesis of fructose 6-phosphate by means of phosphatase and Ca(H,POe)p,and thus preventing the formation of a 2,Gring in the fructose molecule, a definite synthesis of sucrose was observed over a period of 18 days. Referring to the proposed mechanism for the enzymic production of lactic acid, i t is easily seen why it is necessary to postulate the existence of an active glucose. Normal tissue will form lactic acid from hexose monophosphate and in order to accomplish this a ring shift from the (1-5) or the pyranose form to the ( 1 4 ) or the furanose form must be postulated. The increased glycolysis in cancer implies a supply of carbohydrate in an available form, as the more sugar in the medium the greater the glycolysis. In the blood of cancer patients (and the blood is the environing medium or 4 in our model concept) Woodward and Fry (14), in our laboratories, have found that there is a relative increase of twenty per cent. in blood sugar, which makes the additional amount available. In addition, Hueper,

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tissue, leucocytes, and by the retinal tissue. For these tissues, however, there is a pure carbohydrate oxidation where the R. Q. = 1 (the Respiratory Quotient is the ratio of oxygen to carbon dioxide), and in the case of cancer tissue this value is never approached. Injured tissues will have a glycolysis after the cancer manner, but, with recovery from the injury, the normal metabolism is restored. When the oxidative mechanism of a cell is injured, it may (1) die, (2) grow and divide, producing much lactic acid anaerobically, but when respiration becomes normal and aerobic glycolysis disappears, the cells are normal again, or (3) the cells grow and divide while their property of abobic glycolysis persists and is handed on to successive generations of cells as in the case of cancerous tumors. In cancer cells, aerobic glycolysis is inherited and, in other pathological cases, this is th6 result of injury and disappears with the recovery from the injury. In cancer cells, not only must the normal respiration be re-established, but it must be passed on to successive generations. Non-malignant cells die under anaerobic conditions, while malignant cells do not do so if enough glucose is added. In cancer, therefore, there is a defect in the respiration, and this defect is connected with the oxidation of carbohydrates. The anaerobic and abobic glycolysis of cancer cells is shared by other tissues such as the retina; but the respiratory quotient is unity. In the metabolism of cancers the rate of growth and glycolysis resemble embryonic tissue, but the respiratory quotient is low, which differentiates their mechanism from that of the normal ? embryonic cells. The nature of the injury to the oxidative processes in the cell, as has been stated by McDonald (18),is the fundamental metabolic problem in cancer and the cure of cancer will come through the production of a more oxidizing potential than the limiting oxidation-reduction potential necessary to cell division. The next step in cancer research is to fmd out how the cancer cell can be transformed back, in its metabolism, to the normal cell, to improve its oxidative capacity and to reduce its fermentative capacity. If the cells of a cancer can be reduced in their energy adaptations to the quality and amount of metabolism necessary for the maintenance of normal cells, then the cancer cells would be normal. In such a case, the cancer cells present in a tumor would not continue to divide and the cancer would not extend and be malignant any more. The growing cancer cells are more susceptible to injury than the normal differentiated adult cells and so would gradually die and disappear. The cancer would be cured. Like weeds in a field of grain, if the cells can be prevented from spreading and growing, they become innocuous. But the job is to find out how to alter the metabolism so as to cause their destruction without destroying the healthy grain. The differences in reactions and metabolism of the cancer and the normal cells that have been found permit a more intelligent and

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scientific search for a cure. A chemical cure of cancer is only a m a t t e r of time and trouble. H o w much time and how much trouble remains to b e seen.

Literature Cited MAND , D. M., Proc. Roy. Soc., 99B,173 (1926). (1) N ~ E D H AJ., C., ibid., 93B,410 (1922). (2) SHEARER, O., "The Metabolism of Tumors," Constable & Co., London, 1930. (3) WARBURG, 0.. Biochem. Z., 157,459 (1925). (4) MEYERHOF, O.,ibid., 142,317,334 (1923). (5) WARBURG, (6) MURPHY, J. B., AND HAWKINS, J. A,, 3. Ga.Phyrid., 8, 115 (1925). (7) WATERMAN, Arch. n&rland physiol., 9, 573 (1924). Brit. 1.Exe. Path., 10, 19 (1929). (8) BAKER, DICKENS, A N 0 GALLIMORE, AND HIIRRISON, Bio~hem.J., 24, 141 (1930). (9) MELLANBY (10) HOPKINS,F. G., ibid., 19,787 (1925). K., Biochem. Z., 178,444 (1926). (11) LOHMANN, H., Science, 73,500 (1931). (12) HIBBERT, AND KURSSONOW, Biochem. Z., 239,l (1931). (13) OPARIN G. E., AND FRY,E. G., "Hyperglycemia in Cancer" (in press). (14) WOODWARD, WOODWARD, AND FRY,Am. J. Caxncer, 15,2666 (1931). (15) HUEPER, E., Med. 1.& Record, 125,795(1927). (16) MCDONALD, WOODWARD, TORRANCE, FRY,AND MCDONALD, J. Lab.Clin. Med.. (17) SCHOONOVER, 16, 704 (1931). E., Science, 74, 55, (1931). (18) MCDONALD,

Some chemical aspects of cancer research - Journal of Chemical

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