Chemicals for Cancer

by C. P. RHOADS, M.D.

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THE control of cancer, at one time apparently as inaccessible as Everest, now seems to be an attainable goal. Scientific principles recently discovered may have converted cancer from an unfathomable mystery to a problem susceptible of solution by methods similar to those which have eliminated other incurable diseases. Certain of these new principles have come out of a scientific program established seven years ago at the SloanKettering Institute for Cancer Research.

The program was based upon a simple concept, now proved sound by experience. Cancer was envisioned as “a fast-spreading weed that suddenly invades the healthiest lawn, and erodes and kills it.”The work undertaken follows, accordingly, the established botanical principle of search for a chemical means of eliminating the cancer (analogous to weeds) without destroying the normal tissues (analogous to grass). This work is conducted under three divisions: —

1. Endocrinology of Cancer (changing the chemical composition of the blood which provides nutrients to the cancer cells). Analogous to altering the soil, thus making the growth of weeds impossible.

2. Chemotherapy of Cancer (chemical destruction of cancer cells). Analogous to poisoning the weeds with 2-4D.

3. Radiobiology of Cancer (deposit of destructive radioactive atoms within the cancer cells). Analogous to burning out the individual weeds.

Significant advances have been made in the second category — namely, cancer control by selective poisoning of the cancer by chemicals. Surgery and x-rays, although useful in the cure of localized cancer, are without avail in the 50 to 75 per cent of patients in whom cancer is diagnosed only after it has already scattered widely throughout the body. There is therefore an urgent need for an agent which can eradicate cancer in its advanced stage by seeking out and destroying its every cell, wherever it may be, without undue harm to the normal structures of the body.

Chemical agents today cure certain infectious diseases by destroying the organisms which cause them. These invading parasites or bacteria are now regarded as analogous, in some degree, to cancer cells. A vigorous search is under way for substances which will act as specifically against cancer cells as the sulfonamides and antibiotics do against bacteria. Several have been discovered which cure certain types of transplanted cancer in an early stage in animals. These also temporarily check a few types of the disease in man. The search, therefore, has already proved to be a feasible one, in principle.

The compound 6-mercaptopurine (6-MP), for example, is useful in the treatment of leukemia in man. This substance, recently discovered, temporarily restores to almost complete health about 60 per cent of children and some adults with either chronic or acute leukemia of some types, and appears to benefit more types of leukemia than other agents currently in use. When given by mouth, 6-MP exerts few harmful side effects. Hence, treatment of all but the most critically ill can be carried out in the doctor’s office.

Furthermore, 6-MP appears to act differently from other chemicals in use, and in animals it is substantially more effective. Indeed, it is the first actually to cure one form of transplantable animal cancer widely employed in research. Certain new scientific principles established by the work which produced 6-MP have made possible the preparation of an extensive series of similar chemicals which restrain cancer in animals and may well exert even more salutary effects in man. The new principles are the product of a particular biochemical study of cancer which was begun at the very outset of the Sloan-Kettering program and which constitutes the foundation of its effort to achieve effective cancer chemotherapy. This study, then unique, was chosen in the belief that knowledge of the chemical differences between normal and cancer cells must yield definition of the vulnerable points at which cancer can be selectively poisoned. Accordingly, a comparative analysis of these cells was early undertaken and has become a most productive and promising activity.

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TO ANALYZE living mammalian cells is difficult. Each is a complex organization of many different chemicals, carrying out an infinite number of reactions. The study was simplified, however, by employing bacteria as models. Bacteria are living unicellular organisms sufficiently like the cells of mammals in their composition to be useful for study purposes. In such simple cells it is easy to observe the change whereby offspring different from the parent cells suddenly appear. These changed offspring, sometimes called mutants, are usually feeble creatures and die out quickly. Occasionally, however, mutants are born — one or many —of a hardier nature than the parents, perhaps because better suited to the environment. They prosper and multiply, vigorously passing on competitive ability to an ever-increasing progeny. Like cancer cells, some of these more vigorous bacteria thrive by destroying the normal related bacteria1 community.

All available evidence proves unequivocally that the changed cells, whether bacteria or cancer, derive their aggressive properties from modifications of the characteristic constitutions of their chromosomes— rodlike bodies present in the nucleus of every cell.¹ These, with related structures, determine the inherited traits passed from parent cell to offspring. They guide every detail of each cell s constitution, function, and reproduction, acting as minute living control boards of its immensely complex functional organization. Somewhere within the chemistry of the chromosome must lie the key to the special qualities of each type of cell, including cancer cells.

Certain chemical and physical agents, atomic radiation for example, are known to change the structure of the chromosome. In so doing they change the inherited characteristics of all forms of life, from the single-cell bacterium or yeast to the complex multicellular organisms such as mammals. Such agents are called mutagens. Some of our most beautiful flowers are the result of changes in plants induced deliberately with such chemicals by the botanist. Other mutagens cause cancer. This fact proves what had been long suspected: that mutation and the change which is the development of cancer clearly are similar and almost surely due to a related mechanism.

Strong evidence indicates, furthermore, that the mechanism of cell change (mutation) involves the induction of a change in the constitution of a complex chemical present in the chromosomes of all cells. This chemical, nucleic acid, is the key component, possessing the vital function of controlling the inherited characteristics and activity pattern of the cell.

Clearly, then, since normal and cancer cells differ from each other and nucleic acid is responsible for cell differences, a comparative analysis of the nucleic acids of these cells should disclose the long-sought difference between the two. Once found, it should be possible to direct a chemical attack at this point, and so to kill the cancer cells without intolerable injury to essential normal cells.

Cells are not static but are, instead, incredibly busy chemical factories, constantly wearing out and being repaired and replaced. Each cell selects from its supply line, the blood, a characteristic assortment of chemicals needed for these processes. Like other cell components, nucleic acid also must be repaired. Since the difference between normal and cancer cells must be due to their differently composed chromosomal nucleic acids, the search for cancer control began with a study of the requirements of normal and cancer cells for chemicals needed in nucleic acid repair. Methods were developed for preparing synthetically a dozen or so special and characteristic components of nucleic acid. Each one was marked with an atomic tag by which it could be traced and identified wherever it might be. Both heavy and radioactive atoms were employed — the former obtained from Eastman Kodak and the latter from the Atomic Energy Commission as a constructive by-product of atom bomb study.

Each of the atomically labeled components was injected into rats, and the nucleic acid of their tissues was subsequently examined for the presence of the labels. Of several components no trace was found. Then came the break — the atomic labels revealing the presence of a particular compound were recovered; and not from just anywhere in the cell, but actually from the very key structure, its control board, the chromosome itself.

Furthermore, and even more important, it was found that the administered complex molecules of nucleic acid repair chemicals had been incorporated entire rather than broken up and rebuilt. This was revolutionary indeed. It had always been believed that cells would use only simple, tiny chemical molecules such as are employed throughout the body — the equivalent of nuts and bolts and uncut lumber in house construction. The new observation proved that the cells will accept prefabricated parts. This had most practical implications for cancer treatment since it gave a clue to the characteristic structure and repair requirements of special units like cancer cells.

As time went on, the new methods began to be used in other laboratories and understanding developed of the repair patterns of the nucleic acids of mammalian cells. The next step was the crucial one in cancer research. It was to determine whether different cell types vary from each other in the prefabricated chemicals they will use in repair: in other words, whether each kind of cell has its own characteristic uptake pattern. Accordingly, the tagged components—potential building blocks of nucleic acid — were injected in another species, the mouse. Our postulate was supported; this animal incorporated the component used by the rat. but also took up u second one. Clearly, different prefabricated parts of nucleic acid are picked up and used by different species.

It was a most promising lead and was amply confirmed and extended in subsequent experiments. Differences were observed in the uptake of nucleic acid even between different cell types in the same organ. Indeed, these differences were found in even very closely related cells, whose composition varied only slightly; and still more, individual parts of the same cell with different functions showed similar differences.

Thus an important landmark in cancer research was established: the fact that cell characteristics and differences are reflected in the cells’ uptake pattern, their selection for repair and reproduction, of complex prefabricated nucleic acid building blocks. With this the whole field of selective chemical injury of particular kinds of cells, including cancer, was thrown wide open.

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HE next problem was to apply this knowledge to destroy cancer cells without harming the normal cells. The sulfonamides gave a clue as to how this could be done. They slop the growth of virulent bacteria, and so cure, because they resemble closely in composition a vitamin, an essential chemical, needed by some bacterial cells but not by the cells of the body in general. Such spurious, unusable likenesses of vital nutrients are called antimetabolites. The bacteria will ingest a sulfonamide, mistaking it for the vitamin. The result is the same as feeding a horse straw instead of hay. The sulfonamide does not function as the vitamin does, and the cell breaks down, starved for the vital vitamin and so unable either to repair itself or to reproduce. It should be possible to prepare and administer cancer antimetabolites — modified, unusable forms of the chemicals particularly needed by cancer cells — which would break down their vital control and reproductive machinery’.

To tost our concept of specific action, a potential antimetabolite, a chemical closely resembling one of the components of nucleic acid which had been proved to be used in different amounts by different kinds of mammalian cells, was prepared and then sent for testing to a tissue culture laboratory. There a very delicate method had been worked out with great precision for growing normal and cancer cells of animals side by side and, most important, at the same rate, in parallel rows in glass containers. By this method the minute effects of infinitely small amounts of test substances on cancer and normal cells could be compared directly.

The new chemical was next added carefully to the test tube cult ure of cancer and normal cells. A trace amount of it damaged the cancer cells severely’. Many times as much was required to exert the same effect on the normal cells adjacent. For the first time proof was at band that cancer cells are more vulnerable to specific chemical destruction than their normal relatives growing with equal speed.

The new compound was next put to test in animals with cancer. It did not cure any cancer. It did, however, prolong the lives of mice with leukemia. Kventually cancer cells became resistant, as insects do to DDT. Then came a limited trial against human cancer, and therewith disappointment. Human cancer cells, perhaps because of differences from those of animals in their requirements for building blocks of nucleic acid, were insusceptible to damage by the chemical at concentrations tolerated by normal tissues. Nevertheless, although not useful in man, the discovery of this chemical and its properties remains an important step in cancer progress. A broad program of synthesis and trial of new, related compounds was instituted to exploit in terms of cancer cure the difference between cancer and normal cells in their needs for chemical building blocks of nucleic acid.

Working agreements had been made with many pharmaceutical and university laboratories to prepare and supply agents of the types it was desired to test. In the laboratories of Burroughs-Wellcome and Company a program was found well under way for the preparation of antimetabolites of nucleic acid, as defined by preliminary experiments. A number of them already had been produced in an effort to get better drugs for the cure of malaria and other diseases caused by parasites. Production was greatly increased by a cooperative agreement, implemented by aid from the Charles F. Kettering Foundation, arranged through the Sloan-Kettering Institute. As a result, about 750 chemicals have been supplied to various laboratories for trial against cancer and other types of invading cells.

As the new compounds were prepared and tested in a steadily increasing flow, it became clear that although the majority were poisonous to both normal and cancer tissue, a substantial number of them exerted specific effects on special types of cells. Some damaged cancer more than normal cells; sometimes the converse was true. Cellular selectivity of toxic action, so long sought and so long deemed nonexistent, was no longer idealistic theory. It was an established fact. 3. They enable us now to define, to a limited extent, the pattern according to which substances selected from the blood stream are modified for use and channeled into the controlling chromosomes of cancer cells. Knowledge of this repair pattern of nucleic acid permits the planning and preparation of new compounds for treatment on a more rational basis than any heretofore existing. These, singly or in combination, should be more effective than the substances available at present.

Furthermore, as data accumulated, it began to be possible to predict roughly what sort of alterations in these nucleic acid repair units would make them selectively poisonous to animal cancer. Some correlation could be drawn between molecular structure and biological activity. The percentage, therefore, of trial compounds showing restraining activity against cancer steadily increased. The search for anti-cancer agents was slowly changing from a blind, occasionally profitable groping to an orderly, methodical climb toward a visible and accessible, though still distant, goal.

The next step, required because of the difficulty of working directly with cancer cells, was to develop a simple, rapid test system to accelerate the work. Once more, mutant bacteria functioned as prototypes of cancer cells, and their control in test tube experiments became one of several pilot plants for cancer chemot herapy.

Just as the mouse differed from the rat in nucleic acid building patterns, closely related types of bacteria were found to vary in their requirements for replacement chemicals of nucleic acid. Moreover, it was proved that mutant bacterial cells, analogous to cancer, are entirely different in their use of these specific components, and therefore in their susceptibility to damage by the chemical’s false twin. This gave strong support for our use of bacteria as cancer prototypes.

Also, as an unexpected result, it was found that in some cases in which both the parent and mutant cells were vulnerable to damage by the same false repair chemical, the administration of a related normal building block might protect one and not the other from injury. This revealed a second, and a wholly unexpected, important new possibility for cancer chemotherapy, and another new principle. Subsequently proof developed that this selective defense can be accomplished for animal as well us bacterial cells. So far only cancer cells have been protected — the reverse of the desired effect, but it is reasonable to suppose that the converse is possible. Instead of using a chemical rifle aimed only at the cancer, perhaps a toxic chemical barrage can be laid on all the cells and only the normal ones protected.

As the work progressed, evidence rapidly accumulated that the different types of cancer varied in the degree to which their growth was restrained by the chemicals used in treatment. A study was accordingly instituted to ascertain whether the requirements of the different cancer U’pes for the chemicals used in nucleic acid repair also varied. This quickly proved to be the case. Special types of animal cancer showed characteristic requirements as revealed by uptake or “appetite” patterns.

An argument frequently advanced to decry the possibility of cancer control by chemicals is that there are several different types of cancer and no one agent could benefit all. Now, perhaps, special antimetabolites, individual poisons for each principal kind of cancer, will prove predictable on the basis of the chemical needs of each.

While ihis work was in progress, a complementary and major technical advance was made. A method was discovered in the Sloan-Kettering laboratories which made possible for the first time the regular and sustained growth, on a large scale, of some types of human cancer in laboratory animals. This may well revolutionize the methodology of cancer research. The ability to grow the bacterial cells of human infection in the test tube opened the way for the dramatic achievements of the past, against infectious diseases, such as pneumonia and tuberculosis. History tends to repeat itself, and the ability to grow human cancers under uniform conditions of laboratory control may signal the breakthrough on the cancer front. It makes possible, at last, the study of the uptake by human cancer cells of nucleic acid building blocks and their poisonous antimetabolites. It may eliminate many of the costly, time-consuming stops of applying results achieved in laboratory animals to the more complex problems of human cancer. Rats and hamsters bearing human cancer transplants now are being supplied to other laboratories.

The results so far achieved have implications of exceedingly practical importance, as follows: —

1. They remove an important and long-standing psychological barrier to cancer research. Only a few years ago an eminent investigator, representative of a large group, expressed the pessimism which has long shrouded the subject by comparing the search for cancer-controlling chemicals to the quest for an agent which would “dissolve a man’s left ear and not his right.” As we study, alter, and manipulate the cancer cell, it appears much less like a stubbornly integral part of the human body and much more like an invading bacterium whose conquest by chemotherapy is now, at last, confidently expected.

2. They have led to the painstaking creation of a broad and inclusive coöperative enterprise in cancer chemotherapy. This involves many different but pertinent skills of scientists in both industry and the universities. All are impelled by the conviction that together They surely can achieve their common goal: improved, and really effective, means for the control of cancer in man.

The long, complex, expensive, and often discouraging search for better control of cancer in man began with a concept, a logical conclusion from the evidence available. Because of the unusual facilities which were created, because of the generosity of individuals and public agencies, and because of the talent, dedication, persistence, and particularly the willingness to coöperate of many scientists of varied interests, it has been possible to pursue this concept and to develop it to a limited practical accomplishment which may justify hope for the future.

Coming events cast their shadows before, in medical science as in every human activity. From the moment the first plane rose a few inches, flew a few feet, and landed in a few seconds, modern aviation was as inevitable as the tides. No matter, then, that our present means for cancer control are feeble and unsatisfactory. To have any means (and we now have several) is the indicator so long wanting, an indicator as unerring as the North Star. The basic advances which have been made foretell the future development of more effective treatment as certainly as the day follows the night. The progress achieved so far is the accomplishment of the many generous, public-spirited men and women whose patient aid and unswerving conviction that cancer must and will be solved are making, with the working scientist, the vital steps toward its solution.